Distal monosomy 15q is a rare chromosomal anomaly syndrome characterized by pre- and postnatal growth restriction, developmental delay, variable degrees of intellectual disability, hand and foot anomalies (e.g. brachy-/clinodactyly, talipes equinovarus, nail hypoplasia, proximally placed digits) and mild craniofacial dysmorphism (incl. microcephaly, triangular face, broad nasal bridge, micrognathia). Neonatal lymphedema, heart malformations, aplasia cutis congenita, aortic root dilatation, and autistic spectrum disorder have also been reported.


A partial deletion of the long arm of chromosome 17 characterized by hypotonia, growth delay, severe global developmental delay, microcephaly, seizures, congenital heart anomalies, hand and foot anomalies (syndactyly, symphalangism) and dysmorphic facial features, including round face, hypertelorism, upslanting palpebral fissures, and micrognathia. Reported deletions involve regions 17q21-q24.


Distal monosomy 19p13.3 is a rare chromosomal anomaly associated with a wide range of phenotypic features depending on the size of the deletion. It may present with intrauterine growth retardation, failure to thrive, global developmental delay, dysmorphic features (such as broad forehead, midface retrusion, broad nasal bridge, micrognathia, smooth philtrum, low-set, dysplastic ears), congenital anomalies (such as atrial septal defect, gastrointestinal anomalies, renal and urogenital malformations, agenesis of the corpus callosum) and other clinical features (such as hearing loss, visual impairment and immune dysregulation).


A rare chromosomal anomaly characterized by an intellectual deficiency, progressive microcephaly, seizures, growth delay, distinct facial dysmorphic features and various midline defects including cardiac, corpus callosum, gastro-oesophalgeal and urogenital anomalies.


Distal monosomy 3p is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the short arm of chromosome 3, with a highly variable phenotype typically characterized by pre- and post-natal growth retardation, intellectual disability, developmental delay and craniofacial dysmorphism (microcephaly, trigonocephaly, downslanting palpebral fissures, telecanthus, ptosis, micrognathia). Postaxial polydactyly, hypotonia, renal anomalies and congenital heart defects (e.g. atrioventricular septal defect) may be associated.


A rare partial autosomal monosomy characterized by variable combination of craniofacial, developmental, digital, skeletal, and cardiac features: hypotonia, developmental delay, growth deficiency, cleft palate, cardiovascular malformations, abnormalities of the hands and feet and typical dysmorphic features, such as microcephaly, rounded facies, small eyes, broad nasal bridge, upturned nose, full cheeks, small mouth and chin.


Distal monosomy 6p is responsible for a distinct chromosome deletion syndrome with a recognizable clinical picture including intellectual deficit, ocular abnormalities, hearing loss, and facial dysmorphism.

Summary:
Epidemiology
Pure deletions have been described in less than 10 patients.
Clinical description
Ocular abnormalities mainly affect the anterior chamber of the eye. Dysmorphic features include hypertelorism, broad forehead, down-slanting palpebral fissures, low-set ears, midface hypoplasia, and micrognathia. Intellectual deficit is variable in severity.
Etiology
Breakpoints are within 6p24-pter subtelomeric bands and microdeletions are detected by specific subtelomeric probes or comparative genomic hybridization (array-CGH).

                            Last update:
                            December 2010

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


Distal monosomy 7p is a partial autosomal monosomy characterized by developmental delay and intellectual disability, digital anomalies, congenital heart and urogenital anomalies, and specific craniofacial features, commonly including craniosynostosis.


Distal monosomy 9p is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the short arm of chromosome 9, with a highly variable phenotype typically characterized by intellectual disability, craniofacial dysmorphism (trigonocephaly, upslanting palpebral fissures, hypoplastic supraorbital ridges), abnormal digits (long middle phalanges with short distal phalanges), as well as frequent association with genitourinary abnormalities (cryptorchidism, hypospadias, ambiguous genitalia, 46,XY testicular dysgenesis). Congenital hypothyroidism and cardiovascular defects have been reported in some cases. Patients present an increased risk for gonadoblastoma.


Distal trisomy of the long arm of chromosome 10 (10q) is characterized by pre- and postnatal growth retardation, a pattern of specific facial features, hypotonia, and developmental and psychomotor delay.

Summary:
Epidemiology
To date, approximately 40 cases of trisomy 10q have been reported.
Clinical description
Most cases are diagnosed in infancy or in childhood. The range and severity of symptoms and physical findings may vary from case to case, depending upon the exact length and location of the duplicated portion of chromosome 10q. Characteristic craniofacial findings include a flat round face with full cheeks and a large prominent forehead, highly arched eyebrows, short and narrow palpebral fissures (blepharophimosis), widely spaced eyes with telecanthus, a short nose, a bow-shaped mouth with a prominent upper lip, and a small mandible. A few major malformations have also been reported, including renal and cardiac anomalies. Minor defects of the hands and/or feet, bone anomalies and cryptorchidism are frequent signs.
Etiology
The duplicated region almost always includes 10qter, with the most frequent proximal breakpoint at 10q24 (with variation from q22 to q25). Interstitial duplications of 10q have also been reported. Most cases of distal trisomy 10q result from of a parental balanced translocation or pericentric inversion, and may be accompanied by another chromosomal imbalance. Intrachromosomal duplications or de novo translocations are also observed.
Diagnostic methods
Diagnosis is suspected on the basis of the clinical features and is confirmed by karyotyping and fluorescence in situ hybridization (FISH) with specific 10q probes.
Antenatal diagnosis
Prenatal diagnosis is possible using cytogenetic tools.
Genetic counseling
The risk of recurrence for siblings depends on the parental karyotypes.
Management and treatment
Management is multidisciplinary and symptomatic only. Early educational (speech, occupational and physical therapy) and rehabilitation programs should be offered to all patients.
Prognosis
Prognosis is variable. A number of reported patients died in infancy from respiratory problems.

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Dr Catherine TURLEAU


Distal trisomy 11q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 11, with high phenotypic variability principally characterized by craniofacial dysmorphism (brachycephaly/plagiocephaly, low-set, posteriorly rotated ears, short philtrum, micrognathia) and intellectual disability. Short stature and seizures, as well as cardiac (e.g. atrial septal defect), skeletal (incl. brachy/syndactyly) and genital (e.g. micropenis, cryptorchidism) abnormalities may also be associated. Neurodevelopmental anomalies (pain insensitivity, sensorineural hearing loss, expressive language deficiency) and neuropsychiatric disorders (autistic features, auditory hallucination, self-talking) have also been reported.


Distal trisomy 13q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 13, with variable phenotype principally characterized by intellectual disability, psychomotor delay, craniofacial dysmorphism (incl. microcephaly, bushy eyebrows, long curled eyelashes, hypotelorism, low-set ears, prominent nasal bridge, long philtrum, high palate, thin upper lip), short neck, polydactyly, and hemangiomas. Cardiac, urogenital and neural tube defects, as well as umbilical and inguinal hernias, seizures and hypotonia, have also been reported.


Distal trisomy 14q is a rare, partial duplication of the long arm of chromosome 14 characterized by variable clinical features, most commonly including growth retardation and low birth weight, hypotonia, developmental delay, intellectual disability, short stature, microcephaly, facial dysmorphism (frontal bossing, hypertelorism, bulbous nose, micrognathia, sparse hair and eyebrows), congenital heart defects, spasticity and hyperreflexia.


Distal trisomy 16q is a rare chromosomal anomaly syndrome, resulting from the partial trisomy of the long arm of chromosome 16, with variable phenotype principally characterized by developmental delay, severe intellectual disability, hypotonia, facial dysmorphism (incl. high, prominent forehead, epicanthic folds, dysplastic ears, broad/depressed nasal bridge, malar hypoplasia, narrow and arched palate, thin upper lip vermilion, micrognathia) and hand/feet anomalies (e.g. arachnodactyly, talipes equinovarus). Cardiac defects, genitourinary malformations and vertebral anomalies are also associated. Thrombocytopenia and recurrent infections have also been reported.


Distal trisomy 17q is a rare chromosomal anomaly syndrome with variable phenotype principally characterized by intellectual disability, developmental delay, short stature, craniofacial dysmorphism (incl. microcephaly, low posterior hairline, frontal bossing, bitemporal narrowing, low-set and malformed ears, flat nasal bridge, long philtrum, wide mouth with downturned corners, thin upper lip) and a short, webbed neck, as well as skeletal anomalies (e.g. brachyrhizomelia, poly-/syndactyly) and joint hyperlaxity. Cardiac, cerebral, and urogenital anomalies are also frequently associated.


A rare, partial autosomal trisomy characterized by a variable phenotype that includes hypotonia, motor delay, mild to severe intellectual disability, seizures, variable cerebral anomalies, finger/toe syndactyly, fifth finger clinodactyly, strabismus, short neck and dysmorphic facial features.


Distal trisomy 19q is a rare chromosomal anomaly syndrome characterized by low birth weight, developmental delay, intellectual disability, short stature, craniofacial dysmorphism (incl. microcephaly, midface hypoplasia, hypertelorism, flat nasal bridge, ear anomalies, short philtrum, downturned corners of the mouth, micrognathia) and a short neck with redundant skin folds. Additional features may include hypotonia, skeletal anomalies (e.g. clino/camptodactyly), seizures and congenital cardiac, urogenital and gastrointestinal malformations.


Distal trisomy 1p36 is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 1, characterized by borderline to mild intellectual disability, mild developmental delay, metopic craniosynostosis and mild craniofacial dysmorphism (incl. slopping forehead, bitemporal narrowing, blepharophimosis). Other associated abnormalities may include growth retardation, microcephaly, large hands, syndactyly, supernumerary ribs, rectal stenosis and/or anterior displacement of anus. Congenital heart malformations (e.g. atrial septal defect, patent ductus arteriosus) have also been reported.


Distal trisomy 20q is a rare chromosomal anomaly syndrome, resulting from the partial trisomy of the long arm of chromosome 20, with high phenotypic variability mostly characterized by neurodevelopmental delay, cardiac malformations (e.g. ventricular septal defect, coarctation of aorta) and facial dysmorphism (incl. large/high forehead, microphthalmia, upslanting palpebral fissures, epicanthus, large, long, low-set ears, anteverted nares, protruding upper lip, cleft lip/palate, micro/retrognathia, dimpled chin). Skeletal (brachydactyly, scoliosis, pectus excavatum) and cerebral anomalies have also been reported.


Distal trisomy 22q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 22, with variable phenotype principally characterized by varying degrees of intellectual disabilty and developmental delay, pre- and postnatal growth deficiency, hypotonia, and craniofacial dysmorphism (incl. microcephaly, hypertelorism, narrow and upslanted palpebral fissures, epicanthic folds, low-set dysplastic ears, broad and depressed nasal bridge, cleft lip an/or palate, long philtrum, retro/micrognathia). Congenital heart defects, as well as cerebral, skeletal, renal and genital anomalies, have also been reported.


Distal trisomy 2p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 2, with a highly variable phenotype principally characterized by pre- and post-natal growth failure, global developmental delay, facial dysmorphism (incl. high forehead/frontal bossing, abnormal ear shape and/or position, hypertelorism/telecanthus, broad/depressed nasal bridge) and ocular anomalies (e.g. exophthalmos, retinal hypopigmentation, optic nerve and foveal hypoplasia). Other reported anomalies include generalized hypotonia, pectus excavatum, long fingers and toes, syndactyly, congenital heart (e.g. ventricular and atrial septal defects) and neural tube defects, seizures, pulmonary hypoplasia, diaphragmatic hernia and urogenital anomalies.


Distal trisomy 2q is a rare chromosomal anomaly, resulting from the partial duplication of the long arm of chromosome 2, characterized by moderate psychomotor delay, mild intellectual disability, facial dysmorphism (high hairline, prominent forehead, hypertelorism, upslanting palpebral fissures, large, low-set and/or posteriorly rotated ears, depressed/broad nasal bridge, prominent nasal tip, thin upper lip vermillion), clino-/camptodactyly and normal or increased body measurements. On occasion genital anomalies (hypospadias, cryptorchidism, shawl scrotum) and short stature may be observed.


Distal trisomy 3p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 3, with highly variable phenotype principally characterized by craniofacial dysmorphism (incl. brachy-/microcephaly, square facies, frontal bossing, bitemporal indentation, hypertelorism/telecanthus, low-set and/or dysmorphic ears, short nose with broad, flat nasal bridge, prominent cheeks and philtrum, downturned corners of mouth, micrognathia/retrognathia, short neck) associated with psychomotor delay, moderate to severe intellectual disability, cardiac (e.g. patent ductus arteriosus) and urogenital (e.g. renal hypoplasia, hypogenitalism) abnormalities, as well as seizures and presence of whorls on fingers.


Distal trisomy 4q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 4, with highly variable phenotype typically characterized by psychomotor delay, intellectual disability, craniofacial dysmorphism (microcephaly, low-set, prominent ears, downslanting palpebral fissures, hypertelorism, epicanthic folds, broad, prominent nasal bridge, high arched and cleft palate, micro-/retrognathia), seizures, as well as tooth and digital anomalies (clinodactyly, polydactyly). Cardiac malformations, renal anomalies, cryptorchidism, hypotonia and hearing impairment have also been reported.


Distal trisomy 5q is a rare chromosomal anomaly syndrome, resulting from a partial duplication of the long arm of chromosome 5, characterized by short stature, moderate intellectual disability, and craniofacial dysmorphism (microcephaly, flat facies, large, low-set dysplastic ears, down-slanted, almond-shaped palpebral fissures, hypertelorism, epicanthal folds, small nose, long philtrum, small mouth with thin upper lip, and micrognathia). Patients also frequently present speech and cognitive delay, cardiac (ventriculomegaly, ventricular septum defect) and skeletal abnormalities (craniosynostosis, radial agenesis, ulnar hypoplasia, brachydactyly) and genital malformations (hypospadias, cryptorchidism).


Distal trisomy of the short arm of chromosome 6 is characterized by pre- and postnatal growth retardation, a pattern of specific facial features (mostly of the eyes), microcephaly, and developmental delay.

Summary:
Epidemiology
To date, approximately 40 cases of trisomy 6p have been reported.
Clinical description
Characteristic craniofacial findings include a prominent forehead, small and short palpebral fissures (blepharophimosis), upper lid ptosis, close-set eyes with a prominent nasal bridge, a short bulbous nose, a small mouth with thin lips, a small and pointed chin, and low-set ears with poorly developed lobes. A few major malformations have been reported, including congenital heart defects (atrial septal defect, ventricular septal defect and patent arterial duct; see these terms) and renal abnormalities including hydronephrosis and hypoplastic kidney. Cataracts, microcornea and strabismus may be observed.
Etiology
The duplicated region almost always includes 6pter, with proximal breakpoints ranging from 6p21 to 6p25. Interstitial duplications of 6p have also been reported with different phenotypes depending on their size and location. Most cases of distal trisomy 6p result from missegregation of a familial balanced translocation, or pericentric inversion, and are accompanied by another chromosomal imbalance. Intrachromosomal duplications or de novo translocations are also observed.
Diagnostic methods
Diagnosis is based on clinical features and confirmed by karyotyping and fluorescence in situ hybridization (FISH) with specific 6p probes. The risk of recurrence for siblings depends on the parental karyotypes.
Antenatal diagnosis
Cytogenetic prenatal diagnosis is possible.
Management and treatment
Management is multi-disciplinary and symptomatic only. Early educational and rehabilitation programs should be offered to all patients.
Prognosis
The prognosis is variable. A number of patients have died in infancy from respiratory or severe feeding problems.

                            Last update:
                            February 2009


Distal trisomy 6q is a rare chromosomal anomaly syndrome resulting from the partial duplication of the long arm of chromosome 6, with highly variable phenotype, typically characterized by growth and developmental delay, intellectual disability, craniofacial dysmorphism (microcephaly, flat facial profile, frontal bossing, hypertelorism, downward-slanting palpebral fissures, flat nasal bridge, anteverted nares, bow shaped mouth, micrognathia), short webbed neck and joint contractures. Cardiac, urogenital, ophthalmologic and hand and foot anomalies, as well as umbilical hernia, spasticity, and seizures, are other features that have been reported.


Distal trisomy 7p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 7, with highly variable phenotype typically characterized by severe to profound psychomotor delay, intellectual disability, dysmorphic features (incl. dolichocephaly, microbrachycephaly, high and/or broad forehead, large anterior fontanel, hypertelorism, downslanting palpebral fissures, low-set, dysplastic ears, low, broad and prominent nasal bridge, abnormal palate, micro-/retrognathia), and hypotonia. Cardiovascular, gastrointestinal, skeletal and urogenital anomalies have commonly been reported.


Distal trisomy 8q is a rare chromosomal anomaly syndrome resulting from the partial duplication of the long arm of chromosome 8, with a highly variable phenotype, typically characterized by growth and developmental delay, intellectual disability, short stature, craniofacial dysmorphism (microcephaly, prominent forehead, hypertelorism, abnormal palpebral fissures, low-set, large ears, anteverted tip of nose, micro/retrognathia), congenital heart defects and skeletal and limb anomalies. Other reported features include ophthalmologic abnormalities (e.g. megalocornea), cryptorchidism, hypertrichosis, and neurologic manifestations (e.g. hypotonia, hearing loss, and seizures).


Distal trisomy 9q is a rare chromosomal anomaly, resulting from the partial trisomy of the long arm of chromosome 9, with a variable phenotype mostly characterized by psychomotor and speech delay, intellectual disability, hypotonia, long narrow habitus, craniofacial dysmorphism (incl. micro/dolichocephaly, facial asymmetry, narrow palpebral fissures, deep-set eyes, strabismus, microphthalmia, abnormally shaped ears, microstomia, micro/retrognathia) and hand and feet anomalies (incl. arachnodactyly, camptodactyly, abnormal implantation of digits). Congenital flexion contractures and limited joint movements have also been observed.


Distal hereditary motor neuropathy type 1 is a rare neuromuscular disease characterized by slowly-progressive lower limb muscular weakness and atrophy, without sensory impairment. Additional clinical features may include pes cavus, hammertoe and increased muscle tone.


Distal hereditary motor neuropathy type 2

A rare autosomal dominant distal hereditary motor neuropathy characterized by onset of slowly progressive distal limb weakness and atrophy between the second and fifth decades of life. Sensory involvement is typically less pronounced or absent. The severity of the condition is variable, and both lower and upper extremities may be involved.


Distal hereditary motor neuropathy type 5

A rare autosomal dominant distal hereditary motor neuropathy disease characterized by muscle weakness and wasting predominantly affecting the hands, in particular the thenar and first dorsal interosseus muscles, and/or marked foot deformity and gait disturbance. Sensation is normal, although reduced response to vibration has been described. The disease is slowly progressive with an age of onset within the first few decades of life.


Distal hereditary motor neuropathy type 7

A rare, slowly progressive genetic peripheral neuropathy characterized by distal atrophy and weakness affecting the upper limbs (with a predilection for the thenar eminence) and subsequently the lower limbs, associated with uni- or bilateral vocal cord paresis leading to hoarse voice and breathing difficulties, and facial weakness.


Distal hereditary motor neuropathy, Jerash type

A rare, genetic, neuromuscular disease characterized by progressive, symmetrical, moderate to severe, distal muscle weakness and atrophy, without sensory involvement, first affecting the lower limbs (towards the end of the first decade) and then involving (within two years) the upper extremities. Patients typically develop foot drop, pes varus, hammer toes and claw hands. Pyramidal tract signs (such as brisk knee reflexes and positive Babinski sign) with absent ankle reflexes are initially associated but regress as disease stabilizes (~10 years after onset).


Distal limb deficiencies-micrognathia syndrome

The distal limb deficiencies-micrognathia syndrome is characterized by the combination of symmetric severe distal limb reduction deficiencies affecting all four limbs (oligodactyly), microretrognathia, and microstomia with or without cleft palate.

Summary:
Epidemiology
It has been reported in four patients; two of them were siblings and had moderate intellectual deficiency.
Clinical description
Two non-related subjects also had severe myopia, bilateral conductive hearing loss and a renal change, referred to as oligomeganephronia, or renal hypoplasia.
Etiology
Using high resolution oligoarray-based comparative genomic hybridization (aCGH), a 10q24 duplication or triplication was recently detected in all these patients, similar to the duplication detected in an isolated form of split hand foot malformation (SHFM; see this term).

                            Last update:
                            June 2010


Distal monosomy 7q36 is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 7, with a highly variable phenotype typically characterized by holoprosencephaly, growth restriction, developmental delay, facial dysmorphism (facial clefts, prominent forehead, hypertelorism, low-set ears, flat and broad nasal bridge, large mouth), abnormal fingers and palm or sole creases, ocular abnormalities, and other congenital malformations (incl. genital anomalies and caudal deficiency sequence). Cardiopathies have been occasionally reported.


Distal myopathy with anterior tibial onset

A rare, genetic neuromuscular disease characterized by a progressive muscle weakness starting in the anterior tibial muscles, later involving lower and upper limb muscles, associated with an increased serum creatine kinase levels and absence of dysferlin on muscle biopsy. Patients become wheelchair dependent.


Distal myopathy with posterior leg and anterior hand involvement, also named distal ABD-filaminopathy, is a neuromuscular disease characterized by a progressive symmetric muscle weakness of anterior upper and posterior lower limbs.

Summary:
Epidemiology
It has been described in several members of an Australian and an Italian family.
Clinical description
The disease usually manifests during the third decade of life with thenar muscle weakness resulting in reduced grip strength. The disease is slowly progressive and generally proceeds with calf muscle weakness appearing during the fourth decade and proximal muscles becoming perceptibly affected in the fifth decade. The tibial anterior muscle is spared, so is respiratory function. Mild cardiomyopathy can sometimes be observed.
Etiology
The disease is due to mutations on the actin-binding domain of the FLNC gene that encodes filamin C, a muscle specific filamin that is also associated with myofibrillar myopathy when mutations affect other parts of the protein. The disease mechanism seems to be linked to an increased actin-binding affinity of filamin C.
Genetic counseling
Transmission is autosomal dominant.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Rachael DUFF


Distal myopathy, Tateyama type is a rare, genetic, slowly progressive, distal myopathy disorder characterized by muscle atrophy and weakness limited to the small muscles of the hands and feet (in particular, thenar and hypothenar muscle atrophy), increased serum creatine kinase, and severely reduced caveolin-3 expression on muscle biopsy. Some patients may also show calf hypertrophy, pes cavus, and signs of muscle hyperexcitability.


A rare distal myopathy characterized by weakness in the distal upper extremities, usually finger and wrist extensors which later progresses to all hand muscles and distal lower extremity, primarily in toe and ankle extensors.

Summary:
Epidemiology
Distal myopathy, Welander type (WDM) prevalence is unknown. The condition is mainly restricted to a geographical area around the Baltic Sea especially in Finland and Sweden (mid-eastern region), where the estimated prevalence is 1/10,000. However, some patients have been reported in the United Kingdom.
Clinical description
WDM is a late adult-onset disorder (onset between 40 and 60 years) characterized by initial weakness of index finger extensors followed by extension weakness in the other fingers. Weakness slowly progresses to all hand and lower leg muscles. In the lower limb, the anterior tibial muscle and toe extensors are typically affected leading to walking difficulties and steppage gait. Proximal limb muscles are only rarely involved. Muscle stretch reflexes are preserved (except ankle reflexes which may be lost later in the disease). Cardiac muscle involvement has not been observed. Rare homozygotes individuals show an earlier onset and proximal muscle involvement with faster progression.
Etiology
WDM is caused by a missense change (c.1362G>A; p.E384K) in TIA1 gene (2p13) which encodes nucleolysin TIA1 isoform p40, a key component of stress granules (SGs). Under conditions of cellular stress or metabolic changes, nucleolysin TIA1 isoform p40 promotes messenger ribonucleoprotein (mRNP) complexes to assemble in SGs to repress translation. The mutation leads to reduced dynamics of the SGs and abnormal autophagic processing with rimmed vacuolar pathology. In addition, the WDM phenotype has been reported in patients with a digenic combination of a SQSTM1 mutation and TIA1-N357S variant.
Diagnostic methods
Diagnosis relies on molecular genetic testing. Additional examinations include muscle biopsy of distal muscles showing dystrophic features and prominent rimmed vacuoles. Sensory examination is usually normal, although some deficits on quantitative temperature and vibration testing have been described. The serum creatine kinase (CK) level is usually normal or slightly elevated. Needle electromyography (EMG) shows small brief 'myopathic' motor units, although a mixed 'myopathic-neuropathic' pattern may be observed. Fibrillations and complex repetitive discharges are often, but not invariably, present. Muscle magnetic resonance imaging shows considerable involvement of posterior calf muscles besides fatty degenerative changes in the anterior compartment.
Differential diagnosis
Differential diagnosis includes sporadic inclusion body myositis (sIBM), MATR3 distal myopathy, and muscle filaminopathy.
Genetic counseling
WDM is inherited as an autosomal dominant trait. Where one parent is affected, there is a 50% risk of disease transmission to offspring. Penetrance is 100% by age 75 years.
Management and treatment
Management is mainly symptomatic and includes the help of an occupational and a physical therapists and practical tools for finger and hand weakness. Foot drop and wrist weakness may be helped by orthoses.
Prognosis
The progression is benign and life expectancy is normal although the fine motor hand skills are usually lost. Homozygotes exhibit earlier onset, faster progression, and patients become wheelchair-bound by the age of 50 years.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Pr Bjarne UDD


Distal myopathy refers to a group of muscle diseases which share the clinical pattern of predominant weakness and atrophy beginning in the feet and/or hands.

Summary:
Epidemiology
The estimated prevalence of distal myopathy in the northern region of England is 1/300,000. Some forms have been identified with greater frequency in certain populations. For example, tibial muscular dystrophy is frequent in Finland with a prevalence of 1/5,000 and Welander distal myopathy occurs with greater frequency in Sweden.
Clinical description
Distal myopathy is characterized by progressive muscular weakness and atrophy beginning in the distal parts of upper and lower limbs with an extremely variable age of onset. Distal myopathy is a genetically heterogeneous group (currently comprising more than 20 genetic types) which affects different regions of the distal extremities and is classified according to clinical features, inheritance pattern, histopathological criteria, and molecular genetics. The main autosomal dominant forms of distal myopathy are Welander distal myopathy (weakness in the distal upper extremities which later progresses to distal lower extremity), tibial muscular dystrophy (mainly affects the front of the lower leg), distal myotilinopathy (progressive distal muscle weakness and peripheral neuropathy with hyporeflexia), late-onset distal myopathy, Markesbery-Griggs type (ZASP-related myofibrillar myopathy), Laing early-onset distal myopathy, distal myopathy with posterior leg and anterior hand involvement (distal ABD-filaminopathy), and adult-onset distal myopathy due to VCP mutation. The genetically confirmed autosomal recessive forms are distal myopathy, Nonaka type (GNE-myopathy, weakness in the anterior distal legs), Miyoshi myopathy (weakness in the distal lower extremity posterior compartment), nebulin-related early-onset distal myopathy and distal anoctaminopathy. The age at onset is extremely variable and for recessive varieties of distal myopathy, symptoms usually develop in early adult life whereas in the dominant Welander and tibial muscular dystrophy, the onset is usually later. However, in some disorders (i.e. Laing early-onset distal myopathy and nebulin-related early-onset distal myopathy) the onset may be during childhood, and even in infancy.
Etiology
Distal myopathy is caused by defect or lack of specific proteins that play an essential role in the proper function and health of muscle cells. 15 causative genes have to date been associated with distal myopathy: ANO5 (11p15.1), CRYAB (11q22.3-q23.1), DES (2q35), DYSF (2p13.3), FLNC (7q32-q35), GNE (9p13.1), KLHL9 (9p22), LDB3 (10q22.3-q23.2), MATR3 (5q31.3), MYH7 (14q11.2-q13),  MYOT (5q31.2),  NEB (2q22), TIA1 (2p13), TTN (2q31) and VCP (9p13.3).
Genetic counseling
Distal myopathy can be inherited as an autosomal dominant or as an autosomal recessive trait.

                            Last update:
                            June 2015

                            - Expert reviewer(s):
                            Dr Johanna PALMIO  - Pr Bjarne UDD


A rare, late adult-onset myofibrillar myopathy characterized by progressive distal muscle weakness associated with peripheral neuropathy and hyporeflexia. Ambulation may be lost within a few years.


Distal nebulin myopathy is a rare, slowly progressive, autosomal recessive distal myopathy characterized by early onset of predominantly distal muscle weakness and atrophy affecting lower leg extensor muscles, finger extensors and neck flexors. Muscle histology does not always show nemaline rods.

Summary:
Epidemiology
To date, the disease has been described in 13 patients from five unrelated Finnish families and four non-Finnish families.
Clinical description
Distal nebulin myopathy manifests initially, in early childhood or young adulthood, by foot drop, but the first symptoms can be seen as early as one year of age. The most severely affected muscles include the ankle dorsiflexors, the finger extensors and the neck flexors. Patients are usually not able to walk on their heels and later in the disease course, there is a mild proximal muscle involvement. Additional features include early-onset moderate facial weakness and mild respiratory problems, such as shortness of breath on strenuous exercise (although only one patient presenting decreased vital capacity has been reported). Cardiac muscle is usually not affected, however cardiomyopathy has been described in one patient.
Etiology
Distal nebulin myopathy is caused by biallelic mutations (with at least one of them being missense mutation) in the gene NEB (2q22) which encodes the protein nebulin. The latter is expressed in the thin filaments of striated muscle and is required for the proper assembly of the thin filaments, for the maintenance of their lengths and for their contractile function.
Diagnostic methods
Diagnosis is based on clinical, muscle histology and laboratory examinations. Muscle histology shows a marked fiber size variation, presence of hypertrophic fibers with internal nuclei, and variably abundant nemaline rods. CK levels are normal or slightly increased. Diagnosis is confirmed by genetic screening of NEB.
Differential diagnosis
Differential diagnosis includes other distal myopathies, especially Laing distal myopathy.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.
Management and treatment
Currently no specific treatment is available. Management is mainly symptomatic and includes the help of an occupational and a physical therapists. Foot drop may be aided by orthoses. Occasional monitoring of respiratory function is recommended.
Prognosis
Prognosis is good with patients typically remaining ambulant although proximal weakness may occur at the later stages.

                            Last update:
                            September 2018

                            - Expert reviewer(s):
                            Dr Johanna PALMIO  - Pr Bjarne UDD


Distal renal tubular acidosis with anemia

A rare form of distal renal tubular acidosis characterized by a defect in renal acidification and hereditary hemolytic anemia.


A rare genetic or acquired renal tubular disease characterized by hyperchloremic metabolic acidosis. Primary distal renal tubular acidosis (dRTA) is often associated with hypokalemia, other forms with hypokalemia, hyperkalemia or normokalemia.

Summary:
Epidemiology
Prevalence is unknown. Hereditary forms are more prevalent in areas of high consanguinity (Arabic peninsula and North Africa) whereas acquired dRTA has been reported more frequently in Western countries.
Clinical description
Disease onset can occur at any age, depending on cause. Hereditary forms include autosomal dominant (AD) and autosomal recessive (AR) dRTA. AR, less frequently AD, subtypes associated with hemolytic anemia and ovalocytosis, stomatocytosis or spherocytosis have also been described in Southeast Asia. AR forms are frequently diagnosed in infants and young children, AD dRTA mostly in adolescents and young adults. Patients with primary dRTA can be asymptomatic or present with polyuria, polydipsia, weakness, and fatigue (symptoms associated with hypokalemia). Failure to thrive, rickets, stunting of growth (in children) and osteomalacia or osteopenia (in adults) are a result of urinary calcium wastage and loss of calcium salts from the bones. Hypercalciuria, nephrolithiasis and nephrocalcinosis usually occur. Low plasma potassium levels in the classic form can also cause cardiac arrhythmias, paralysis and even death. In AR forms, bilateral sensorineural hearing loss (SNHL) may be present at diagnosis or appear later, following a progressive and irreversible course of highly variable severity.
Etiology
AD dRTA, the most common dRTA, is usually due to mutations in the SLC4A1 gene (17q21.31). ATP6V1B1 (2p13) or ATP6V0A4 (7q34) mutations cause AR dRTA with or without SNHL. AR dRTA without or with late onset SNHL has been mainly described in patients with ATP6V0A4 mutations. These 3 genes explain 60-80% of primary dRTA. Other rare genetic causes are FOXI1 mutations causing dRTA associated with early hearing loss, and variants in WDR72, which have been described in milder dRTA. Acquired forms of dRTA are thought to be caused by autoimmune diseases or secondary to other conditions like sickle cell anemia, chronic obstructive uropathy, or post-renal transplantation.
Diagnostic methods
The disease is characterized by hyperchloremic metabolic acidosis. The inability to lower urine pH below 5.5 and a positive urine anion gap during spontaneous metabolic acidosis are indicative of dRTA. Provocative tests for further diagnosis include the NH4Cl acidifying test and the furosemide test. Patients also show renal potassium wasting except in the hyperkalemic type. Extra-renal manifestations may facilitate the diagnosis, which can be confirmed by molecular genetic testing, preferably using a next-generation-sequencing-based panel for all potential causative genes.
Differential diagnosis
Main differential diagnosis is proximal RTA along with other causes of chronic metabolic acidosis. A transient proximal tubular dysfunction associated with severe acidosis resembling incomplete Fanconi syndrome is commonly observed in infants with dRTA at diagnosis. Incomplete dRTA refers to an impaired ability to acidify the urine below 5.5 in the absence of overt metabolic acidosis and is diagnosed predominantly in adults with nephrocalcinosis, recurrent nephrolithiasis, osteopenia or hypocitraturia.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variants have previously been identified in a family member.
Genetic counseling
In families with AR dRTA, genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation), informing them that there is a 25% risk of having an affected child at each pregnancy. In AD dRTA, genetic counseling should be offered to affected individuals, informing them that there is a 50% risk of having an affected child at each pregnancy..
Management and treatment
Alkali therapy, usually with sodium bicarbonate or sodium citrate, is the standard treatment (to achieve normal serum bicarbonate levels). Children require very high doses (4-8 meq/kg/day) as compared to adults (1-2 meq/kg/day). Potassium replacement, usually with potassium citrate, is necessary in hypokalemic patients. Hyperkalemic types require low dietary potassium intake and other therapies.
Prognosis
All forms of dRTA are chronic and may have significant effects on growth and development. With treatment, life expectancy is normal and renal failure uncommon but progressive chronic kidney disease is more often observed than expected in the long term, associated with non-adherence, recurrent kidney stones, and when nephrocalcinosis is very severe.

                            Last update:
                            March 2022

                            - Expert reviewer(s):
                            Pr Gema ARICETA  - Dr Daniel BATLLE


Distal spinal muscular atrophy type 3 is a rare neuromuscular disease characterized by progressive muscular weakness and atrophy predominantly affecting distal parts of limbs, later involvement of proximal and trunk muscles with marked hyperlordosis and late diaphragmatic dysfunction.


A rare syndromic X-linked intellectual disability characterized by cognitive impairment, behavioral and psychiatric problems, obesity, recurrent infections, atopic diseases, and distinctive facial features in males. Females are clinically asymptomatic or mildly affected, presenting mild learning difficulties and facial dysmorphism.


A rare group of infectious disease characterized by the infection of different organs (liver, lungs, or intestines) by flat worms live in contact with epitheliums. Clinical symptoms vary depending on the infected organ. In liver infection, (often presents with inflammation and obstruction of the biliary ducts) fever, allergic reactions (dermographism), abdominal pain, nausea, diarrhoea, hypereosinophilia and angiocholitis attacks can be observed. In lung infection, tuberculosis-like clinical signs (cough or haemoptysis) are observed without fever, however erratic cases may also exist. In intestine infection, painful diarrhea, abdominal pain, oedema (face, abdomen or legs), vomiting, anorexia, or intestinal obstruction can be observed, some patients can also be asymptomatic.


A rare, genetic, autoinflammatory syndrome with immune deficiency disease characterized by recurrent and severe flares of generalized pustular psoriasis associated with high fever, asthenia, and systemic inflammation, due to IL36R antagonist deficiency. Psoriatic nail changes (e.g. pitting and onychomadesis) and ichthyosis may occasionally be associated.


DK1-CDG is characterised by muscular hypotonia and ichthyosis. It has been described in four children from two consanguineous families. All the affected children died during early infancy, two from dilated cardiomyopathy. The syndrome is caused by a deficiency in dolichol kinase 1 (DK1), an enzyme involved in the de novo biosynthesis of dolichol phosphate. The mutations identified in the DK1 gene led to a 96 to 98% reduction in DK activity.


DNA2-related mitochondrial DNA deletion syndrome

A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by either late-onset myopathy with progressive external ophthalmoplegia and muscular weakness (predominantly limb-girdle) or early-onset myopathy presenting with decreased fetal movements, congenital ptosis, progressive external ophthalmoplegia, hypotonia and, variably, joint contractures. Reduced content and multiple deletions of mitochondrial DNA is observed in muscle biopsy.


DNAJB2-related Charcot-Marie-Tooth disease type 2

A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by adolescent or adult onset of slowly progressive muscle weakness and atrophy of the distal lower limbs progressing to involve also the upper limbs and proximal muscles, and sensory impairment. Patients present gait disturbances and loss of reflexes, at later stages loss of ambulation, dysarthria, dysphagia, facial weakness, and impairment of respiratory muscles requiring assisted ventilation.


DNAJB6-related limb-girdle muscular dystrophy D1

A subtype of autosomal dominant limb-girdle muscular dystrophy characterized by an adult-onset of slowly progressive, proximal pelvic girdle weakness, with none, or only minimal, shoulder girdle involvement, and absence of cardiac and respiratory symptoms. Mild to moderate elevated creatine kinase serum levels and gait abnormalities are frequently observed.


A rare multiple congenital defects/dysmorphic syndrome characterized by variable degrees of bony syngnathia associated with variable additional abnormalities, including growth retardation, intellectual disability, microcephaly, iris coloboma, nystagmus, deafness, and vertebral segmentation defects, as well as genital, limb and additional facial malformations, among others.


Dominant beta-thalassemia is a form of beta-thalassemia (see this term) resulting in moderate to severe anemia.

Summary:
Epidemiology
Prevalence of this form is not known.
Clinical description
Patients present with moderate to severe anemia, jaundice and splenomegaly.
Etiology
Rare mutations in the beta-globin HBB gene result in synthesis of extremely unstable beta-globin variants which precipitate in erythroid precursors causing ineffective erythropoiesis.
Diagnostic methods
The presence of hyper-unstable hemoglobin should be suspected in any individual with beta-thalassemia intermedia (see this term) when both parents are hematologically normal (de novo mutations), or in families with a pattern of autosomal dominant transmission of beta-thalassemia intermedia. Diagnosis is based on beta-globin gene sequencing.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA


Dominant hypophosphatemia with nephrolithiasis or osteoporosis

A rare, genetic renal tubular disease characterized by phosphate loss in the proximal tubule, leading to hypercalciuria and recurrent urolithiasis and/or osteoporosis.

Summary:
Epidemiology
More than 10 cases have been identified to date.
Clinical description
Disease onset is in adulthood with presentation of nephrolithiasis, renal phosphate wasting and skeletal abnormalities variably including osteopenia, osteoporosis and increased susceptibility to fractures. Cases of spinal deformity have also been described.
Etiology
Heterozygous mutations have been identified in two genes SCL34A1 (5q35), and SLC9A3R1 (17q25.1). SCL34A1 encodes the main sodium-phosphate cotransporter, sodium-dependent phosphate transport protein 2A (NPT2a), located in the apical membrane of renal proximal tubular cells.  SLC9A3R1 encodes the Na(+)/H(+) exchange regulatory cofactor (NHERF1), a cytoplasmic protein essential for recruitment of transporter or signaling proteins to the plasma membrane which stabilize NaPi-IIa, the parathyroid hormone (PTH) receptor 1, and phospholipase C at the brush border membrane and creates a platform for PTH signaling to NaPi-IIa . SLC9A3R1 mutations decreases NPT2a expression directly or indirectly via an increase in PTH-responsive downregulation of NaPi-IIa. The decreased serum phosphate levels stimulate 1,25-dihydroxy-Vitamin D synthesis leading to absorptive hypercalciuria, which together with elevated urinary phosphate levels can trigger the formation of calcium-phosphate crystals favoring the development of renal calcifications.
Diagnostic methods
Diagnosis is usually based on clinical features, plasma and urine electrolytes showing hypophosphatemia, hyperphosphaturia, hypercalciuria and increased serum 1,25-dihydroxy-Vitamin D in response to phosphate deprivation. A definitive diagnosis can be achieved by genetic testing.
Differential diagnosis
The differential diagnosis includes other forms of inherited hypophosphatemia such as X-linked hypophosphatemia, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria.
Genetic counseling
The pattern of inheritance is autosomal dominant. There is a 50% risk of the disease occurring in a sibling or being transmitted to the offspring of affected individuals.
Management and treatment
Supportive treatment is with phosphate and low‐ dose vitamin D supplementation.
Prognosis
There is no information available on outcomes.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Pr Elena LEVTCHENKO | ERKNet*

                                * European Reference Network


A multiple congenital malformation syndrome characterized by typical facial dysmorphism, myopia and other ocular findings, hearing loss, agenesis of the corpus callosum, low-molecular-weight proteinuria, and variable intellectual disability. Congenital diaphragmatic hernia (CDH) and/or omphalocele are common.

Summary:
Epidemiology
The prevalence and incidence of Donnai-Barrow syndrome (DBS) are difficult to estimate. Fewer than 50 individuals from about 20 families have been reported. DBS affects all ethnicities; it is more commonly diagnosed in the offspring of consanguineous unions. Males and females are affected equally.
Clinical description
Almost all patients have the following features: agenesis/hypogenesis of the corpus callosum, enlarged anterior fontanelle, marked sensorineural hearing loss and hypertelorism. Characteristic facial features include: down-slanting palpebral fissures, short nose with flat nasal bridge, tall broad forehead, widow's peak in the anterior hairline, and sometimes prominent globes. About 40% of patients have CDH and/or omphalocele. Developmental delay and variable intellectual deficit are frequent. High myopia (> 6 diopters), a distinctive optic nerve head dysgenesis, and an increased risk of retinal detachment may lead to progressive loss of vision. Iris coloboma, Focal segmental glomerulosclerosis and proximal tubule dysfunction (rarely progressing to renal insufficiency) are reported occasionally.
Etiology
DBS is an autosomal recessive disorder caused by loss of function variants in the LRP2 low-density lipoprotein receptor-related protein 2 gene (2q31.1) encoding the protein megalin, expressed on multiple absorptive epithelia, notably in the brain, kidney, and eye. Megalin plays an important role in endocytosis of numerous ligands and in various signaling pathways.
Diagnostic methods
Diagnosis is suggested by a combination of clinical and neuroimaging features along with a typical pattern of low-molecular-weight proteinuria, increased urinary levels of retinol-binding protein (RBP) and RBP/creatinine ratio. The diagnosis is confirmed by molecular genetic testing.
Differential diagnosis
DBS has a characteristic constellation of clinical features limiting differential diagnoses. However, some overlapping signs are found in tetrasomy 12p, Fryns, Chudley-McCullough, Acrocallosal, and Craniofrontonasal syndromes. The renal phenotype partly resembles Dent disease and Lowe syndrome. The ocular phenotype may be suggestive of Stickler syndrome.
Antenatal diagnosis
Detection of hypertelorism, agenesis of the corpus callosum, and either CDH or omphalocele by prenatal imaging should raise suspicion of DBS. Prenatal diagnosis for at-risk pregnancies is possible and requires prior identification of the disease-causing mutation in the family.
Genetic counseling
DBS is an autosomal recessive disorder. Genetic counseling should be provided to parents of affected children and to their relatives. Parents of an affected child are obligate carriers for the disease-causing allele. The sole exception reported to date is a patient with DBS due to uniparental disomy (UPD).
Management and treatment
Regular screening of vision, hearing, and renal function should be established. Corrective lenses, preventive treatment for retinal detachment, and hearing aids and/or cochlear implants may be required. CDH and/or omphalocele, when present, necessitate surgical intervention. Specific adapted education for vision, hearing and intellectual disabilities should be provided as is needed for affected children.
Prognosis
Affected individuals can achieve useful vision and hearing with correction. Overall health status in patients is generally good in childhood and adolescence. End-stage kidney failure is a rare and life-threatening complication. Pre- or peri-natal presentation with diaphragmatic and abdominal wall defects requires surgical intervention and is associated with elevated morbidity and mortality.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr Mauro LONGONI  - Dr Barbara POBER


DONSON-related microcephaly-short stature-limb abnormalities spectrum

A rare autosomal recessive microcephalic primordial dwarfism characterized by congenital microcephaly and craniofacial features associated with a spectrum of limb abnormalities ranging from mild to severe. Short stature is frequently observed and often is severe.

Summary:
Epidemiology
The exact prevalence of DONSON-related microcephaly associated with short stature and limb abnormalities spectrum is unknown; slightly more than 50 patients have been reported to date. The Microcephaly Micromelia syndrome is more frequent in a First Nations population in northern Saskatchewan, Canada.
Clinical description
Presentation is with intrauterine growth retardation or at birth with low birth weight (- 2.9 SD on average), short birth length (-3.7 SD) and congenital microcephaly (-5.1 SD). Craniofacial features include broad nasal bridge, short palpebral fissures, microstomia, and micrognathia. Congenital limb abnormalities vary in severity and involve both upper and lower limbs, with upper limbs more severely affected. The mildest malformations are clinodactyly, camptodactyly, syndactyly, or brachymesophalangia and are mainly associated with the clinical subtype, microcephaly-short stature-limb abnormalities syndrome. Severe malformations are usually associated with microcephaly-micromelia syndrome. Limbs are short with hypoplasia of the radius, ulna, thumb and/or Vth finger. Lower limbs may be underdeveloped (fibula, patella, I and Vth toes). Feet may be clubbed. Perinatal mortality is very high in the microcephaly-micromelia syndrome due to respiratory failure. Subglottic stenosis, diaphragmatic hernia and choanal atresia have been described in some patients with short stature and milder limb abnormalities. Gyration is usually simplified on brain imaging. Intellectual abilities ranges from normal to moderate intellectual disability.
Etiology
The disorder is due to bi-allelic mutations in the downstream neighbor of SON, DONSON  (21q22.11), a replisome component that stabilizes forks during genome replication.
Diagnostic methods
Diagnosis is based on clinical signs. Congenital microcephaly, short stature combined with at least minor, I and Vth finger malformations or even hypoplasia/malformations of the upper and/or the lower limbs. Targeted sequencing and whole exome sequencing identify coding variants responsible for the disease. However pathogenic noncoding variants may only be identified using integrative transcriptomic and genomic sequencing.
Differential diagnosis
There is considerable clinical overlap with Fanconi anemia (FA), and several patients were originally diagnosed with FA. Additional differential diagnosis includes VACTERL, Meier Gorlin syndrome, and Taiby Linder syndrome.
Antenatal diagnosis
The disorder may be identified prenatally using ultrasound. However, absence of microcephaly and limb malformation does not rule out the diagnosis, especially for the mildest types. Once the molecular diagnosis has been established in a family member, prenatal diagnosis is possible.
Genetic counseling
If both parents are heterozygous for a pathogenic DONSON variant, the risk of having an affected child is 25% for each pregnancy.
Management and treatment
Treatment is symptomatic. Adequate nutritional intake, using naso-gastric tube-feeding if needed, should be ensured during the first years of life. Epilepsy is treated with antiepileptic medication. Physiotherapy and speech therapy may be beneficial.
Prognosis
Life expectancy is much reduced in microcephaly-micromelia syndrome; all reported patients died, mostly in the perinatal period. In milder forms, the prognosis and quality of life will depend on the severity of the limb malformations and the intellectual disability.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Sandrine PASSEMARD | ITHACA*

                                * European Reference Network


A rare multiple congenital anomalies-intellectual disability syndrome characterized by sensorineural hearing loss (deafness), onychodystrophy, osteodystrophy, mild to profound intellectual disability, and seizures.

Summary:
Epidemiology
The prevalence is unknown; about 50 cases have been reported to date.
Clinical description
Disease onset usually presents shortly after birth, but may present in infancy, with profound sensorineural deafness, small or absent nails, and short distal phalanges of hands and feet. About 1/4 of patients have long, finger-like thumbs. Facial features are highly variable and only a broad nasal bridge is present in 1/2 of all cases. Other facial signs, reported infrequently, include anteverted nares, long philtrum, thin upper vermilion and low set ears. Craniosynostosis has been reported in one patient. Optic atrophy leading to blindness, retinal detachment, strabismus, nystagmus, high myopia and cataracts are sometimes reported. Developmental delay is noted from infancy and can range from mild delays in early motor milestones to generalized and lifelong hypotonia. Seizures (often generalized tonic-clonic) are seen in most cases, usually begin in the first year of life and become more marked with age. Along with learning difficulties, behavioral problems may also be noted. Rare manifestations include dental (hypoplastic enamel, abnormal size of teeth), and internal organ (congenital heart defects, unilateral renal agenesis, cystic kidney, duplicated kidney) malformations. The disease is non-progressive.
Etiology
DOORS (deafness-onychodystrophy-osteodystrophy-intellectual disability syndrome) syndrome is caused by mutations in the TBC1D24 gene (16p13.3) encoding a protein involved in the regulation of membrane trafficking. It seems likely that DOORS syndrome will prove to be a genetically heterogeneous disease and other causal genes will be identified in the future.
Diagnostic methods
Patients are checked for each of the 5 major characteristics by conducting X-rays of the hands and feet, a brain stem auditory evoked response test for hearing loss, and an electroencephalogram (EEG). Elevated levels of 2-oxoglutaric acid in the urine and plasma have repeatedly been reported mostly in patients with TBC1D24  mutations. If present, DOORS syndrome is suspected, although elevated levels can also occur in other disorders. Molecular genetic testing identifying a TBC1D24 mutation may confirm the diagnosis but absence of the mutation does not mean a diagnosis of DOORS syndrome is incorrect.
Differential diagnosis
Differential diagnoses include Coffin-Siris syndrome, intellectual disability-sparse hair-brachydactyly syndrome, Zimmermann-Laband syndrome, fetal alcohol syndrome and Temple-Baraitser syndrome, autosomal dominant deafness-onychodystrophy syndrome, and disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
DOORS syndrome is inherited autosomal recessively. If the clinical diagnosis has been established with a high degree of certainty, genetic counseling should be provided accordingly.
Management and treatment
Treatment is supportive. Long-term management involves regular ophthalmologic and hearing tests as well as neurological exams such as EEGs. A feeding tube may be necessary in infants with feeding difficulties. Antiepileptic medication may be used to prevent or decrease the frequency of seizures but is not always effective.
Prognosis
Life expectancy is usually normal. Intellectual disability is lifelong but there is no known correlation between clinical manifestations and cognition. The number of known adults with DOORS syndrome is at present too small to predict the long term prognosis. Parkinsonism was reported in an adult.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Philippe CAMPEAU


Dopa-responsive dystonia due to sepiapterin reductase deficiency

Dopa-responsive dystonia (DRD) due to sepiapterin reductase deficiency (SRD) is a very rare neurometabolic disorder characterized by dystonia with diurnal fluctuations, axial hypotonia, oculogyric crises, and delays in motor and cognitive development.

Summary:
Epidemiology
The prevalence is unknown. There have been approximately 43 cases reported to date.
Clinical description
Onset usually occurs before the first year of life with manifestations of dystonia, motor and language delays, weakness, axial hypotonia (and hypotonia in a tetraplegic distribution) and oculogyric crises that show diurnal fluctuations (worse at night and better in the morning after sleeping). Sleep disturbances and psychological symptoms (anxiety, irritability) are common later in childhood. Intellectual deficits are frequently noted but some may only experience mild to moderate learning disabilities. Less common features include parkinsonism (tremor, bradykinesia, rigidity, masked facies), dysarthria, hyperreflexia, limb hypertonia, and autonomic signs. Frequently, dystonia and obvious diurnal fluctuations only develop during the course of the disease, whereas common presenting symptoms in infancy such as developmental delay and hypotonia are unspecific.
Etiology
DRD due to an SRD is due to mutations in the SPR gene (2p14-p12), encoding the enzyme sepiapterin reductase (SR). Various mutations in this gene lead to reduced SR activity and consequently to a reduced production of monoamine neurotransmitters.
Diagnostic methods
Distinctive cerebrospinal fluid (CSF) findings include low levels of 5-hydroxyindoleacetic (5-HIAA) and homovanillic acid (HVA), and elevated total biopterin and dihydrobiopterin (BH2). SR activity in fibroblasts is usually reduced or absent. Molecular genetic testing can identify mutations in the SPR gene, confirming the diagnosis.
Differential diagnosis
Differential diagnoses include other forms of DRD such as autosomal recessive DRD and autosomal dominant DRD, infantile dystonia-parkinsonism, infantile-onset spastic paraplegia, some forms of epilepsy and cerebral palsy.
Antenatal diagnosis
Prenatal diagnosis is possible in those with a known SPR mutation.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible and recommended.
Management and treatment
Like other forms of DRD, DRD due to an SRD responds dramatically to levodopa (L-dopa) therapy. L-dopa is often combined with a peripheral decarboxylase inhibitor such as carbidopa or benserazide. Treatment should be initiated as early as possible to avoid irreversible neurological damage. The dosage of L-dopa given can range from 0.1 to 16.0 mg/kg/day. Transient dyskinesias frequently occur initially as a result of treatment but are usually resolved by decreasing the dosage. In patients with insufficient improvement of symptoms under L-dopa therapy, 5-hydroxytrytophan (5-HTP) at a dosage of 0.14 to 6 mg/kg/day should be given with carbidopa (to reduce side effects), since combination therapy may result in further improvements of motor and sleep symptoms. Treatment is life-long.
Prognosis
Prognosis depends on if treatment is initiated early and on disease severity. Those who receive treatment show significant improvement, but most still experience mild motor and sometimes severe cognitive symptoms if treatment is delayed.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


Dopa-responsive dystonia (DRD) describes a group of neurometabolic disorders characterized by dystonia that typically shows diurnal fluctuations, that responds excellently to levodopa (L-dopa) and that is comprised of autosomal dominant dopa-responsive dystonia (DYT5a), autosomal recessive dopa-responsive dystonia (DYT5b) and dopa responsive dystonia due to sepiapterin reductase (SR) deficiency.

Summary:
Epidemiology
The estimated European prevalence of DRD ranges from 1/1,000,000-1/200,000.
Clinical description
DRD usually has a pediatric onset, typically with lower limb dystonia that leads to gait disturbances and that usually worsens during the course of the day and is improved in the morning after sleeping. Parkinsonism can develop at a later age in some patients. Anxiety, depression, sleep disturbances and obsessive-compulsive disorders have also been reported in a few patients with DYT5a. Rarer subtypes which are inherited in an autosomal recessive manner typically show a much more severe phenotype, with onset in the first year of life with additional manifestations of global developmental delay, axial hypotonia, oculogyric crises and encephalopathy. DRD responds dramatically and continuously to L-dopa therapy, and patients usually experience a significant improvement of symptoms once treatment is initiated. If untreated, patients can become wheelchair bound.
Etiology
DRD is due to mutations in genes that encode proteins essential for the biosynthesis of dopamine. DYT5a is due to mutations in the GTP cyclohydrolase 1 (GCH1) gene (14q22.1 to q22.2) which encodes an enzyme needed for the biosynthesis of tetrahydrobiopterin, the essential co-factor for tyrosine hydroxylase. DYT5b is caused by mutations in the tyrosine hydroxylase TH gene (11p15.5) encoding tyrosine hydroxylase, the enzyme responsible for catalyzing the conversion of tyrosine to L-dopa, the precursor of dopamine. Finally, DRD due to an SRD is due to mutations in the SPR gene (2p14-p12), encoding the enzyme sepiapterin reductase (SR), which is also required for the biosynthesis of tetrahydrobiopterin.
Genetic counseling
DRD can be inherited in an autosomal dominant or autosomal recessive manner, depending on the subtype. It can also occur due to de novo mutations.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


A very rare primary monoamine neurotransmitter synthesis disorder with norepinephrine and adrenaline deficiency that leads to young-onset severe orthostatic hypotension and eyelid ptosis.

Summary:
Epidemiology
The prevalence of dopamine beta-hydroxylase (DBH) deficiency is unknown. Only 25 patients have been reported to date.
Clinical description
DBH deficiency is mainly characterized by severe early onset orthostatic hypotension. In the neonatal period hypothermia and hypoglycemia can occur. First symptoms of orthostatic hypotension generally occur in early childhood with reduced exercise intolerance. Orthostatic hypotension is profound and can lead to syncope. Other symptoms and signs of the selective noradrenergic failure of the sympathetic nervous system are eyelid ptosis, nasal congestion, and primary enuresis. Sweating is normal. The central nervous system appears to be largely spared. Reduced kidney function, anemia and hypomagnesemia are common.
Etiology
DBH deficiency is caused by mutations in the DBH gene (9q34), encoding the enzyme dopamine beta hydroxylase which converts dopamine to noradrenaline. It results in undetectable levels of noradrenaline and adrenaline, and highly increased levels of dopamine in plasma, urine and cerebrospinal fluid.
Diagnostic methods
Plasma measurements of catecholamines shows undetectable levels of noradrenaline and adrenaline and increased levels of dopamine. Diagnosis is confirmed by genetic testing of the DBH gene. Diagnosis can be supported by testing DBH enzyme activity in plasma, however this can be falsely absent due to a common polymorphism in the healthy population.
Differential diagnosis
Orthostatic hypotension due to CYB561 mutations gives a comparable clinical picture but levels of dopamine are normal.
Antenatal diagnosis
Prenatal diagnosis is possible when the pathogenic variant has been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Excellent and sustained clinical response can be achieved by precursor therapy with L-threo-dihydroxyphenylserine (L-DOPS/ Droxidopa). Oral administration of 100 to 500 mg of L-DOPS, twice or three times a day, reverses the orthostatic intolerance. For children, a starting dose of 2 mg/kg/d in 2-3 doses eventually increasing to 5-10 mg/kg/d in 2-3 doses seems reasonable. Dose should be titrated individually based on clinical response. Blood pressure should be monitored regularly and (nightly) hypertension should be avoided (last dose of medication should be given more than 4 hours before bedtime). Regular follow-up of kidney function, electrolytes and hematological parameters is advised.
Prognosis
With L-DOPS treatment, clinical response is excellent and sustained, with improvement of quality of life and exercise intolerance. Mild ptosis can persist under treatment. Catecholamine profile in plasma does not normalize completely.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN* - Dr Tessa WASSENBERG | MetabERN*

                                * European Reference Network


Double-outlet left ventricle (DOLV) is an extremely rare congenital cardiac malformation in which both the aorta and the pulmonary artery arise, either exclusively or predominantly, from the morphologic left ventricle.

Summary:
Epidemiology
Prevalence is unknown. The birth prevalence is estimated at less than 1/ 200,000 live births.
Clinical description
DOLV usually manifests during the neonatal period with cyanosis, tachypnea, exertional dyspnea, failure to thrive, sweating (especially during feeding), unresponsiveness and/or fatigue. DOLV occurs most commonly in the form of atrial situs solitus with atrioventricular (AV) concordance but is often associated with cardiac anomalies such as a ventricular septal defect (VSD), an atrial septal defect, pulmonary stenosis, right ventricular hypoplasia, patent ductus arteriosus, and tricuspid atresia (see these terms). The clinical manifestations depend largely on the type of the associated cardiac defects, e.g. pulmonary or aortic outflow tract obstruction resulting from pulmonary or aortic valve stenosis respectively. DOLV is classified into two sub-types depending on the location of the VSD and the position of the great arteries: DOLV with normal great arteries (DOLV NGA type) with subpulmonary or doubly committed subarterial VSD and levo-position of the anterior pulmonary artery; and DOLV with transposition of the great arteries (DOLV TGA type) with subaortic or doubly committed subarterial VSD and levoposition of the anterior aorta. The two sub-types are almost clinically indistinguishable, apart from cyanosis being more prominent in TGA type.
Etiology
The etiopathology is not clearly understood. Embryologically, DOLV could result from excessive leftward shift of the embryonic conotruncus, anomalous differential absorption of sub-pulmonic and sub-aortic conus, or anomalous differential conal growth.
Diagnostic methods
Diagnosis is based on 2-D echocardiography combined with magnetic resonance imaging (MRI) showing both great arteries arising from the morphologic left ventricle. Chest X-ray and/or cardiac catheterization can also be performed.
Differential diagnosis
Differential diagnosis includes transposition of the great arteries and double outlet right ventricle (see these terms).
Antenatal diagnosis
Prenatal echocardiographic diagnosis is possible but very difficult.
Genetic counseling
DOLV is a sporadic disease.
Management and treatment
Biventricular repair is the usual treatment for DOLV and is usually accomplished by an intraventricular baffle procedure, by the Rastelli procedure or by a variant of the Lecompte operation. Pulmonary root translocation from the left to the right ventricle can also be performed and provides excellent anatomic and hemodynamic repair. When other cardiac malformations are present, other techniques can be used such as Fontan-type cavopulmonary derivation in the presence of right ventricular hypoplasia.
Prognosis
DOLV is associated with high mortality, generally due to heart failure, myocardial infarction or aortic thrombosis. With surgery, the five-year survival rate is estimated at 70-75%. Most patients will continue to present with residual cardiac anomalies, such as aortic or mitral valve regurgitation, arrhythmias or hypertension.

                            Last update:
                            March 2014

                            - Expert reviewer(s):
                            Dr Hiromi KUROSAWA


A rare cono-truncal anomaly in which both the aorta and pulmonary artery originate, either entirely or predominantly, from the morphologic right ventricle.

Summary:
Epidemiology
Double outlet right ventricle (DORV) accounts for about 2-3% of all congenital heart defects, with a birth prevalence rate of 1/ 10,000.
Clinical description
The clinical picture varies widely, depending on the combination of the abnormalities present. Symptoms are generally observed during the first days or weeks of life. Cyanosis is the most frequent sign. Tachypnea or breathlessness, poor feeding and slow weight gain are also common. Tachycardia and/or heart murmur may also be observed. DORV is always associated with a ventricular septal defect (VSD) that allows blood to drain from the left ventricle. DORV is classified into sub-types, based on the relationship of the VSD (subaortic, doubly committed, subpulmonary or non-committed) with the great arteries. Other cardiac anomalies frequently associated with DORV include pulmonary stenosis, various degrees of left and right ventricular hypoplasia, atrioventricular (AV) septal defects, and straddling AV valves. Extracardiac anomalies, such as heterotaxy (polysplenia, asplenia, situs ambiguous) intestinal malrotation and ciliary dysfunction could be associated. It is important to figure out that DORV is not a congenital heart disease per se but a mode of ventriculo-arterial connection. Therefore there are several clinical types of DORV, depending on the presence of a pulmonary stenosis and of associated lesions. The functional classification has identified 5 types of DORV: DORV-VSD type, DORV-Fallot, DORV-Taussig Bing, DORV-non committed VSD, DORV-AVSD-heterotaxy. Each type has a specific clinical presentation and surgical treatment.
Etiology
DORV results from a failure in the fetal development of the cono-truncus, which is the primary outlet of the heart during embryonic development. The cono-truncal anomalies result in neural crest and second heart field dysfunction. Cardiac progenitor cells are controlled by various genes, such as GDF1 (19p13.11) and CFC1 (2q21.2), which when mutated can result in DORV. DORV is associated with chromosomal anomalies such as 22q11.2 deletion syndrome, trisomy 13, trisomy 18 and CHARGE syndrome and others.
Diagnostic methods
Diagnosis is based on 3D echocardiography showing both great arteries arising from the right ventricle. In complex forms, cardiac catheterization-angiography, magnetic resonance imaging (MRI) and /or computed tomography (CT) scan are required. Recently, 3D printed models have been very useful to plane the surgery.
Differential diagnosis
Differential diagnosis includes transposition of the great arteries, tetralogy of Fallot, ventricular septal defect, and double outlet left ventricle.
Antenatal diagnosis
DORV can be diagnosed by fetal echocardiography with a good degree of accuracy when the two vessels arise entirely from the right ventricle.
Genetic counseling
DORV is a sporadic disease. Consanguinity seems to be a risk factor. Genetic counseling is not possible.
Management and treatment
In the presence of two viable ventricles, biventricular repair is the optimal treatment for DORV and it is quite safely achieved in the simple forms (DORV-VSD type, DORV-Fallot type and DORV-TGA type). In the complex forms (DORV with non-committed VSD, DORV-atrioventricular septal defect-pulmonary stenosis-heterotaxy), univentricular repair (Fontan operation) is often preferred by a number of teams, while biventricular repair is performed in selected cases in advanced pediatric heart surgery centers.
Prognosis
Without treatment, prognosis is poor due to severe cyanosis, congestive heart failure or pulmonary hypertension. With biventricular repair, patients have, on average, a normal life expectancy, with possible risk or re-operation. All patients that have received surgery for a DORV require life-long surveillance by a cardiologist. Univentricular palliation requires a very close follow up.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr François LACOUR-GAYET


Double uterus-hemivagina-renal agenesis syndrome

A rare congenital urogenital anomaly characterized by the presence of double uterus (didelphys, bicornuate or septum-complete or partial), unilateral cervico-vaginal obstruction (obstructed hemivagina-communicant, not communicant or septate and unilateral cervical atresia) and ipsilateral renal anomalies (renal agenesis and/or other urinary tract anomalies). Patients are usually diagnosed at puberty after menarche due to recurrent severe dysmenorrhea, chronic pelvic pain, excessive foul smelling mucopurulent discharge, spotting and intermenstrual bleeding (depending on the existence of uterine or vaginal communications). Fever, dyspareunia, and a palpable abdominal, pelvic or vaginal mass (mucocolpos or pyocolpos) may also be present.


A rare, congenital, non-syndromic heart malformation characterized by a single fibrous annulus with two orifices opening into the left ventricle. Clinical presentation is variable and related to the degree of resulting mitral insufficiency and/or stenosis, and depending on the associated heart disease, most commonly atrioventricular septal defect, obstructive left-sided lesions, and cyanotic heart disease. Rare cases of isolated disease have been reported.


A rare, genetic, hyperpigmentation of the skin disease characterized by adulthood-onset of reticular, reddish-brown to dark-brown, macular and/or comedone-like, hyperkeratotic papules with hypopigmented macules, predominantly affecting flexural areas and, on occasion, progressing to involve trunk and acral regions. Histologically, epidermal acanthosis, thin, branch-like, rete ridges, and a tendency for acantholysis and pigmentary incontinence is observed.


A total autosomal trisomy that is caused by the presence of a third (partial or total) copy of chromosome 21 and that is characterized by variable intellectual disability, muscular hypotonia, and joint laxity, often associated with a characteristic facial dysmorphism and various anomalies such as cardiac, gastrointestinal, neurosensorial or endocrine defects.

Summary:
Epidemiology
Prevalence at birth of Down syndrome (DS) in a country depends largely on non-medical factors, i.e. public policies regarding prenatal diagnosis and care for disabled people, and view of the population for DS and for abortion. In brief, it varies from 1/400 to 1/3000 live births. The risk of having a baby with Down syndrome (DS) increases with maternal age, identically in every population.
Clinical description
Clinical features include variable (often mild) intellectual disability, almost constant muscular hypotonia and joint laxity, associated with morphological signs, malformations (half of cases) and increased risks of some medical complications all-life-long. Morphological features (upslanting palpebral fissures, epicanthus, flat neck, round face, small nose, bilateral single palmar crease) can be mild and are not pathognomonic of the condition. The main potential malformations and complications include: short stature, congenital cataract, conductive hearing loss, heart defects (atrio-ventricular canal), digestive malformations (duodenal atresia), Hirschsprung disease, seizures, sleep apnea, sensory deficiencies, leukemia, auto-immune and endocrine pathologies (hypothyroidism, celiac disease, diabetes mellitus type 1, alopecia areata, earlier aging and early-onset Alzheimer disease.
Etiology
In 95% of the cases, trisomy 21 is an additional independent chromosome 21 (47,+21): the extra chromosome is due to an accidental non-disjunction during meiosis. 2-3% of those cases are in a mosaic state. In the remaining 5%, the supernumerary chromosome 21 or portion of chromosome 21 is translocated to another chromosome (Robertsonian translocation in most cases).
Diagnostic methods
The diagnosis is based on karyotyping.
Differential diagnosis
Differential diagnosis includes Zellweger syndrome, 9qter deletion or other chromosomal abnormalities. We can also mention the exceptional Aymé-Gripp syndrome.
Antenatal diagnosis
In 70-75% of fetuses, increased nuchal translucency can be seen on first-trimester ultrasonography. On the second-trimester, malformations (essentially cardiac and digestive) are present in 60% of the cases, and can be associated with minor morphological signs. Prenatal diagnosis can be confirmed by fetal karyotype on amniocentesis or chorionic villous sampling. Non-invasive prenatal screening on maternal blood is now available in several countries in case of an increased risk of DS on prenatal screening.
Genetic counseling
For the parents of a child affected by regular trisomy 21, the recurrence risk is only slightly modified (1% until the age of 40 years, linked to maternal age afterwards). In case of DS caused by translocation, the risk is raised only if one of the parents has a balanced rearrangement. For a person with Down syndrome, the risk of transmitting the disease to the descendants is 1/3 (maybe less for males with DS).
Management and treatment
Early physiotherapy, psychomotor therapy and speech therapy (including alternative non-verbal communication tools, namely sign language and picture exchange, in order to stimulate early communication and induce oral skills) are essential. A person with DS should be involved as soon as possible in decision-making through self-determination. A well-adapted program, including re-education, schooling and social aspects, should be proposed, aiming at obtaining the best possible integration in society (i.e. more than half of people with DS has capabilities to read and write, even partially). Neuropsychological evaluations are important to recognize the specific difficulties and abilities of each person with DS and thus propose cognitive remediation. An adapted medical follow-up is very important in order to detect and treat as soon as possible medical complications. Guidelines have been published. It can be necessary to maintain some support in the adult age, including re-education. Research in medical treatment to improve cognition in people with Down syndrome is active with ongoing clinical trials.
Prognosis
Median life expectancy is now above the age of 60 years in developed countries.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Renaud TOURAINE


DPAGT1-CDG is a form of congenital disorders of N-linked glycosylation characterized by hypotonia, intractable seizures, developmental delay, microcephaly and severe fetal hypokinesia. Additional features that may be observed include apnea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties. The disease is caused by loss-of-function mutations in the gene DPAGT1  (11q23.3).


A rare disorder of multiple glycosylation pathways characterized by global developmental delay, motor skills delay, hypotonia, seizures, microcephaly and eye abnormalities (including retinopathy, nystagmus, strabismus) with varying onset and severity. Additional clinical features may include peripheral neuropathy, dysmorphic features (facial and limb abnormalities), ataxia and severe gastrointestinal involvement.


DPM3-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case by muscle weakness, waddling gait and dilated cardiomyopathy (see this term).


Dracunculiasis (Guinea worm disease) is a neglected tropical disease (NTD) characterized by a painful burning skin lesion from which the Dracunculus medinensis parasite emerges approximately 1 year after infection resulting from consumption of unsafe drinking water containing parasite-infected copepods (Cyclops spp., microcrustacea also called water fleas).

Summary:
Epidemiology
In 2012, 542 cases were reported in 4 countries (Chad, Ethiopia, Mali, and South Sudan), a decrease of >99% since 1990. The global dracunculiasis program aims to eradicate the parasite from the last remaining endemic villages located in difficult to reach areas.
Clinical description
Clinical manifestations appear 10-14 months after infection and include constitutional symptoms (such as low-grade fever, itchy rash, nausea, vomiting, diarrhea, dizziness) followed by a localized swelling developing into a painful blister, most often on a lower limb. On contact with water, the adult female worm (70-100 cm) bursts through the blister, depositing her larvae in the water where they are consumed by copepods, starting the cycle anew. Local inflammation and secondary bacterial infection of the lesion are common, potentially causing cellulitis, abscess formation, tetanus (see this term), sepsis, and septic arthritis. If the lesion is near a joint, this may lead to joint contractures and permanent disability. If the worm is not fully removed it can create an intense inflammatory reaction that further exacerbates the pain, swelling, and cellulitis.
Etiology
Dracunculiasis is caused by the parasitic worm Dracunculus medinensis. Transmission occurs after drinking water contaminated with copepods that act as intermediate hosts to the infective parasite larvae. Copepod digestion in the gastrointestinal tract releases the larvae, which migrate to subcutaneous tissues where they mate and pregnant female worms mature.
Diagnostic methods
Dracunculiasis diagnosis is based on the typical appearance of a skin lesion with a protruding worm, commonly on a lower limb.
Differential diagnosis
Occasionally, another parasitic worm called Onchocerca volvulus, pieces of connective tissue, or fly larvae are confused with emerging  Dracunculus medinensis worms.
Management and treatment
There is no effective medication or vaccine for dracunculiasis. Infected persons do not become immune to subsequent infection. Treatment is a long painful process consisting of pulling out the emerging worm by rolling it around a piece of gauze or a small stick, a few centimeters a day, in combination with wound cleaning and dressing with antibiotic ointment to prevent secondary bacterial infection.
Prognosis
Dracunculiasis is not life threatening itself but, rarely, death due to secondary sepsis has been reported. More commonly, the patient is disabled by pain during worm removal, on average for 8.5 weeks, which often has a great impact on everyday life in endemic areas. Joint contractures and permanent disability can occur in some cases.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                             Mark EBERHARD  -  Sharon ROY


A rare, genetic, developmental and epileptic encephalopathy characterized by infantile onset of intractable seizures that are often febrile, and associated with cognitive and motor impairment.

Summary:
Epidemiology
The average prevalence at birth of Dravet syndrome is 1/30,000 (range 1/15,000-40,000).
Clinical description
Onset of the first seizure is mainly in the first year of life (usually at 5-8 months) in previously healthy infants. Seizures include clonic seizure, often unilateral that alternates between left and right, and generalized tonic-clonic seizures. Seizures are often febrile and long lasting, presenting as febrile status epilepticus (SE). SE is mainly frequent in the first years. Other seizures types may also occur, such as focal or atypical absence seizures, as well as possible clusters of nocturnal tonic or tonic-clonic seizures between age 4 and 11. Photosensitivity, high temperatures, photic stimulation and exercise may trigger seizures. Developmental delay is often apparent by age 2, followed by cognitive plateauing. Speech impairment, progressive gait deterioration with crouching, and sleeping difficulties may also appear at this stage.
Etiology
Around 85% of cases are due to a mutation or deletion in the SCN1A gene (2q24.3), encoding a voltage-gated sodium channel. Most mutations are de novo but might be part of a familial spectrum of genetic epilepsy with febrile seizures-plus (GEFS+) in 5-10%. Mutations in the PCDH19 gene (Xq22.1), might account for about 5% of female cases. In about 10% of cases, the etiology is unknown. Somatic mosaic deletions or mutations in SCN1A are found in about 3% of the patients that are initially negative. Few patients are reported with pathogenic variants in other genes such as GABRG2 (5q34), GABRA1 (5q34), STXBP1 (9q34.11), SCN1B (19q13.12), and SCN2A (2q24.3).
Diagnostic methods
Diagnosis is based on clinical and electroencephalographic (EEG) findings. At onset, EEG is usually normal but later spikes or poly spike-waves with a slowing of background and multifocal discharges are recorded. Brain magnetic resonance imaging is usually normal. SCN1A pathogenic variants can confirm the diagnosis in the clinical setting of Dravet syndrome.
Differential diagnosis
Differential diagnosis includes myoclonic atonic epilepsy.
Genetic counseling
In families with a known SCN1A mutation, inheritance is autosomal dominant and genetic counselling is possible, even though the phenotypic range in families can be wide. In cases with de novo mutations, counselling may helpful.
Management and treatment
The main aim of treatment is to reduce seizure frequency and prevent SE. Valproate, clobazam, stiripentol and bromide may control the febrile seizures early in the disease. Stiripentol may be effective in reducing the duration and the frequency of seizures in combination with valproate and clobazam. The ketogenic diet, topiramate and levetiracetam may provide substantial efficacy as adjunctive therapy as well as cannabidiol in association with clobazam. Ongoing clinical trials showed substantial efficacy of fenfluramine as an add-on. Vagus nerve stimulation can be also considered. Sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine and phenytoin) should be avoided as they worsen seizures. Benzodiazepines are used to treat acute seizures. Children with prominent seizures with falls need protective head gear. Treatment management should be handled by clinicians with expertise in rare and complex epilepsies.
Prognosis
Seizures can decrease in frequency in adulthood but often remain refractory to therapies. Moderate to severe cognitive impairment and intractable epilepsy into adulthood is common. Children present a progressive cognitive decline after early language and visual function impairment. Intellectual deficiency is present in around 86% of patients. Autism spectrum disorder can also appear in 31%. Preventing the occurrence of convulsive SE in children may improve the long-term prognosis.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Nicole CHEMALY | EpiCARE* - Pr Rima NABBOUT | EpiCARE*

                                * European Reference Network


Drug or radiation exposure-related interstitial lung disease

A rare secondary interstitial lung disease (ILD) characterized by development of the condition after exposure to certain drugs or radiation therapy. Diagnostic criteria include clear temporal association, identification of a characteristic reaction pattern to the respective drug, and exclusion of other causes of the ILD. Clinically, drug-induced ILD (DI-ILD) may occur as acute ILD with respiratory failure, or as subacute/chronic DI-ILD. Radiation injury to the lung can develop during or following radiation therapy and depends on the nature and dose of the ionizing radiation, as well as the direction of the radiation beam.


Drug reaction with eosinophilia and systemic symptoms

A rare hypersensitivity reaction characterized by a generalized infiltrated skin rash with face edema, fever, enlarged lymph nodes, eosinophilia, lymphocytosis and more or less severe visceral involvement (e.g. hepatitis, nephritis, pneumonitis, myocarditis ect.) and, in some patients, reactivation of human herpes virus 6, Epstein-Barr virus and/or cytomegalovirus. Onset usually occurs 2-8 weeks after administration of the causal medication and is most frequently associated with anticonvulsants, antibacterial sulfonamides and allopurinol but many other medications have also been implicated. Histology is characterized by interface dermatitis, sometimes mixed with eczematous and an acute generalized exanthematous pustulosis-like pattern. Auto-immune sequelae may occur.


Drug- or toxin-induced pulmonary arterial hypertension (PAH) is a form of pulmonary arterial hypertension (PAH, see this term) secondary to the exposition to drugs. Drug- or toxin-induced PAH is characterized by elevated pulmonary arterial resistance leading to right heart failure. Drug or toxin induced PAH is progressive and potentially fatal.

Summary:
Epidemiology
Drug or toxin -induced PAH represented 9.5% of PAH cases in a French Registry, prevalence is hence estimated to be 1/700,000 adults.
Clinical description
Drug -or toxin-induced PAH has a clinical course similar to idiopathic pulmonary arterial hypertension (IPAH, see this term). Initial symptoms include dyspnea, fatigue, syncope, chest pain, non-productive cough and hemoptysis. Precordial signs include loud and palpable second heart sound, right ventricular heave, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation. In more advanced cases patients present dyspnea at rest. Sudden death has been reported in some cases. 70% of patients present heart failure (classed as New York heart association functional classification (NYHA FC) III or IV). More rarely, clubbing of digits, ascites, pedal edema and Raynaud phenomenon (mostly in females) may be observed.
Etiology
Drug or toxin -induced PAH may be directly induced by a wide range of drugs and toxins. Anorexigens (aminorex, fenfluramine derivatives (leading to heart valve disease, potentially causing drug or toxin -induced PAH) and benfluorex have been confirmed to be risk factors for PAH and were withdrawn from the market. PAH induced by anorexigens occurs months to years after treatment. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary arterial smooth muscle cells.Amphetamines, cocaine, phentermine and mazindol are also considered as possible risk factors for PAH. Dasatinib, a dual Src/Abl kinase inhibitor, used in the treatment of chronic myeloid leukaemia (see this term) was associated with cases of severe PAH, in part reversible after its withdrawal. Recently few cases of PAH have been reported with interferon therapy whose supposed mechanism is suspected to be linked to endothelial dysfunction. PAH may be a rare complication of other drugs including: nasal decongestants, (e.g. phenylpropanolamine), dietary supplement - L-Tryptophan, and drugs that could act on 5HT2B receptors (e.gpergolide). Mutations in PAH predisposing genes (mainly in BMPR2 gene (2q33) and also in ACVRL1(12q13), Endoglin(9q34), CAV1 (7q31), KCNK3(2p23), Smad9 (13q12) and TBX4 (17q21) could be identified in drug or toxin -induced PAH. These genes are well known to predispose to PAH as an autosomal dominant trait with incomplete penetrance (heritable PAH, see this term) and drug or toxin exposure could act as a second hit in such patients.
Genetic counseling
Patients developing Drug or toxin -induced PAH should be screened for PAH predisposing mutations.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Barbara GIRERD  - Pr David MONTANI