10q22.3q23.3 microdeletion syndrome is a rare partial autosomal monosomy characterized by a mild facial dysmorphism variably including macrocephaly, broad forehead, hypertelorism or hypotelorism, deep-set eyes, upslanting or downslanting palpebral fissures, low-set ears, flat nasal bridge, smooth philtrum, thin upper lip), cleft palate, cerebellar and cardiac malformations, psychomotor development delay, and behavioral abnormalities (attention deficit hyperactivity disorder, autism). Other rare features may include congenital breast aplasia, arachnodactyly, joint hyperlaxity, club feet, feeding difficulties, failure to thrive.


A rare, chromosomal anomaly characterized by variable clinical features that may include developmental delay, mild intellectual disability and dysmorphic facial features. In some cases, microcephaly, growth retardation and congenital heart defects have been reported.


A rare partial autosomal trisomy/tetrasomy characterized by obesity, global developmental delay and intellectual disability, facial dysmorphism (synophrys, high-arched eyebrows, large posteriorly rotated ears, upturned nose, long smooth philtrum, overbite and high palate), large hands and limb hypotonia. Additional features include seizures and behavioral abnormalities.


A rare chromosomal anomaly characterized by mild intellectual disability, developmental delay, short stature, hypotonia and dysmorphic facial features. Anxiety and short attention span have also been reported.


A rare chromosomal anomaly syndrome, resulting from the partial deletion of the short arm of chromosome 12, characterized by intellectual disability, global developmental delay with prominent language impairment, behavioral abnormalities and mild facial dysmorphism (incl. frontal bossing, downslanting palpebral fissures, epicanthal folds, broad, depressed nasal bridge with bulbous nasal tip, low-set ears with underdeveloped helices). Other associated features may include skeletal abnormalities (butterfly vertebrae, scoliosis), strabismus, optic nerve hypoplasia, and brain malformations.


12q14 microdeletion syndrome is characterised by mild intellectual deficit, failure to thrive, short stature and osteopoikilosis. It has been described in four unrelated patients. The syndrome appears to be caused by a heterozygous deletion at chromosome region 12q14, which was detected in three of the four patients. The deleted region contains the LEMD3 gene: mutations in this gene have already been implicated in osteopoikilosis.


12q15q21.1 microdeletion syndrome is a rare chromosomal anomaly syndrome resulting from a partial deletion of the long arm of chromosome 12, with a highly variable phenotype, typically characterized by developmental delay, learning disability, intra-uterine and postnatal growth retardation, and mild facial dysmorphism that changes with age. Nasal speech and hypothyroidism are also associated.


13q12.3 microdeletion syndrome is a rare chromosomal anomaly characterized by moderate intellectual disability, speech delay, postnatal microcephaly, eczema or atopic dermatitis, characteristic facial features (malar flattening, prominent nose, underdeveloped alae nasi, smooth philtrum, and thin vermillion of the upper lip), and reduced sensitivity to pain.


14q11.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, hypotonia and facial dysmorphism.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 3 patients.
Clinical description
All three children have similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow, full lower lip and similar auricular anomalies.
Etiology
This syndrome is caused by an interstitial deletion encompassing 14q11.2. These de novo deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size with the smallest region of overlap of 35 kb including only two genes, SUPT16H and CHD8, which are good candidate genes for the phenotype.

                            Last update:
                            May 2011

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


14q11.2 microduplication syndrome is a rare chromosomal anomaly characterized by developmental delay, mild to severe intellectual disability with speech impairment and epilepsy. Additionally, it may include dysmorphic features (such as hypo- or hypertelorism, dysplastic ears, short palpebral fissures), microcephaly or macrocephaly, behavioral abnormalities, stereotyped hand movements, ataxia, hypotonia, cleft palate.


14q22q23 microdeletion syndrome is a rare partial deletion of the long arm of chromosome 14 characterized by ocular anomalies (anopthalmia/microphthalmia, ptosis, hypertelorism, exophthalmos), pituitary anomalies (pituitary hypoplasia/aplasia with growth hormone deficiency and growth retardation) and hand/foot anomalies (polydactyly, short digits, pes cavus). Other clinical features may include muscular hypotonia, psychomotor development delay/intellectual disability, dysmorphic signs (facial asymmetry, microretrognathia, high-arched palate, ear anomalies), congenital genitourinary malformations, hearing impairment. Smaller 14q22 deletions may have variable expression.


14q24.1q24.3 microdeletion syndrome is a rare, genetic, syndromic intellectual disability characterized by mild intellectual disability, delayed speech development, congenital heart defects, brachydactyly and dysmorphic facial features.


14q32 duplication syndrome is a rare chromosomal anomaly syndrome resulting from the partial duplication of the long arm of chromosome 14 that results in a predisposition to a number of adult-onset myeloproliferative neoplasms, including acute myeloid leukemia, chronic myelomonocytic leukemia, and especially essential thrombocythemia. Progression to myelofibrosis and secondary acute myeloid leukemia can be observed.


A rare partial autosomal trisomy/tetrasomy characterized by facial dysmorphism (long thin face, prominent forehead, down-slanting palpebral fissures, prominent nose with broad nasal bridge, prominent chin), pre- and postnatal overgrowth, renal anomalies (e.g. horseshoe kidney, renal agenesis, hydronephrosis), mild to severe learning difficulties and behavioral abnormalities. Additional features may include craniosynostosis and macrocephaly.


15q11.2 microdeletion syndrome is a rare partial autosomal monosomy with a variable phenotypic expression and reduced penetrance associated with an increased susceptibility to neuropsychiatric or neurodevelopmental disorders including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, epilepsy or seizures. It may also include mild non-specific dysmorphic features (such as dysplastic ears, broad forehead, hypertelorism), cleft palate, neurological and neuroimaging abnormalities (such as ataxia and muscular hypotonia).


The 15q11-q13 microduplication (dup15q11-q13) syndrome is characterized by neurobehavioral disorders, hypotonia, cognitive deficit, language delay and seizures. Prevalence is unknown.

Summary:
Epidemiology
To date, about 30 cases with syndrome of maternal origin have been reported.
Clinical description
The syndrome of maternal origin manifests in early childhood by developmental delay particularly in language, hypotonia, seizures often resistant, behavioral problems sometimes falling within the autism spectrum disorders (ASDs), and subtle or no dysmorphic features (macrocephaly, down-slanting palpebral fissures, epicanthal folds, expressionless face, clinodactyly, syndactyly) and short stature. A late-onset Lennox-Gastaut syndrome has been described. Cardiac defects have occasionally been reported. The clinical picture is highly variable even within the same family. Paternal duplications are rarely symptomatic (developmental delay/ behavioral disorders).
Etiology
The syndrome is due to interstitial duplications that encompass the imprinted Prader-Willi/Angelman critical region (PWACR), of which deletions lead to Prader-Willi and Angelman syndromes (see these terms). The chromosome 15q proximal region is unstable and rich in low-copy repeat (LCR) sequences that are often substrates of clinically relevant rearrangements with various parent-of-origin effects, including duplications that occur preferentially on the maternal chromosome. The causative genes are imprinted and expressed from the maternal allele. Only two maternally expressed genes, UBE3A and ATP10C, are located in the imprinted domain. Interstitial duplications are of an almost uniform 4 Mb size, sharing the same breakpoints with deletions, and about 2/3 of them appear to arise from an interchromosomal event, the remaining being intrachromosomal. Interstitial triplications have rarely been reported. Interstitial duplications occur usually de novo and are much less frequent than inverted duplications leading to the inv dup(15) syndrome (see this term).
Diagnostic methods
Diagnosis should be suspected in any child with early hypotonia, minor dysmorphic features, developmental delay/intellectual disability, ASD and seizures. Diagnosis is confirmed by standard cytogenetics (G-R-banding, able to identify most but not all duplications) and interphase fluorescence in situ hybridization (FISH) using probes from both proximal chromosome 15 and the PWACR, which shows the dup15q11-q13 encompassing the PWACR. Molecular studies (microsatellite analysis on parental DNA and methylation-specific PCR on proband DNA) are needed to detect the parent-of-origin. Comparative genomic hybridization microarray (aCGH) is a powerful method to detect the duplication extent.
Differential diagnosis
Differential diagnosis includes the other causes of developmental delay, ASD, and epilepsy. Severe early hypotonia may lead to genetic evaluation for PWS, showing the dup15q11-q13. Genetic testing rules out other disorders with a similar clinical picture and associated with supernumerary marker chromosome (SMC) derived from 15, such as inv dup(15) or, more rarely, double SMC resulting in partial hexasomy of the maternally inherited PWACR.
Antenatal diagnosis
Prenatal diagnosis is possible. Cells, obtained by choriocentesis or amniocentesis, can be analyzed by a combination of cytogenetic (G-R-banding, FISH), and molecular (methylation analysis) methods.
Genetic counseling
Genetic counseling should be cautious as the dup15q11-q13 syndrome is usually sporadic and rarely familial.
Management and treatment
The multidisciplinary management includes a comprehensive neurological and developmental evaluation. A video-EEG study is recommended to characterize the seizures and to determine the first choice pharmacotherapy. Regular follow-up is essential, as the seizures may be hard to control. Developmental evaluations allow planning early physical, occupational and speech interventions. Cardiac ultrasound should be performed in all carriers to exclude a cardiac defect.
Prognosis
Survival is not significantly reduced.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Marie-France PORTNOI


15q13.3 microdeletion (microdel15q13.3) syndrome is characterized by a wide spectrum of neurodevelopmental disorders with no or subtle dysmorphic features.

Summary:
Epidemiology
Its prevalence is unknown; nearly 150 cases have been reported, including a subset of healthy relatives of affected individuals. Males are more likely to be symptomatic.
Clinical description
The syndrome manifests in childhood or later in life. Patients present with developmental delay, mainly in speech acquisition, cognitive impairment in about half of the cases (usually mild, sometimes moderate to severe), idiopathic generalized epilepsy (IGE, including childhood or juvenile absence epilepsy, juvenile myoclonic epilepsy (see these terms) and epilepsies with generalized tonic-clonic seizures), neurobehavioral disorders of the autistic or psychotic spectrum (including impaired expressive language, poor eye contact, repetitive movements, hyperactivity, impulsive and/or aggressive behavior, and disturbed social interactions). Subtle dysmorphic features may be present (down-slanting palpebral fissures, prominent nasal tip, large ears, strabismus, clinodactyly of the 5th finger, pigmented naevi). Short stature, macrocephaly and hypotonia are common. Congenital heart defects are rare. Asymptomatic carriers may have a history of learning difficulties.
Etiology
The syndrome is due to submicroscopic deletions in the proximal 15q region, known for its instability and high density of low-copy repeat (LCR) sequences mediating non-allelic homologous recombination (NAHR), resulting in genomic rearrangements. Six breakpoints (BPs), clustered in LCRs, are mapped to the 15q11q14 region. 15q13.3 recurrent 1.5 Mb deletion between BP4 and BP5, results in loss of six known genes including CHRNA7. Haplo-insufficiency of CHRNA7 might be responsible for most of the neurodevelopmental disorders associated with the deletion. Occasional larger BP3-BP5 deletions do not seem to differ clinically.
Diagnostic methods
Diagnosis should be suspected in any infant or child with developmental delay/intellectual disability, autism, schizophrenia, seizures, hypotonia, and/or minor dysmorphic features. Microdel15q13.3 is not detected using conventional karyotyping (G-banding) but can be detected by fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization (aCGH).
Differential diagnosis
Differential diagnosis comprises the other causes of intellectual deficit, schizophrenia, autism and epilepsy. Genetic testing rules out the other 15q proximal anomalies associated with a similar clinical picture.
Antenatal diagnosis
Prenatal diagnosis is possible through chorionic villus sampling or amniocentesis analyzed by cytogenetic (FISH) and molecular methods.
Genetic counseling
Around 25% of deletions occur de novo while 75% are inherited in an autosomal dominant manner with variable expressivity and incomplete penetrance. Of the inherited cases, approximately 25% are inherited paternally and 75% maternally. Genetic counseling should be offered cautiously as the syndrome may be either sporadic or familial. In cases where the deletion is inherited, siblings have a 50% risk of inheriting the deletion. However, not all carriers will develop the syndrome.
Management and treatment
The clinical picture should guide treatment. Early educational interventions are recommended in patients with cognitive impairment and autism. Epilepsy, autism and/or schizophrenia should be treated according to standard guidelines. Cardiac ultrasound should be performed in all carriers to exclude a congenital heart defect. Management in healthy carriers is not necessary, although medical awareness of signs that may become apparent later in life, e.g. schizophrenia, is recommended.
Prognosis
Prognosis depends on the clinical features. Carriers with learning difficulties in childhood often function normally in adulthood. Survival does not seem to be reduced in the absence of a congenital heart defect.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr B. [Boukje] DE VRIES  - Dr Marie-France PORTNOI


15q24 microdeletion syndrome is a rare chromosomal anomaly characterized cytogenetically by a 1.7-6.1 Mb deletion in chromosome 15q24 and clinically by pre- and post-natal growth retardation, intellectual disability, distinct facial features, and genital, skeletal, and digital anomalies.

Summary:
Epidemiology
The prevalence of 15q24 deletion syndrome is unknown. To date, 19 cases with clinical data and detailed mapping of genomic breakpoints have been reported.
Clinical description
At birth, approximately 1/3 of patients have low birth weight consistent with intrauterine growth retardation. Feeding difficulties and failure to thrive are reported in about 20%. In later childhood, 30% show growth retardation and short stature and 17% obesity. Growth hormone (GH) deficiency may be present. Growth delay, feeding difficulties, and distinct facial features (long face with high anterior hairline, epicanthal folds, hypertelorism, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, long smooth philtrum, and small mouth with full lower lip) are the most common early presenting symptoms. Most patients (90%) have digital deformities (proximally implanted and/or hypoplastic thumbs, clinodactyly, brachydactyly, overriding toes, toe syndactyly, small hands). Approximately 60% have skeletal complications (joint laxity and scoliosis). Hernias are found as well as hypotonia (60%). Eye abnormalities are common (nystagmus and strabismus). Ear abnormalities are variable but common (large ears, ear lobe pits, anteverted ear lobes, and protuberant ears). Genital abnormalities are common in males (60%). Mild to moderate developmental delay is found in all patients. Behavior abnormalities, such as autism, hyperactivity, aggression, and attention deficit are reported in 37%. Approximately 50% of patients have abnormal brain imaging on magnetic resonance imaging (MRI). Nearly 40% have a history of recurrent infections. Recurrent ear infections may be a predisposing factor to hearing loss (25%). Microcephaly is uncommon (20%). Other congenital malformations, while rare, can be severe and include cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele (see these terms).
Etiology
The syndrome is caused by a microdeletion of 1.7 to 6.1 Mb in size in chromosome 15q24 which usually results from nonallelic homologous recombination (NAHR). The smallest region of overlap (SRO) spans a 1.2 Mb region including several candidate genes that may predispose to many of the clinical features: CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK.
Diagnostic methods
Oligonucleotide array CGH (aCGH) with confirmation by fluorescent in-situ hybridization (FISH) detects most, if not all, deletions of 15q24. Karyotypes are typically normal.
Differential diagnosis
Differential diagnoses include other genetic syndromes, particularly monosomy 22q11, Prader-Willi, and Noonan syndromes (see these terms).
Antenatal diagnosis
Deletion of 15q24 can be detected in amniotic fluid or chorionic villi samples. Since routine karyotyping is not sufficient to detect the deletion, aCGH should be performed.
Genetic counseling
The deletion occurred as a de novo event in all reported patients when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling.
Management and treatment
Management should be multi-disciplinary with the primary care physician and clinical geneticist playing crucial roles in appropriate screening, surveillance, and care. At the time of diagnosis, baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments are needed. Growth and feeding should be monitored closely.
Prognosis
The prognosis is variable and depends on the severity and extent of congenital malformations.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Dr Ayman EL-HATTAB


16p11.2-p12.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay and facial dysmorphism.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 5 patients.
Clinical description
Facial features include flat facies, downslanting palpebral fissures, low-set and malformed ears. Orofacial clefting, heart defects, short stature, feeding difficulties and hypotonia can be observed.
Etiology
This syndrome is caused by an interstitial deletion encompassing 16p11.2-p12.2. These deletions arise de novo and are flanked by segmental duplications suggesting that the underlying mechanism is non-allelic homologous recombination (NAHR). They were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH).

                            Last update:
                            May 2011

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


16p11.2p12.2 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from the partial duplication of the short arm of chromosome 16 with a highly variable phenotype typically characterized by developmental/psychomotor delay (particularly of speech), intellectual disability, autism spectrum disorder and/or obsessive and repetitive behavior, behavioral problems (such as aggression and outbursts), dysmorphic facial features (triangular face, deep set eyes, broad and prominent nasal bridge, upslanting or narrow palpebral features, hypertelorism). Additionally, finger/hand anomalies, short stature, microcephaly and slender build are frequently described.


16p12.1p12.3 triplication syndrome is a rare chromosomal anomaly syndrome resulting from the partial triplication of the short arm of chromosome 16 characterized by global developmental delay, pre- or post-natal growth delay and distinctive craniofacial features, including short palpebral fissures, epicanthal folds, bulbous nose, thin upper vermillion border, apparently low-set ears and large ear lobes. Variable clinical features that have been reported include congenital heart disease, genitourinary abnormalities, visual anomalies or, less commonly, infantile hepatic disease. Patients are also reported to have tapered fingers.


16p13.11 microdeletion syndrome is a recently described syndrome characterized by developmental delay, microcephaly, epilepsy, short stature, facial dysmorphism and behavioral problems.

Summary:
Epidemiology
It has been clinically and molecularly characterized in fewer than 15 patients.
Clinical description
Facial features include down-slanting palpebral fissures, short nose, low-set ears, wide mouth and thin upper lip. Variable congenital anomalies can also be observed.
Etiology
This syndrome is caused by an interstitial deletion encompassing 16p13.11. The deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). The underlying mechanism is non-allelic homologous recombination (NAHR).
Genetic counseling
Microdeletions appear de novo or are inherited from mildly affected or completely normal parents in an autosomal dominant manner, suggesting that the microdeletion has incomplete penetrance and variable expressivity. Two genes within the deleted region, NDE1 (nudE nuclear distribution gene E homolog 1) and NTAN1 (N-terminal asparagine amidase) may contribute to the neuro-cognitive phenotype.

                            Last update:
                            May 2011

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


16p13.11 microduplication syndrome is a recently described syndrome associated with variable clinical features including behavioral abnormalities, developmental delay, congenital heart defects and skeletal anomalies.

Summary:
Epidemiology
It has been clinically and molecularly characterized in fewer than 20 patients.
Clinical description
Behavioral abnormalities include attention deficit/hyperactivity disorder, aggression and disruptive temperament, and autistic spectrum disorders. Skeletal manifestations include hypermobility, craniosynostosis and polydactyly.
Etiology
This syndrome is caused by interstitial duplications encompassing 16p13.11. The size of the rearrangements is variable. The duplications were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). The underlying mechanism is non-allelic homologous recombination (NAHR). The microduplications appear de novo or are inherited from mildly affected or completely normal parents, suggesting that the microduplication has incomplete penetrance and variable expressivity. Two genes, NDE1 (nudE nuclear distribution gene E homolog 1) and NTAN1 (N-terminal asparagine amidase) included in the duplicated region may contribute to the neurobehavioral phenotype. As the duplication is present in phenotypically normal parents of patients, as well as in the general population, the clinical significance of the 16p13.11 microduplication is still unclear.

                            Last update:
                            May 2011

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


16p13.3 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 and manifesting with a variable phenotype which is mostly characterized by: mild to moderate intellectual deficit and developmental delay (particularly speech), normal growth, short, proximally implanted thumbs and other hand and feet malformations (such as camptodactyly, syndactyly, club feet), mild arthrogryposis and characteristic facies (upslanting, narrow palpebral fissures, hypertelorism, mid face hypoplasia, bulbous nasal tip and low set ears). Other reported manifestations include cryptorchidism, inguinal hernia and behavioral problems.


A partial autosomal monosomy characterized clinically by lethal pulmonary disease that presents as severe respiratory distress and refractory pulmonary hypertension within a few hours after birth and typically results in death from respiratory failure within the first months of life. Characteristic histological features of lung tissue include paucity of alveolar wall capillaries, alveolar wall thickening, muscular hypertrophy of the pulmonary arteries, and malposition of the small pulmonary veins. Various additional congenital malformations may be associated, mostly gastrointestinal (intestinal malrotation and atresias, anular pancreas), genitourinary (dilatation of urinary tracts, duplicated uterus) and cardiovascular anomalies (hypoplastic left heart and other congenital heart defects).


16q24.3 microdeletion syndrome is a recently described syndrome associated with variable developmental delay, facial dysmorphism, seizures and autistic spectrum disorder.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 4 patients.
Clinical description
Facial dysmorphism includes high forehead, large ears, smooth philtrum, pointed chin and wide mouth. Anomalies of the brain and neonatal thrombocytopenia can be observed.
Etiology
This syndrome is caused by an interstitial deletion encompassing 16q24.3. These de novo deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They vary in size, the common region of overlap is only 90 kb and comprises two candidates genes, ANKRD11 (Ankyrin Repeat Domain 11) and ZNF778 (Zinc Finger 778).

                            Last update:
                            May 2011

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


17p11.2 microduplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 17, typically characterized by hypotonia, poor feeding, failure to thrive, developmental delay (particularly cognitive and language deficits), mild-moderate intellectual deficit, and neuropsychiatric disorders (behavioral problems, anxiety, attention deficit hyperactivity disorder, autistic spectrum disorder, bipolar disorder). Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance (obstructive and central sleep apnea) are also frequently associated.


17p13.3 microduplication syndrome is characterized by variable psychomotor delay and dysmorphic features.

Summary:
Epidemiology
It has been recently described in less than ten patients.
Clinical description
Clinical presentation is variable but it is possible to delineate a common clinical spectrum comprising mild to moderate psychomotor delay, hypotonia and discrete craniofacial dysmorphic features including a high forehead with frontal bossing, a small nose and a small mouth.
Etiology
The microduplication was identified by microarray-based comparative genomic hybridization (a-CGH). It encompasses the same region that is deleted in Miller-Dieker (17p13 deletion) syndrome (see this term).. The variable size of this de novo duplication indicates that mechanisms other than nonallelic homologous recombination (NAHR) may be responsible. Additional patients will further substantiate the significance of 17p13.3 duplication and contribute to delineation of the clinical spectrum.

                            Last update:
                            February 2010

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


17q11 microdeletion syndrome is a rare severe form of neurofibromatosis type 1 (NF1; see this term) characterized by mild facial dysmorphism, developmental delay, intellectual disability, increased risk of malignancies, and a large number of neurofibromas.

Summary:
Epidemiology
The prevalence of 17q11 microdeletion syndrome is not known. About 5% of NF1 cases are reported to have deletions of the entire NF1 gene. More than 170 affected patients have been reported to date.
Clinical description
Affected individuals often have unusual body habitus and facial dysmorphism including facial coarsening, prominent forehead, ptosis, down-slanting palpebral fissures, hypertelorism, broad nose and nasal bridge, low set ears, and micrognathia. Patients develop a large number of neurofibromas, often with early onset, including multiple cutaneous neurofibromas, and less commonly plexiform neurofibromas. Other characteristic features include attention deficit/hyperactivity disorder (AD/HD), delayed cognitive development and intellectual disability. Some patients are reported to have microcephaly or macrocephaly, optic pathway glioma, iris coloboma (see these terms), heart defects (mitral valve prolapse, aortic dilatation), large hands and feet, connective tissue dysplasia (joint hyperflexibility, soft palm skin), muscular hypotonia, scoliosis, pectus excavatum, and bone cysts. A higher risk of malignancy for NF1 and non-NF1 tumors is reported: malignant peripheral nerve sheath tumors (lifetime risk of 16-26%), retroperitoneal fibrosarcoma, and medulloblastoma with extensive nodularity (see this term).
Etiology
Germline and mosaic microdeletions of the NF1 gene and its flanking regions caused by non-allelic homologous recombination are reported in patients with this disorder. Most occur de novo.
Genetic counseling
As most cases are de novo, recurrence risk for offspring of unaffected parents is very low. Affected individuals have a 50% risk of transmitting the microdeletion, and prenatal and preimplantation genetic diagnosis is possible.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Eric LEGIUS


17q11.2 microduplication syndrome is characterized by dysmorphic features and intellectual deficit.

Summary:
Epidemiology
It has been described in seven patients within one family.
Clinical description
There is a marked clinical heterogeneity between patients. Striking findings are intellectual deficit, early onset of baldness (15 years of age) and dental enamel hypoplasia. Craniofacial dysmorphic features include microcephaly, long midface, malar hypoplasia, sparse eyebrows and thin upper lip. Short stature is common.
Etiology
17q11.2 microduplication encompasses the NF1 region. This region is involved in the NF1 microdeletion syndrome (neurofibromatosis type 1, see this term). The microduplication was recently identified by microarray-based comparative genomic hybridization (array-CGH). The underlying mechanism may be non-allelic homologous recombination (NAHR). The study of pedigree suggests that this microduplication segregates within the family for at least two generations.
Genetic counseling
Two patients displayed a normal clinical presentation, suggesting an autosomal dominant pattern of inheritance with incomplete penetrance.

                            Last update:
                            November 2010

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


17q12 microdeletion syndrome is a rare chromosomal anomaly syndrome resulting from the partial deletion of the long arm of chromosome 17 characterized by renal cystic disease, maturity onset diabetes of the young type 5, and neurodevelopmental disorders, such as cognitive impairment, developmental delay (particularly of speech), autistic traits and autism spectrum disorder. Müllerian aplasia in females, macrocephaly, mild facial dysmorphism (high forehead, deep set eyes and chubby cheeks) and transient hypercalcaemia have also been reported.


17q12 microduplication syndrome is a rare chromosomal anomaly with variable phenotypic expression and reduced penetrance associated with developmental delay, mild to severe intellectual disability, speech delay, seizures, microcephaly, behavioral abnormalities, autism spectrum disorder, eye or vision defects (such as strabismus, astigmatism, amblyopia, cataract, coloboma, and microphthalmia), non-specific dysmorphic features, hypotonia, cardiac and renal anomalies, schizophrenia.


The newly described 17q21.31 microduplication syndrome is associated with a broad clinical spectrum, of which behavioral disorders and poor social interaction seem to be the most consistent.

Summary:
Epidemiology
Only five patients have been reported to date.
Clinical description
All patients have behavioral disorders suggesting that some of the genes within the duplication interval may be candidates for the autistic spectrum. Intellectual skills range from normal to mild intellectual deficiency. Other features are variable with no striking common phenotypic features.
Etiology
This microduplication syndrome was identified by microarray-based comparative genomic hybridization (aCGH). It seems reasonable to postulate that the underlying mechanism is a non-allelic homologous recombination (NAHR). Moreover, an inversion within 17q21.31, present in the Western European population at a frequency of 20%, was shown to be closely associated with the rearrangement. Parental origin was investigated in 3 patients. In all cases duplication was of maternal origin.

                            Last update:
                            February 2010

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


17q23.1q23.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, microcephaly, short stature, heart defects and limb abnormalities.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 7 patients.
Clinical description
All individuals had mild to moderate developmental delay, in particular speech delay. All except one had heart defects, including mainly patent ductus arteriosus or atrial septal defect. Limb abnormalities include long, thin fingers and toes, and hypoplasia of patellae. Scoliosis is also present. Patients had some mild and unspecific dysmorphic facial features.
Etiology
The syndrome is caused by an interstitial deletion encompassing 17q23.1q23.2. The deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). The underlying mechanism is non-allelic homologous recombination (NAHR). Parental FISH testing in five of the seven cases confirmed a de novo origin. The minimal deletion region of 2.2 Mb encompasses 2 transcription factors, TBX2 and TBX4, which are good candidate genes for explaining the phenotype.

                            Last update:
                            May 2011

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


A rare, genetic, multiple congenital anomalies/dysmorphic features-intellectual disability syndrome characterized by developmental and speech delay, intellectual disability, feeding difficulties, failure to thrive, growth retardation, and associated malformations such as abnormality of fingers and toes (i.e. clinodactyly of the 5th finger, 2-3 toe syndactyly), microcephaly, heart defects, and upper airways anomalies. Observed facial dysmorphism includes hypertelorism, small, narrow or downslanting palpebral fissures, ptosis, epicanthus, ear malformations, broad nasal bridge, bulbous/prominent nose, short philtrum, thin lips, retrognathia/micrognathia, arched/cleft palate, and dental anomalies. Additional variable manifestations include hearing and visual impairment, seizures, joint anomalies, obesity, and behavioral/psychiatric disorders.


19p13.12 microdeletion syndrome is a newly described syndrome characterized by moderate to severe developmental delay, language delay, bilateral sensorineural and/or conductive hearing loss and facial dysmorphism.

Summary:
Epidemiology
It has been reported in 6 patients to date.
Clinical description
Facial dysmorphism includes brachycephaly, anteverted nares, and ear malformations. Cardiac defects and abnormal behavior characterized by auto- and hetero-aggressivity and hyperactivity can be observed.
Etiology
This interstitial microdeletion was identified by comparative genomic hybridization (CGH) microarray and its size is variable.

                            Last update:
                            April 2011

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


A rare partial autosomal monosomy characterized by global developmental delay, moderate intellectual disability, macrocephaly, overgrowth, hypotonia, and facial dysmorphism (frontal bossing, down-slanting palpebral fissures). Other associated features variably include ataxia, seizures, ventriculomegaly, ocular abnormalities (strabismus, optic nerve hypoplasia) and gastrointestinal problems (abdominal pain, vomiting, constipation).


A rare, genetic, syndromic intellectual disability characterized by intrauterine growth retardation, microcephaly, hypotonia, motor and neurodevelopmental delay, speech delay, intellectual disability, and mild dysmorphic features.


The 19q13.11 microdeletion is characterized by several major features including pre and postnatal growth retardation, slender habitus, severe postnatal feeding difficulties, microcephaly, intellectual deficit with speech disturbance, hypospadias and ectodermal dysplasia presented by scalp aplasia, thin and sparse hair, eyebrows and eyelashes, thin and dry skin and dysplasic nails.

Summary:
Epidemiology
To date, the syndrome has been identified in five patients.
Clinical description
Minor dysmorphic features include a long face, high forehead, retrognathia, thin lips, V shaped nasal tip, hypoplastic alae nasi, prominent columella, and large and simple ears.
Etiology
The microdeletion was identified by microarray-based comparative genomic hybridization (aCGH). Haploinsufficiency of one or more genes in the 19q13.11 region could cause this microdeletion syndrome. The careful clinical examination and the molecular characterization of additional patients with a similar chromosomal anomaly are needed to further delineate the clinical features and refine the minimal critical region.

                            Last update:
                            February 2010

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


1p21.3 microdeletion syndrome is an extremely rare chromosomal anomaly characterized by severe speech and language delay, intellectual deficiency, autism spectrum disorder(see this term).

Summary:
Epidemiology
Less than 10 cases have been reported to date.
Clinical description
1p21.3 microdeletion syndrome is characterized by severe speech and language delay, a borderline-mild to mild-moderate intellectual deficiency, autism spectrum disorder (see this term) features, and minor dysmorphic facial features such as long ears, deep set eyes, a broad nasal tip and a thick lower lip. Affected individuals have normal gross motor development without major abnormalities, they are often very shy and friendly with a tendency to overeat.
Etiology
1p21.3 microdeletion syndrome is caused by a hemizygous interstitial microdeletion on the short arm of chromosome 1, occurring mostly de novo, that implicates DPYD (dihydropyrimidine dehydrogenase) and MIR137 genes associated with miRNA pathways.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                            Pr T. [Tjitske] KLEEFSTRA


1p31p32 microdeletion syndrome is a rare chromosomal anomaly syndrome, resulting from the partial deletion of the short arm of chromosome 1, characterized by developmental delay, corpus callosum agenesis/hypoplasia and craniofacial dysmorphism, such as macrocephaly (caused by hydrocephalus or ventriculomegaly), low-set ears, anteverted nostrils and micrognathia. Urinary tract defects (e.g. vesicoureteral reflux, urinary incontinence) are also frequently associated. Other reported variable manifestations include hypotonia, tethered spinal cord, Chiari type I malformation and seizures.


A rare chromosomal anomaly characterized by an intrauterine and postnatal growth retardation, short stature, developmental delay, learning difficulties, hearing loss, hypermetropia,and a recognisable facial dysmorphism including prominent forehead, long, myopathic facies, fine eyebrows, small mouth and micrognathia.


A rare chromosomal anomaly characterized by distinctive facial dysmorphic features, hypotonia, developmental delay, intellectual disability, seizures, heart defects, poor/absent speech, and prenatal onset growth deficiency.

Summary:
Epidemiology
1p36 deletion syndrome is considered one of the most common chromosome deletion syndromes; in the USA, the birth prevalence is estimated at 1/ 5,000. A higher frequency is observed among females.
Clinical description
Patients share recognizable craniofacial dysmorphism with microbrachycephaly, a large, late-closing anterior fontanel (>3 cm at birth), straight eyebrows, deep-set eyes, broad and depressed nasal bridge, midface retrusion, posteriorly rotated, low-set, abnormal ears, long philtrum, and pointed chin. Brachydactyly, camptodactyly and short feet are also characteristic. Almost all patients suffer from congenital hypotonia, contributing to feeding difficulties, delay in motor development and fine motor skills, and delayed or absent speech. A variable level of intellectual disability is observed in all patients. Other symptoms include prenatal-onset growth deficiency, structural brain abnormalities, seizures, congenital heart defects, eye/vision problems, hearing loss (sensorineural or conductive/glue ear), skeletal anomalies, abnormalities of the external genitalia and, less frequently, renal abnormalities and hypothyroidism.
Etiology
1p36 deletion syndrome is caused by a partial heterozygous deletion that primarily involves the distal part of the short arm of chromosome 1, with breakpoints ranging from 1p36.13 to 1p36.33. About 50% of cases are due to a de novo terminal 1p36 deletion, around 29% to an interstitial deletion; remaining cases comprise more complex chromosome rearrangements.
Diagnostic methods
Diagnosis is based on the clinical picture and is confirmed by chromosomal analysis. Molecular techniques are used for the genetic characterization of the deletion (fluorescence in situ hybridization, comparative genomic hybridization array). An evaluation for congenital heart defects with an echocardiogram and electrocardiagram; brain abnormalities with magnetic resonance imaging; seizures with an electroencephalogram; a neurodevelopmental assessment, and standard examinations for eye/vision problems, hearing loss, and skeletal and renal abnormalities are recommended.
Differential diagnosis
Differential diagnosis includes Rett syndrome, Angelman syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, Cohen syndrome, and Aicardi syndrome.
Antenatal diagnosis
Antenatal testing is feasible when a 1p36 chromosome rearrangement is already identified in a family member.
Genetic counseling
Most cases are sporadic, but an unbalanced translocation may be inherited from a parent with a balanced rearrangement.
Management and treatment
Management should be multi-disciplinary and include a regular follow-up. Early diagnosis and access to personalized rehabilitation therapies focusing on motor development, cognition, communication, and social skills are highly recommended. The use of sign language is helpful. Some congenital heart defects may resolve on their own, others may require medication or surgery. Epileptic seizures are treated with standard antiepileptics. Infantile spasms are responsive to corticotrophin. Feeding and growth should be monitored as feeding difficulties are common early on. Triiodothyronine, thyroxine, and thyrotropin levels should be evaluated at diagnosis, and, then, once a year.
Prognosis
The severity of the 1p36 deletion syndrome varies between affected individuals. Seizures and other medical issues seem to improve with time. Patients will remain dependent on others for most activities of daily living and will require medical support throughout life. Individuals with 1p36 deletion syndrome survive well into adult life.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Agatino BATTAGLIA


1q21.1 microdeletion syndrome is a newly described recurrent deletion syndrome with variable clinical manifestations but without the clinical picture of thrombocytopenia - absent radius (TAR) syndrome.

Summary:
Epidemiology
It has been described in 46 patients to date.
Clinical description
The clinical phenotype is extremely variable; the most common but non-constant clinical findings include microcephaly, developmental delay or mild intellectual deficit, slight facial dysmorphic features and eye abnormalities. Congenital malformations are not common. Autism spectrum disorders, schizophrenia or attention deficit hyperactivity disorder have been noted occasionally.
Etiology
This syndrome is caused by a recurrent 1.35Mb deletion in the distal 1q21.1 region distinct from the deletion region implicated in TAR syndrome (see this term).
Diagnostic methods
This microdeletion was identified by comparative genomic hybridization (CGH) microarray and is only diagnosed by molecular cytogenetics. It cannot be identified by routine chromosome analysis.
Genetic counseling
The underlying mechanism is non-allelic homologous recombination (NAHR). Deletions appear de novo or can be inherited in an autosomal dominant manner from mildly affected or completely normal parents. This suggests that the distal 1q21.1 microdeletion has incomplete penetrance and variable expressivity.

                            Last update:
                            March 2011

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


1q21.1 microduplication syndrome is a rare partial autosomal trisomy/tetrasomy with incomplete penetrance and variable expression characterized by macrocephaly, developmental delay, intellectual disability, psychiatric disturbances (autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, mood disorders) and mild facial dysmorphism (high forehead, hypertelorism). Other associated features include congenital heart defects, hypotonia, short stature, scoliosis.


1q41q42 microdeletion syndrome is a chromosomal anomaly characterized by a severe developmental delay and/or intellectual disability, typical facial dysmorphic features, brain anomalies, seizures, cleft palate, clubfeet, nail hypoplasia and congenital heart disease.


1q44 microdeletion syndrome is a newly described syndrome associated with facial dysmorphism, developmental delay, in particular of expressive speech, seizures and hypotonia.

Summary:
Epidemiology
It has been reported in four unrelated patients.
Clinical description
The most common facial features include microcephaly, hypertelorism and thin upper lip. An abnormal corpus callosum (agenesis, hypogenesis or slightly reduced thickness) is observed in all affected patients.
Etiology
This microdeletion was identified by array CGH (comparative genomic hybridization).

                            Last update:
                            October 2010

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


A rare disorder of lysine and tryptophan metabolism characterized by 2-aminoadipic and 2-oxoadipic aciduria. Patients may also present with increased urinary excretion of alpha-hydroxyadipic acid. Variable clinical presentations have been found in patients including hypotonia, developmental delay, mild to severe intellectual disability, ataxia, epilepsy, and behavioral disorders (most commonly attention deficit hyperactivity disorder). However, many individuals with the biochemical phenotype are completely asymptomatic and thus the clinical significance of the condition is questionable.


2-Hydroxyglutaric aciduria is a group of neurometabolic disorders with a wide clinical spectrum ranging from severe neonatal presentations to progressive forms, and asymptomatic cases, characterized biochemically by increased levels of 2-hydroxyglutaric acid in the plasma, cerebrospinal fluid and urine.

Summary:
Epidemiology
The exact prevalence and incidence of the disorders are not known, but fewer than 300 patients have been reported to date.
Clinical description
There are two enantiomeric forms of 2-hydroxyglutaric acid, i.e. D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid. L-2-hydroxyglutaric aciduria (see this term) is characterized by psychomotor retardation, cerebellar ataxia and epilepsy, and D-2-hydroxyglutaric aciduria (see this term) is characterized by variable metabolic, neurological and dysmorphic manifestations.
Etiology
Mutations in the L2HGDH gene (14q22.1) gene have been implicated in L-2-hydroxyglutaric aciduria, and mutations in the D2HGDH (2q37.3) and IDH2 (15q26.1) genes in D-2-hydroxyglutaric aciduria.
Genetic counseling
L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria caused by mutations in the L2HGDH and D2HGDH genes, respectively, follow an autosomal recessive pattern of inheritance. In contrast, D-2-hydroxyglutaric aciduria caused by a specific heterozygous gain-of-function mutation in the IDH2 gene, is an autosomal dominant trait and is usually caused by de novo mutations.

                            Last update:
                            June 2012

                            - Expert reviewer(s):
                            Dr E.A. [Eduard] STRUYS


A rare organic aciduria characterized by impaired isoleucine degradation with increased plasma or whole blood C5 acylcarnitine levels (typically observed in newborn screening) and increased urinary excretion of N-methylbutyrylglycine. The condition is usually clinically asymptomatic, although patients with muscular hypotonia, developmental delay, and seizures (among others) have been reported.


20p12.3 microdeletion syndrome is a recently described syndrome characterized by Wolff-Parkinson-White syndrome (see this term), variable developmental delay and facial dysmorphism.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 3 patients.
Clinical description
Dysmorphic features include macrocephaly, hypertelorism, down-slanting palpebral fissures and microstomia.
Etiology
This syndrome is caused by an interstitial deletion encompassing 20p12.3. All these deletions except one occurred de novo and were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size with the smallest region of overlap including only one gene, BMP2, which is a good candidate gene for explaining the phenotype of Wolff-Parkinson-White syndrome.

                            Last update:
                            June 2011

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


20p13 microdeletion syndrome is a rare chromosomal anomaly characterized by developmental delay, mild to moderate intellectual disability, epilepsy, and unspecific dysmorphic signs. High palate, delayed permanent tooth eruption, hypoplastic fingernails, clinodactyly and short fingers have also been reported.


A rare, genetic, syndromic intellectual disability characterized by psychomotor delay, hypotonia, feeding difficulties, failure to thrive, anomalies of the hands and feet (clinodactyly, camptodactyly, brachydactyly, feet malposition), and craniofacial dysmorphism. Associated prenatal growth retardation, and gastrointestinal, heart and eye anomalies have been reported.


20q11.2 microduplication syndrome is a rare chromosomal anomaly syndrome, due to partial duplication of the long arm of chromosome 20, characterized by psychomotor and developmental delay, moderate intellectual disability, metopic ridging/trigonocephaly, short hands and/or feet and distinctive facial features (epicanthus, hypoplastic supraorbital ridges, horizontal/downslanting palpebral fissures, small nose with depressed nasal bridge and anteverted nostrils, prominent cheeks, retrognathia and small, thick ears). Growth delay and cryptororchidism are often associated features.


A rare chromosomal anomaly syndrome resulting from the partial deletion of the long arm of chromosome 20 with a highly variable phenotype typically characterized by hypotonia, intellectual disability, cognitive and language deficits (including decreased or absent speech), pre and post-natal growth retardation, feeding difficulties, microcephaly, and malformed hands and feet. Neurodevelopmental disorders (including hyperactivity, social interactive problems and autism spectrum disorder), seizures and dysmorphic facial features (high forehead, hypertelorism, malformed ears, broad nasal bridge, bulbous nasal tip, thin upper lip, small chin) are frequently associated.


Monosomy 21 is a chromosomal anomaly characterized by the loss of variable portions of a segment of the long arm of chromosome 21 that leads to an increased risk of birth defects, developmental delay and intellectual deficit.

Summary:
Epidemiology
Monosomy 21 is a very rare condition with less than 50 cases described in the literature. Full monosomy 21 is probably not compatible with life.
Clinical description
The severity of the phenotype depends on the location and size of the deleted area. In general, proximal and distal deletions lead to a milder phenotype (e.g. few dysmorphic features or congenital anomalies, and mild to moderate intellectual deficit), whereas deletions involving band 21q22 have a more severe effect on the phenotype. In the later case, the most common clinical features include intrauterine and postnatal growth retardation, microcephaly, prominent occiput, and facial dysmorphism characterized by up or down-slanted small palpebral fissures, prominent nasal bridge with a broad nose, and large ears. Multiple malformations including structural brain malformations (e.g. cerebral atrophy, cortical dysplasia, and corpus callosum dysgenesis) and heart defects (e.g. patent ductus arteriosus, septal defects) are also frequently observed. Severe intellectual deficit is common. Joints may be stiff and held in an unusual position. Abnormal muscle tone, respiratory infections and seizures are usual. Specific blood disorders (e.g. thrombocytopenia, myelodysplasia) have been reported.
Etiology
The disease is due to the loss of variable portions of the long arm of chromosome 21. Partial 21q deletions are interstitial or terminal. They occur de novo or as the result of a parental rearrangement. Monosomy due to malsegregation of a parental rearrangement is usually associated with another imbalance that could complicate the phenotype. Some cases result from formation of a ring chromosome 21.
Diagnostic methods
Diagnosis is based on clinical findings that lead to chromosomal analysis. Depending on their size, partial 21q deletions may be diagnosed by classical or molecular karyotyping. Molecular techniques are necessary for the genetic characterization of the deletion.
Antenatal diagnosis
Prenatal diagnosis of 21q deletion is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis.
Genetic counseling
The risk of having another affected child is higher if a chromosomal rearrangement is present in one of the parents.
Management and treatment
Management is multi-disciplinary and requires evaluation and treatment by a general pediatrician, and relevant specialists. Children will benefit from early assessment and access to the major developmental therapies. Physiotherapy may be important to improve both the muscle tone and the joints flexibility.
Prognosis
Prognosis depends on the size and location of the deletion. It is severe if band 21q22 is involved, with vital prognosis depending on the severity of congenital malformations.

                            Last update:
                            January 2012

                            - Expert reviewer(s):
                            Dr Catherine TURLEAU


A rare, genetic, chromosomal anomaly syndrome resulting from a partial deletion of the long arm of chromosome 21 characterized by pre- and post-natal growth delay, short stature, intellectual disability, developmental delay with severe language impairment, thrombocytopenia, and craniofacial dysmorphism which may include microcephaly, downslanted palpebral ﬁssures, low-set ears, broad nose, thin upper vermillion, and downturned corners of the mouth. Brain MRI abnormalities (such as agenesis of the corpus callosum), behavioral problems and seizures may be associated.


A rare chromosomal anomaly which causes a congenital malformation disorder that is typically characterized by cardiac defects, palatal anomalies, facial dysmorphism, developmental delay and immune deficiency.

Summary:
Epidemiology
The worldwide prevalence at birth is estimated at 1/4,500-1/10,000.
Clinical description
22q11.2 deletion syndrome shows a variable clinical phenotype that can range from mild to severe. Congenital heart defects (two-thirds of cases) include mainly conotruncal malformations such as ventricular septal defect, truncus arteriosus, tetralogy of Fallot and interrupted aortic arch. Anomalies of the aortic arch and vascular ring are frequent. More than 65% of patients present with palatal anomalies (e.g. velopharyngeal incompetence, submucous cleft palate or bifid uvula) that may lead to hypernasal speech and feeding difficulties. Overt cleft palate and cleft lip are less frequent. Most patients display subtle but recognizable facial features (e.g. ptosis, hypertelorism, epicanthal folds, prominent nasal root, malar flatness, small ears). Immune deficiency is the consequence of thymic aplasia/hypoplasia and improvement in T-cell production occurs over time. Patients have a higher risk of developing an autoimmune disease such as idiopathic thrombocytopenic purpura and juvenile idiopathic arthritis. Hypocalcemia as a consequence of hypoparathyroidism is frequent in the neonatal period and usually resolves but can reappear at any age. Additional clinical findings may include gastrointestinal anomalies (intestinal malrotation, imperforate anus), hearing loss, renal anomalies (renal agenesis), dental anomalies (enamel hypoplasia), and skeletal anomalies (scoliosis, clubfoot). Learning difficulties and developmental delay are almost always present. Psychiatric illness (anxiety, depression, schizophrenia) and Parkinson's disease are more frequent than in the general population.
Etiology
In most cases, the syndrome is due to a 3 million base pair (Mb) deletion on the chromosomal region 22q11.2 that is flanked by low copy number repeats. The deletion is due to a non-allelic meiotic recombination during spermatogenesis or oogenesis. In ~15% of cases, the deletion is nested within the 3 Mb DiGeorge critical region and varies in size. Most deletions include the TBX1 gene that has been shown to be implicated in cardiac, parathyroid, thymus and facial structure development. The variable expression of the 22q11.2 phenotype is thought to be due to genetic modifiers on either the other 22q11.2 allele or on other chromosomes.
Diagnostic methods
Diagnosis is suspected upon clinical examination and confirmed by detection of the 22q11.2 deletion, using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH) or genome-wide SNP (single nucleotide polymorphism) microarrays.
Differential diagnosis
Differential diagnosis includes Smith-Lemli-Opitz syndrome, CHARGE syndrome, Alagille syndrome, VATER syndrome, Goldenhar syndrome and isotretinoin embryopathy.
Antenatal diagnosis
Prenatal diagnosis is possible in familial cases by chorionic villus sampling or amniocentesis, and in pregnancies where associated anomalies have been noted by fetal echocardiography. Preimplantation genetic diagnosis is possible.
Genetic counseling
The deletion arises de novo in ~90% of the cases. The recurrence risk in the sibship of a de novo case is 2-3% due to of low-grade germline parental mosaicism. Affected individuals have a 50% risk of having an affected child.
Management and treatment
Management is symptom-based and requires a multidisciplinary approach. It may consist of heart and/or palate surgery, nasogastric feeding, calcium supplementation, occupational, physical, and speech therapy, educational and behavioral therapy, as well as support and treatment for psychiatric disease. Tonsillectomy is not recommended unless indicated by a center of expertise. A regular surveillance of calcium, thyroid function and blood cell count is necessary. Immune function must be evaluated before administering live vaccines.
Prognosis
The prognosis is variable and depends on the severity of the disease. The infant mortality rate is relatively low (~4%); in adults mortality is higher than that of the rest of the adult population. Most congenital malformations and medical problems can be managed. Prognosis in adults depends on the degree of autonomy.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Dr Tiffany BUSA | ITHACA* - Pr Nicole PHILIP | ITHACA*

                                * European Reference Network


A rare chromosomal anomaly characterized by an extremely variable clinical phenotype and may include heart defects, urogenital abnormalities, velopharyngeal insufficiency with or without cleft palate, and ranging from multiple defects to mild learning difficulties with some individuals being essentially normal.

Summary:
Epidemiology
Up till now more than 50 unrelated cases have been reported with a high frequency of familial duplications.
Clinical description
The age at diagnosis is variable and depends on the clinical manifestations. The clinical presentation of patients shares features with 22q11.2 deletion syndrome (DG/VCFS), including heart defects, velopharyngeal insufficiency with or without cleft palate. The clinical picture is highly variable with incomplete penetrance, ranging from multiple defects with severe intellectual disability to mild learning difficulties with some individuals being essentially normal. Bladder exstrophy, a very rare malformation in the general population, is significantly associated with the duplication. A high rate of autism spectrum disorder is found. Congenital heart defects and urogenital anomalies can be detected in utero, whereas asymptomatic individuals are usually diagnosed after the birth of a severely affected relative.
Etiology
The basis of this clinical variability remains unclear. The low-copy repeats spanning the region 22q11.2 (LCR22) predispose to homologous recombination events, often nonallelic, that result in rearrangements of 22q11.2. The large majority of affected individuals have identical 3Mb microduplications; however, proximal nested 1.5 Mb duplications or larger duplications are also reported. The 3Mb duplication encompasses a region containing 40 genes including the TBX1 gene that has been shown to be the major disease gene responsible for DG/VCFS. Interestingly, TBX1 gain-of-function mutations resulting in the same phenotypic spectrum as haploinsufficiency have been observed, and suggests that TBX1 overexpression might be responsible for the 22q11.2 duplication syndrome.
Diagnostic methods
The 22q11.2 duplication is detected by fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification, array comparative genome hybridization (aCGH) or genome-wide SNP (single nucleotide polymorphism) microarrays.
Differential diagnosis
The main differential diagnosis is DG/VCFS.
Antenatal diagnosis
Detection of the duplication on fetal sample by FISH or a-CGH should be discussed with the parents of an index case during subsequent pregnancies or when a parent carries the microduplication.
Genetic counseling
Transmission is autosomal dominant. Most cases are inherited from a pauci or asymptomatic parent. An affected individual has a 50% risk of transmitting the duplication.
Management and treatment
Symptomatic treatment should be proposed by a multidisciplinary team including pediatricians, child psychiatrists.
Prognosis
Prognosis is variable. Marked inter and intrafamilial variability is observed among patients. Some patients have been reported to have significant cardiovascular malformations leading to early death.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Dr Tiffany BUSA | ITHACA* - Pr Nicole PHILIP | ITHACA*

                                * European Reference Network


A rare partial autosomal monosomy characterized by global development delay, intellectual disability, behavioral abnormalities (hyperactivity, attention deficit and autistic behaviors), brachycephaly and variable facial dysmorphism. Other associated features may include vertebral fusions, mild contractures of knees and elbows, and feeding difficulties during infancy.


2p15p16.1 microdeletion syndrome is a recently described syndrome characterized by developmental delay and facial dysmorphism.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 5 patients.
Clinical description
Dysmorphic features include receding forehead, telecanthus, epicanthic fold, short and down-slanting palpebral fissures, ptosis, broad and high nasal bridge, retrognathia, flat philtrum, small mouth with high, narrow palate and everted lower lip. Ophthalmologic examination in 4 patients revealed bilateral optic atrophy/hypoplasia. Microcephaly, short stature, genitourinary abnormalities and behavioral problems are common.
Etiology
This syndrome is caused by an interstitial deletion 2p15p16.1 (present in mosaic in one patient). These de novo deletions were characterized by comparative genomic hybridisation (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size from 570 kb to 5.7 Mb and encompass several genes. Haploinsufficiency of these genes could contribute to the phenotype.

                            Last update:
                            June 2011


2p21 microdeletion syndrome without cystinuria is a rare partial autosomal monosomy characterized by weak fetal movements, severe infantile hypotonia and feeding difficulties that spontaneously improve with time, urogenital abnormalities (hypospadias or hypoplastic labia majora), global development delay, mild intellectual disability and facial dysmorphism (dolichocephaly, frontal bossing, bilateral ptosis, midface retrusion, open mouth with tented upper lip vermilion). Affected individuals have borderline elevated serum lactate but no cystinuria.


The 2p21 microdeletion syndrome consists of cystinuria, neonatal seizures, hypotonia, severe growthand developmental delay, facial dysmorphism, and lactic acidemia.

Summary:
Epidemiology
It has been described in seven patients from three families of a small Bedouin clan.
Clinical description
Dysmorphic features include frontal bossing, almond-shaped eyes, long eyelashes, depressed nasal bridge, and large, posteriorly rotated ears. Renal lithiasis occurs at an early age in all patients. Reduced activity of the respiratory chain complexes I, III, IV and V was found in patients examined.
Etiology
The syndrome is caused by homozygous deletion of at least four contiguous genes on chromosome 2: SLC3A1, PREPL, PPM1B and C2orf34 (2p21).

                            Last update:
                            November 2010


The newly described 2q23.1 microdeletion syndrome includes severe intellectual deficit with pronounced speech delay, behavioral abnormalities including hyperactivity and inappropriate laughter, short stature and seizures.

Summary:
Epidemiology
To date, fifteen patients have been reported.
Clinical description
Dysmorphic features include microcephaly, wide and open mouth, a tented upper lip, and prominent incisors. The majority of cases present with stereotypic repetitive behavior, a disturbed sleep pattern and a broad-based gait. Skeletal abnormalities include generalized brachydactyly with small hands and feet.
Etiology
The microdeletion was identified by microarray based comparative genomic hybridization (aCGH). The size of the deletions is variable; the critical region includes a single gene, MBD5. Another gene, EPC2, is deleted in patients who have a broader phenotype than those with a deletion of MBD5 only.

                            Last update:
                            May 2010

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


2q23.1 microduplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 2, primarily characterized by global developmental delay, hypotonia, autistic-like features and behavioural problems. Craniofacial dysmorphism (arched eyebrows, hypertelorism, bilateral ptosis, prominent nose, wide mouth, micro/retrognathia) and an affable personality are also commonly associated. Minor digital anomalies (fifth finger clinodactyly and large, broad first toe) have occasionally been reported.


2q31.1 microdeletion syndrome is a well-defined and clinically recognisable syndrome characterized by moderate to severe developmental delay, short stature, facial dysmorphism and variable limb defects.

Summary:
Epidemiology
It has been reported in 20 patients.
Clinical description
Dysmorphic features include microcephaly, downslanting palpebral fissures, flat and long philtrum, micrognathia and low-set and dysplastic ears. The spectrum of limb defects ranges from monodactylous ectrodactyly, brachydactyly and syndactyly to camptodactyly. The lower limbs tend to be more often and more severely affected than the upper limbs.
Etiology
This microdeletion was identified by comparative genomic hybridization (CGH) microarray and its size is variable. The critical region encompasses the HOXD genes, haploinsufficiency of which results in the skeletal phenotype.

                            Last update:
                            March 2011

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


A rare autosomal monosomy characterized by a variable phenotype with moderate to severe intellectual disability, behavioral problems, short stature, microcephaly, dysplastic nails, sparse hair, cleft palate and dysmorphic craniofacial features.


A rare chromosomal anomaly involving deletion of chromosome band 2q37 and characterized by a broad spectrum of clinical findings including mild-moderate developmental delay/intellectual disability, brachymetaphalangy of digits 3-5, short stature, obesity, hypotonia, specific facial dysmorphism, abnormal behavior, autism or autism spectrum disorder, joint hypermobility/dislocation, and scoliosis.

Summary:
Epidemiology
To date, more than 150 individuals have been reported worldwide. Females are more frequently affected (60%).
Clinical description
A congenital malformation syndrome with a variable presentation. The phenotype includes mild-to-moderate developmental delay or intellectual deficit, hypotonia (50 to 65% of patients), seizures (20%-35%), brachymetaphalangism (50%), short stature (23%), characteristic facial dysmorphism (sparse scalp hair, round face, prominent forehead, upslanting palpebral fissures, sparse and arched eyebrows, deep-set eyes, midface hypoplasia, a depressed nasal bridge, deficient nasal alae and prominent columella, V-shaped appearance of the nasal tip, thin vermillion border of the lips, and a high-arched palate) and a tendency toward obesity with age. Behavioral disorders are common and may include repetitive behavior, severe communication and social interaction deficits, stereotypic movements, intermittent aggressiveness, hyperactivity, attention deficit disorder, obsessive-compulsive disorder and sleep disturbances. The following clinical features are also frequent: widely set, distally placed or supernumerary nipples, fifth finger clinodactyly, syndactyly, and small hands/feet, syndactyly of the fingers or toes, persistent fetal finger pads and a single palmar crease, and microcephaly or macrocephaly. Eczema is often present. Major malformations occur in 30% of patients with 2q37 deletions and may include congenital heart, gastrointestinal (30% of patients), genitourinary (11% of cases) and central nervous system malformations (6% of patients).
Etiology
The deletion involves the terminal region of chromosome 2 with breakpoints at or within band 2q37. A few genotype-phenotype correlations have been identified including a critical region for the Albright hereditary osteodystrophy-like phenotype. The genes in 2q37 involved in the clinical signs previously mentioned include CAPN10, PRLH, HDLBP, PER2 for the weight, GBC1, GPR35, STK25, PDCD1, GBX2, TWIST2, FARP2, PER2 for skeletal disorders, GBX2, TWIST2, FARP2, PER2, PRLH, HDLBP, TRPM8, AGAP1, KIF1A, PASK, ATG4B for behavioral disorders, and HDAC4 which is essential for the development of the brain, muscle, and bone. The deletion of Mir-562 is linked to Wilms tumor.
Diagnostic methods
Diagnosis relies on cytogenetic analysis and molecular characterization. Screening for a translocation should also be conducted as the deletion may be the result of the transmission of a derivative chromosome.
Differential diagnosis
The differential diagnosis should include other segmental aneusomy syndromes and Prader-Willi syndrome. The group of pseudohypoparathyroidism with Albright hereditary osteodystrophy should also be included in the differential diagnosis but calcium, phosphorus, and parathyroid hormone levels are in the normal range in patients with deletion 2q37.
Antenatal diagnosis
Genetic antenatal diagnosis is feasible where the deletion or associated rearrangement has previously been identified in a family member. A prenatal diagnosis might be proposed as for any de novo abnormal chromosomal rearrangement because of potential germinal mosaicism.
Genetic counseling
Most cases arise de novo; however, familial chromosomal rearrangements have been identified in a small proportion of cases. The subsequent risk to siblings of a proband depends on the specific chromosome rearrangement in the parent. Theoretically, a patient with pure 2q37 deletion will have a 50% risk to transmit the deletion.
Management and treatment
Management should be multidisciplinary and include a comprehensive evaluation of the major clinical criteria. Speech, physical and occupational therapy are required. The patients will need careful medical screening between birth and 5 years, for potential associated malformation, and follow up in referal centers for intellectual disabled patients.
Prognosis
The prognosis is very different between children some are mildly affected and other have severe intellectual disability. They have often cognitive difficulties and most of them attend special schools. At the age of 20 most of them are not autonomous and some develop psychiatric disorders.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Martine DOCO-FENZY | ITHACA*

                                * European Reference Network


A rare organic aciduria, due to deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase characterized by episodes of metabolic decompensation with hypoketotic hypoglycemia triggered by periods of fasting or infections.

Summary:
Epidemiology
3-hydroxy-3-methylglutaric aciduria (3HMG) occurs in all ethnic groups. The conditions is extremely rare in the United States, Taiwan and mainland China where incidence is estimated at less than 1/1,000,000; however, it is more frequently observed in Saudi Arabia, Portugal and Spain. In Portugal, the birth prevalence is estimated at 1/125,000 live births.
Clinical description
The clinical presentation is heterogeneous, ranging from severe neonatal onset with potentially fatal outcome to presentation in adulthood. Most patients became symptomatic within the first year of life (50% in neonatal period) with episodes of metabolic decompensation triggered by periods of fasting or infections, which when left untreated may lead to neurological sequelae. Newborns or infants present with acidosis and hypoglycemia, accompanied by vomiting, dehydration, hypotonia and lethargy. Acute decompensation is triggered by infections, vaccinations, and dietary changes. The typical laboratory findings include hypoglycemia, acidosis, an increased anion gap, hyperammonemia and elevated transaminases. Long-term neurological complications are common. Half of the patients have a normal cognitive development while the remainder shows psychomotor deficits. Speech and motor developmental delay are frequent. Cerebral MRI frequently reveals diffuse abnormality in signal intensity of the cerebral white matter, thalami and basal ganglia. Other manifestations may include macrocephaly, dilated cardiomyopathy, arrhythmias, hepatomegaly and acute pancreatitis. Children are usually healthy between episodes; subsequent acute crises may be preceded by anorexia, lethargy, behavioral changes, irritability and muscle weakness. Hypoketotic hypoglycemia is characteristic.
Etiology
3HMG is caused by mutations of the gene HMGCL (1p36.11).
Diagnostic methods
Diagnosis is based on the tandem mass spectrometry profile of plasmatic acylcarnitines (increased C5OH and C6DC) and urinary organic acid (high levels of acids: 3-hydroxy-3-methylglutaric, 3-hydroxyisovaleric, 3-methylglutaconic and 3-methyglutaric). The diagnosis can be confirmed by mutation analysis.
Differential diagnosis
Differential diagnosis includes sepsis, fatty acid oxidation disorders, organic acidurias and Reye's syndrome.
Antenatal diagnosis
During the third trimester of gestation, amniotic fluid organic acid levels, as well as maternal urinalysis may indicate 3HMG; confirmation requires testing of cultured amniocytes or chorionic villi for molecular study.
Genetic counseling
3HMG is an autosomal recessive genetic disorder. Genetic counselling should be offered to all families.
Management and treatment
Patients must be treated by intravenous 10% glucose and supportive treatment during acute metabolic crises. Maintenance treatment requires protein/leucine-restricted diet with a leucine free amino acid mixture, restricted fat intake and regular feeding (every 3-6 hours). Carnitine supplementation is often given.
Prognosis
Prognosis is good for those patients who are rapidly diagnosed and survive past childhood.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Anabela BANDEIRA  - Dr Laura VILARINHO


3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMG-CoA synthase deficiency) is a rare autosomal recessively inherited disorder of ketone body metabolism (see this term), reported in less than 20 patients to date, characterized clinically by episodes of decompensation (often associated with gastroenteritis or fasting) that present with vomiting, lethargy, hepatomegaly, non ketotic hypoglycemia and, in rare cases, coma. Patients are mostly asymptomatic between acute epidodes. HMG-CoA synthase deficiency requires an early diagnosis in order to avoid hypoglycemic crises that can lead to permanent brain damage or death.


A rare classic organic aciduria characterized by tissue accumulation and elevation of urinary excretion of 3-hydroxyisobutyric acid. The clinical phenotype ranges from recurrent mild episodes of vomiting with normal cognitive development, to massive acidosis, seizures, and failure to thrive with profound intellectual disability and early death. Dysmorphic craniofacial features (such as microcephaly, triangular face, short, sloping forehead, long, prominent philtrum, and micrognathia) and variable cerebral anomalies have also been described.


A rare inherited disorder of leucine metabolism characterized by a highly variable clinical picture ranging from metabolic crisis in infancy to asymptomatic adults.

Summary:
Epidemiology
The birth prevalence in Europe is estimated at 1/50,000-1/30,000. The introduction of neonatal screening programs based on tandem mass spectrometry has revealed a high frequency of this disorder, and it now appears to be the most common organic aciduria in some populations.
Clinical description
Patients with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) have a variable clinical phenotype with the vast majority of patients being asymptomatic and a small subgroup displaying symptoms of an organic aciduria, usually in association with environmental triggering factors. Many newborns now diagnosed through expanded newborn screening tests remain asymptomatic, indicating that the disease has a very low clinical penetrance. Most symptomatic patients have normal growth and development until presenting with an acute metabolic crisis, usually following a minor infection, fasting or introduction of a protein-rich diet, between the ages of 2-33 months. Symptoms include vomiting, coma and apnea. Rarely, neurological abnormalities (i.e. metabolic stroke, hemiparesis, and encephalopathy), weakness, muscular hypotonia and developmental delay have been reported. Between episodes of metabolic crisis patients are usually asymptomatic. Some patients with 3-MCCD may not develop symptoms until adulthood, manifesting with weakness and fatigue, while others may never show symptoms.
Etiology
3-MCCD is due to mutations in the MCCC1 (3q27.1) or MCCC2 (5q12-q13) genes. These two genes encode MCCase subunit alpha and MCCase subunit beta, which together catalyze the fourth step in the leucine catabolic pathway. Mutations in these genes lead to reduced or absent 3-MCC activity, thereby allowing the toxic byproducts of leucine processing to build up and cause clinical symptoms. Evidence is emerging that consanguinity with homozygosity for damaging mutations in a second rare disease gene may be associated with non-specific severe phenotypes of 3-MCCD.
Diagnostic methods
Newborn screening using tandem mass spectrometry reveals an elevation of C5-hydroxy acylcarnitine on blood spots. Urine organic acid analysis shows elevation of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Carnitine serum levels can be decreased. Lymphocyte and fibroblast assays show low to absent 3-MCC activity while other carboxylase enzymes have normal activity. Laboratory findings during an acute metabolic crisis include metabolic acidosis, hypoglycemia, and in some cases, mild hyperammonemia. Molecular genetic testing identifying two disease causing alleles confirms diagnosis. Newborn screening programs are available in the U.S. and some European countries.
Differential diagnosis
The differential diagnosis includes other organic acidurias such as multiple carboxylase deficiency as well as Reye's syndrome.
Antenatal diagnosis
Antenatal diagnosis is possible in families with known disease causing mutations.
Genetic counseling
3-MCCD is inherited autosomal recessively and genetic counseling is recommended.
Management and treatment
Early diagnosis may help in properly managing 3-MCCD and reducing the risk of severe metabolic crisis. Treatment is often not necessary in asymptomatic individuals. Some patients may require oral L-carnitine supplementation. A diet restricted in leucine is usually not warranted. Avoidance of fasting and of other precipitating stresses is recommended (mainly in infants and young children), as is the regular monitoring of free carnitine concentrations. An emergency regimen (IV glucose and the correction of acidosis) is recommended during intercurrent illness.
Prognosis
The prognosis is usually good but depends on the severity of symptoms experienced.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Matthias BAUMGARTNER


3-methylglutaconic aciduria (3-MGA) type I is an inborn error of leucine metabolism with a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia.

Summary:
Epidemiology
The disorder is very rare with less than 20 cases reported in the literature.
Clinical description
Clinical manifestations usually become apparent in the neonatal period or during infancy but the diagnosis may not be made until childhood. Some of the reported patients also displayed hypoglycaemia, spastic quadriparesis, microcephaly, progressive neurological deficit, seizures, vomiting, atrophy of the basal ganglia, severe hypotonia and hepatomegly.
Etiology
The syndrome is caused by mutations in the AUH gene (chromosome 9) encoding 3-methylglutaconyl-CoA hydratase, an enzyme involved in leucine degradation.
Diagnostic methods
As the clinical picture is variable and nonspecific, diagnosis can be made by assay of 3-methylglutaconyl-CoA hydratase activity in fibroblasts or leukocytes, quantitative analysis of urinary organic acid excretion or, more recently, analysis of bodily fluids by NMR spectroscopy.
Differential diagnosis
Patients with 3-MGA type I can be distinguished from those with other forms of 3-MGA (types II, III and IV; see these terms) by the distinctive pattern of metabolite excretion: 3-methylglutaconic acid levels are highly elevated (higher than those detected in other forms of 3-MGA) whereas methylglutaric acid levels are usually only slightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other forms of 3-MGA).
Antenatal diagnosis
Prenatal diagnosis should be possible through detection of high levels of 3-hydroxyisovaleric acid in the amniotic fluid or through enzyme analysis of cultured amniocytes.
Genetic counseling
The syndrome is inherited as an autosomal recessive trait.
Management and treatment
Treatment is largely symptomatic but dietary management with a modest leucine restriction and supplementation with L-carnitine may be beneficial in some cases.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Pr Pascale DE LONLAY


3-methylglutaconic aciduria type III (MGA III) is an organic aciduria characterised by the association of optic atrophy and choreoathetosis with 3-methylglutaconic aciduria.

Summary:
Epidemiology
The vast majority of reported cases involved the Iraqi-Jewish population, in which the prevalence of the disorder has been estimated at around 1 in 10 000.
Clinical description
Onset of the optic atrophy occurs during infancy with a progressive decrease in visual acuity. The choreoathetoid movement disorder manifests later, usually within the first ten years of life. Other clinical features may include spastic paraparesis, mild ataxia and cognitive deficit, dysarthria, and nystagmus.
Etiology
MGA III is caused by mutations in the OPA3 gene (19q13.2-q13.3). The biological function of the OPA3 gene product remains to be defined but MGA III is hypothesised to be a primary mitochondrial disorder.
Diagnostic methods
Diagnosis may be suspected up on presentation with early-onset optic atrophy and choreoathetosis (particularly in individuals of Iraqi-Jewish origin) and by detection of an elevation in the levels of 3-methylglutaconic and 3-methylglutaric acid in the urine. Diagnosis can be confirmed by detection of mutations in the OPA3 gene.
Differential diagnosis
MGA type III can be distinguished from other forms of MGA (types I, II and IV; see these terms) on the basis of the clinical phenotype and, more specifically, from 3-MGA type I by the absence of an elevation in 3-hydroxyisovaleric acid levels and normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. The differential diagnosis may also include Behr syndrome (see this term) and cerebral palsy.
Antenatal diagnosis
Prenatal testing is clinically available for affected families through molecular analysis of amniocytes or chorionic villus samples.
Genetic counseling
MGA III is transmitted as an autosomal recessive trait.
Management and treatment
Treatment is symptomatic only and should be managed by a multidisciplinary team.
Prognosis
The long-term prognosis remains unknown: although the disease progresses during childhood, it appears to stabilise during early adulthood.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Pr Pascale DE LONLAY


3-methylglutaconic aciduria (3-MGA) type IV, or unclassified 3-MGA, is a clinically heterogeneous disorder characterised by increased 3-methylglutaconic acid excretion in individuals that cannot be classified as having one of the other forms of 3-MGA (3-MGA I, II or III).

Summary:
Epidemiology
The prevalence of this disorder is unknown.
Clinical description
Patients usually present during the first year of life with neurological findings including psychomotor retardation, hypotonia, developmental delay, seizures and progressive spasticity, together with severe failure to thrive. Cardiomyopathy, hepatic dysfunction, eye anomalies, microcephaly, deafness, dysmorphism, neonatal hypoglycaemia, thrombocytopaenia and lactic acidosis have also been reported. Cerebellar dysgenesis may be revealed by magnetic resonance imaging. In contrast, a small number of asymptomatic patients have been diagnosed as having 3-MGA type IV.
Etiology
The aetiology remains unknown: unlike patients with 3-MGA type I, individuals with 3MGA type IV display normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. Mitochondrial respiratory chain abnormalities have been detected in some 3MGA type IV patients but the clinical heterogeneity associated with this disorder suggests that the 3-methylglutaconic aciduria seen in 3-MGA type IV patients may result from a variety of causes and genetic factors.
Diagnostic methods
3-methylglutaconic aciduria can be diagnosed by analysis of urinary organic acid excretion but specific diagnosis of 3-MGA type IV requires exclusion of all other forms of 3-MGA. As the genetic factors responsible for the other forms of 3-MGA have now been determined, molecular analysis provides a valuable tool for accurate diagnosis.
Differential diagnosis
3-MGA type IV can be distinguished from the type I disorder by normal excretion of 3-hydroxyisovaleric acid. 3-MGA type II may be excluded by the mode of inheritance (transmission is X-linked recessive in 3-MGA type II) and on the basis of the clinical phenotype (the type II disorder is characterised by neutropaenia, skeletal myopathy, dilated cardiomyopathy and growth delay). Depending on the manifestations present, clinical differentiation of types III and IV may be more problematic, but the occurrence of 3-MGA type III is largely restricted to the Iraqi-Jewish population. In addition to other forms of 3-MGA, the differential diagnosis should also include cerebral palsy, dilated cardiomyopathy with ataxia (see this term) and other organic acidurias.
Genetic counseling
The disorder has been reported to be inherited as an autosomal recessive trait.
Management and treatment
At present there is no effective treatment for 3-MGA type IV and a leucine-restricted diet appears to be of no benefit.
Prognosis
The prognosis depends on the clinical phenotype but the neurological complications can be severe with a potentially fatal disease course.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Pr Pascale DE LONLAY


A rare organic aciduria characterized by neonatal onset of hypotonia, recurrent apneic episodes, lack of psychomotor development, feeding difficulties, extrapyramidal signs, and seizures. Other reported features include microcephaly, sensorineural deafness, bradycardia, and neutropenia. Laboratory studies show increased serum lactate and urinary excretion of 3-methylglutaconic acid. Brain imaging may reveal progressive cerebral atrophy. The disease is lethal in infancy.


A rare organic aciduria characterized by early onset of global developmental delay with severe intellectual disability, seizures, and 3-methylglutaconic aciduria. Additional features are hypotonia, hyperactivity and aggressive behavior, optic atrophy, or spasticity. Brain imaging may show generalized cerebral atrophy and white matter abnormalities.


3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome

A rare organic aciduria characterized by increased urinary excretion of 3-methylglutaconic acid, variably associated with neutropenia (sometimes causing recurrent severe infections and potentially resulting in leukemia) and progressive neurologic manifestations, such as global developmental delay, intellectual disability, hypotonia, movement disorder, and seizures. Microcephaly, cataract, facial dysmorphism, growth retardation, endocrine abnormalities, and cardiomyopathy have also been reported. Brain imaging may show cerebral or cerebellar atrophy, or abnormalities of the basal ganglia.


3-phosphoglycerate dehydrogenase deficiency, infantile/juvenile form

3-Phosphoglycerate dehydrogenase deficiency (3-PGDH deficiency) is an autosomal recessive form of serine deficiency syndrome (see this term) characterized clinically in the few reported cases by congenital microcephaly, psychomotor retardation and intractable seizures in the infantile form and by absence seizures, moderate developmental delay and behavioral disorders in the juvenile form


3-phosphoserine phosphatase deficiency, infantile/juvenile form

3-Phosphoserine phosphatase deficiency is an extremely rare form of serine deficiency syndrome (see this term) characterized clinically by congenital microcephaly and severe psychomotor retardation in the single reported case to date, which was associated with Williams syndrome (see this term).