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A rare, genetic, syndromic intellectual disability characterized by short stature, sparse hair, characteristic coarse face, brachydactyly with prominent interphalangeal joints, seizures and intellectual disability. Facial characteristics include triangular shaped face, dense and prominent eyelashes, rounded premaxilla, broad nasal base, thick alae nasi, upturned nasal tip, broad philtrum, thin upper vermilion, thick and everted lower vermilion and wide mouth.
ORPHA:3051Classification level: Disorder
Although the prevalence of the disorder is unknown, it is thought to be less than 1/1,000,000. To date, there are fewer than 100 molecularly confirmed, affected individuals reported in the literature. No significant difference in male-to-female ratio or geographical distribution has been reported.
At birth, patients may be small for gestational age (one-third of cases), have facial hypertrichosis, a low anterior-lateral hairline, and microcephaly (one-quarter). Postnatally, microcephaly and proportional short stature is present in over half of the patients. Sparse scalp hair is present in almost all patients and may be evident in the first months of life. Prominent inter-phalangeal joints due to decreased subcutaneous fat, are the most characteristic sign, and may be accompanied by fetal pads (half of patients). Radiological findings of the hands include short metacarpals, short phalanges, cone-shaped epiphyses, and ivory epiphyses in a few cases. Patients can show mild shortening of the toes, sandal gap and some thickening of the distal phalanx of the hallux. Most of these characteristics, particularly limbs and facial features, tend to be more evident with time. Hypotonia is reported in one third of patients, but major motor milestones such as sitting and walking independently are usually not very delayed. Intellectual disability (ID) is severe in nearly half, moderate in a third, and mild in the remainder of cases. Nearly a third never develop speech or language skills. Epilepsy occurs in two-thirds of patients, with onset between 18 to 24 months, and may correlate with regression. Seizure type is variable, even within the same individual and can be difficult to manage. Disposition is generally happy and very friendly, but temper outbursts and bouts of aggression are possible. Other congenital anomalies are variably observed.
The disorder is due to missense variants (80% of case) or intragenic deletions in SMARCA2 (9p24.3). This gene encodes a protein belonging to the ATP-dependent chromatin remodeling enzymes, implicated in the regulation of gene expression and cell cycle control. In almost 17% of patients, no variant has been identified.
Diagnosis is suspected on peculiar combination of facial features with sparse hair, intellectual disability, brachydactyly with prominent interphalangeal joints and seizures. Molecular diagnosis is based on identification of variants in SMARCA2.
Differential diagnosis includes Coffin-Siris syndrome, Williams syndrome and Cornelia de Lange syndrome.
If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at theoretic increased risk is possible.
Transmission is autosomal dominant. To date, all affected individuals have had a de novo SMARCA2 pathogenic variant, suggesting a low risk to siblings. However, because of the theoretic possibility of parental germline mosaicism, the empiric recurrence risk to siblings is approximately 1%.
Management and treatment
Clinical management requires periodical evaluation by a child neurologist/neuropsychiatrist in order to monitor the evolution of the intellectual development or onset of seizures. Enabling and supporting therapies (including non-verbal communication) and special school program are required. Anti-epileptic drugs appear necessary for controlling seizures, sometimes unsuccessfully and with consequent need for hospitalization. Regular follow up of ophthalmologic and/or audiologic abnormalities is recommended.
Prognosis is variable and is predominantly influenced by the age of onset of seizures and the difficulty in managing it. Independent living depends on the degree of intellectual disability, and is likely never totally achieved.
A summary on this disease is available in Deutsch (2006) Français (2006) Italiano (2006) Español (2021) Nederlands (2021)
- Clinical practice guidelines
- Français (2021) - PNDS
Disease review articles
- Clinical genetics review
- English (2015) - GeneReviews
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