SMARCA2- Related Nicolaides-Baraitser Syndrome

Excerpt

Clinical characteristics: SMARCA2-related Nicolaides-Baraitser syndrome (SMARCA2-NCBRS) is characterized by commonly shared dysmorphic features including sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly (typically acquired), seizures, and developmental delay / intellectual disability. Developmental delay / intellectual disability is severe in nearly half of affected individuals, moderate in one third, and mild in the remainder. Nearly one third never develop speech or language skills. Seizures are of various types and can be difficult to manage, requiring multiple anti-seizure medications to achieve reasonable control. Regression or lack of developmental progress has been noted with the onset of seizures in some affected individuals. Behavioral issues can include autistic-like features (perseveration, hyperacusis), with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder. Cryptorchidism is common in males. About half of affected individuals have growth deficiency and short stature. Delayed tooth eruption with hypo- or oligodontia has also been reported. Radiographic findings may include cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays) of the hands; platyspondyly; flat intervertebral disc space; and pelvic/femoral anomalies. Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects.

Diagnosis/testing: The diagnosis of SMARCA2-NCBRS is established in a proband with suggestive findings and a heterozygous SMARCA2 pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: Standard therapy for developmental delay / intellectual disability, behavioral issues, epilepsy, poor growth, myopia, astigmatism, hearing loss, dental issues, cryptorchidism, and congenital heart defects.

Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor those with seizures; assess for new manifestations; monitor developmental progress and educational needs; assess for behavioral issues such as short attention span, sensitivity to loud noises, and oral sensitivity; and evaluate mobility and self-help skills. Dental evaluation at least every six months after the eruption of first dentition. Annual audiology evaluation in childhood. Ophthalmology evaluation per treating ophthalmologist.

Genetic counseling: SMARCA2-NCBRS is expressed in an autosomal dominant manner and typically caused by a de novo SMARCA2 pathogenic variant; the risk to other family members is presumed to be low. Once a SMARCA2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.