Clinical characteristics: CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by generalized overgrowth, developmental delay / intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, sleep disturbance, and gastrointestinal issues The most common findings are the development of macrocephaly (most often during infancy) and tall stature (most typically during puberty), which is often accompanied by ASD and/or DD/ID. Most, if not all, affected individuals have some degree of DD, most commonly speech and motor delays. When present, ID is most often in the mild-to-moderate range. Sleep disturbance is characterized by difficulty with both initiation (delayed sleep onset) and maintenance (frequent night awakenings) of sleep. The most common gastrointestinal issue is constipation with or without periods of diarrhea. Less common features are hypotonia (about 30% of affected individuals), seizures (10%-15%), dystonia (rare), and Chiari I malformation (rare).
Diagnosis/testing: The diagnosis of CHD8-NDD is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in CHD8 by molecular genetic testing.
Management: Treatment of manifestations: Sleep disturbance may be addressed through behavioral interventions and/or pharmacologic treatment; if Chiari I malformation is present, surgical treatment may be required; standard treatment for DD/ID, seizures, and bowel dysfunction.
Surveillance: At each visit: measurement of growth parameters (including head circumference); assessment of developmental progress and educational needs; monitor for signs and symptoms of anxiety, attention-deficit/hyperactivity disorder, and aggressive or self-injurious behavior; assess for new manifestations, such as seizures, changes in tone, and signs/symptoms of cerebrospinal fluid obstruction and/or spinal cord dysfunction; screen for signs/symptoms of sleep disturbance; monitor for constipation. Consider serial imaging for asymptomatic or minimally symptomatic Chiari I malformation as clinically indicated.
Genetic counseling: CHD8-NDD is inherited in an autosomal dominant fashion. However, most probands reported to date whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CHD8 pathogenic variant. Each child of an individual with CHD8-NDD has a 50% chance of inheriting the CHD8 pathogenic variant. Once the CHD8 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
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