Bryant-Li-Bhoj Neurodevelopmental Syndrome

Clinical description: Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is characterized by developmental delay / intellectual disability (typically in the severe range) and nonspecific craniofacial abnormalities. Many affected individuals do not achieve independent sitting, walking, or speaking, although there is a range of developmental outcomes. The presentation is highly variable and can include hypotonia, epilepsy, other neurologic findings (spasticity, loss of developmental milestones, worsening gait, and/or camptocormia – forward flexion of the spine when standing that resolves when lying down), growth abnormalities (most commonly poor growth), craniosynostosis (of any suture), and ocular involvement. Congenital anomalies are rare but can include congenital heart defects, brain malformations, and genitourinary abnormalities in males.

Diagnosis/testing: The diagnosis of BRYLIB is established in a proband with suggestive findings and a heterozygous pathogenic variant in either H3-3A (H3F3A) or H3-3B (H3F3B) identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding issues and poor weight gain may benefit from feeding therapy; in individuals with persistent feeding issues, gastrostomy tube may be considered. Standard treatment for developmental delay / intellectual disability, attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety, epilepsy, spasticity, constipation, craniosynostosis, vision issues, hearing loss, congenital heart defects, undescended testes, and hypothyroidism.

Surveillance: At each visit: measure growth parameters; assess nutrition safety and oral intake; monitor for constipation; assess for new manifestations, such as seizures and changes in tone and/or gait; monitor developmental progress and educational needs; and assess for behavioral issues, such as mobility and self-help skills. Annually or as clinically indicated: ophthalmology evaluation, audiology evaluation, and thyroid function tests.

Genetics counseling: BRYLIB is expressed in an autosomal dominant manner and typically caused by a de novo H3-3A (H3F3A) or H3-3B (H3F3B) pathogenic variant. Therefore, the risk to other family members is presumed to be low. Once an H3-3A (H3F3A) or H3-3B (H3F3B) pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.