El-Hattab-Alkuraya Syndrome

Excerpt

Clinical characteristics: El-Hattab-Alkuraya syndrome is characterized by microcephaly (often early onset and progressive); severe-to-profound developmental delay; refractory and early-onset seizures; spastic quadriplegia with axial hypotonia; and growth deficiency with poor weight gain and short stature. Characteristic findings on brain imaging include cerebral atrophy that is disproportionately most prominent in the frontal lobes; ex vacuo ventricular dilatation with notable posterior horn predominance; brain stem volume loss with flattening of the belly of the pons; and symmetric under-opercularization. Neurologic involvement is progressive, with significant morbidity and mortality.

Diagnosis/testing: The diagnosis of El-Hattab-Alkuraya syndrome is established in a proband by identification of biallelic pathogenic variants in WDR45B on molecular genetic testing.

Management: Treatment of manifestations: Standardized treatments for seizures, spasticity, mobility, feeding issues, and ocular manifestations; developmental services and educational interventions for developmental delay and intellectual disability.

Surveillance: Monitor for changes in seizures, tone, movement disorders, nutrition, and safety of oral intake at each visit. Monitor development, educational needs, behavior, vision, and hearing annually or as needed.

Genetic counseling: El-Hattab-Alkuraya syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a WDR45B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the WDR45B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.