Weiss-Kruszka Syndrome

Clinical characteristics: Weiss-Kruszka syndrome is characterized by metopic ridging or synostosis, ptosis, nonspecific dysmorphic features, developmental delay, and autistic features. Brain imaging may identify abnormalities of the corpus callosum. Developmental delay can present as global delay, motor delay, or speech delay. Affected individuals may also have ear anomalies, feeding difficulties (sometimes requiring placement of a gastrostomy tube), and congenital heart defects. There is significant variability in the clinical features, even between affected members of the same family.

Diagnosis/testing: The diagnosis of Weiss-Kruszka syndrome is established in a proband with suggestive features and by identification of a heterozygous pathogenic variant in ZNF462 or deletion of 9p31.2 involving ZNF462; rarely chromosome rearrangements that disrupt ZNF462 have been reported.

Management: Treatment of manifestations: Referral to a craniofacial team and/or neurosurgeon for those with craniosynostosis; feeding therapy for those with feeding difficulties; gastrostomy tube placement for those with persistent feeding issues and/or dysphagia. Standard treatment for ptosis, developmental delay, autism, hearing loss, and congenital heart defects.

Surveillance: Assessment of head circumference and shape at each evaluation in infancy and early childhood. Measurement of growth parameters, evaluation of nutrition status and safety of oral intake, and assessment of developmental progress and educational needs at each visit. Ophthalmology and audiology evaluations based on degree of clinical suspicion.

Genetic counseling: Weiss-Kruszka syndrome is inherited in an autosomal dominant manner. Approximately 95% of affected individuals have Weiss-Kruszka syndrome as the result of an apparently de novo pathogenic variant. Each child of an individual with Weiss-Kruszka syndrome has a 50% chance of inheriting the ZNF462 pathogenic variant. Children who inherit a ZNF462 pathogenic variant may be more or less severely affected than the affected parent because of intrafamilial clinical variability. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the ZNF462 pathogenic variant in the family has been identified.