Intellectual Disability and Microcephaly With Pontine and Cerebellar Hypoplasia in Adults: Severity Spectrum and Diversity of the CASK Gene Aberrations.

Intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) is a rare X-linked neurodevelopmental disorder characterized by severe developmental delay, microcephaly, and distinctive brain MRI findings, predominantly affecting females due to loss-of-function variants in the calcium/calmodulin-dependent serine protein kinase (CASK) gene. We describe three adult female patients with MICPCH, aged 31, 43, and 50 years, exhibiting core symptoms of severe intellectual disability, postnatal microcephaly, and growth retardation. Patients 1 and 2 failed to achieve standing, had severe scoliosis, and received tube feedings. Patient 3 had mild symptoms, could gain ambulation, had mild scoliosis, and could take food orally. Genetic analyses of the CASK gene revealed a heterozygous nonsense variant, c.1609C>T, p.(Arg537*) in patient 1, a novel frameshift deletion, c.1079_1089del, p.(Leu360Glnfs*2) in patient 2, and a copy number variant, a heterozygous duplication of exons 12-14 in patient 3. Our adult cases expand the known age spectrum and phenotypic variability of MICPCH associated with CASK aberrations. Despite relatively similar MRI findings, the patients exhibited substantial differences in functional severity, epilepsy burden, and scoliosis progression, highlighting the dissociation between radiological and clinical severity in MICPCH. These findings emphasize the importance of long-term multidisciplinary management in adult patients.