Clinical heterogeneity and diagnostic challenges in CASK-related neurodevelopmental disorders: a longitudinal observational study.

BACKGROUND

Pathogenic variants in the CASK gene cause a broad spectrum of X-linked phenotypes ranging from microcephaly with pontine and cerebellar hypoplasia (MICPCH) to only mild intellectual disability (ID). Variable clinical pictures pose significant diagnostic challenges.

METHODS

We conducted a retrospective observational study with longitudinal follow-up at a tertiary pediatric neurology center over a 10-year period (6,179 patients were hospitalized and evaluated). Since 2015, genetic testing using next-generation sequencing gene (NGS) panels, including CASK gene, was performed in patients with MICPCH and the first patient was confirmed through hereditary ataxia NGS panel. Two additional patients were identified among 105 children with suspected genetic neurodevelopmental disorders undergoing CentoNeuro panel (including 1,902 genes), which was available during a period (2023-2024). Clinical, neuroimaging, and genetic data were analyzed during follow-up.

RESULTS

Two female patients carried de novo loss-of-function CASK variants and presented with MICPCH, progressive developmental impairment, abnormal muscle tone, postnatal growth retardation, and epilepsy in one case. The male patient carried an inherited likely pathogenic missense variant and exhibited severe ID, drug-resistant epilepsy, autistic features, and a cerebral palsy-like phenotype without microcephaly or pontocerebellar malformations. All patients demonstrated periods of developmental arrest or regression, suggesting non-linear developmental trajectories. Marked intrafamilial phenotypic variability was observed.

CONCLUSIONS

CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy-like phenotypes, even in the absence of characteristic neuroimaging findings. A cerebral palsy-like phenotype, postnatal growth retardation, and variable ID should raise suspicion for CASK-related disorders. Comprehensive genetic testing, including next-generation sequencing, is essential for accurate diagnosis.