P 916. Lissencephaly and Prolonged Survival of a Male Infant with MICPCH and a Noval Mutation in the CASK Gene, Xp11.4

Background: The calcium/calmodulin-dependent serine protein kinase gene (CASK, chromosome Xp11.4, MIM*300172) mutations are associated with a broad spectrum of phenotypes in both females and males. There are two main types of clinical presentation: microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK and X-linked intellectual disability with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. The X-linked CASK gene mutations leading to MICPCH are predominantly identified in female patients and it has been hypothesized that CASK loss-of-function mutations are associated with reduced male viability or in utero lethality. So far only a few male patients with CASK mutations exhibiting a severe phenotype with perinatal lethality or death within the first months of life have been reported. We delineate the clinical course of a male infant with a novel mutation of the CASK gene, prolonged survival and lissencephaly.

Aims: Case report

Question: Case report

Methods: Magnetic resonance imaging (MRI) and neurophysiological investigations were done. Array CGC analysis were performed.

Results: The index patient is the second child of healthy nonconsanguineous Caucasian parents. Postnatally, he exhibited the complex symptoms of MICPCH, retrognathia, abnormal ear morphology, and he developed refractory neonatal seizures. The EEG revealed hypsarrhythmia. Despite frequent hospitalizations to the pediatric intensive care unit due to status epilepticus and respiratory failure, he survived into the third year of life. At the age of 2 years, the boy is not able to sit or grab and has a severe encephalopathy without interacting. On clinical examination, he has a tetraparesis, profound dysphagia, bilateral blindness, and deafness. MRI at the age of 5 weeks revealed olivopontocerebellar hypoplasia and lissencephaly with predominant frontal reduced number of gyri. The Array CGH analysis revealed a novel variant (duplication arrXp11.4 [41.327.450–41.409.539] × 2) in exon 8–14(/27) of the CASK gene.

Conclusion: So far, only a few male patients with loss-of-function alterations of CASK have been reported, all presenting with a severe neurological phenotype. To the best of our knowledge, this is the first male infant with a severe MICPCH phenotype surviving into early childhood (third year of life) and exhibiting a lissencephaly. So far, two further male patients have been described with a mildly reduced number and complexity of the frontal gyri. CASK not only plays a role in synaptic protein targeting but also contributes to neural development and regulation of gene expression. Several CASK-interacting proteins have been identified. To mention here is Reelin, which is critical for neural development and migration. Our findings expand the phenotypic spectrum of CASK-related disorders as an important differential diagnosis in pontocerebellar hypoplasia with signs of a neuronal migration disorders.