Pediatric Familial Cerebral Cavernous Malformation Associated With a Novel KRIT1 Initiation-Region Frameshift Variant

Familial cerebral cavernous malformation (CCM) is an autosomal dominant vascular disorder with age-dependent penetrance and marked intrafamilial variability. KRIT1 loss-of-function variants are the most common genetic cause, but pediatric genotype-phenotype correlations remain limited.

Clinical, radiological, histopathological, and molecular findings of a pediatric family with suspected familial CCM were reviewed. Brain and spinal MRI, calvarial histopathology, whole-exome sequencing, segregation analysis, and targeted literature review were performed.

The index patient was a 14-year-old boy presenting with focal seizure and a progressively enlarging right parietal calvarial mass. MRI revealed multiple cerebral and cerebellar CCMs with a cervical intramedullary cavernous malformation. The calvarial lesion was excised and confirmed as hemangioma. Whole-exome sequencing identified a previously unreported heterozygous KRIT1 initiation-region duplication, NM_004912.4: c.2dup, predicted to result in p.(Met1IlefsTer31) with loss of all major functional domains. The same variant was detected in the clinically asymptomatic sibling with MRI-confirmed multiple CCMs, whereas the mother was negative. The father had died from intracerebral hemorrhage, but genetic testing was unavailable.

This report expands the KRIT1 mutational spectrum and illustrates the wide clinical range of familial CCM, from asymptomatic radiological disease to epilepsy and fatal hemorrhage within one family. These findings support early molecular diagnosis, cascade screening, and susceptibility-sensitive MRI surveillance.