As part of a larger study of neurological complications in cardiofaciocutaneous syndrome (CFC), this analysis examined genotype-phenotype correlation, neurocognitive functioning, and treatment outcomes within a sub-cohort of patients with a history of infantile spasms. 

Infantile spasms (IS) are a severe form of childhood epilepsy with considerable risk for neurodevelopmental sequelae. Investigations of molecular pathways underlying IS could illuminate relationships between etiology and prognosis while refining potential treatment avenues. CFC syndrome is a rare multi-system genetic disorder caused by pathogenic variants in the RAS-MAPK signaling pathway.

A cohort of 138 individuals with CFC syndrome was recruited. Data pertaining to neurological presentation was obtained via review of medical records and a caregiver-completed electronic survey that included validated measures of adaptive and gross motor function.

IS presented in 14/138 (10.1%) of those enrolled, including 12 participants with BRAF gene variants and 2 with MAP2K1 gene variants. Remarkably, all IS-associated BRAF variants were located in exons 11-16 (kinase domain CR3), despite only 56% of total variants affecting this region. All patients with a history of IS had intellectual disability, and 10/14 patients were nonverbal. The mean age of onset of IS was 6.3 months (range: 3.6-15.6 months). 5/14 patients (35.7%) had treatment-resistant IS. Among the 9 patients whose IS responded to therapy, 7 were prescribed hormone therapy (6 receiving ACTH and 1 receiving prednisone) and 2 were prescribed vigabatrin. A substantial majority of CFC patients with IS (85%) subsequently developed other seizure types and medically refractory epilepsy. 

IS are relatively common in CFC, affecting over 10% of patients; certain molecular genetic variants are more likely to yield an IS phenotype. About 1/3 cases of CFC-associated IS are treatment-resistant. As with other epilepsy syndromes, IS in CFC are associated with elevated risk of subsequent medically refractory epilepsy and neurodevelopmental disability.