Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype

Am J Med Genet C Semin Med Genet. 2022 Dec;190(4):501-509. doi: 10.1002/ajmg.c.32022. Epub 2022 Nov 29.


Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.

Keywords: BRAF; KRAS; MAP2K1; MAP2K2; RASopathies; seizures.

MeSH terms

  • Epilepsy* / genetics
  • Genotype
  • Humans
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / therapeutic use
  • Spasm / complications
  • Spasms, Infantile* / complications
  • Spasms, Infantile* / drug therapy
  • Spasms, Infantile* / genetics
  • Syndrome


  • Proto-Oncogene Proteins B-raf