Abstract
Objective: Cardiofaciocutaneous syndrome (CFCS) is a rare developmental disorder caused by upregulated signaling through the RAS-mitogen-activated protein kinase (MAPK) pathway, mostly resulting from de novo activating BRAF mutations. Children with CFCS are prone to epilepsy, which is a major life-threatening complication. The aim of our study was to define the natural history of epilepsy in this syndrome and exploring genotype–phenotype correlations. Methods: We performed an observational study, including 34 patients with molecularly confirmed diagnosis (11 males, mean age: 15.8 years). The mean follow-up period was 9.2 years. For all patients, we performed neurological examination, cognitive assessment when possible, neuroimaging, electrophysiological assessment and systematic assessment of epilepsy features. Correlation analyses were performed, taking into account gender, age of seizure onset, EEG features, degree of cognitive deficits, type of mutation, presence of non-epileptic paroxysmal events and neuroimaging features. Results: Epilepsy was documented in 64% of cases, a higher prevalence compared to previous reports. Patients were classified into three groups based on their electroclinical features, long-term outcome and response to therapy. A genotype–phenotype correlation linking the presence/severity of epilepsy to the nature of the structural/functional consequences of mutations was observed, providing a stratification based on genotype to improve the clinical management of these patients.
Highlights
The RAS/mitogen-activated protein kinase (MAPK) pathway controls a wide array of cellular processes, and its proper function is required for the accomplishment of developmental programs as well as for neuronal function [1,2]
The relative prevalence of each BRAF mutation in the studied cohort reflected the distribution reported in the NSEuroNet database, an international repository dedicated to RASopathies, indicating that the composition of the subjects enrolled in the study is representative of the general CFCS population with BRAF
The relative prevalence of mutations affecting residues located in the two major functional domains of the kinase, which represent the mutational hot spots of CFCScausing BRAF mutations, was comparable (CRD, 32.4% vs. 37.7%; CR3, 67.7% vs. 62.0%)
Summary
The RAS/mitogen-activated protein kinase (MAPK) pathway controls a wide array of cellular processes, and its proper function is required for the accomplishment of developmental programs as well as for neuronal function [1,2]. Germline mutations in components of the RAS/MAPK cascade cause a family of clinically related developmental disorders, collectively known as “RASopathies” [3–5]. These multi-system diseases are characterized by variable neurological features, including developmental delay (DD)/intellectual disability (ID) and behavioral anomalies. Children affected by one of these disorders, cardiofaciocutaneous syndrome (CFCS, OMIM #PS115150), show pervasive neurological involvement, with hypotonia and moderate/severe DD/ID as major features [6]. In these children, epilepsy is a clinically relevant complication, being reported in a variable proportion of affected individuals [6–9]. A subset of these patients is affected by developmental and epileptic encephalopathy [12–14]
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