Journal Article

The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic–Therapeutic Implications

Di Ludovico, Armando, Chimenz, Roberto, Di Rosa, Gabriella, Mangano, Giuseppe Donato, Calì, Elisa, Leoni, Chiara, Mankad, Kshitij, Nardello, Rosaria, La Bella, Saverio, Gitto, Eloisa, Ceravolo, Giorgia, Scorrano, Giovanna, David, Emanuele

2023

Overview

Cardiofaciocutaneous (CFC) syndrome is one of the rarest RASopathies characterized by multiple congenital ectodermal, cardiac and craniofacial abnormalities with a mild to severe ocular, gastrointestinal and neurological involvement. It is an autosomal dominant syndrome, with complete penetrance, caused by heterozygous pathogenic variants in the genes BRAF, MAP2K1/MEK1, MAP2K2/MEK2, KRAS or, rarely, YWHAZ, all part of the RAS-MAPK pathway. This pathway is a signal transduction cascade that plays a crucial role in normal cellular processes such as cell growth, proliferation, differentiation, survival, metabolism and migration. CFC syndrome overlaps with Noonan syndrome, Costello syndrome, neurofibromatosis type 1 and Legius syndrome, therefore making the diagnosis challenging. Neurological involvement in CFC is more severe than in other RASopathies. Phenotypic variability in CFC patients is related to the specific gene affected, without a recognized genotype–phenotype correlation for distinct pathogenic variants. Currently, there is no specific treatment for CFC syndrome. Encouraging zebrafish model system studies suggested that, in the future, MEK inhibitors could be a suitable treatment of progressive phenotypes of CFC in children. A multidisciplinary care is necessary for appropriate medical management.

• Publisher: MDPI AG
• Subject: Animals / Cardiomyopathy / Cardiovascular disease / Cell differentiation / Cell growth / Cell survival / Child / Child development / Congenital diseases / Convulsions & seizures / Danio rerio / ectoderm / Ectodermal Dysplasia - diagnosis / Ectodermal Dysplasia - genetics / Ectodermal Dysplasia - therapy / Epilepsy / gastrointestinal system / Genes / Genetic variability / Genotype & phenotype / genotype-phenotype correlation / Genotypes / Growth factors / Heart Defects, Congenital - diagnosis / Heart Defects, Congenital - genetics / Heart Defects, Congenital - therapy / heterozygosity / Humans / Hydrocephalus / Kinases / Magnetic resonance imaging / MAP kinase / MEK inhibitors / Metabolism / Mutation / Neurofibromatosis / Noonan's syndrome / Pathogenesis / penetrance / Phenotypes / phenotypic variation / Prognosis / Recklinghausen's disease / Signal transduction / Zebrafish - genetics