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Review
. 2023 Nov 22;14(12):2111.
doi: 10.3390/genes14122111.

The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications

Giovanna Scorrano  1 , Emanuele David  2 , Elisa Calì  3 , Roberto Chimenz  4 , Saverio La Bella  1 , Armando Di Ludovico  1 , Gabriella Di Rosa  5 , Eloisa Gitto  6 , Kshitij Mankad  7 , Rosaria Nardello  8 , Giuseppe Donato Mangano  8 , Chiara Leoni  9 , Giorgia Ceravolo  3
Affiliations
Review

The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications

Giovanna Scorrano et al. Genes (Basel). .

Abstract

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.

Keywords: BRAF mutation; CFC; Cardiofaciocutaneous syndrome; KRAS mutation; MEK1 mutation; MEK2 mutation; RASopathies; hypertrophic cardiomyopathy; neurodevelopment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The RAS-MAPK pathway.
Figure 2
Figure 2
Neuroradiological findings in patient with CFC. Magnetic resonance imaging (MRI) scan of the brain of a 2-year-old patient with a MAP2K1 variant in CFC Syndrome. (A) Sagittal T1: Reduced cerebral volume anteriorly with associated thinning of the corpus callosum. (B) Coronal T1: Bilateral hippocampal malrotation. (C) Axial T1: Delayed myelination within the temporal lobes. (D) Axial T2: Abnormal signal within the dentate nuclei.
Figure 3
Figure 3
Distinctive craniofacial features in a CFC patient through time. At 12 months (A), 5 years (B) and 16 years of age (C,D), respectively.
See this image and copyright information in PMC

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Supplementary concepts