Cardiofaciocutaneous syndrome

CFC syndrome is caused by germline heterozygous gain-of-function pathogenic variants in genes encoding components of the Ras/mitogen-activated protein kinase (Ras/Raf/MEK/ERK) signal transduction cascade, placing the condition among the RASopathies. Pathogenic variants are reported in BRAF (~75%), MAP2K1 (~25%), MAP2K2 (~25%), and KRAS (<2%). The vast majority of variants are missense variants or small in-frame deletions producing constitutive activation of BRAF, MEK1, MEK2, or KRAS protein, with consequent increased phosphorylation of ERK1/ERK2 and dysregulated MAPK signalling.

CFC syndrome is inherited in an autosomal dominant manner. Affected siblings of a proband whose parents do not carry the pathogenic variant are uncommon, although germline mosaicism cannot be excluded. Prenatal molecular testing is possible once the familial pathogenic variant has been identified.

The diagnosis of CFC syndrome is established by molecular genetic testing identifying a heterozygous germline pathogenic variant in BRAF, MAP2K1, MAP2K2, or KRAS in an individual with suggestive clinical findings. No biochemical marker or pathognomonic imaging finding establishes the diagnosis; clinical assessment supports the suspicion that prompts molecular confirmation.

Main differential diagnoses include:

• : short stature, pulmonary valve stenosis, webbed neck, lymphatic dysplasias, and variable developmental delay; PTPN11, SOS1, RAF1, LZTR1, and others.
• : coarse facial features, loose skin with deep palmar creases, perioral papillomata, hypertrophic cardiomyopathy with supraventricular tachycardia, and ~15% lifetime malignancy risk; HRAS.

• Establishing the molecular diagnosis confirms the clinical suspicion and concludes the diagnostic work-up.
• A confirmed molecular diagnosis enables specific and individualised surveillance and clinical management, and is the prerequisite for targeted medical care planned by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive testing of at-risk relatives can clarify carrier status and inform their individual clinical follow-up.

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