The cardiofaciocutaneous syndrome

• Published in: Journal of Medical Genetics 2006-11, Vol.43 (11), p.833-842
• Main Authors: Roberts, A, Allanson, J, Jadico, S K, Kavamura, M I, Noonan, J, Opitz, J M, Young, T, Neri, G
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - epidemiology; Abnormalities, Multiple - genetics; Age; ASD; atrial septal defect; Biological and medical sciences; cardiofaciocutaneous; CFC; Diagnosis, Differential; Digestive System Abnormalities - diagnosis; Ears & hearing; ERK; extracellular signal-regulated kinase; Eye Abnormalities - diagnosis; Facies; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Hair; Heart Defects, Congenital - diagnosis; Hematologic Diseases - diagnosis; Humans; Intellectual disabilities; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Nervous System Malformations - diagnosis; Noonan Syndrome - diagnosis; Noonan Syndrome - genetics; Patients; protein-tyrosine phosphatase nonreceptor type II encoding Tyrosine Phosphate SHP2; PTPN11; pulmonary valve stenosis; PVS; Review; Skin Abnormalities - diagnosis; Skin Abnormalities - pathology; Support groups; Syndrome
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2006.042796

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation. It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward-slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. The cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous haemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. The developmental delay usually is moderate to severe. The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen-activated protein/extracellular signal-regulated kinase MEK1 and MEK2, all belonging to the same RAS–extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis. The CFC syndrome is a member of a family of syndromes that includes the Noonan and Costello syndromes, presenting with phenotypic similarities. Noonan syndrome is caused by mutations in the protein tyrosine phosphatase SHP-2 gene (PTPN11), with a few people having a mutation in KRAS. Costello syndrome is caused by mutations in HRAS. The protein products of these genes also belong to the RAS–ERK pathway. Thus, the clinical overlap of these three conditions, which often poses a problem of differential diagnosis, is explained by their pathogenetic relatedness.