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1 Harvard Medical School, Partners Healthcare System, Center for Genetics and Genomics, Boston, Massachusetts, USA
2 Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; University of Ottawa, Ottawa, Ontario, Canada
3 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
4 Medical Genetics, Federal University of São Paulo, São Paulo, Brazil
5 Department of Pediatrics, University of Kentucy, Lexington, Kentucky, USA
6 Departments of Pediatrics (Medical Genetics), University of Utah Medical School, Salt Lake City, Utah, USA
7 Departments of Ophthalmology and Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
8 Istituto di Genetica Medica, Facoltà di Medicina, A Gemelli, Università Cattolica del S Cuore, Roma, Italy
Correspondence to:
G Neri
Istituto di Genetica Medica, Università Cattolica, Largo F Vito, 1, 00168 Roma, Italy;gneri{at}rm.unicatt.it]
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.
Abbreviations: ASD, atrial septal defect; CFC, cardiofaciocutaneous; ERK, extracellular signal-regulated kinase; PTPN11, protein-tyrosine phosphatase nonreceptor type II encoding Tyrosine Phosphate SHP2; PVS, pulmonary valve stenosis
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