title: Cardio-facio-cutaneous syndrome: does genotype predict phenotype?
abstract: Cardio-facio-cutaneous (CFC) syndrome is a sporadic multiple congenital anomalies/mental retardation condition principally caused by mutations in BRAF, MEK1, and MEK2. Mutations in KRAS and SHOC2 lead to a phenotype with overlapping features. In approximately 10–30% of individuals with a clinical diagnosis of CFC, a mutation in one of these causative genes is not found. Cardinal features of CFC include congenital heart defects, a characteristic facial appearance, and ectodermal abnormalities. Additional features include failure to thrive with severe feeding problems, moderate to severe intellectual disability and short stature with relative macrocephaly. First described in 1986, more than 100 affected individuals are reported. Following the discovery of the causative genes, more information has emerged on the breadth of clinical features. Little, however, has been published on genotype–phenotype correlations. This clinical study of 186 children and young adults with mutation-proven CFC syndrome is the largest reported to date. BRAF mutations are documented in 140 individuals (approximately 75%), while 46 (approximately 25%) have a mutation in MEK 1 or MEK 2. The age range is 6 months to 32 years, the oldest individual being a female from the original report [Reynolds et al. (1986); Am J Med Genet 25:413–427]. While some clinical data on 136 are in the literature, 50 are not previously published. We provide new details of the breadth of phenotype and discuss the frequency of particular features in each genotypic group. Pulmonary stenosis is the only anomaly that demonstrates a statistically significant genotype–phenotype correlation, being more common in individuals with a BRAF mutation.
authors.affiliation: Department of Genetics at Children’s Hospital of Eastern Ontario. allanson@cheo.on.ca
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allanson
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.forename: Yoki
authors.initials: Y
authors.lastname: Aoki
authors.forename: Christine M
authors.initials: CM
authors.lastname: Armour
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bondeson
authors.forename: Helene
authors.initials: H
authors.lastname: Cave
authors.forename: Karen W
authors.initials: KW
authors.lastname: Gripp
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.forename: Anna-Maja
authors.initials: AM
authors.lastname: Nystrom
authors.forename: Katia
authors.initials: K
authors.lastname: Sol-Church
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000473:pathology; D019066:Facies; D005183:Failure to Thrive / Q000235:genetics / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011666:Pulmonary Valve Stenosis / Q000235:genetics*
chemical_list: C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human