title: Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome.
abstract: Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS-negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS-negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS-negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term "Costello syndrome" should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily.
authors: Department of Genetics, AP-HP, Hôpital Robert Debré, Paris, France.
authors: Caroline
authors: C
authors: Nava
authors: Nadine
authors: N
authors: Hanna
authors: Caroline
authors: C
authors: Michot
authors: Sabrina
authors: S
authors: Pereira
authors: Nathalie
authors: N
authors: Pouvreau
authors: Tetsuya
authors: T
authors: Niihori
authors: Yoko
authors: Y
authors: Aoki
authors: Yoichi
authors: Y
authors: Matsubara
authors: Benoit
authors: B
authors: Arveiler
authors: Didier
authors: D
authors: Lacombe
authors: Eric
authors: E
authors: Pasmant
authors: Béatrice
authors: B
authors: Parfait
authors: Clarisse
authors: C
authors: Baumann
authors: Delphine
authors: D
authors: Héron
authors: Sabine
authors: S
authors: Sigaudy
authors: Annick
authors: A
authors: Toutain
authors: Marlène
authors: M
authors: Rio
authors: Alice
authors: A
authors: Goldenberg
authors: Bruno
authors: B
authors: Leheup
authors: Alain
authors: A
authors: Verloes
authors: Hélène
authors: H
authors: Cavé
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005145:Face / Q000002:abnormalities*; D005260:Female; D011905:Genes, ras; D005838:Genotype; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012868:Skin Abnormalities / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D013577:Syndrome
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
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