ORIGINAL ARTICLES

Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype–phenotype relationships and overlap with Costello syndrome

Caroline Nava¹, Nadine Hanna², Caroline Michot¹, Sabrina Pereira¹, Nathalie Pouvreau¹, Tetsuya Niihori³, Yoko Aoki³, Yoichi Matsubara³, Benoit Arveiler⁴, Didier Lacombe⁴, Eric Pasmant², Béatrice Parfait², Clarisse Baumann¹, Delphine Héron⁵, Sabine Sigaudy⁶, Annick Toutain⁷, Marlène Rio⁸, Alice Goldenberg⁹, Bruno Leheup¹⁰, Alain Verloes¹, Hélène Cavé¹

¹ Department of Genetics, AP-HP, Hôpital Robert Debré, Paris, France
² INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
³ Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
⁴ Department of Medical Genetics, CHU Pellegrin, Bordeaux, France
⁵ Department of Medical Genetics, CHU Pitié Salpétrière, Paris, France
⁶ Department of Medical Genetics, CHU La Timone, Marseille, France
⁷ Department of Medical Genetics, CHU Clocheville, Tours, France
⁸ Department of Medical Genetics, CHU Necker, Paris, France
⁹ Department of Medical Genetics, CHU Charles Nicolle, Rouen, France
¹⁰ Department of Medical Genetics, CHU Brabois, Nancy, France

Hélène Cavé, Laboratoire de Biochimie Génétique, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France; helene.cave{at}rdb.aphp.fr

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.

Abbreviations: CFC, cardio-facio-cutaneous; CHD, congenital heart defects; CS, Costello syndrome; GEF, guanosine exchange factor; JMML, juvenile myelomonocytic leukaemia; NF1, neurofibromatosis type 1; NS, Noonan syndrome

Keywords: CFC syndrome; Costello syndrome; Noonan syndrome; KRAS; BRAF; HRAS; MEK1; MEK2

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