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CFC and Noonan syndromes due to mutations in RAS/MAPK signaling pathway: genotype/phenotype relationships and overlap with Costello syndrome
  1. Caroline Nava
  1. Hôpital Robert Debré, France
    1. Nadine Hanna
    1. INSERM U745, France
      1. Caroline Michot
      1. Hôpital Robert Debré, France
        1. Sabrina Pereira
        1. Hôpital Robert Debré, France
          1. Nathalie Pouvreau
          1. Hôpital Robert Debré, France
            1. Tetsuya Niihori
            1. Tohoku university school of Medecine, Japan
              1. Yoko Aoki
              1. Tohoku university school of Medecine, Japan
                1. Yoichi Matsubara
                1. Tohoku university school of Medecine, Japan
                  1. Benoit Arveiler
                  1. CHU Pellegrin, France
                    1. Didier Lacombe
                    1. CHU Pellegrin, France
                      1. Eric Pasmant
                      1. INSERM U745, France
                        1. Béatrice Parfait
                        1. INSERM U745, France
                          1. Clarisse Baumann
                          1. Hôpital robert Debré, France
                            1. Delphine Héron
                            1. Hôpital de la Pitié-Salpétrière, France
                              1. Sabine Sigaudy
                              1. CHU La Timonne, France
                                1. Annick Toutain
                                1. CHU Clocheville, France
                                  1. Marlène Rio
                                  1. Hôpital Necker, France
                                    1. Alice Goldenberg
                                    1. CHU Charles Nicolle, France
                                      1. Bruno Leheup
                                      1. CHU Brabois, France
                                        1. Alain Verloes
                                        1. Hôpital Robert Debré, France
                                          1. Hélène Cavé (helene.cave{at}rdb.aphp.fr)
                                          1. Hôpital Robert Debré, France

                                            Abstract

                                            Introduction: Cardio-facio-cutaneous (CFC), Noonan (NS), and Costello (CS) syndromes are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signaling pathway.

                                            Methods: We performed mutation analysis of KRAS, BRAF, MEK1, MEK2 in 40 patients with a clinical diagnosis of CFC, 20 patients from the French Costello family support group without HRAS mutations, and 70 patients with NS without PTPN11 or SOS1 mutations.

                                            Results: We found BRAF mutations in 14/40 CFC patients (35%) and 8/20 CS HRAS-negative patients (40%); KRAS mutations in 1/40 CFC (2.5%), 2/20 CS HRAS-negative patients (10%) and 4/70 NS patients (5.7%); MEK1 mutations in 4/40 CFC patients (10%), 4/20 CS HRAS-negative patients (20%), 3/70 NS patients (4.3%); and MEK2 mutations in 4/40 CFC patients (10%). 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 associated with BRAF or MEK mutations.

                                            Discussion: Because of its peculiar cancer risk, “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 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 easily NS from CFC.

                                            • BRAF
                                            • MEK
                                            • Noonan
                                            • RAS
                                            • cardiofaciocutaneous

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