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Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype–phenotype relationships and overlap with Costello syndrome
  1. Caroline Nava1,
  2. Nadine Hanna2,
  3. Caroline Michot1,
  4. Sabrina Pereira1,
  5. Nathalie Pouvreau1,
  6. Tetsuya Niihori3,
  7. Yoko Aoki3,
  8. Yoichi Matsubara3,
  9. Benoit Arveiler4,
  10. Didier Lacombe4,
  11. Eric Pasmant2,
  12. Béatrice Parfait2,
  13. Clarisse Baumann1,
  14. Delphine Héron5,
  15. Sabine Sigaudy6,
  16. Annick Toutain7,
  17. Marlène Rio8,
  18. Alice Goldenberg9,
  19. Bruno Leheup10,
  20. Alain Verloes1,
  21. Hélène Cavé1
  1. 1
    Department of Genetics, AP-HP, Hôpital Robert Debré, Paris, France
  2. 2
    INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
  3. 3
    Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
  4. 4
    Department of Medical Genetics, CHU Pellegrin, Bordeaux, France
  5. 5
    Department of Medical Genetics, CHU Pitié Salpétrière, Paris, France
  6. 6
    Department of Medical Genetics, CHU La Timone, Marseille, France
  7. 7
    Department of Medical Genetics, CHU Clocheville, Tours, France
  8. 8
    Department of Medical Genetics, CHU Necker, Paris, France
  9. 9
    Department of Medical Genetics, CHU Charles Nicolle, Rouen, France
  10. 10
    Department of Medical Genetics, CHU Brabois, Nancy, France
  1. Hélène Cavé, Laboratoire de Biochimie Génétique, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France; helene.cave{at}


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.

  • CFC syndrome
  • Costello syndrome
  • Noonan syndrome
  • KRAS
  • BRAF
  • HRAS
  • MEK1
  • MEK2

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  • The first three authors contributed equally to this work

    Parental/guardian informed consent was obtained for publication of figures 2 and 3.

    Note added in proof: Since submission of this manuscript, Gripp et al28 has reported a series of eight patients with BRAF and five with MEK1 mutations, for which the clinical diagnosis was felt to be CS. Comparison with HRAS-mutated showed similar trends to our own observations. They also favoured a molecular definition of CS.

  • Funding: The work was supported in part by the Programme Hospitalier de Recherche Clinique (grant PHRC-AOM02 004).

  • Competing interests: none declared.

  • Abbreviations:
    congenital heart defects
    Costello syndrome
    guanosine exchange factor
    juvenile myelomonocytic leukaemia
    neurofibromatosis type 1
    Noonan syndrome