Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.

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  1. Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, Japan

    • Yoko Narumi
    • , Yoko Aoki
    • , Tetsuya Niihori
    • , Tomoko Kobayashi
    • , Afag Guliyeva
    • , Shigeo Kure
    •  & Yoichi Matsubara
  2. Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan

    • Masahiro Sakurai
    •  & Koichi Tabayashi
  3. Department of Genetics, Hôpital Robert Debré (APHP), Paris, France

    • Hélène Cavé
    •  & Alain Verloes
  4. Department of Clinical Genetics, Seirei Hamamatsu General Hospital, Hamamatsu, Japan

    • Kimio Nishio
  5. Nishio Family Clinic, Hamamatsu, Japan

    • Kimio Nishio
  6. Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan

    • Hirofumi Ohashi
  7. Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan

    • Kenji Kurosawa
  8. Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan

    • Nobuhiko Okamoto
  9. Division of Medical Genetics, Nagano Children's Hospital, Nagano, Japan

    • Hiroshi Kawame
  10. Department of Pediatrics, Central Hospital, Aichi Human Service Center, Aichi, Japan

    • Seiji Mizuno
  11. Division of Developmental Disability, Misakaenosono Mutsumi Developmental, Medical, and Welfare Center, Isahaya, Japan

    • Tatsuro Kondoh
  12. Department of Medical Genetics, CHU Vaudois, Lausanna, Switzerland

    • Marie-Claude Addor
  13. Department of Medical Genetics, CHRU de Lille, Lille, France

    • Anne Coeslier-Dieux
  14. CH d'Arras, Arras, France

    • Catherine Vincent-Delorme
  15. Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan

    • Masashi Aoki


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Corresponding author

Correspondence to Yoko Aoki.

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