Narumi Yoko, Aoki Yoko, Niihori Tetsuya, Sakurai Masahiro, Cavé Hélène, Verloes Alain, Nishio Kimio, Ohashi Hirofumi, Kurosawa Kenji, Okamoto Nobuhiko, Kawame Hiroshi, Mizuno Seiji, Kondoh Tatsuro, Addor Marie-Claude, Coeslier-Dieux Anne, Vincent-Delorme Catherine, Tabayashi Koichi, Aoki Masashi, Kobayashi Tomoko, Guliyeva Afag, Kure Shigeo, Matsubara Yoichi
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
J Hum Genet. 2008;53(9):834-841. doi: 10.1007/s10038-008-0320-0. Epub 2008 Jul 24.
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.
努南综合征（NS）和心脏-颜面-皮肤综合征（CFC）是常染色体显性疾病，其特征为心脏缺陷、面部畸形、外胚层异常和智力发育迟缓。NS和CFC综合征在临床上有显著重叠，但外胚层异常和智力发育迟缓在CFC综合征中更为常见。已在NS患者中鉴定出PTPN11和KRAS的突变，在CFC综合征患者中鉴定出KRAS、BRAF和MAP2K1/2的突变，确立了RAS/MAPK信号通路在人类发育中的新作用。最近，在NS患者中也鉴定出了七号无翅型基因（SOS1）的突变。为了阐明携带SOS1突变患者的临床谱，我们分析了24例NS患者，包括一个三代家族中的3例患者，以及30例无PTPN11、KRAS、HRAS、BRAF和MAP2K1/2（MEK1/2）突变的CFC综合征患者。我们在4例NS患者中鉴定出2个SOS1突变，包括上述三代家族中的3例患者。在具有CFC表型的患者中，在1例CFC患者以及2例同时具有NS和CFC表型的患者中鉴定出3个突变，其中包括一个新的三氨基酸插入突变。这3例患者表现出外胚层异常，如卷发、眉毛稀疏和皮肤干燥，其中2例有智力发育迟缓。我们的结果表明，携带SOS1突变的患者的临床谱涵盖从NS到CFC综合征。
