Molven Anders, Søvik Oddmund, von der Lippe Charlotte, Steine Solrun J, Njølstad Pål R, Houge Gunnar, Prescott Trine E
Gades institutt, Universitetet i Bergen og Avdeling for patologi Haukeland universitetssykehus 5021 Bergen, Norway.
Tidsskr Nor Laegeforen. 2009 Nov 19;129(22):2358-61. doi: 10.4045/tidsskr.09.0267.
Mutations in genes of the mitogen-activated protein kinase (MAPK) cascade have recently been shown to cause several syndromes characterized by dysmorphic facial features, growth retardation, cognitive impairment, heart disease and cutaneous abnormalities. This signalling pathway involves RAS and RAF proteins, and is central in the regulation of normal growth and the development of cancer.
We have studied 23 Norwegian patients for whom there was a clinical suspicion of Costello, Noonan or cardio-facio-cutaneous syndrome. Patients suspected of having Noonan syndrome had previously tested negative for mutations in the tyrosine phosphatase gene PTPN11. The material was examined for mutations in the HRAS, KRAS, RAF1 and BRAF genes. Two patients are described to illustrate diagnostic challenges and the usefulness of genetic testing.
Ten of 23 patients (43 %) had mutations affecting the RAS/MAPK signalling pathway. Mutations in HRAS were most common (five cases), while three patients had mutations in KRAS and two in RAF1. Spontaneous mutations were demonstrated in eight cases. Our data indicate an annual incidence of 1-2 new cases of congenital RAS/RAF mutations in Norway.
Upon clinical suspicion of syndromes of the RAS/MAPK signalling pathway, molecular genetic analyses may be essential for a correct diagnosis. Certain mutations are associated with an increased cancer risk, exemplifying that results of genetic laboratory testing may influence medical management.
丝裂原活化蛋白激酶（MAPK）级联反应相关基因的突变最近已被证明会导致几种综合征，其特征为面部畸形、生长发育迟缓、认知障碍、心脏病和皮肤异常。该信号通路涉及RAS和RAF蛋白，在正常生长调节和癌症发展中起核心作用。
我们研究了23名挪威患者，临床怀疑他们患有科斯特洛综合征、努南综合征或心脏-颜面-皮肤综合征。疑似患有努南综合征的患者此前酪氨酸磷酸酶基因PTPN11的突变检测呈阴性。对这些样本进行了HRAS、KRAS、RAF1和BRAF基因的突变检测。描述了两名患者以说明诊断挑战和基因检测的有用性。
23名患者中有10名（43%）发生了影响RAS/MAPK信号通路的突变。HRAS突变最为常见（5例），3例患者发生KRAS突变，2例发生RAF1突变。8例为自发突变。我们的数据表明，挪威先天性RAS/RAF突变的年发病率为1 - 2例新发病例。
临床怀疑RAS/MAPK信号通路相关综合征时，分子遗传学分析对于正确诊断可能至关重要。某些突变与癌症风险增加相关，这表明基因实验室检测结果可能会影响医疗管理。
