Pelc Magdalena, Ciara Elżbieta, Jezela-Stanek Aleksandra, Kugaudo Monika, Cieślikowska Agata, Jurkiewicz Dorota, Janeczko Magdalena, Chrzanowska Krystyna, Krajewska-Walasek Małgorzata, Skórka Agata
aDepartment of Medical Genetics, The Children's Memorial Health Institute bDepartment of Paediatrics, Medical University of Warsaw, Warsaw cDepartment of Medical Genetics, Medical College, Jagiellonian University, Cracov, Poland.
Clin Dysmorphol. 2017 Apr;26(2):83-90. doi: 10.1097/MCD.0000000000000165.
Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p.G12S (n=4) and p.G12A (n=3), and a novel pathogenic variant p.G60V in one child with an unusually severe, lethal course of the syndrome. In addition, a fatal course of CS was present in one patient with the p.G12A mutation and in another with p.G12S, there was a co-occurrence of Turner syndrome because of the distal Xp deletion. A severe clinical manifestation with a lethal outcome in an individual with p.G60V in HRAS and contrary observations of an attenuated phenotype in CS patients with other mutations at glycine-60 residue may suggest that the nature of the substituted amino acid plays a significant role in the clinical variability observed in some CS cases.
科斯特洛综合征（CS）是一种罕见的先天性疾病，属于RAS病范畴，其特征为独特的面部外观、生长发育迟缓、心脏和皮肤异常、智力残疾以及易患肿瘤。CS与原癌基因HRAS的种系突变有关，HRAS是一种来自Ras家族的小GTP酶。在本研究中，对8名具有科斯特洛表型的波兰患者进行了分子和临床分析。分子检测显示，7名患者的该基因第一个编码外显子存在两个已知的杂合突变：p.G12S（n = 4）和p.G12A（n = 3），一名患有异常严重、致命性综合征病程的儿童存在一种新的致病变体p.G60V。此外，一名携带p.G12A突变的患者和另一名携带p.G12S突变的患者出现了CS的致命病程，后者因Xp远端缺失同时患有特纳综合征。HRAS基因中存在p.G60V的个体出现严重临床表现并导致致命后果，而甘氨酸-60残基处存在其他突变的CS患者出现表型减弱的相反观察结果，这可能表明被取代氨基酸的性质在某些CS病例中观察到的临床变异性中起重要作用。
