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.

中文翻译：

---

在波兰Costost综合征患者中，HRAS基因的新型致病变异具有致命的结局和广泛的表型谱。

Costello综合征（CS）是RASopathies组中的一种罕见的先天性疾病，其特征是独特的面部外观，failure壮的衰弱，心脏和皮肤异常，智力残疾以及易患肿瘤。CS与原癌基因HRAS（一种来自Ras家族的小GTP酶）中的种系突变相关。在这项研究中，对八名具有Costello表型的波兰患者进行了分子和临床分析。一项分子测试显示，在7名患者中，该基因的第一个编码外显子中有两个已知的杂合突变：p.G12S（n = 4）和p.G12A（n = 3），以及一个患病儿童中的新型致病性变体p.G60V。该综合征异常严重，致命的病程。此外，一名患有p.G12A突变的患者和另一名患有p.G12S突变的患者存在CS的致命病程，由于远端Xp缺失而导致同时发生Turner综合征。严重的临床表现在HRAS中患有p.G60V的个体具有致死性，并且在甘氨酸60残基有其他突变的CS患者中观察到减毒表型的相反观察结果可能表明，取代氨基酸的性质在HRAS中起着重要作用。在某些CS病例中观察到的临床变异性。