Lorenz Sybille, Petersen Christine, Kordaß Ulrike, Seidel Heide, Zenker Martin, Kutsche Kerstin
Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
Eur J Med Genet. 2012 Nov;55(11):615-9. doi: 10.1016/j.ejmg.2012.07.007. Epub 2012 Aug 7.
Costello syndrome (CS) is a rare congenital disorder characterized by severe failure to thrive, coarse facial appearance, cardiac and skin abnormalities, developmental delay, intellectual disability, and predisposition to malignancies. Heterozygous de novo germline mutations in the proto-oncogene HRAS cause CS. About 80% of patients share the same mutation resulting in the amino acid change p.G12S and present a relatively homogeneous phenotype. Other less common lesions in HRAS can induce a milder phenotype on the one hand and a more severe phenotype on the other broadening the spectrum of clinical manifestations in CS-affected individuals. We report two new patients with the HRAS p.G12C and p.G12D substitutions and a severe neonatal manifestation causing death at the age of three months and 13 days, respectively. Both patients had particularly severe heart involvement with hypertrophic cardiomyopathy and tachyarrhythmia, generalized edema, and respiratory distress. In one case, hypertrophic cardiomyopathy was already noted prenatally. These cases together with other individuals harboring the rare HRAS mutations p.G12C, p.G12V, p.G12D, and p.G12E provide further evidence for a genotype-phenotype correlation that could be of importance for counseling and medical management.
科斯特洛综合征（CS）是一种罕见的先天性疾病，其特征为严重生长发育迟缓、面部粗糙、心脏和皮肤异常、发育延迟、智力残疾以及易患恶性肿瘤。原癌基因HRAS中的杂合性新生种系突变导致CS。约80%的患者具有相同的突变，导致氨基酸改变p.G12S，并呈现相对一致的表型。HRAS中的其他较不常见的病变一方面可诱导较轻的表型，另一方面可诱导较严重的表型，从而拓宽了受CS影响个体的临床表现谱。我们报告了两名新患者，分别具有HRAS p.G12C和p.G12D替代突变，并有严重的新生儿表现，分别在3个月零13天时死亡。两名患者均有特别严重的心脏受累，伴有肥厚型心肌病和快速性心律失常、全身性水肿和呼吸窘迫。在其中一例中，产前就已发现肥厚型心肌病。这些病例以及其他携带罕见HRAS突变p.G12C、p.G12V、p.G12D和p.G12E的个体，为基因型-表型相关性提供了进一步的证据，这对于咨询和医疗管理可能具有重要意义。
