Schirwani Schaida, Fraser Sheila, Mushtaq Talat, Chengot Preetha, Mavrogiannis Lampros A, Jewell Rosalyn, Adlard Julian
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Department of Endocrine Surgery, Leeds Teaching Hospitals, Leeds, UK.
Eur J Med Genet. 2021 Feb;64(2):104141. doi: 10.1016/j.ejmg.2021.104141. Epub 2021 Jan 12.
Multiple endocrine neoplasia type 2 (MEN2) is a dominantly inherited condition with defined correlations between the genetic variant and clinical presentations. The location of pathogenic variants in the RET gene is a significant determinant of disease presentation and is associated with variable gene activation. Heterozygous pathogenic variants in codon 634 result in earlier onset of medullary thyroid carcinoma and higher incidence of phaeochromocytoma. Here we describe a consanguineous family with MEN2A that includes two children homozygous for the established pathogenic variant p. Cys634Trp. Both parents and a sibling were confirmed to being heterozygotes. Previous reports of biallelic or multiple RET variants have been limited to weakly activating variants. We present the first report of individuals homozygous for the highly activating RET p. Cys634Trp pathogenic variant and discuss disease severity and onset in this rare occurrence.
2型多发性内分泌肿瘤（MEN2）是一种显性遗传疾病，其基因变异与临床表现之间存在明确的相关性。RET基因中致病变异的位置是疾病表现的重要决定因素，并与可变的基因激活相关。密码子634处的杂合致病变异导致甲状腺髓样癌发病更早，嗜铬细胞瘤发病率更高。在此，我们描述了一个患有MEN2A的近亲家庭，其中包括两名对于已确定的致病变异p.Cys634Trp纯合的儿童。父母和一名兄弟姐妹被证实为杂合子。此前关于双等位基因或多个RET变异的报道仅限于弱激活变异。我们首次报告了对于高度激活的RET p.Cys634Trp致病变异纯合的个体，并讨论了这种罕见情况下的疾病严重程度和发病情况。
