Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China; Department of Prenatal Diagnosis, Bao'an Maternity and Child Health Hospital, Shenzhen, China.
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Gene. 2018 Aug 30;669:42-46. doi: 10.1016/j.gene.2018.05.050. Epub 2018 May 17.
Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by low levels of gonadotropins and delayed or absent sexual development. Most of the patients are diagnosed in late adolescence or early adulthood. Determining the diagnosis of IHH in prepubertal patients can be challenging. Making a timely, correct diagnosis has important clinical implications. Here we aimed to identify the genetic cause of IHH in three prepubertal siblings from a Chinese Han family and give appropriate treatment advice. Using whole exome sequencing (WES), we identified a novel homozygous GNRHR mutation (NM_000406; c.364C>T, p.L122F) in two prepubertal boys with cryptorchidism and micropenis. Sanger sequencing showed that their younger asymptomatic sister also had the homozygous GNRHR mutation. This mutation was inherited from the father and the mother. Immunofluorescence analysis showed that in permeabilized cells, expression of the mutant receptor on the cell membrane was significantly lower than that of wild-type. Calcium mobilization assays demonstrated that c.364C>T in the GNRHR gene is a complete loss-of-function mutation that caused IHH. These results may contribute to the genetic diagnosis of the three prepubertal siblings with IHH. According to this diagnosis, timely hormonal treatment can be given for the three prepubertal patients to induce pubertal development, especially for the asymptomatic female.
特发性低促性腺激素性性腺功能减退症（IHH）的特征是促性腺激素水平低，性发育延迟或缺失。大多数患者在青春期后期或成年早期被诊断出来。在青春期前的患者中确定 IHH 的诊断可能具有挑战性。及时、正确地做出诊断具有重要的临床意义。在这里，我们旨在确定一个来自中国汉族家庭的 3 名青春期前兄弟姐妹的 IHH 的遗传原因，并提供适当的治疗建议。使用全外显子组测序（WES），我们在 2 名患有隐睾和小阴茎的青春期前男孩中发现了一种新的 GNRHR 突变（NM_000406; c.364C>T，p.L122F）。Sanger 测序显示，他们年龄较小的无症状妹妹也携带 GNRHR 突变的纯合子。该突变是从父亲和母亲那里遗传来的。免疫荧光分析显示，在细胞膜通透的细胞中，突变受体在细胞膜上的表达明显低于野生型。钙动员测定表明，GNRHR 基因中的 c.364C>T 是一个完全丧失功能的突变，导致 IHH。这些结果可能有助于对 3 名患有 IHH 的青春期前兄弟姐妹进行遗传诊断。根据这一诊断，可以及时对 3 名青春期前患者进行激素治疗，以诱导青春期发育，特别是对无症状的女性。
