Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People's Republic of China.
BMC Endocr Disord. 2022 Jan 28;22(1):30. doi: 10.1186/s12902-022-00940-9.
Idiopathic hypogonadotropic hypogonadism (IHH) is a type of congenital disease caused by a variety of gene variants leading to dysfunction in the secretion of hypothalamic gonadotropin-releasing hormones (GnRHs). Clinically, IHH can be divided into Kallmann syndrome (KS) with dysosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) according to the presence or absence of an olfactory disorder.
We retrospectively evaluated 25 IHH patients (8 KS and 17 nIHH) who were diagnosed at the Department of Endocrinology of Shanghai Children's Hospital from 2015 to 2021. We analysed the patients' clinical data, including their hormone levels and gene sequences.
All male patients exhibited small phalli, and 35% of them exhibited cryptorchidism. A significant difference was observed in the levels of dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation (P = 0.028) between the KS group and the nIHH group. Missense variants were the major cause of IHH, and the main pathogenic genes were FGFR1, PROKR2/PROK2, and KAl1. Nine reported and 13 novel variants of six genes were identified. De novo variants were detected in 16 IHH patients; eight patients inherited the variants from their mothers, while only three patients inherited variants from their fathers. One patient had both KAl1 and PROKR2 gene variants, and another patient had two different PROKR2 gene variants. These two patients both had the hot spot variant c.533G > C (p. Trp178Ser) of the PROKR2 gene.
IHH should be highly suspected in patients with a small phallus and cryptorchidism. Compared with nIHH patients, KS patients exhibited a higher level of DHT after HCG stimulation. Missense variants were the major cause of IHH, and most of the inherited variants were from their mothers who exhibited no obvious clinical symptoms. We identified 9 reported variants and 13 novel variants that led to IHH. A small proportion of patients were at risk of inheriting either the oligogenic variant or the compound heterozygous variant. The hot spot variant c.533G > C (p. Trp178Ser) of PROKR2 might be involved in oligogenic inheritance and compound heterozygous inheritance. These findings provide deeper insight into the diagnosis and classification of IHH and will contribute to its clinical assessment.
特发性低促性腺激素性性腺功能减退症（IHH）是一种由多种基因突变导致下丘脑促性腺激素释放激素（GnRH）分泌功能障碍的先天性疾病。临床上，根据是否存在嗅觉障碍，IHH 可分为伴有嗅觉障碍的卡尔曼综合征（KS）和无嗅觉障碍的特发性低促性腺激素性性腺功能减退症（nIHH）。
我们回顾性分析了 2015 年至 2021 年在上海儿童医学中心内分泌科诊断为 IHH 的 25 例患者（8 例 KS 和 17 例 nIHH）的临床资料，包括激素水平和基因序列。
所有男性患者均表现为阴茎短小，其中 35%存在隐睾。KS 组和 nIHH 组在人绒毛膜促性腺激素（HCG）刺激后二氢睾酮（DHT）水平上有显著差异（P=0.028）。错义变异是 IHH 的主要病因，主要致病基因为 FGFR1、PROKR2/PROK2 和 KAl1。共发现 6 个基因的 9 个已报道和 13 个新变异。16 例 IHH 患者检测到新生变异，8 例患者从母亲遗传变异，仅 3 例患者从父亲遗传变异。1 例患者同时存在 KAl1 和 PROKR2 基因突变，另 1 例患者存在 2 种不同的 PROKR2 基因突变。这 2 例患者均存在 PROKR2 基因热点变异 c.533G>C（p.Trp178Ser）。
对于阴茎短小和隐睾的患者应高度怀疑 IHH。与 nIHH 患者相比，KS 患者 HCG 刺激后 DHT 水平更高。错义变异是 IHH 的主要病因，大多数遗传变异来自无明显临床症状的母亲。本研究共发现 9 个已报道的变异和 13 个导致 IHH 的新变异。一小部分患者有遗传寡基因变异或复合杂合变异的风险。PROKR2 基因 c.533G>C（p.Trp178Ser）的热点变异可能与寡基因遗传和复合杂合遗传有关。这些发现为 IHH 的诊断和分类提供了更深入的认识，并有助于其临床评估。
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