Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.