Barnabas Rohit, Jadhav Swati, Lila Anurag Ranjan, Kusuma Boddu Sirisha, Memon Saba Samad, Arya Sneha, Hegishte Samiksha Chandrashekhar, Karlekar Manjiri, Patil Virendra A, Sarathi Vijaya, Shah Nalini S, Bandgar Tushar
Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India.
Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, India.
Endocr Connect. 2024 Oct 4;13(11). doi: 10.1530/EC-24-0246. Print 2024 Oct 1.
The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series.
We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of three patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described.
Three 46,XY patients (age 6-18 years) from our center, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n = 70, 56 raised as females) presented with pubertal delay (n = 41) or atypical genitalia (n = 17). Sinnecker score ≥3 (suggesting antenatal human chorionic gonadotropin (hCG) inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/mL) in 77.4% (24/31), whereas puberty/postpubertal age, high luteinizing hormone (LH) (97.6%, 41/42) and low (<1.0 ng/mL) basal testosterone (94.9%, 37/39) was observed in most. Follicle stimulating hormone was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs 0/5, P = 0.033). 46,XX patients (n = 18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2-38).
In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential actions for LH and hCG.
双等位基因促黄体生成素/绒毛膜促性腺激素受体（LHCGR）失活变异导致的莱迪希细胞发育不全（LCH）的数据仅限于病例系列。
我们旨在描述我们的患者，并对文献中携带LHCGR失活变异的患者进行系统评价。描述了来自我们中心的3例患者以及来自文献中59个携带LHCGR失活变异家族的85例患者（46,XY：67例；46,XX：18例）的详细表型和基因型数据。
我们中心的3例46,XY患者（年龄6 - 18岁），其中2例自幼被当作女性抚养，其LHCGR有两个新变异。系统评价（包括我们的患者）显示88例患者中有72个变异。46,XY患者（n = 70，56例自幼被当作女性抚养）表现为青春期延迟（n = 41）或生殖器发育异常（n = 17）。80%（56/70）的患者辛内克评分≥3（提示产前人绒毛膜促性腺激素（hCG）无作用），77.4%（24/31）的患者hCG刺激后的睾酮水平低（< 1.1 ng/mL），而大多数患者处于青春期/青春期后年龄，促黄体生成素（LH）水平高（97.6%，41/42），基础睾酮水平低（< 1.0 ng/mL，94.9%，37/39）。这些患者中有21/51的卵泡刺激素水平升高。受体功能< 10% 的变异仅见于辛内克评分4/5的队列（10/15 vs 0/5，P = 0.033）。46,XX患者（n = 18）表现为月经过少/闭经和/或无排卵性不孕，患有多囊卵巢（7/9），LH中位数为10 IU/L（1.2 - 38）。
总之，本研究全面描述了LHCGR变异，揭示了基因型 - 表型相关性，并为LCH的临床管理提供了依据。在46,XY LCH患者中，青春期LH无作用是一致的，产前hCG无作用的严重程度各不相同。很少有突变的LHCGR对LH和hCG有不同作用。
