Table_2_Correlation Analysis of Genotypes and Phenotypes in Chinese Male Pediatric Patients With Congenital Hypogonadotropic Hypogonadism.xlsx

Congenital hypogonadotropic hypogonadism (CHH) can be divided into Kallmann syndrome (KS) and normosmic HH (nHH). The clinical and genetic characteristics of CHH have been studied in adults, but less in pre-adults. The medical records of patients with CHH in our gonad disease database from 2008 to 2020 were evaluated. In total, 125 patients aged 0 to 18 years were enrolled in our study. KS patients had a higher incidence of micropenis compared with nHH (86.2% vs. 65.8%, p=0.009), and 7 patients (5.6%) had hypospadias. Among the 39 patients with traceable family history, delayed puberty, KS/nHH, and olfactory abnormalities accounted for 56.4%, 17.9%, and 15.4%, respectively. In total, 65 patients completed the hCG prolongation test after undergoing the standard hCG test, and the testosterone levels of 24 patients (22.9%) were still lower than 100 ng/dL. In 77 patients, 25 CHH-related genes were identified, including digenic and trigenic mutations in 23 and 3 patients, respectively. The proportion of oligogenic mutations was significantly higher than that in our previous study (27.7% vs. 9.8%). The most common pathogenic genes were FGFR1, PROKR2, CHD7 and ANOS1. The incidence rate of the genes named above was 21.3%, 18.1%, 12.8% and 11.7%, respectively; all were higher than those in adults (<10%). Most mutations in CHH probands were private, except for W178S in PROKR2, V560I in ANOS1, H63D in HS6ST1, and P191L and S671L in IL17RD. By analyzing family history and genes, we found that both PROKR2 and KISS1R may also be shared between constitutional delay of growth and puberty (CDGP) and CHH. L173R of PROKR2 accounts for 40% of the CHH population in Europe and the United States; W178S of PROKR2 accounts for 58.8% of Chinese CHH patients. Micropenis and cryptorchidism are important cues for CHH in children. They are more common in pediatric patients than in adult patients. It is not rare of Leydig cell dysfunction (dual CHH), neither of oligogenic mutations diagnosed CHH in children. Both PROKR2 and KISS1R maybe the potential shared pathogenic genes of CDGP and CHH, and W178S in PROKR2 may be a founder mutation in Chinese CHH patients.

先天性促性腺激素低下性腺功能减退症（Congenital hypogonadotropic hypogonadism, CHH）可分为卡尔曼综合征（Kallmann syndrome, KS）与嗅觉正常型促性腺激素低下性腺功能减退症（normosmic HH, nHH）。现有研究已对成人CHH的临床与遗传特征开展了广泛探索，但针对未成年群体的相关研究仍较为匮乏。本研究对本院2008年至2020年性腺疾病数据库中收录的CHH患者病历进行了回顾性分析，共纳入125例年龄介于0至18岁的未成年患者。与nHH患者相比，KS患者的小阴茎（micropenis）发生率更高（86.2% vs. 65.8%，p=0.009），另有7例（5.6%）患者合并尿道下裂（hypospadias）。在39例具有可追溯家族史的患者中，青春期延迟、KS/nHH表型及嗅觉异常的占比分别为56.4%、17.9%与15.4%。共计65例患者完成了标准人绒毛膜促性腺激素（hCG）激发试验后的延长hCG试验，其中24例（22.9%）患者的睾酮水平仍低于100 ng/dL。在77例患者中，共检出25个与CHH相关的致病基因，其中23例患者携带双基因突变、3例携带三基因突变；寡基因突变（oligogenic mutations）的检出比例显著高于本团队既往研究（27.7% vs. 9.8%）。最常见的致病基因为FGFR1、PROKR2、CHD7与ANOS1，其检出率分别为21.3%、18.1%、12.8%与11.7%，均高于成人CHH患者的检出水平（均<10%）。CHH先证者（probands）中的绝大多数突变为私有突变（private mutations），仅PROKR2基因的W178S、ANOS1基因的V560I、HS6ST1基因的H63D以及IL17RD基因的P191L与S671L为常见突变。通过对家族史与基因检测结果的联合分析，本研究发现PROKR2与KISS1R可能同时参与生长发育与青春期延迟（constitutional delay of growth and puberty, CDGP）及CHH的致病过程。PROKR2基因的L173R突变在欧美CHH人群中占比达40%，而PROKR2基因的W178S突变则在中国CHH患者中占比达58.8%。小阴茎与隐睾症（cryptorchidism）是儿童CHH的重要预警体征，其在儿科患者中的发生率显著高于成人患者。儿童CHH患者中，莱迪希细胞功能障碍（又称双重CHH）及经寡基因突变确诊的病例并不少见。PROKR2与KISS1R可能是生长发育与青春期延迟与CHH共享的潜在致病基因，而PROKR2基因的W178S突变可能是中国CHH患者的奠基者突变（founder mutation）。