Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Department of Endocrinology, Genetics and Metabolism, National Center for Children's Health, Beijing, China.
Front Endocrinol (Lausanne). 2022 May 20;13:846801. doi: 10.3389/fendo.2022.846801. eCollection 2022.
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 , , and 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 , V560I in , H63D in , and P191L and S671L in . By analyzing family history and genes, we found that both and may also be shared between constitutional delay of growth and puberty (CDGP) and CHH. L173R of accounts for 40% of the CHH population in Europe and the United States; W178S of 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 and maybe the potential shared pathogenic genes of CDGP and CHH, and W178S in may be a founder mutation in Chinese CHH patients.
先天性低促性腺激素性性腺功能减退症（CHH）可分为卡尔曼综合征（KS）和正常嗅觉 HH（nHH）。CHH 的临床和遗传特征已在成人中进行了研究，但在未成年中研究较少。我们从 2008 年至 2020 年的性腺疾病数据库中评估了 CHH 患者的病历。共有 125 名 0 至 18 岁的患者入组本研究。KS 患者的小阴茎发生率高于 nHH（86.2% vs. 65.8%，p=0.009），7 名患者（5.6%）存在尿道下裂。在可追溯家族史的 39 名患者中，青春期延迟、KS/nHH 和嗅觉异常分别占 56.4%、17.9%和 15.4%。共有 65 名患者在接受标准 hCG 测试后完成了 hCG 延长测试，其中 24 名患者（22.9%）的睾酮水平仍低于 100ng/dL。在 77 名患者中，鉴定出 25 种与 CHH 相关的基因，包括双基因和三基因突变，分别为 23 例和 3 例。寡基因突变的比例明显高于我们之前的研究（27.7% vs. 9.8%）。最常见的致病性基因是 、 、 和 。上述基因的发生率分别为 21.3%、18.1%、12.8%和 11.7%，均高于成人（<10%）。CHH 先证者的大多数突变是个体的，除了 中的 W178S、 中的 V560I、 中的 H63D 和 中的 P191L 和 S671L。通过分析家族史和基因，我们发现 和 可能也存在于体质性青春发育延迟（CDGP）和 CHH 之间。欧洲和美国 CHH 人群中 的 L173R 占 40%；中国 CHH 患者中 的 W178S 占 58.8%。小阴茎和隐睾是儿童 CHH 的重要线索。在儿科患者中比在成年患者中更为常见。儿童的莱迪希细胞功能障碍（双 CHH）并不罕见，寡基因突变诊断为 CHH 也不罕见。 和 可能是 CDGP 和 CHH 的潜在共同致病基因， 中的 W178S 可能是中国 CHH 患者的一个奠基突变。
