Sawano Kentaro, Nagasaki Keisuke, Suzuki Erina, Ogiwara Yasuko, Kageyama Ikuko, Fukami Maki, Kuroki Yoko
Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Front Endocrinol (Lausanne). 2025 Jun 18;16:1565316. doi: 10.3389/fendo.2025.1565316. eCollection 2025.
Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder characterized by gonadal dysfunction attributed to impaired gonadotropin secretion. CHH is associated with approximately 60 genes including . Nevertheless, the nucleotide variants of these genes are only related to less than half of the cases. Herein, we report a case of CHH caused by a novel mechanism. A 6-year-old boy presented with hypomasculinized genitalia, hyposmia, and syndactyly. Endocrine examinations showed impaired gonadotropin secretion. Short-read next-generation sequencing (NGS) identified the absence of mutations in the major causative genes for CHH. However, it detected an accumulation of discordant and split reads in a genomic region within the gene. Array-based comparative genomic hybridization did not detect copy-number abnormalities. Targeted long-read NGS and Sanger sequencing identified a 333-bp insertion in exon 9 of the gene. A similarity search revealed that the insertion was an Alu element. This insertion caused a frameshift and resulted in premature termination (p. His409fsTer31). Further, it had several hallmarks of retrotransposition such as target site duplication, an endonuclease cleavage site-like motif, and a poly-A tail. The study results broadened the genetic basis of CHH that considered retrotransposon insertions. Importantly, this case emphasizes the need for additional genomic analyses in patients with CHH who had negative results on short-read NGS and array-based comparative genomic hybridization.
先天性低促性腺激素性性腺功能减退症（CHH）是一种罕见的内分泌疾病，其特征是由于促性腺激素分泌受损导致性腺功能障碍。CHH与大约60个基因相关，包括……然而，这些基因的核苷酸变异仅与不到一半的病例有关。在此，我们报告一例由新机制引起的CHH病例。一名6岁男孩出现男性化不足的生殖器、嗅觉减退和并指畸形。内分泌检查显示促性腺激素分泌受损。短读长下一代测序（NGS）未发现CHH主要致病基因的突变。然而，它在……基因内的一个基因组区域检测到不一致和分裂读段的积累。基于阵列的比较基因组杂交未检测到拷贝数异常。靶向长读长NGS和桑格测序在……基因的外显子9中鉴定出一个333 bp的插入。相似性搜索显示该插入是一个Alu元件。这种插入导致移码并导致提前终止（p.His409fsTer31）。此外，它具有逆转录转座的几个特征，如靶位点重复、内切酶切割位点样基序和多聚A尾。研究结果拓宽了考虑逆转座子插入的CHH的遗传基础。重要的是，该病例强调了对短读长NGS和基于阵列的比较基因组杂交结果为阴性的CHH患者进行额外基因组分析的必要性。
