FGFR1-related congenital hypogonadotropic hypogonadism: a case report and literature review

Congenital hypogonadotropic hypogonadism (CHH) is a rare condition characterized by incomplete pubertal development, infertility, and gonadotropin-releasing hormone deficiency, associated with mutations in more than 50 genes. We aimed to conduct an etiological analysis of a CHH Chinese family and summarize the clinical presentations and genetic changes of reported similar cases. Whole-exome sequencing (WES) was performed to identify the molecular cause in the proband. In silico tools were employed to analyze the pathogenicity of the variants. Reported cases with similar clinical features and associated genes were summarized by searching through PubMed/MEDLINE using keywords ‘FGFR1,’ ‘CHH,’ and ‘Kallmann syndrome (KS).’ Genetic analysis revealed a novel likely pathogenic deletion mutation in the FGFR1 gene (NM_023110.3: c.263_264del (Val88Alafs*22)) in a Chinese family exhibiting micropenis and underdeveloped testes. A total of 38 cases with CHH or KS have been previously reported. This study identified a novel FGFR1 deletion variant responsible for CHH, expanding the known mutational spectrum of FGFR1. Typical manifestations include delayed puberty and diverse presentations. The genotype–phenotype correlation in CHH remains unclear and may involve oligogenic effects and epigenetic regulation.先天性促性腺激素低下性腺功能减退症（Congenital hypogonadotropic hypogonadism, CHH）是一类以青春期发育不全、不育及促性腺激素释放激素缺乏为特征的罕见病症，目前已发现超过50个与其相关的致病基因突变。本研究旨在对一个中国先天性促性腺激素低下性腺功能减退症家系开展病因学分析，并汇总已报道的同类病例的临床表现与遗传学改变。研究通过全外显子组测序（Whole-exome sequencing, WES）明确先证者的分子致病原因，并采用计算机模拟（in silico）工具对变异的致病性进行分析。本研究以"FGFR1"、"CHH"及"卡尔曼综合征（Kallmann syndrome, KS）"为关键词检索PubMed/MEDLINE数据库，汇总具有相似临床特征及关联基因的病例资料。遗传学分析显示，在一个表现为小阴茎及睾丸发育不全的中国家系中，FGFR1基因（NM_023110.3: c.263_264del (Val88Alafs*22)）存在1个新的疑似致病性缺失突变。目前已有共计38例先天性促性腺激素低下性腺功能减退症或卡尔曼综合征病例被报道。本研究发现了1个可导致先天性促性腺激素低下性腺功能减退症的FGFR1基因新缺失变异，拓展了FGFR1基因已知的突变谱。该病典型临床表现包括青春期延迟及多样化表型。先天性促性腺激素低下性腺功能减退症的基因型-表型关联仍不明确，其发病机制可能涉及寡基因效应与表观遗传调控。