Orphanet Journal of Rare Diseases | Clinical and Genetic Characteristics of Male Patients with Idiopathic Hypogonadotropic Hypogonadism

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This study reviews clinical, genetic, and treatment response data from 51 male patients with idiopathic hypogonadotropic hypogonadism (IHH) in southern China, revealing a high prevalence of mutations in FGFR1, ANOS1, and CHD7. It also identifies significant correlations between age and phenotypes, as well as between genotypes and phenotypes. The study emphasizes that integrating clinical, biochemical, and genetic criteria can enable early diagnosis of IHH and offers potential differential diagnostic indicators for different genotypes.

 

Literature Overview
The article titled Clinical characteristics, genetic spectrum and therapeutic effects of 51 male patients with idiopathic hypogonadotropic hypogonadism from southern China, published in Orphanet Journal of Rare Diseases, summarizes the clinical features, genetic variant profiles, and treatment outcomes of 51 male patients with idiopathic hypogonadotropic hypogonadism (IHH) from southern China. By retrospectively analyzing patients' genetic mutations, hormone levels, imaging features, and treatment responses, the study found that FGFR1 is the most common disease-causing gene (45.10%), followed by ANOS1 (21.57%) and CHD7 (17.65%), and identified 23 novel variants. It also found significant correlations between age and penile length, testicular volume, testosterone levels, and inhibin B levels, indicating differences in family history, olfactory impairment, CHARGE phenotype, and baseline hormone levels among genotypes, which may serve as molecular typing markers.

Background
Idiopathic hypogonadotropic hypogonadism (IHH) is a rare inherited endocrine disorder characterized by defective gonadotropin-releasing hormone (GnRH) secretion, resulting in delayed or absent sexual development. The condition is further classified into Kallmann syndrome, which includes olfactory dysfunction, and normosmic IHH, where olfactory function is preserved. Mutations in genes such as FGFR1, ANOS1, and CHD7 have been widely associated with IHH, but approximately 50% of IHH cases still lack a genetic diagnosis. This study expands the known mutation spectrum of IHH in southern China and provides new biomarkers and diagnostic clues for early diagnosis and personalized treatment. High genetic heterogeneity and complex phenotypes remain challenges, but next-generation sequencing (NGS) has improved the molecular diagnostic rate, enabling earlier interventions. This study focuses on analyzing the mutational profile and treatment responses of southern Chinese IHH patients, offering clinical and genetic evidence for disease diagnosis and molecular subtyping.

 

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Study Methods and Experimental Design
The study included 51 male IHH patients diagnosed between November 2015 and December 2024 at the Guangzhou Women and Children’s Medical Center, all of whom were Han Chinese from non-consanguineous families. Clinical data, imaging features, hormone levels, and genetic variants were retrospectively analyzed. The study integrated molecular testing and treatment follow-up to assess genotype-phenotype correlations and therapeutic outcomes.

Key Findings and Perspectives

• FGFR1 is the most common causative gene in IHH (45.10%), followed by ANOS1 (21.57%) and CHD7 (17.65%)
• A total of 45 different variants were identified, including 22 known and 23 novel; no hotspots were found
• 98.04% of patients presented with micropenis, 86.84% had abnormal gonadal ultrasound, and all had subnormal testosterone levels
• Age was significantly correlated with penile length, testicular volume, testosterone levels, and inhibin B
• Patients with ANOS1 mutations frequently had family history and olfactory dysfunction, whereas CHD7 mutations were more often associated with CHARGE phenotype and elevated gonadotropin levels
• Treatment follow-up showed that HCG, HMG, or GnRH pulsatile therapy significantly increased testosterone and gonadotropin levels, promoting penile development

Significance and Future Directions
This study expands the IHH mutation spectrum, particularly identifying 23 novel variants, offering new molecular clues for genetic diagnosis. It emphasizes that integrating clinical, hormonal, and genetic data improves early diagnostic accuracy and suggests that hormonal and phenotypic features differ among genotypes, aiding molecular subtyping. Further patients are needed for GnRH stimulation tests to refine diagnostic criteria. Additionally, HCG therapy showed significant improvement in penile length and hormone levels, highlighting the importance of personalized treatment strategies.

 

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Conclusion
This study systematically analyzed the clinical and genetic features of 51 male IHH patients from southern China and found that FGFR1, ANOS1, and CHD7 are the most common causative genes. Significant correlations between age and phenotypes were observed, as well as correlations between genotypes and hormone levels, olfactory dysfunction, and CHARGE phenotype. Treatment follow-up demonstrated that HCG alone or in combination with HMG effectively elevated testosterone and gonadotropin levels and promoted gonadal development. The study recommends integrating family history, hormone testing, and genetic sequencing in clinical practice for early diagnosis of IHH. The 23 newly identified pathogenic variants provide a valuable resource for further molecular mechanism studies. Future research may explore genotype-phenotype correlations in treatment response to support personalized therapeutic strategies.

 

Huiying Sheng, Cuili Liang, Jing Cheng, Li Liu, and Yunting Lin. Clinical characteristics, genetic spectrum and therapeutic effects of 51 male patients with idiopathic hypogonadotropic hypogonadism from southern China. Orphanet Journal of Rare Diseases.