Clinical Manifestations, Genetic Variants and Therapeutic Evaluation in Sporadic Chinese Patients with Idiopathic Hypogonadotropic Hypogonadism

Abstract

Purpose

Genetic factors account for a large proportion of idiopathic hypogonadotropic hypogonadism (IHH) etiologies, although not necessarily a complete genetic basis. This study aimed to characterize the clinical presentations, genetic variants, and therapeutic outcomes of patients with sporadic IHH, which may be helpful for genetic counseling and treatment decisions.

Patients and Methods

Eleven Chinese patients with IHH were retrospectively analyzed. Rare genetic variants were evaluated using whole-exome sequencing and bioinformatics analysis and were further classified according to the ACMG-AMP guidelines. The therapeutic responses of patients were further evaluated.

Results

Six heterozygous variants of SOX10, WDR11, PROKR2, CHD7 and FGF17 were detected in five Kallmann syndrome (KS) patients, whereas two heterozygous variants of CHD7 and PROKR2 were detected in two normosmic IHH (nIHH) patients. Among these variants, a novel likely pathogenic variant in the SOX10 (c.429–1G>C) was considered to cause the KS phenotype in patient 02, and two potential variants of uncertain significance (VUS) in CHD7 (c.3344G>A and c.7391A>G) possibly contributed to the KS phenotype in patient 05 and the nIHH phenotype in patient 07, which need to be confirmed by further evidence. Additionally, long-term testosterone or estradiol replacement treatment effectively improved the development of sexual characteristics in patients with IHH.

Conclusion

Next-generation sequencing is a powerful tool for identifying the molecular etiology and early diagnosis of IHH. Efficient therapeutic outcomes strongly indicate a need for timely treatment.

Keywords:

• Kallmann syndrome
• normosmic idiopathic hypogonadotropic hypogonadism
• luteinizing hormone
• follicle-stimulating hormone
• genetic variant
• hormone treatment

Acknowledgments

We thank the patients with IHH and their parents, who donated blood samples for this study.

Ethics Approval and Consent to Participate

This study was approved by the Ethics Committee of the Affiliated Hospital of Jining Medical University (2021C123, Jining, Shandong, China) in accordance with the principles outlined in the Declaration of Helsinki. All participants and/or their legal guardians provided written informed consent for participation in clinical and genetic studies.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by the Research Fund for Academician Lin He New Medicine (JYHL2019FZD01) and Shandong Traditional Chinese Medicine Science and Technology Development Plans Project (2019-0486). This study was partially supported by the PhD Research Foundation of the Affiliated Hospital of Jining Medical University (2018-BS-007).