Molecular diagnosis and phenotypic analysis of Kallmann syndrome caused by a novel mutation in the ANOS1 gene：a case report and literature review

Liu Mengting; Zhao Yuhang; Liu Fangchao; Yuan Ying; Wang Yangang; Wang Wenjing; Gao Peihan; Sun Xiaofang

doi:10.13406/j.cnki.cyxb.004013

您当前的位置：

首页 >

文章列表页 >

Molecular diagnosis and phenotypic analysis of Kallmann syndrome caused by a novel mutation in the ANOS1 gene：a case report and literature review

Endocrine regulation and metabolic diseases\—hereditary endocrine and metabolic diseases | 更新时间：2026-10-26

- Molecular diagnosis and phenotypic analysis of Kallmann syndrome caused by a novel mutation in the ANOS1 gene：a case report and literature review
- Journal of Chongqing Medical University Vol. 51, Issue 10, Pages: 1398-1403(2026)
- 作者机构：
  
  青岛大学附属医院内分泌与代谢性疾病科，青岛 266000
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.004013
  CLC： R597
- Received：13 October 2025，
  
  Revised：2025-11-23，
  
  Accepted：11 December 2025，
  
  Published：28 October 2026
- 稿件说明：
移动端阅览
刘梦婷，赵宇航，刘方超，等.ANOS1基因新突变类型致卡尔曼综合征罕见病例的分子诊断与表型分析及文献综述[J].重庆医科大学学报，2026，51（10）：1398-1403.

Liu Mengting,Zhao Yuhang,Liu Fangchao,et al.Molecular diagnosis and phenotypic analysis of Kallmann syndrome caused by a novel mutation in the ANOS1 gene：a case report and literature review[J].Journal of Chongqing Medical University,2026,51(10):1398-1403.
刘梦婷，赵宇航，刘方超，等.ANOS1基因新突变类型致卡尔曼综合征罕见病例的分子诊断与表型分析及文献综述[J].重庆医科大学学报，2026，51（10）：1398-1403. DOI： 10.13406/j.cnki.cyxb.004013.

Liu Mengting,Zhao Yuhang,Liu Fangchao,et al.Molecular diagnosis and phenotypic analysis of Kallmann syndrome caused by a novel mutation in the ANOS1 gene：a case report and literature review[J].Journal of Chongqing Medical University,2026,51(10):1398-1403. DOI： 10.13406/j.cnki.cyxb.004013.

摘要

目的

分析

ANOS1

基因突变相关的卡尔曼综合征（Kallmann syndrome，KS）的基因型与临床表型，为KS的临床诊治提供分子诊断依据与个体化治疗策略。

方法

收集1例男性KS患者的临床资料，并采集外周血DNA，对其家系进行基因突变检测，进而对既往发表的

ANOS1

基因突变致KS的相关文献进行综述。

结果

先证者以发育迟缓起病，辅助检查提示睾酮（testosterone，T）、促黄体生成素（luteinizing hormone，LH）、卵泡刺激素（follicle-stimulating hormone，FSH）低，全外显子测序显示其携带新发现的ANOS1基因移码突变（p.Ser596Alafs*24），导致ANOS1蛋白质结构的明显改变；其母亲同样存在该突变，但无性腺功能低下的临床表现。通过文献复习，发现

ANOS1

基因突变在性腺功能方面可导致KS和特发性低促性腺激素性性腺功能减退症（idiopathic hypogonadotropic hypogonadism，IHH）；此外，患者还表现出一系列其他非生殖特征，这可能与突变位点的不同有关。

结论

KS是一种罕见病，遗传学分析是诊断该病的核心，

ANOS1

基因突变可导致KS；在治疗方面，促性腺激素释放激素脉冲泵治疗有助于促进KS患者的第二性征发育、精子生成，改善患者的整体生活质量。

Abstract

Objective

To investigate the genotype and clinical phenotype of Kallmann syndrome（KS） associated with ANOS1 gene mutations，and to provide molecular diagnosis and individualized treatment for the clinical diagnosis and treatment of KS.

Methods

Clinical data were collected from a male KS patient，and peripheral blood DNA was collected. Gene mutation detection was performed for his family. A literature review was performed for the articles on KS caused by ANOS1 gene mutations.

Results

The proband had developmental delay as the initial presentation. Auxiliary examinations showed low levels of testosterone，luteinizing hormone，and follicle-stimulating hormone. Whole-exome sequencing showed that the proband carried a novel frameshift mutation of p.Ser596Alafs*24 in the ANOS1 gene，which induced a significant alteration in the structure of ANOS1 protein，and the mother of the proband also carried this mutation，but without the clinical manifestation of hypogonadism. The literature review showed that as for gonadal function，ANOS1 gene mutations could cause KS and idiopathic hypogonadotropic hypogonadism，and in addition，there might be a series of other non-reproductive features，which may be associated with different mutation sites.

Conclusion

KS is a rare genetic disorder，and genetic analysis plays a central role in the diagnosis of this condition. ANOS1 gene mutations may cause KS. In terms of treatment，pulsatile gonadotropin-releasing hormone therapy can effectively promote the development of secondary sexual characteristics and spermatogenesis in patients with KS，thereby improving the overall quality of life of patients.

关键词

Keywords

references

Franco B ， Guioli S ， Pragliola A ， et al . A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules [J ] . Nature ， 1991 ， 353 （ 6344 ）： 529 - 536 ．

Hardelin JP ， Levilliers J ， Blanchard S ， et al . Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome [J ] . Hum Mol Genet ， 1993 ， 2 （ 4 ）： 373 - 377 ．

Chen K ， Wang HY ， Lai YX . Kallmann syndrome due to heterozygous mutation in SOX10 coexisting with waardenburg syndrome type Ⅱ：case report and review of literature [J ] . Front Endocrinol ， 2021 ， 11 ： 592831 .

Bonomi M ， Libri DV ， Guizzardi F ， et al . New understandings of the genetic basis of isolated idiopathic central hypogonadism [J ] . Asian J Androl ， 2012 ， 14 （ 1 ）： 49 - 56 ．

Wen J ， Pan L ， Xu X ， et al . Clinical data and genetic mutation in Kallmann syndrome with CHARGE syndrome：Case report and pedigree analysis [J ] . Medicine ， 2018 ， 97 （ 27 ）： e11284 ．

Zeng W ， Li JD ， Wang XY ， et al . ANOS1 variants in a large cohort of Chinese patients with congenital hypogonadotropic hypogonadism [J ] . Zhong Nan Da Xue Xue Bao Yi Xue Ban ， 2022 ， 47 （ 7 ）： 847 - 857 ．

Li H ， Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform [J ] . Bioinformatics ， 2010 ， 26 （ 5 ）： 589 - 595 ．

Zhang L ， Zhang J ， Yang J ， et al . PriVar：a toolkit for prioritizing SNVs and indels from next-generation sequencing data [J ] . Bioinformatics ， 2013 ， 29 （ 1 ）： 124 - 125 ．

Riggs ER ， Andersen EF ， Cherry AM ， et al . Technical standards for the interpretation and reporting of constitutional copy-number variants：a joint consensus recommendation of the American College of Medical Genetics and Genomics（ACMG） and the Clinical Genome Resource （ClinGen） [J ] . Genet Med ， 2020 ， 22 （ 2 ）： 245 - 257 ．

Leahy DJ ， Aukhil I ， Erickson HP . 2.0 A crystal structure of a four-domain segment of human fibronectin encompassing the RGD loop and synergy region [J ] . Cell ， 1996 ， 84 （ 1 ）： 155 - 164 ．

Kim HG ， Bhagavath B ， Layman LC . Clinical manifestations of impaired GnRH neuron development and function [J ] . Neurosignals ， 2008 ， 16 （ 2/3 ）： 165 - 182 ．

Bonomi M ， Vezzoli V ， Krausz C ， et al . Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism（IHH） [J ] . Eur J Endocrinol ， 2018 ， 178 （ 1 ）： 23 - 32 ．

Boehm U ， Bouloux PM ， Dattani MT ， et al . Expert consensus document：European Consensus Statement on congenital hypogonadotropic hypogonadism：pathogenesis，diagnosis and treatment [J ] . Nat Rev Endocrinol ， 2015 ， 11 （ 9 ）： 547 - 564 ．

Chen J ， Yuan K ， He MF ， et al . Clinical and genetic features of Kallmann syndrome：an analysis of 5 cases [J ] . Zhongguo Dang Dai Er Ke Za Zhi = Chin J Contemp Pediatr ， 2018 ， 2011 ： 925 - 929 .

Stamou MI ， Georgopoulos NA . Kallmann syndrome：phenotype and genotype of hypogonadotropic hypogonadism [J ] . Metabolism ， 2018 ， 86 ： 124 - 134 ．

Kaplan JD ， Bernstein JA ， Kwan A ， et al . Clues to an early diagnosis of Kallmann syndrome [J ] . Am J Med Genet A ， 2010 ， 152 （ 11 ）： 2796 - 2801 ．

Chu GM ， Li PP ， Zhao Q ， et al . Mutation spectrum of Kallmann syndrome：identification of five novel mutations across ANOS1 and FGFR1 [J ] . Reprod Biol Endocrinol ， 2023 ， 21 （ 1 ）： 23 ．

Fraietta R ， Zylberstejn DS ， Esteves SC . Hypogonadotropic hypogonadism revisited [J ] . Clinics ， 2013 ， 68 （ Suppl 1 ）： S81 - S88 ．

Sarfati J ， Bouvattier C ， Bry-Gauillard H ， et al . Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life [J ] . Orphanet J Rare Dis ， 2015 ， 10 ： 71 ．

Hamada AJ ， Esteves SC ， Agarwal A . A comprehensive review of genetics and genetic testing in azoospermia [J ] . Clinics ， 2013 ， 68 （ Suppl 1 ）： S39 - S60 ．

Hu YL ， Sun Z ， Eaton JT ， et al . Extended and flexible domain solution structure of the extracellular matrix protein anosmin-1 by X-ray scattering，analytical ultracentrifugation and constrained modelling [J ] . J Mol Biol ， 2005 ， 350 （ 3 ）： 553 - 570 ．

de Castro F ， Seal R ， Maggi R . ANOS1 a unified nomenclature for Kallmann syndrome 1 gene（ KAL1 ） and anosmin-1 [J ] . Brief Funct Genomics ， 2017 ， 16 （ 4 ）： 205 - 210 ．

Ernest S ， Guadagnini S ， Prévost MC ， et al . Localization of anosmin-1a and anosmin-1b in the inner ear and neuromasts of zebrafish [J ] . Gene Expr Patterns ， 2007 ， 7 （ 3 ）： 274 - 281 ．

Arora S ， Yeliosof O ， Chin VL . A case of novel mutation in ANOS1 （KAL1） gene and review of Kallmann syndrome [J ] . Endocrinol Diabetes Metab Case Rep ， 2023 （ 2 ）: 220310 ．

Jiang XH ， Li DM ， Gao YZ ， et al . A novel splice site variant in ANOS1 gene leads to Kallmann syndrome in three siblings [J ] . Gene ， 2020 ， 726 ： 144177 ．

郝　明 . Kallmann综合征伴ANOS1基因突变患者的特征分析和促性腺激素治疗部分性CHH患者的生精疗效研究 [D ] . 北京：中国医学科学院北京协和医学院， 2020 ．

Hao M . The ANOS1 Genotype-Phenotype Spectrum：Kallmann Syndrome Features and Successful Gonadotropin-Induced Spermatogenesis [D ] . Beijing ： Peking Union Medical College Hospital ， 2020 ．

Rey RA . Recent advancement in the treatment of boys and adolescents with hypogonadism [J ] . Ther Adv Endocrinol Metab ， 2022 ， 13 ： 20420188211065660 ．

Dwyer AA ， Stamou M . Reversal of congenital hypogonadotropic hypogonadism [J ] . J Clin Endocrinol Metab ， 2025 ：dgaf610．

HyunK . Congenital hypogonadotropic hypogonadism and kallmann syndrome：past，present，and future [J ] . Endocrinol Metab ， 2015 ， 30 （ 4 ）： 456 - 466 ．

中华医学会男科学分会，下丘脑促性腺激素释放激素脉冲泵在男科疾病中应用专家共识编写组 . 下丘脑促性腺激素释放激素脉冲泵在男科疾病中应用专家共识 [J ] . 中华男科学杂志， 2022 ， 28 （ 3 ）： 273 - 280 ．

Chinese Medical Association Society of Andrology , Expert Consensus Panel on the Application of Hypothalamic Gonadotropin-Releasing Hormone Pulse Pump in Andrological Diseases . Expert consensus on the application of hypothalamic gonadotropin-releasing hormone pulse pump in andrology diseases [J ] . Natl J Androl ， 2022 ， 28 （ 3 ）： 273 - 280 ．

牛永华，徐　浩，陈胤伟，等 . GnRH脉冲治疗男性先天性低促性腺激素性性腺功能减退症的有效性和安全性分析 [J ] . 中华男科学杂志， 2024 ， 30 （ 5 ）： 404 - 409 ．

Niu YH ， Xu H ， Chen YW ， et al . Efficacy and safety analysis of GnRH pulse in the treatment of male congenital hypogonadism [J ] . Natl J Androl ， 2024 ， 30 （ 5 ）： 404 - 409 ．

Seminara SB ， Hayes FJ ， Jr Crowley WF . Gonadotropin-releasing hormone deficiency in the human（idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome）：pathophysiological and genetic considerations [J ] . Endocr Rev ， 1998 ， 19 （ 5 ）： 521 - 539 ．

Young J ， Xu C ， Papadakis GE ， et al . Clinical management of congenital hypogonadotropic hypogonadism [J ] . Endocr Rev ， 2019 ， 40 （ 2 ）： 669 - 710 ．

Meczekalski B ， Podfigurna-Stopa A ， Smolarczyk R ， et al . Kallmann syndrome in women：from genes to diagnosis and treatment [J ] . Gynecol Endocrinol ， 2013 ， 29 （ 4 ）： 296 - 300 ．

Sungurtekin U ， Fraser IS ， Shearman RP . Pregnancy in women with kallmann’s syndrome [J ] . Fertil Steril ， 1995 ， 63 （ 3 ）： 494 - 499 ．

Noorian S ， Savad S ， Khavandegar A ， et al . A family with novel X-linked recessive homozygous mutation in ANOS1（c.628_629 del，p.1210fs） in kallmann syndrome associated unilateral ptosis：case report and literature review [J ] . AACE Clin Case Rep ， 2021 ， 7 （ 3 ）： 216 - 219 ．

Laitinen EM ， Vaaralahti K ， Tommiska J ， et al . Incidence，phenotypic features and molecular genetics of Kallmann syndrome in Finland [J ] . Orphanet J Rare Dis ， 2011 ， 6 ： 41 ．

Zhang P ， Fu JY . X-linked recessive Kallmann syndrome：A case report [J ] . World J Clin Cases ， 2022 ， 10 （ 25 ）： 8990 - 8997 ．

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Guideline for the diagnosis and treatment of childhood atypical teratoid/rhabdoid tumor of the central nervous system （2026 edition）——The Zhimiao Pediatric Oncology Expert Panel

Interpretation of key points in the American Diabetes Association’ Obesity Association Standards of Care in Overweight and Obesity

Congenital neuroblastoma：a clinical analysis of 17 cases

Value of the Valsalva maneuver breath-holding strategy in reducing transient severe motion artifact in the arterial phase of Gd-EOB-DTPA-enhanced magnetic resonance imaging

Impact of hospice care on medical costs and quality of life in elderly patients with end-stage chronic diseases

Related Author

The Zhimiao Pediatric Oncology Expert Panel

Dong Xiaoying

Cui Long

Yin Jingxia

Gui Jing

Pu Danlan

Liao Yong

Li Ning

Related Institution

Department of Endocrinology，Yubei District People’s Hospital of Chongqing

Department of Endocrinology，Chongqing Armed Police Corps Hospital

Department of Hematology and Oncology，Children’s Hospital Affiliated to Zhengzhou University/ Henan Children’s Hospital Zhengzhou Children’s Hospital

Department of Hematology and Oncology，Children’s Hospital Affiliated to Zhengzhou University

Department of Nuclear Medicine，Peking Union Medical College Hospital，Chinese Academy of Medical Sciences & Peking Union Medical College

⁰