Exploration of the pathogenic causes of a child with congenital hypospadias

doi:10.3969/j.issn.1009-976X.2025.04.007

Abstract

Abstract: This article provides a detailed account of the complete diagnosis and treatment process of a child with congenital hypospadias and growth retardation, and thoroughly analyzes the pathogenic factors that led to the clinical phenotype of this child. The article systematically reviews the entire process of the child's visit due to hypospadias, including the results of specialized physical examinations, various laboratory test data, and the implementation of subsequent surgical treatment; at the same time, it dynamically tracks the imaging examination results, laboratory biochemical and endocrine-related detection indicators, as well as the detection data of whole exome sequencing （Whole Exome Sequencing, WES） and chromosomal microarray analysis （Chromosomal Microarray Analysis, CMA） after the surgery. Through the systematic analysis of the above detection results, combined with the latest literature in related fields at home and abroad, a comprehensive judgment is made, and finally, it is determined that this child is a patient with SRY-negative 46,XX developmental abnormality caused by duplication of the upstream enhancer region of the SOX9 gene. This study aims to report this case of SRY-negative 46,XX developmental abnormality combined with hypospadias and growth retardation caused by duplication of the upstream enhancer region of the SOX9 gene, to deeply explore the association between the clinical phenotype and genotype, provide specific case references for the precise diagnosis of similar complex developmental abnormalities, and emphasize the key role of comprehensive genetic testing in the diagnosis and treatment process.

Key words: congenital hypospadias, SOX9 gene, disorders/differences of sex development （DSD）

摘要： 本文详细报道了1例先天性尿道下裂合并生长发育迟缓患儿的完整诊疗过程,并深入剖析了引发该患儿临床表型的致病因素。文中系统梳理了该患儿因尿道下裂就诊的全流程,包括专科体格检查结果、各项实验室检测数据及后续手术治疗的实施情况;同时动态追踪了患儿术后的影像学检查结果、实验室生化与内分泌相关检测指标,以及全外显子测序（WES）和染色体微阵列分析（CMA）的检测数据。通过对上述检测结果的系统分析,结合国内外相关领域前沿文献展开综合研判,最终明确该患儿为SOX9基因上游增强子区域重复所致的SRY阴性46,XX性发育异常患者。本研究旨在报道这一由SOX9基因上游增强子区域重复引发的SRY阴性46,XX性发育异常合并尿道下裂、生长发育迟缓的病例,深入探讨其临床表型与基因型的关联,为类似复杂性发育异常的精准诊断提供具体案例参考,并强调综合遗传学检测在诊疗过程中的关键作用。

关键词: 先天性尿道下裂, SOX9基因, 性发育异常

CLC Number:

R681.5

CHENG Bing, PENG Xiao-fang, XIAO Xiao-qin, LIAO Rong-huang, SUN Xi, LIANG Li-yang. Exploration of the pathogenic causes of a child with congenital hypospadias[J]. Lingnan Modern Clinics In Surgery, 2025, 25(04): 250-257.

程兵, 彭小芳, 萧晓琴, 廖荣煌, 孙熹, 梁立阳. 一例先天性尿道下裂患儿的致病原因探讨[J]. 岭南现代临床外科, 2025, 25(04): 250-257.

References

[1] 中华医学会小儿外科学分会泌尿学组. 尿道下裂专家共识[J].中华小儿外科杂志, 2018, 39(12): 883-888.
[2] 高可欣,汪亚平,谢华等.尿道下裂的遗传学进展[J].中华小儿外科杂志, 2024, 45(2):169-175.
[3] Baxter RM, Vilain E.Translational genetics for diagnosis of human disorders of sex development[J]. Annu Rev Genom Hum Genet, 2013, 14: 371-392.
[4] De la Chapelle A. The etiology of maleness in XX men[J]. Hum Genet, 1981, 58(1):105-116.
[5] Hughes IA, Houk C, Ahmed SF, et al.Consensus statement on management of intersex disorders[J]. Arch Dis Child, 2006, 91(7): 554-563.
[6] 中华医学会男科学分会,46,XX性发育异常基因诊断专家共识编写组,刘国昌等. 46,XX性发育异常基因诊断专家共识[J].中华男科学杂志,2023,29(5):467-477.
[7] Camelia Alkhzouz, Simona Bucerzan, Maria Miclaus, et al.46,XX DSD: Developmental, Clinical and Genetic Aspects[J]. Diagnostics (Basel), 2021, 11(8): 1379.
[8] Reyes AP, León NY, Frost ER, Harley VR.Genetic control of typical and atypical sex development[J]. Nat Rev Urol, 2023, 20(7): 434-451.
[9] Larson A, Nokoff NJ, Travers S.Disorders of sex development: clinically relevant genes involved in gonadal differentiation[J]. Discov Med, 2012, 14(78): 301-309.
[10] Rockich BE, Hrycaj SM, Shih HP, et al.Sox9 plays multiple roles in the lung epithelium during branching morphogenesis[J]. Proc Natl Acad Sci USA, 2013, 110(47): E4456-E4464.
[11] Symon A, Harley V.SOX9: a genomic view of tissue specific expression and action[J]. Int J Biochem Cell Biol, 2017, 87: 18-22.
[12] Gordon CT, Tan TY, Benko S, et al.Long-range regulation at the SOX9 locus in development and disease[J]. J Med Genet, 2009, 46(10): 649-656.
[13] Croft B, Ohnesorg T, Hewitt J, et al.Human sex reversal iscaused by duplication or deletion of core enhancers upstream of SOX9[J]. Nat Commun, 2018, 9(1): 5319-5329.
[14] 杨敏,林思远,杨长淇,等. SOX9及其增强子在哺乳动物性别决定中的研究进展[J]. 遗传, 2024,46(9):677-689.
[15] 46,XX SEX REVERSAL 2; SRXX2[EB/OL].[2025-03-15] (2021-02-08) https://omim.org/entry/278850
[16] 46,XY SEX REVERSAL 10; SRXY10[EB/OL].[2025-03-15] (2021-02-08)https://omim.org/entry/616425
[17] CAMPOMELIC DYSPLASIA; CMPD[EB/OL].[2025-03-15] (2023-07-23)https://omim.org/entry/114290
[18] Huang B, Wang S, Ning Y, et al.Autosomal XX sex reversal caused by duplication of SOX9[J]. Am J Med Genet, 1999, 87(4): 349-353.
[19] Ushijima K, Ogawa Y, Terao M, et al.Identification of the first promoter-specific gain-of-function SOX9 missense variant (p.E50K) in a patient with 46, XX ovotesticular disorder of sex development[J]. Am J Med Genet A, 2021, 185(4): 1067-1075.
[20] Foster JW, Dominguez-Steglich MA, Guioli S, et al.Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene[J]. Nature, 1994, 372(6506): 525-530.
[21] Wagner T, Wirth J, Meyer J, et al.Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9[J]. Cell, 1994, 79(6): 1111-1120.
[22] Jakobsen LP, Ullmann R, Christensen SB, et al.Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2[J]. J Med Genet, 2007, 44(6): 381-386.
[23] 金龙虎,耿红全,姜大朋等.分子诊断在性别发育异常诊断中的应用[J].中华小儿外科杂志,2016, 37(7):532-536.
[24] Sajan SA, Brown CM, Davis-Keppen L, et al.The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development[J]. Am J Med Genet A, 2023, 191(12): 2831-2836.
[25] Benko S, Gordon CT, Mallet D,et al.Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development[J]. J Med Genet, 2011, 8(12): 825-830.
[26] Pinti E, Piko H, Lengyel A, et al.Similar Cause, Different Phenotype: SOX9 Enhancer Duplication in a Family[J]. Horm Res Paediatr, 2019, 92(5): 335-339.
[27] 秦雪艳,董文科,王伟等. 46,XX男性综合征患儿五例的临床特征及基因分析[J].中华儿科杂志,2016,54(11):840-842.
[28] Qin Y, Poirier C, Truong C, et al.A major locus on mouse chromosome 18 controls XX sex reversal in Odd Sex (Ods) mice[J]. Hum Mol Genet, 2003, 12(5): 509-515.
[29] Pop R, Zaragoza MV, Gaudette M, et al.A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion[J]. Hum Genet, 2005, 117(1): 43-53.
[30] 刘爱玲,张兰雪,徐鸿雁等.SRY阴性46,XX性别发育异常致病原因分析[J].中华医学遗传学杂志,2020,37(12):1403-1406.
[31] Délot EC, Vilain EJ. Nonsyndromic46,XX Testicular Disorders/Differences of Sex Development. // Adam MP, Feldman J, Mirzaa GM, et al. GeneReviews^®[M/OL]. Seattle (WA): University of Washington,2003.[2025-03-20]. https://pubmed.ncbi.nlm.nih.gov/20301589/