Gonadal Genetics and Germ Cell Tumor Risk in SRY-Negative 46,XX Testicular/Ovotesticular Disorders of Sex Development

Hao Yang; Hongjuan Tian; Dehua Wu; Weizhong Gu; Daxing Tang; Junfen Fu

doi:10.1159/000548934

Gonadal Genetics and Germ Cell Tumor Risk in SRY-Negative 46,XX Testicular/Ovotesticular Disorders of Sex Development

Horm Res Paediatr. 2025 Oct 18:1-9. doi: 10.1159/000548934. Online ahead of print.

Authors

Hao Yang¹, Hongjuan Tian¹, Dehua Wu¹, Weizhong Gu², Daxing Tang¹, Junfen Fu³

Affiliations

¹ Department of Urology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
² Department of Pathology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
³ Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.

PMID: 41108712
DOI: 10.1159/000548934

Abstract

Introduction: The gonadal genetics and germ cell tumor (GCT) risk in SRY-negative 46,XX testicular and ovotesticular disorders of sex development (DSD) are poorly understood and debated. This study aimed to investigate the gonadal genetic etiology and evaluate GCT risk in an independent cohort.

Methods: We conducted a retrospective analysis of SRY-negative 46,XX testicular and ovotesticular DSD patients who underwent gonadal biopsy or gonadectomy. Routine next-generation sequencing was performed on peripheral blood samples. In gonadal tissues, quantitative PCR was utilized for SRY gene detection, while whole exome sequencing and whole genome sequencing provided comprehensive genetic analysis. Gonadal histopathological features were assessed through HE staining and immunohistochemical markers.

Results: Thirty-five individuals with SRY-negative 46,XX testicular or ovotesticular DSD were included, comprising 26 ovotesticular and 9 testicular cases. Two pathogenic NR5A1 variants and one SOX3 gene duplication were identified in peripheral blood of 3 out of 34 patients (8.82%). XX/XY chimerism was detected in gonadal tissue of 1 out of 32 patients (3.13%). Notably, no precursor lesions (GCNIS, gonadoblastoma, or undifferentiated gonadal tissue) or GCTs were found. OCT 3/4 positivity was observed in testicular parenchyma of 7 patients (7/35), with these positive germ cells primarily located at the center of the seminiferous cords and showing negative SCF staining.

Conclusion: The risk of GCTs in individuals with SRY-negative 46,XX testicular and ovotesticular DSD remains contentious. This study underscores the importance of comprehensive genetic and histological evaluations of gonadal tissues. Immunohistochemical findings suggest a relatively low GCT risk; however, long-term follow-up is essential for effective patient monitoring.

Keywords: Genetics; Germ cell tumors; Gonads; Ovotesticular disorders of sex development; SRY-negative 46,XX disorders of sex development; Testicular disorders of sex development.