Endocrine Abstracts

JOINT3655

Background: Disorders of sex development in individuals with a 46XY karyotype pose significant diagnostic and therapeutic challenges due to heterogeneous etiologies and overlapping clinical features. Despite advances in genetic testing, many cases lack a definitive molecular diagnosis, complicating management. The differential diagnosis includes androgen insensitivity syndrome, gonadal dysgenesis, enzymatic defects in androgen biosynthesis, and other endocrine or receptor-related abnormalities. While stimulation tests are widely used, they are costly, time-consuming, and may yield inconclusive results. Whole-exome sequencing has improved diagnostic precision but does not always identify causative mutations, emphasizing the need for a broader approach.

Case Presentation: A male infant with a 46XY karyotype presented at birth with ambiguous genitalia, including penoscrotal hypospadias and bilateral undescended testes. The External Masculinization Score was 3. Laparoscopy confirmed the absence of Mullerian structures, and testicular biopsy revealed normal testicular parenchyma. A comprehensive diagnostic evaluation included genetic and biochemical assessments. Partial androgen insensitivity syndrome was ruled out through androgen receptor gene sequencing. Initial hormonal testing suggested 5-alpha-reductase type 2 deficiency, with a testosterone-to-dihydrotestosterone ratio of 30.8 following human chorionic gonadotropin stimulation. However, repeat testing two years later showed a ratio of 12, challenging this diagnosis. Whole-exome sequencing failed to identify pathogenic variants in SRD5A2 or other relevant genes, further complicating classification.

Management and Follow-up: Due to significant undervirilization, testosterone therapy was initiated before surgical interventions. The patient later underwent bilateral orchidopexy, penile elongation and staged urethroplasty. Ongoing multidisciplinary follow-up, involving endocrinology, urology, and psychological support, remains essential to monitor pubertal development and long-term well-being.

Discussion and Conclusion: This case highlights the complexities of diagnosing and managing 46XY disorders of sex development when biochemical markers suggest an enzymatic defect, yet genetic confirmation is absent. The variability in testosterone-to-dihydrotestosterone ratios underscores the limitations of hormonal assays and the need for functional enzyme activity testing. Stimulation tests, though commonly used, require careful interpretation as they do not always yield definitive results. Whole-exome sequencing has enhanced diagnostic accuracy, yet unexplained cases persist, underscoring gaps in the understanding of sexual differentiation. A standardized, multidisciplinary approach integrating endocrinology, genetics, pediatric urology, and psychological support is crucial for optimizing patient outcomes. Advances in molecular diagnostics and functional assays will be pivotal in refining diagnostic pathways and guiding individualized management.

Keywords: 46XY disorders of sex development, differential diagnosis, 5-alpha-reductase type 2 deficiency, whole-exome sequencing, endocrine-disrupting chemicals.