Endocrine Abstracts

JOINT3376

Introduction: Disorders of sexual steroid biosynthesis are the leading cause of disorders of sex development (DSDs) in non-Western societies. Molecular studies on cohorts have shown that testicular enzyme deficiency-related DSDs due to 17β-hydroxysteroid dehydrogenase type 3 (17HSD3) deficiency are more frequent than previously reported, particularly in the Middle Eastern and North African regions, and are underestimated due to very mild forms. This study aims to characterize, both phenotypically and genotypically, a Tunisian population with 17HSD3 deficiency.

Methods: This is a descriptive study including patients followed for 46,XY DSD secondary to 17HSD3 deficiency at the Department of Endocrinology, University Hospital of Sfax, Tunisia. Phenotypic evaluation was based on Tanner’s sexual maturation staging and Prader’s virilization grading of the genitalia. We measured a panel of sex steroids before and after stimulation with human chorionic gonadotropin (hCG). The molecular study was conducted at the Department of Genetics using next-generation sequencing (NGS).

Results: We identified seven patients, all assigned female at birth. The main reasons for consultation were pubertal virilization (4/7) and genital anomalies (2/7). None of the pubertal-aged patients exhibited signs of sexual maturation (Tanner stage S1). The mean genital differentiation score was 3±1. The hormonal profile showed a low Testosterone/Δ4-Androstenedione ratio after hCG stimulation of <0.8 in all patients. Genetically, we identified the nonsense mutation c.618C>A in the HSD17B3 gene, which was common to all seven patients, confirming its founder effect in our region. The phenotypic expression was variable, even among patients with the same genotype, indicating a weak phenotype-genotype correlation.

Conclusion: DSDs due to defects in the final step of steroidogenesis are common in North African populations, with an increasingly well-defined phylogeny. Phenotypic expression is highly variable and appears to be minimally influenced by genotype. This variability may be attributed to the presence of yet unidentified polymorphisms in the HSD17B3 gene, modifying genes, extragenic polymorphisms, alternative steroidogenesis pathways, environmental factors affecting 17βHSD3 protein activity, and the presence of other 17βHSD isoenzymes.