Endocrine Abstracts

JOINT2932

Introduction: Testicular disorders of sex development (T-DSD) represent a heterogeneous group of congenital anomalies affecting sexual differentiation. In North Africa, these conditions have long been underexplored due to limited access to genetic analysis. This study aims to describe the epidemiology, phenotypic characteristics, and genetic features of T-DSD in this region.

Methods: We conducted a cross-sectional descriptive study including patients diagnosed with DSD and confirmed testicular tissue, followed at the endocrinology reference center in southern Tunisia. All patients underwent clinical assessment of sexual maturation using Tanner and Prader staging, as well as steroid hormone profiling. Genetic analysis was performed using next-generation sequencing (NGS) at the genetics department.

Results: We identified 50 North African patients from 40 families, with two-thirds of cases involving consanguineous unions. The most common etiologies were testosterone biosynthesis defects (38%) and gonadal dysgenesis (32%). The mean age at first consultation was 17.98±11.89 years (range: 1 day–60 years), with no significant difference between etiological subgroups. The most frequent reason for medical consultation was primary amenorrhea (62%), except in 46,XX DSD cases. Complete pure gonadal dysgenesis showed a strong phenotypic correlation with mutations in key sex differentiation genes (SRY and NR5A1), whereas partial pure gonadal dysgenesis exhibited variable male phenotypes associated with MAP3K1 mutations. Androgen receptor abnormalities (AIS: 10%; 5α-reductase deficiency: 12%) presented with diverse phenotypes, with genotype-phenotype correlation established only for the R753X mutation in the AR gene. Patients with testosterone biosynthesis defects showed variable phenotypic expression, but specific traits such as pubertal virilization suggested 17βHSD3 deficiency in which we proved the founder effect for the C206X mutation. Strong phenotype-genotype correlation was observed only in cases of LH resistance. In 46,XX T-DSD cases (n = 3), the degree of masculinization was dictated by the presence of the SRY gene.

Discussion: Testicular DSDs represent a heterogeneous group of disorders. In our cohort, testosterone synthesis defects were the most predominant category, likely due to the high incidence of consanguinity. Unlike larger pediatric series, our cohort primarily included peri-pubertal individuals. Clinical presentation was highly variable but could be guided by static and dynamic hormonal assessments. Molecular analysis has become essential, though sometimes insufficient. Our findings on phenotype-genotype correlations aligned with the literature for CAIS, LH resistance, complete gonadal dysgenesis, 17βHSD3 deficiency, and XX DSD. However, we refuted a previously suggested correlation for the MAP3K1 gene mutation.