Phenotypic Variation and Pubertal Outcomes in Males and Females with 46,XY Partial Gonadal Dysgenesis.

Background: 46,XY gonadal dysgenesis is classified as complete (CGD) or partial (PGD) subtypes. The phenotype of PGD and the long-term outcome is not clearly defined.

Objective: To evaluate clinical features and pubertal outcome of PGD in a large cohort, using CGD as a comparator for diagnostic clarity.

Methods: Patients with 46,XY GD were identified from the I-DSD Registry and data on phenotype, genetics, biochemistry, gonadal histology and pubertal development were collated in three categories; CGD (n=100), PGD assigned female (PGDf, n=107) and male (PGDm, n=103) at birth.

Results: Most individuals with PGD presented with atypical genitalia in infancy, though, 18% of PGDf presented with delayed puberty and 8% with virilisation. A genetic aetiology was identified in 42% of the cohort, with common gene defects in SRY and WT1 in CGD, and NR5A1 in PGD. Gonadal pre/malignancy was found in 33.8% in CGD, 19.7% in PGDf and 8.8% in PGDm. Among the PGDm (>13 years) with at least one gonad, 80% had spontaneous pubertal onset and 59% achieved Tanner G5 without hormone treatment. Labio-scrotal gonads at presentation and testosterone response to hCG predicted onset of spontaneous puberty. In PGDf with gonads, 42% developed spontaneous virilisation at puberty. Sex was reassigned in 16.1% and 5.3% of individuals with PGDf and PGDm, respectively.

Conclusions: This study highlights the heterogeneous phenotype of PGD and the consequent diagnostic challenge. Many PGD patients with preserved gonads have the potential to develop puberty spontaneously, though further study is needed to determine the risk of developing gonadal tumours. (250 words).