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

Abstract

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 3 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 virilization. A genetic etiology 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 1 gonad, 80% had spontaneous pubertal onset and 59% achieved Tanner G5 without hormone treatment. Labioscrotal gonads at presentation and testosterone response to human chorionic gonadotropin predicted onset of spontaneous puberty. In PGDf with gonads, 42% developed spontaneous virilization at puberty. Sex was reassigned in 16.1% and 5.3% of individuals with PGDf and PGDm, respectively.

Conclusion: 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 tumors.

Keywords: 46,XY gonadal dysgenesis; differences/disorders of sex development; gonadectomy; sex reassignment; spontaneous puberty; virilization.

Figure 1.

Distribution of inclusion criteria. The Venn diagram shows the number of individuals with PGD who fulfilled the inclusion criteria (A) testosterone levels after hCG stimulation test less than twice the basal value, low basal testosterone with high gonadotropin levels in minipuberty or puberty, AMH or inhibin B levels below male reference range, or presence of Mullerian duct derivatives, (B) histology consistent with GD, and (C) pathogenic variants in genes associated with GD, in addition to (1) 46,XY karyotype and (2) atypical genitalia.

Figure 2.

Mode of clinical presentation (%). In CGD, 62.5% presented with pubertal delay, followed by incidental karyotype findings and gonadal tumor symptoms such as abdominal pain/discomfort and mild fever. In PGD, the majority presented with atypical genitalia. In PGDf, 17.5% presented with pubertal delay, 8.2% presented with pubertal delay and virilization such as clitoral enlargement and hirsutism.

Figure 3.

Pubertal outcome in individuals with PGD assigned male. There were 45 individuals with PGD assigned male aged ≥13 years with unilateral (n = 8) or bilateral (n = 37) gonads in the cohort. Spontaneous onset of puberty was observed in 80% (n = 36/45; n = 7 unilateral, n = 29 bilateral gonad). In individuals with spontaneous puberty onset, 30.3% (n = 10/33) required testosterone treatment to complete puberty. Data on whether testosterone treatment was given were missing in 6 individuals. At the assessment of puberty completion, 94% (n = 16/17) of the individuals who did not receive testosterone treatment attained Tanner G5 spontaneously. All patients who received testosterone treatment attained Tanner G5. Data on the final Tanner stage were available in 27 individuals.

Figure 4.

Histology of dysgenetic testis. (A) PGDf (hemizygous NR5A1 deletion), gonadectomy performed aged 6 years. This shows increased interstitial stroma, reduced tubular diameter, mostly Sertoli cell only tubules. Arrows indicate germ cells. (B) PGDf (MAP3K1 defect) aged 22 months. (B.1) Intracapsular growth. OCT3/4 staining (B.2) shows peripheral preneoplastic cells (gray arrow) and luminal OCT3/4-positive delayed maturation in white arrow. (C) PGDm (unknown genetic cause). Some tubules and the basement membrane (BM) are extremely thickened and interstitial fibrosis is observed.