46,XY Gonadal Dysgenesis Due to NR0B1 Duplication: A Systematic Review

Gonadal dysgenesis (GD) due to NR0B1 duplication is a subset of 46,XY disorder of sexual differentiation (DSD) characterised by variable external genitalia phenotypes ranging from complete GD (CGD) to partial GD (PGD) and may have syndromic associations. The DSD-phenotype spectrum and its correlation with genotype have not been systematically studied.

A systematic review of 46,XY GD with NR0B1 duplication (n = 47, including two patients from our centre) was conducted to understand DSD phenotypes and their genotypic correlations.

Large and submicroscopic duplications were observed in 61.7% and 38.3%, respectively, and maternal inheritance (asymptomatic carriers, except one) was reported in 63.3%. Median age at presentation was 1.0 (birth to 38) years, and syndromic manifestations were the cause in 55.3% and gonadal dysfunction-related symptoms in 42.5%. CGD, PGD, and typical male genitalia were seen in 66%, 27.7%, and 6.4%, respectively. Gender incongruence and fertility (except for one reported paternity) have not been reported. Gonadoblastoma and gonadal germ cell cancer were noted in 17% (median age: 11 years) and 2.1% (15 years of age) of cases, respectively. Compared with submicroscopic duplications, large duplications were associated with earlier presentation (0.7 vs. 15 years; p = 0.008) and higher prevalence of syndromic features (96.6% vs. 22.2%; p = 0.0001), while external genital phenotype, cryptorchidism, presence of mullerian structures, and gonadoblastoma rates were comparable.

46,XY GD phenotype with NR0B1 duplication does not correlate with duplicated segment size. A delineated spectrum of gonadal dysfunction, gender identity, fertility, and gonadal malignancy risk presented here can help to optimise patient management.