Genetic and Clinical Characteristics of 185 Japanese Children With 46,XY Differences of Sex Development

46,XY differences of sex development (DSD) are heterogeneous in etiology. The detailed phenotypes of 46,XY DSD patients with monogenic disorders have not been fully elucidated.

To estimate the proportion of monogenic disorders in 46,XY DSD and to characterize the clinical phenotypes of patients with monogenic disorders.

A total of 185 Japanese patients (178 families) were enrolled. We sequenced 25 genes related to 46,XY DSD and assessed the pathogenicity of the identified sequence variants according to the American College of Medical Genetics and Genomics guidelines, supplemented by in silico and/or in vitro analyses. We analyzed the clinical phenotypes of patients with monogenic disorders, with particular attention to the external or internal genitalia.

We identified 51 patients (47 families) with any monogenic disorders (26%), who possessed pathogenic variants in AR (11%), SRD5A2 (4.5%), NR5A1 (4.0%), SRY (2.8%), WT1 (1.1%), STAR (1.1%), CYP17A1 (0.56%), HSD3B2 (0.56%), or MAP3K1 (0.56%). The proportion of monogenic disorders was significantly higher in subjects with detected Müllerian derivatives (57%) than in those undetected (26%) (P = .029), and in subjects with female-typical genitalia (91%) than in those with ambiguous genitalia (19%) (P < .001).

The proportion of monogenic disorders in Japanese 46,XY DSD patients was approximately 26%. Monogenic disorders were frequent among patients with severe undermasculinization of the external or internal genitalia.