NR5A1 variants are rare causes of 46,XY DSD with scarce literature from India. A systematic review of genotype–phenotype correlation is lacking. We aim to describe clinical, biochemical, histological, and genotype–phenotype correlation in 46,XY DSD with NR5A1 variants.

Retrospective monocentric review of 11 genetically-proven probands and systematic review including these and 288 from the literature.

Eleven probands of 46,XY DSD with NR5A1 variants from our centre exhibited phenotypic variability, female-to-male social-gender change in ∼two-thirds (4/7), primary adrenal insufficiency (PAI) in one, and five novel variants. Systematic review included 299 probands (age: 4.0 [0.3–13] years; Sinnecker score: 4 [3–4]) with 218 different NR5A1 variants. Systematic review reported female-to-male gender-change (27/166, 16.3%), spontaneous puberty/pubertal virilization (37/86, 43%), DSD in siblings (25/299, 8.3%), paternal hypospadias (7/299, 2.3%), maternal premature ovarian insufficiency (19/299, 6.4%), bilateral labio-scrotal gonads (71/214, 33.2%), absent Mullerian structure (187/232, 80.6%), PAI (5/222, 2.2%) and gonadal malignancy (2/111, 1.8%) in probands. Serum LH was elevated in mini-puberty, pre-puberty, and peri/post-puberty in 35.4% (17/48), 46.2% (18/39), and 63.6% (49/77) patients, respectively. Germ cells were present in 55.6% (5/9) in mini-pubertal age and absent in 96.8% (61/63) at later age. Sertoli cells were reported normal in 100% (7/7), and 70.4% (38/54) in mini-pubertal and later ages, respectively. Presence of Mullerian structures and Sinnecker score of 4/5 were associated with LBD variants (54.5%vs. 30.6%, P=0.003) and protein start-lost/deletion (7.3% vs. nil, P=0.004), respectively.

46,XY DSD with NR5A1 variants is characterized by progressive decline in Sertoli and Leydig cell function, pubertal virilization, frequent partial gonadal dysgenesis and probably lower gonadal malignancy risk than gonadal dysgenesis of other origin. Further studies are warranted to validate these observations.