Long-term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis

Background Follow-up data on patients with 46,XY partial gonadal dysgenesis (PGD) until adulthood are scarce, making information on prognosis difficult. Objective To analyse the long-term outcomes of patients with 46,XY PGD regarding testosterone production, germ cell tumour risk, genotype and psychosexual adaptation. Methods A retrospective longitudinal study of 33 patients (20 assigned male and 13 patients assigned female at birth). Molecular diagnosis was performed by Sanger sequencing or by targeted massively parallel sequencing of 63 genes related to disorders of sex development (DSDs). Results Age at first and last visit ranged from 0.1 to 43 and from 17 to 53 years, respectively. Spontaneous puberty was observed in 57% of the patients. During follow-up, six of them had a gonadectomy (four due to female gender, and two because of a gonadal tumour). At last evaluation, five of six patients had adult male testosterone levels (median 16.7 nmol/L, range 15.3-21.7 nmol/L) and elevated LH and FSH levels. Germ cell tumours were found in two postpubertal patients (one with an abdominal gonad and one patient with Frasier syndrome). Molecular diagnosis was possible in 11 patients (33%). NR5A1 variants were the most prevalent molecular defects (n = 6), and four of five patients harbouring them developed spontaneous puberty. Gender change was observed in four patients, two from each sex assignment group; all patients reported satisfaction with their gender at final evaluation. Sexual intercourse was reported by 81% of both gender and 82% of them reported satisfaction with their sexual lives. Conclusion Spontaneous puberty was observed in 57% of the patients with 46,XY PGD, being NR5A1 defects the most prevalent ones among all the patients and in those with spontaneous puberty. Gender change due to gender dysphoria was reported by 12% of the patients. All the patients reported satisfaction with their final gender, and most of them with their sexual life.