[Pubertal characteristics in patients with NR5A1-related 46, XY disorders of sex development]

Objective: To summarize the pubertal clinical characteristics of patients with NR5A1-related 46, XY disorders of sex development (DSD). Methods: This was a retrospective case-series study. Clinical data, including clinical phenotypes and hormone profiles were collected and analyzed from 21 pediatric DSD cases who carried NR5A1 heterozygous variants and entered puberty during the study period at Beijing Children's Hospital, Capital Medical University from January 2010 to December 2024. Results: Twenty-one patients were included in this study. The age at initial presentation was 10.5 (3.8, 12.4) years. Of these, 14 patients had already entered puberty at the time of their first visit, and 7 entered puberty during long-term follow-up. The pubertal onset could be traced in 18 patients. Among the 7 patients raised as males, all spontaneously entered puberty at an age of 11.0 (10.0, 12.5) years, with manifestations including growth acceleration, external genital development, and pubic hair development. Among the 11 patients raised as females, the age at pubertal onset was 10.0 (10.0, 11.0) years, characterized by clitoral hypertrophy, pubic hair development, voice change, and primary amenorrhea. Of the 14 children with palpable testes on physical examination, 10 showed no significant age-related increase in testicular volume during pubertal progression, with the exception of cases 4, 10, 14, and 21. All patients demonstrated progressive increases in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during pubertal progression. Throughout puberty, FSH levels remained persistently above the upper limit of normal in 17 patients, and LH levels exceeded the normal range in 8 patients at the last follow-up. The 21 patients were followed up for a median of 4.1 (0.9, 8.0) years. During the entire follow-up period, no gonadal cancer occurred in all patients. Ten of the 13 female patients were subsequently reassigned to male. Two patients (case 8 and 9) received gonadotropin-releasing hormone analog treatment to delay pubertal progression pending final gender assignment. At 13.5 years of age, case 13 was assigned female sex and subsequently underwent orchiectomy and feminizing genitoplasty, followed by estrogen replacement therapy. Eight male patients with ambiguous genitalia at birth underwent multiple surgeries during infancy or prepubertal period to reconstruct male-typical external genitalia. Four patients were treated with testosterone replacement therapy during follow-up. Conclusions: Patients with NR5A1-related 46, XY DSD can spontaneously enter puberty. Those initially raised as females may undergo gender reassignment to male. Testicular function progressively declines with age in these patients, highlighting the importance of early fertility assessment and preservation.