Pubertal development in 46,XY patients with NR5A1 mutations

Abstract

Purpose Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age. Methods We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition. Results Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty. Conclusion Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.

Case Report: Longitudinal follow-up and testicular sperm extraction in a patient with a pathogenic NR5A1 (SF-1) frameshift variant: p.(Phe70Serfs*5)

“…The normal or subnormal testosterone levels with elevated LH levels suggested a compensated primary hypofunction of Leydig cells and explained the virilisation signs observed in the patient at puberty. This description is in line with that of Mönig et al., who studied 10 NR5A1 mutated patients during adolescence and puberty ( 24 ). Other authors also showed an impaired Sertoli cell function with a normal or subnormal Leydig cell function conserved at least until puberty ( 23 , 25 , 27 ).…”

“…However, Mönig et al. reported an early pubertal development with an early increase in testosterone levels in three out of 10 cases ( 24 ).…”

“…Herein, AMH levels were already low at birth. Then, a decrease in TV can occur during or after puberty ( 24 ); it was not significant herein perhaps because TV was initially too low. Finally, a progressive increase in the FSH and LH levels and a progressive decrease in testosterone and inhibin B levels with age were reported ( 9 , 24 , 25 , 31 ).…”

NR5A1-related 46,XY partial gonadal dysgenesis: A case report and literature review

“…[11] Ten NR5A1 variations were identified among German patients with 46,XY DSD with varying phenotypes in a cohort study. [12] In our case, a 12-year-old girl was diagnosed with 46,XY DSD due to NR5A1 mutation. The individual with 46,XY karyotype was noticed to have clitoromegaly, but otherwise normal female external genitalia, she has vellus hair on the upper lip, longer hair on the arms and legs, undescended dysplasia testes, no uterus, and ovaries.…”

“…[ 11 ] Ten NR5A1 variations were identified among German patients with 46,XY DSD with varying phenotypes in a cohort study. [ 12 ]…”