Phenotype and Molecular Characterizations of 30 Children From China With NR5A1 Mutations

Abstract

Background: Patients harboring NR5A1 mutations have a wide spectrum of phenotypes.Objective: To investigate the phenotype of patients with NR5A1 gene mutations from a 30 Chinese patient cohort.Methods: We reported the clinical features of children with NR5A1 gene mutations and compared them between two groups of patients with social genders of male (boys group) and female (girls group).Results: Thirty patients with NR5A1 mutations ranging from 2 months to 17 years of age were studied. There were 11 boys and 19 girls who were identified when they visited the hospital. The patients were verified as having testes without a uterus and ovaries by B-mode ultrasound. There was no difference between boys and girls in terms of the Prader stage (p = 0.086), but the position of the testes was higher in girls than in boys (p = 0.013). The patients’ average height is −0.43 SDS according to the normal boys’ height with SDS (while their average target height was 0.07 SDS). However, there was no such difference between boys and girls (p > 0.05). Although the basal LH and post-hCG testosterone (T) levels were not different (p > 0.05), but the basal FSH level, LH/FSH ratio, and INHB level were decreased in girls (p = 0.002; p = 0.001; p = 0.006). All of the mothers of the patients reported to have normal pregnancies. We found 24 patients (80%) with de novo mutations in the NR5A1 gene; 5 patients had inherited mutations from their mothers, and one inherited from the father. Only the mothers of patients 16 and 18 showed premature ovarian failure at the time of reporting. Among 26 disease associated mutations, 14 novel mutations that have been reported the first time and p.R87C is the most common Among the other 12 had had been reported,the p.R313C is the most common.Conclusion: Patients with 46, XY NR5A1 mutations presented a wide spectrum of external genitalia characteristics and severe Sertoli cell impairment. The p.R87C and p.R313C mutations appeared to be common (10%) in this group, and 14 new mutations were identified, improving our understanding the genotype phenotype correlations.

NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes

“…Our additional 4 patients confirm the variable phenotype of individuals with NR5A1 deficiency. Anyway, a clear genotype-phenotype correlation has not been found in these series as well as in other studies [Warman et al, 2011;Domenice et al, 2016;Song et al, 2018;Fab-bri-Scallet et al, 2020]. This finding is confirmed by comparing the genital phenotype of the present subjects and those with the same genetic background reported in the literature ( Table 3 ).…”

“…Anyway, the 4-year-old female with ambiguous external genitalia described by Mazen et al [2016] also harbored the rare variant c.710A>G in the MAP3K1 gene, which supports the possibility of a dygenic inheritance in some cases and can explain the greater severity of phenotypes observed in that girl ( Table 3 ). Recently, 2 additional Chinese girls harboring a p.Arg313Cys mutation have been reported presenting with severe ambiguous genitalia phenotype [Song et al, 2018]. Taken together, the data summarized in Table 3 indicate that this mutation of NR5A1 is likely spread worldwide and associated with very variable phenotypes.…”

Mutation update for theNR5A1gene involved in DSD and infertility

“…(Cys55Ser), and c.288_304del/p.Met98Glyfs*45, which have not been annotated for NR5A1 before, and the already known c.76G>A/p. (Gly26Arg) (Song, Fan, & Gong, ), c.937C>T/p.Arg313Cys (rs1057517779), or c.877G>A/p.Asp293Asn (rs121918655) variations. Despite the absence of functional studies for p.(Cys55Ser) and p.(Met78Leu) it were predicted to be pathogenic in all mutation prediction algorithms used (see the Supporting Information).…”

Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1

“…According to the literature, variable hormonal findings are found in persons with NR5A1 variants and do not correlate with the phenotype of the external genitalia [ 2 ]. Normal testosterone concentrations, at least in early childhood, have been found in NR5A1 variant patients with cryptorchidism, hypospadias and micropenis [ 7 , 20 ], as well as in 46,XY subjects presenting with a female phenotype [ 21 , 22 ]. In contrast, testosterone synthesis might not be sufficient to start or proceed through puberty.…”

“…Interestingly, Case 1 achieved spontaneous pubertal development, and the female patients presented with signs of (progressive) virilization at different ages. Virilization [ 23 ] or spontaneous pubertal development [ 2 ] have been described in 46,XY DSD individuals with a NR5A1 variant, even with elevated gonadotropin levels [ 7 ], indicating that the Sertoli cell damage might be more severe than the damage to the Leydig cells [ 21 ]. Our 46,XY DSD cases had generally low AMH levels, which might explain why the three female assigned persons had a rudimentary developed uterus, and fallopian tubes were only found in one.…”