Case Report: Severe Gonadal Dysgenesis Causing 46,XY Disorder of Sex Development Due to a Novel NR5A1 Variant

Abstract

Mutations in the nuclear receptor subfamily 5 group A member 1 (NR5A1) are the underlying cause of 10–20% of 46,XY disorders of sex development (DSDs). We describe a young girl with 46,XY DSD due to a unique novel mutation of the NR5A1 gene. An 11-year-old subject, raised as a female, was noticed to have clitromegly. She looked otherwise normal. However, her evaluation revealed a 46,XY karyotype, moderate clitromegly but otherwise normal female external genitalia, undescended atrophied testes, rudimentary uterus, no ovaries, and lack of breast development. Serum testosterone and estradiol were low, and gonadotropins were elevated. Adrenocortical function was normal. DNA was isolated from the peripheral leucocytes and used for whole exome sequencing. The results were confirmed by Sanger sequencing. We identified a novel mutation in NR5A1 changing the second nucleotide of the translation initiation codon (ATG>ACG) and resulting in a change of the first amino acid, methionine to threonine (p.Met1The). This led to severe gonadal dysgenesis with deficiency of testosterone and anti-Müllerian hormone (AMH) secretion. Lack of the former led to the development of female external genitalia, and lack of the latter allowed the Müllerian duct to develop into the uterus and the upper vagina. The patient has a female gender identity. Bilateral orchidectomy was performed and showed severely atrophic testes. Estrogen/progesterone therapy was initiated with excellent breast development and normal cyclical menses. In summary, we describe a severely affected case of 46,XY DSD due to a novel NR5A1 mutation involving the initiation codon that fully explains the clinical phenotype in this subject.

A novel c.64G>T (p.G22C) NR5A1 mutation in a Chinese adolescent with 46, XY disorders of sex development: a case report

“…The novel c.64G > T (p.G22C) mutation reported in the present study is a missense mutation, which reportedly accounts for 58% of NR5A1 mutations [6]. The p.G22C is located in the DBD, which is one of three domains in NR5A1, and previous studies have reported this as the location for multiple mutations in patients with 46, XY DSD [6, 20,23,24]. A previous study identi ed a G35E substitution in the DBD region in a patient with 46, XY DSD presenting adrenal insu ciency along with moderately severe gonadal dysplasia, indicating that this variation results in serious adverse effects on NR5A1 function [20].…”

A novel c.64G > T (p.G22C) NR5A1 variant in a Chinese adolescent with 46,XY disorders of sex development: a case report

“…The novel c.64G > T (p.G22C) variant reported in the present study is a missense variant, which reportedly accounts for 58% of NR5A1 variants [ 6 ]. The p.G22C substitution is located in the DBD, which is one of three domains in NR5A1, and previous studies have reported this as the location for multiple variants in patients with 46,XY DSD [ 6 , 22 , 24 – 26 ]. A previous study identified a G35E substitution in the DBD region in a patient with 46,XY DSD presenting adrenal insufficiency along with moderately severe gonadal dysgenesis, indicating that this variation results in serious adverse effects on NR5A1 function [ 22 ].…”