Novel Insights into 46,XY Disorders of Sex Development due to <b><i>NR5A1</i></b> Gene Mutation

Abstract

The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern. Endocrine evaluation showed hypergonadotropic hypogonadism, and the Sertoli cell markers inhibin B and anti-Müllerian hormone were also low. Several molecular genetic studies were initiated. While analyses of the androgen receptor gene, the SRD5A2 gene and HSD17B3 gene were uninformative, a novel p.L230R mutation was found in the NR5A1 gene. A mutant construct proved a severe dysfunction of this variant in functional analysis after recreation and transfection into HeLa cells. We conclude that the NR5A1 p.L230R mutation most likely leads to a spatial and time-dependent Leydig cell and Sertoli cell dysfunction during development not causing the classical gonadal dysgenesis phenotype. This case demonstrates that the current classification should be updated to encompass the overlapping phenotypes of some genetic conditions within 46,XY DSD.

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

“…Moreover, three of these patients were assigned female at birth owing to their severely undervirilised genitalia. This finding is in agreement with other reports . In those cases, the severe undervirilisation of external genitalia could not predict virilisation in adulthood because testosterone secretion recovered during puberty for unknown reasons …”

“…This patient harboured a NR5A1 variant, was assigned female at birth, presented with virilisation at puberty and changed his gender at 18 years of age . Nonetheless, no gender change was observed among another six PGD patients with NR5A1 defects already described, who had gone through spontaneous virilisation . Together with the already published cases of NR5A1 defects, among the 10 patients assigned female at birth with virilisation at puberty, two patients changed their gender to male.…”

“…[29][30][31][32][33][34][35] In those cases, the severe undervirilisation of external genitalia could not predict virilisation in adulthood because testosterone secretion recovered during puberty for unknown reasons. [29][30][31][32][33][34][35][36] SRY defects have been mostly associated with complete gonadal dysgenesis and rarely with partial gonadal dysgenesis. 25,[37][38][39] The SRY p.Arg30Ile pathogenic allelic variant was identified in one of our patients with spontaneous puberty.…”

<b><i>NR5A1</i></b> Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations

“…The presence of Mül-lerian structures in a 46,XY patient may suggest inadequate fetal Sertoli cell differentiation and AMH secretion. Knowing that SF1 is a transcription factor that regulates AMH expression along with other proteins, such as SOX9, GATA4, WT1, and DAX1, it is reasonable to consider that mutations in its gene can affect the expression of AMH at different levels, which could explain why one patient had a uterus while the others did not [Lasala et al, 2011;Werner et al, 2015].…”

The importance of the multiplex ligation-dependent probe amplification in the identification of a novel two-exon deletion of the NR5A1 gene in a patient with 46,XY differences of sex development

“…The NR5A1 gene, located on chromosome 9q33.3, is composed of 7 exons including the non-coding first exon [10]. To date, the identified variants are mainly missense, nonsense, splicing mutations, small deletions and insertions [11][12][13]. Large scale mutations, such as microdeletion of 9q33 chromosomal region or partial gene deletions involving NR5A1 have been reported in only 5 cases with 46,XY DSD (Table 1) [14][15][16][17][18].…”