Abstract

Introduction: The gene NR5A1 (nuclear receptor subfamily 5 group A member 1, OMIM +184757) encodes for the Steroidogenic factor1 (SF1), a key regulator of the adrenal/gonadal development and function. Disorders/Differences of Sex Development (DSD) are defined as conditions where the chromosomal/anatomical, phenotypic sex is atypical. Heterozygous mutations of NR5A1 gene are associated, in 46, XY DSD patients, with a wide phenotypic spectrum of the external genitalia, with or without adrenal failure. Here we report a 46, XY newborn carrying a novel heterozygous NR5A1 mutation that presents with ambiguous genitalia without adrenal failure.

Case Presentation: newborn with ambiguous genitalia at birth (micropenis, hypospadias) with normal testosterone (T) response to hCG test, with a Müllerian remnant and bilateral inguinal immature gonads. Molecular analyses for AR, SRD5A2 genes did not reveal any mutation. NR5A1 sequence analysis identified a novel substitution c.982G>T (GGG>TGG) in exon 5, which results in the non conservative p.G328W mutation, that arises de novo. Evaluation of the adrenal function was normal and no symptoms or signs of adrenal insufficiency have emerged during follow-up.

Conclusion: This is the first description of the p.G328W mutation (Sequence reference NC_000023.10) of the NR5A1 gene that causes the replacement of a highly conserved residue of the LBD (ligand binding domain) and very likely affects the SF1 action. This finding contributes to choose sex assignment and underlines the importance to perform the analysis of the NR5A1 gene also in 46, XY DSD patients with a PAIS-like phenotype.

Keywords: Disorders of sex development; Differences of sex development; DSD, NR5A1 gene; Steroidogenic factor-1; Ambiguous genitalia

Abbreviations: ACTH: adrenocorticotropic hormone; Δ4A: Δ4Androstenedione; DHEAS: dehydroepiandrosterone sulphate; DHT: dihydrotestosterone; DSD: Disorders or Differences of Sex Development; HCG: Human Chorionic Gonadotropin; MRI: magnetic resonance imaging; PAIS: Partial Androgen Insensitivity Syndrome; SPL: Stretched Penile Length; T: Testosterone