Novel insights into 46,XY disorders of sex development due to NR5A1 gene mutation

Ralf Werner, Isabel Mönig, Julia August, Clemens Freiberg, Ralf Lünstedt, Benedikt Reiz, Lutz Wünsch, Paul Martin Holterhus, Alexandra Kulle, Ulla Döhnert, Stefan A. Wudy, Annette Richter-Unruh, Christoph Thorns, Olaf Hiort*

*Corresponding author for this work
11 Citations (Scopus)


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.

Original languageEnglish
JournalSexual Development
Issue number5
Pages (from-to)260-268
Number of pages9
Publication statusPublished - 01.12.2015

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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