Are NR5A1 Variations a Frequent Cause of 46,XX Ovotesticular Disorders of Sex Development? Analysis from a Single Center and Systematic Review

Abstract

<b><i>Introduction:</i></b> Ovotesticular disorder of sex development (OT-DSD) is a rare condition defined by concomitance of testicular tissue and ovarian tissue (containing follicles) in the same individual. In <i>SRY</i>-negative 46,XX OT-DSD, the presence of testicular tissue may be due to variations in <i>NR5A1</i>. Our aims were to search for <i>NR5A1</i> variants in <i>SRY</i>-negative 46,XX OT-DSD patients and to perform a systematic review on the contribution of <i>NR5A1</i> variations to 46,XX OT-DSD. <b><i>Methods:</i></b> Sanger sequencing of <i>NR5A1</i> was performed in seven <i>SRY</i>-negative 46,XX OT-DSD patients: five simplex cases and two with another sibling with a 46,XX DSD. Systematic review of original studies on <i>NR5A1</i> sequencing of 46,XX OT-DSD patients was performed according to PRISMA-P guideline. Case reports were selected for analysis of clinical features. Individuals with <i>NR5A1</i>-associated testicular DSD were not included. <b><i>Results:</i></b> Sanger sequencing of <i>NR5A1</i> did not reveal pathogenic variants among our patients. Our cohort was included in this systematic review with seven other articles, totalizing fifty-six 46,XX OT-DSD patients investigated by Sanger or whole-exome sequencing. From them, three <i>NR5A1</i> pathogenic variants were identified (5% of the cases). Clinical analysis of these 3 cases and 5 case reports revealed: predominance of ovotestis (13/16 gonads) and bilateral OT-DSD (5/8 cases). <b><i>Conclusion:</i></b> The etiology of most 46,XX OT-DSD cases remains elusive, highlighting the importance of a deeper molecular investigation.