WHEN GENITAL AMBIGUITY LEADS TO GENETIC DISCOVERY

A CASE OF NR5A1-RELATED DISORDERS OF SEXUAL DEVELOPMENT

Abstract

INTRODUCTION
Disorders of sexual development (DSD) encompass a broad, heterogeneous groups of congenital conditions characterized by atypical development of genetic, gonadal, or phenotypic sex accompanied by abnormal development of internal and/or external genitalia. Early diagnosis is crucial to preserve fertility, ensure normal sexual function and support appropriate sex assignment, which significantly impact psychosocial well-being.

CASE
A child assigned female at birth was referred to a Paediatric Endocrinologist at 6 weeks old for evaluation of ambiguous genitalia. Clinical examination revealed penoscrotal hypospadias, rugated labioscrotal folds, palpable gonads with phallus size of 2 cm. The child is the youngest of 2 siblings, with no family history of consanguinity. Notably, the father had hypospadias, which was surgically corrected in childhood. Pelvic ultrasound revealed bilateral oval echogenic structure within labial fold, suggestive of testes, with no visible uterine structure. Hormonal investigations revealed a high testosterone level (13.1 nmol/L) and an antimullerian hormone level of 103 pmol/L, indicating normal Sertoli cell function. Karyotyping confirmed 46,XY genotypes. Further genetic testing identified a heterozygous variant of uncertain significance in the NR5A1 gene. The child was treated with monthly intramuscular testosterone for three months, resulting in phallus growth to 3 cm.

Thorough genital examination during newborn assessment is essential to prevent missed diagnoses of DSD. This patient was diagnosed with an undervirilized male phenotype associated with an NR5A1 mutation – a principal genetic alteration implicated in DSD. The NR5A1 gene plays a crucial role in early gonadal development, testis determination and steroidogenesis.

CONCLUSION
This case highlights the importance of early recognition and management of DSD. Genetic testing for NR5A1 mutation should be considered in cases of 46,XY DSD with ambiguous genitalia, particularly when accompanied by a family history of hypospadias.