Endocrine Abstracts

JOINT3505

Introduction: The NR5A1 gene plays a crucial role in gonadal development, sexual differentiation, and steroidogenesis. In the bipotential gonad, its interaction with SRY activates SOX9, promoting testicular differentiation and the formation of Sertoli cells, which activate the AMH gene, responsible for Müllerian duct regression. Sertoli cells induce the differentiation of Leydig cells, where NR5A1 activates the LH receptor (LHCGR) and INSL3, stimulating the production of testosterone and dihydrotestosterone - both essential for Wolffian ducts differentiation and development of male external genitalia. Mutations in NR5A1 gene can result in a spectrum of phenotypes related to sexual differentiation (e.g., partial or complete gonadal dysgenesis, primary ovarian insufficiency, male infertility – oligo-azoospermia), reflecting its interaction with other key genes, such as GATA4, AMH, WT1, CBX2, and WNT4, affecting the regulatory network of gonadal development.

Case Report: A two-month-old infant was referred to the Endocrinology Clinic due to atypical external genitalia and micropenis. The child was born after an uneventful monitored pregnancy. Prenatal ultrasounds showed no abnormalities, and the fetus was designated as female. Delivery occurred by caesarean section at 42 weeks, with good neonatal adaptation. Due to atypical external genitalia, karyotyping revealed 46,XY and pelvic ultrasound identified testes near the scrotal sacs with no Müllerian structures. Male gender was assigned. At the two-month Endocrinology Clinic visit, the infant presented with penoscrotal hypospadias, micropenis, and testes located in the scrotum. Biochemical assessment excluded congenital adrenal hyperplasia and hormone levels were consistent with mini-puberty. The patient remained under follow-up, with serial ultrasounds consistently showing small testes with hyperechoic foci. At five years of age, molecular testing for androgen insensitivity was performed, but no mutations were identified. At 8 years, testosterone treatment (25 mg monthly for three months) was administered for micropenis, however no response was observed. Due to persistently low gonadotropin and testosterone levels, puberty induction with testosterone was initiated at 12 years, resulting in the development of pubic and axillary hair, penile growth, and the onset of acne. At 16 years, genetic testing identified a likely pathogenic variant, c.442_456del, p.(Glu148Glyfs*44), in heterozygosity, in exon 4 of the NR5A1 gene.

Conclusion: Testing for NR5A1 gene mutations should always be performed in cases of disorders of sexual differentiation, given the broad spectrum of associated phenotypes. Genetic diagnosis in these conditions enables optimised therapeutic management, clearer prognosis assessment, and genetic counselling for family members.