"Variable phenotypic expression of NR5A1 mutation in a family: sex development abnormalities and management challenges"

Muhammad Ahmad; Manju Chandwani; Sumana Chatterjee; Toby Candler; Dinesh Giri; Mark Woodward; Julie Alderson; Emma Kivuva; Tessa Homfray; Klaus Mohnike; Elizabeth Crowne

doi:10.1530/endoabs.110.P1041

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Endocrine Abstracts (2025) 110 P1041 | DOI: 10.1530/endoabs.110.P1041

ECEESPE2025 Poster Presentations Reproductive and Developmental Endocrinology (93 abstracts)

"Variable phenotypic expression of NR5A1 mutation in a family: sex development abnormalities and management challenges"

Muhammad Ahmad ¹ , Manju Chandwani ¹ , Sumana Chatterjee ¹ , Toby Candler ¹ , Dinesh Giri ¹ , Mark Woodward ^1,2 , Julie Alderson ¹ , Emma Kivuva ¹ , Tessa Homfray ¹ , Klaus Mohnike ³ & Elizabeth Crowne ¹

Author affiliations

¹University Hospitals of Bristol and Weston, Paediatric Endocrinology, Bristol, United Kingdom; ²Bristol Children’s Hospital, Department of Paediatric Urology, Bristol, United Kingdom; ³Otto Von Guericke University Magdeburg, Magdeburg, Germany

JOINT1882

Steroidogenic Factor 1 (SF-1/NR5A1) is essential for gonadal and adrenal development. Mutations in NR5A1 are associated with differences in sex development (DSD), presenting a broad phenotypic spectrum from asymptomatic carriers to severe DSD. Despite extensive research, the factors influencing these varied clinical manifestations remain unclear. Oligogenic inheritance may contribute, with multiple genetic variants influencing the phenotype. This case highlights a family with a missense NR5A1 mutation and marked phenotypic variability. Twin 2, from a dichorionic diamniotic pregnancy, presented with ambiguous genitalia, while Twin 1 had normal male genitalia. At birth, Twin 2 had Cilitorophallic enlargement (1 cm), a perineal urethral opening, posterior labioscrotal fusion, and bilateral labioscrotal gonads. The mother had an older phenotypically normal male child and a history of unilateral ovarian germ cell tumour. The maternal aunt, born with genital ambiguity, underwent feminizing genitoplasty and was diagnosed with 46XX ovo-testicular DSD due to a heterozygous NR5A1 variant. She underwent gonadectomy at age nine, with histology revealing intratubular neoplasia. A multidisciplinary team, in agreement with the parents, decided to raise the child as female. Gonapeptyl injections were given until nine months of age to prevent further virilisation. Genetic testing is ongoing for the patient’s two male siblings and maternal grandparents. Future management will involve balancing the risks of malignancy and fertility preservation. The mother had both fertility and malignancy, while the maternal aunt showed malignancy at nine years. If the gonads are retained, a screening protocol will be necessary, along with monitoring for virilisation at puberty. Periodic adrenal function assessment will be required due to the risk of late-onset adrenal insufficiency. Additionally, splenic function will need to be monitored, with appropriate vaccinations, given NR5A1’s role in splenic development.

Twin 2 ’s Investigation Results.
QF-PCR	No evidence of SRY
Karyotype	46XX
(Day 30)
LH	5.1 IU/l
FSH	9.3 IU/l
Testosterone	2.3 nmol/l
AMH	184.1 pmol/l (Reference female range < 25)
Synacthen test	Cortisol 871 nmol/l, ruling out adrenal insufficiency
DSD gene panel	Heterozygous NR5A1 missense variant (NM_004959.5: c.274C>T, p.R92W) was identified in Twin 2, matching the maternal aunt’s and later confirmed in the mother.
Examination Under Anaesthesia	Common channel leading to a normal urethra, bladder, and appropriately sized vagina, but no uterus. The gonads appeared abnormal, with a fallopian tube-like structure on the left and an epididymis on the right. Both were relocated to the pelvis, and bilateral inguinal hernia repair was performed.
Histology	Ovarian tissue with numerous primordial follicles