ODP398 A Novel NR5A1 Gene Mutation Causing 46, XY DSD Without Adrenal Insufficiency in an Immigrant Boy from Dominican Republic
Authors: Yu Yunting , Huerta-Saenz Lina , Bangalore-Krishna Kanthi , Lee Peter 
Published: November 2022

Abstract

Background
The NR5A1 gene encodes steroidogenic factor-1 (SF1), a key transcription factor involved in adrenal and gonadal development. We present a 12-year old boy with a novel, dominant, heterozygous, and probably pathogenic variant of this gene (c.102+1G&gt;C) resulting in incomplete masculinization [46, XY disorder of sex development (DSD)]. Clinical case: This 12-year-old boy, who had immigrated from the Dominican Republic to the United States, was referred at 8 years of age with a diagnosis of congenital adrenal hyperplasia (CAH). He received hCG injections as a neonate and had been prescribed hydrocortisone 7 mg/m 2 /day and fludrocortisone 0.1 mg/day orally for CAH, although compliance was poor. After migrating to the United States, his supply of medications depleted, and he was taken to a local emergency room with fatigue and abdominal pain. Vital signs and electrolyte levels were normal. There was no history of adrenal crisis, testes were not palpable, and inguinal testicles measuring 2.8×1.1 cm on the right and 2.2×1 cm on the left were reported on MRI. When he presented to the pediatric endocrinology clinic, his mother denied history of consanguinity, PCOS, or use of hormones during pregnancy. She reported a history of two spontaneous miscarriages with father of patient and a younger healthy son from another partner. Physical exam showed ambiguous genitalia with underdeveloped scrotum, mild hyperpigmentation, bilateral non-palpable testicles within scrotum, severe penoscrotal hypospadias, stretched penile length (SPL) of 2cm×1.5 cm, and chordee. He had axillary hair and a Tanner stage 2 for pubic hair. A high-dose ACTH stimulation study (250 mcg IV cosyntropin) showed a peak cortisol level at 19.6 μg/dL, peak 17-hydroxyprogesterone of 100 ng/dL, and baseline and peak pregnenolone levels of 6 ng/dL and 43 ng/dL, respectively, with low to normal values of other precursors ruling out CAH. Gonadotropin levels were prepubertal (LH &lt; 0.3 mIU/mL, FSH 2.9 mIU/mL), testosterone &lt;4 ng/dL, and dihydrotestosterone 0.73 ng/dL. Chromosomal studies confirmed 46, XY. With a clinical diagnosis of 46,XY DSD (undervirilized male) and male gender identity, a 2-stage orchiopexy was completed. After a six-month course of monthly 50 mg cypionate testosterone, SPL improved to 4 cm and pubic hair progressed to Tanner stage 3. Surgical repair of penoscrotal hypospadias and chordee were then completed. A 46, XY DSD/complete gonadal dysgenesis DNA panel sequencing identified a novel, dominant, heterozygous, likely pathogenic variant of the NR5A1 gene [c.102+1G&gt;C]. This is a canonical splice donor site of intron 2.

Conclusion
A novel sequence change in the NR5A1 gene causing a severe phenotype of 46,XY undervirilized male is presented here in a boy originally misdiagnosed with CAH. This case emphasizes the need for complete evaluation with molecular genetic screening for those patients with 46,XY DSDs.
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