SUN-205 A Case of 46XY Mixed Gonadal Dysgenesis Presenting with Unilateral Gonad and Hemiuterus: Family History Dictates Sex Assignment

Background: Disorders of sex differentiation (DSDs) result from an atypical congenital development of chromosomal, gonadal, or anatomical sex. Mixed gonadal dysgenesis, a rare DSD, is the presence of both ovarian and testicular tissue. Early sex assignment is challenging due to the variable clinical, cytogenetic, and histopathological presentations. Clinical Case: A 1-day-old born from an uncomplicated pregnancy at 36+4/7 weeks gestation (birth weight 3.7 kg) was noted to have ambiguous genitalia. Upon examination, external genitalia was a bifid scrotum with palpable right scrotal and non-palpable left gonad; no hyperpigmentation. Phallus length was 2.5 cm and width was 1.3 cm with chordee (Prader Stage 3 hypospadias) and a single proximal urogenital sinus (anogenital ratio 1.3). Family history included a paternal uncle and two paternal cousins with ambiguous genitalia requiring surgy. The paternal uncle had two healthy daughters without fertility interventions. Also, three paternal aunts are significantly taller and infertile. Father has gynecomastia. No consanguinity. The initial investigation found normal electrolytes, LH 2.1 mIU/ml, and FSH 3.1 mIU/ml. Anti-Mullerian hormone (AMH, 20.47 ng/mL) and testosterone levels (42.6 ng/dL) were low for a male. High-resolution karyotype showed 46, XY with no mosaicism and a positive FISH SRY. Chromosomal microarray analysis was unremarkable for small deletions or duplications. A high-dose (150 mcg) ACTH stimulation test ruled out adrenal steroid biosynthesis defects. Renin and aldosterone were unremarkable. An hCG stimulation test showed appropriate rise in testosterone (443.1 ng/dL), androstenedione (112 ng/dL), and 5-alpha-dihydrotestosterone (1027.2 pg/mL). Ultrasound showed a single right testicle (~3 mL volume) within the hemiscrotum, a left inguinal hernia containing mesentery, and a left hemiuterus with no ovaries. A genitogram showed a urogenital sinus with a normal-appearing vaginal canal and elongated female urethra. No vesicoureteral reflux or other perineal orifices. The low AMH with an appropriate rise in testosterone following hCG stimulation and the presence of male and female reproductive organs in an undervirulized XY suggests mixed gonadal dysgenesis. Sex assignment was deferred by the medical team until further evaluation, but the parents chose to raise as a male based on their family history. Extended family studies are in process. Conclusion: The wide clinical and molecular variation in mixed gonadal dysgenesis constitutes a challenge for sex assignment. A multi-disciplinary team approach before sex assignment is crucial, including accurate assessment of external and internal genitalia, biochemical gonadal function, and cytogenetic testing. Among the multiple genetic variants known to cause mixed gonadal dysgenesis, highest on our differential is DMRT1.