Endocrine Abstracts

Background: Aromatase deficiency is a rare cause of 46, XX disorder of sex development (DSD) resulting from mutations in the CYP19A1 gene. Virilized genitalia at birth often leads to an initial misdiagnosis of congenital adrenal hyperplasia (CAH), delaying the correct diagnosis.

Methods: We report two adolescents with 46, XX DSD initially managed as CAH, both were subjected to through clinical examination, laboratoty investigations (s.cortisol, ACTH, FSH, LH, Estradiol, serum Sodium and potassium), imaging (Both did MRI and one of them underwent laproscopy), and whole exome sequencing for genetic testing.

Results: Case 1: A 14-year-old patient was born with atypical genitalia and initially assigned as male. Initial basal hormonal evaluation revealed slightly elevated 17- hydroxy progesterone, adrenal androgens. Hydrocortisone therapy was started at 4 months for presumed congenital adrenal hyperplasia (CAH). Karyotype later revealed 46, XX with negative SRY. Feminizing genitoplasty was performed at 1.5 years and reassigned as female. At 14 years old, she presented with severe short stature (height SDS: −3 SD), absent pubertal development, markedly delayed bone age (8 years) while she was maintained on very low dose of hydrocortisone (3mg/m²/day). Hormonal assessment revealed hypergonadotropic hypogonadism, markedly elevated after stimulation (FSH 59.5 mIU/ml, LH 25.6 mIU/ml; low estradiol). Pelvic ultrasound showed an infantile uterus and visible ovaries with normal adrenals. Genetic testing confirmed a mutation in CYP19A1, establishing aromatase deficiency. Hydrocortisone was safely withdrawn and stopped and pubertal induction using estrogen was attempted. Case 2: A 15-year-old patient presented at 2 months with atypical genitalia and was initially diagnosed as CAH with subsequent hydrocortisone therapy. She underwent genitoplasty at 5 years old and female sex reassignment at that age. At 13 years old, she had short stature (height SDS: -2.6 SD), absent pubertal development with elevated gonadotropins (FSH 94.15 mIU/ml, LH 32.26 mIU/ml) and very low estradiol (<5 pg/ml). Abdominal ultrasound and laparoscopy failed to visualize the uterus while ovaries were properly detected. Genetic testing established the diagnosis of aromatase deficiency. The patient declined estrogen therapy for pubertal induction and experienced significant psychosocial distress requiring psychiatric support.

Conclusions: These cases highlight the diagnostic challenges of virilized 46, XX DSD, where aromatase deficiency may be initially misdiagnosed as congenital adrenal hyperplasia. Virilized 46, XX individuals without biochemical evidence of adrenal steroid excess, particularly when associated with hypergonadotropic hypogonadism and markedly low estradiol, should prompt reconsideration of the diagnosis and evaluation for aromatase deficiency. Early genetic testing for CYP19A1 is essential for accurate diagnosis, appropriate pubertal induction, and avoidance of prolonged unnecessary glucocorticoid therapy.