Abstract

Aromatase deficiency (AD) is a rare autosomal recessive disorder caused by pathogenic variants in the CYP19A1 gene, resulting in impaired conversion of androgens to estrogens. Clinical manifestations in 46, XX individuals include ambiguous genitalia, delayed puberty, and reproductive dysfunction. Both sexes may develop metabolic abnormalities, delayed epiphyseal closure, eunuchoid body proportions, and low bone mass. Because of its rarity and overlap with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), diagnosis may be delayed or missed. Gonadal tumors have not been reported in association with AD. We describe a 20-year-old female with ambiguous genitalia at birth who was diagnosed in infancy with 21OHD and treated with hydrocortisone and fludrocortisone. Despite poor treatment adherence, she never developed adrenal insufficiency. At 16 years of age, she was referred for evaluation of primary amenorrhea and absent puberty. Assessment revealed hypergonadotropic hypogonadism with markedly low estradiol levels, normal basal and ACTH-stimulated 17-hydroxyprogesterone levels (17-OHP), and a 46, XX karyotype, findings that were inconsistent with CAH. Additional features included metabolic abnormalities and low bone mass. Whole-genome sequencing identified a homozygous pathogenic CYP19A1 splice-site variant (c.1263+1G>T), confirming AD. Imaging and surgery demonstrated an enlarged right adnexal mass and a hypoplastic left ovary. Histopathology revealed bilateral gonadoblastoma with dysgerminoma arising in the right ovary. This case highlights the diagnostic challenges of AD and emphasizes the importance of reconsidering a diagnosis of CAH when biochemical findings are discordant with the clinical picture. To our knowledge, this is the first reported case of genetically confirmed aromatase deficiency with coexisting gonadoblastoma and dysgerminoma. Whether this coexistence represents a causal association or a coincidental finding remains uncertain.