ESPE Abstracts (2019) 92 P3-234

Diagnostic Dilemma in a 46 XY Female

Richelle Waldner, Elizabeth Rosolowsky, Oana Caluseriu, Chelsey Grimbly


University of Alberta, Edmonton, Canada


Introduction: Disorders of sex development (DSD) are conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex. We present a case of a phenotypic 46 XY female with primary amenorrhea and full thelarche, presence of Mullerian structures, elevated testosterone with no virilization, and bilateral adnexal masses. Our differential diagnosis included Androgen Insensitivity and Gonadal Dysgenesis.

Case Description: A previously healthy phenotypic female presented with primary amenorrhea at 17-years-of age. She had thelarche onset at age 10 and she progressed to Tanner Stage V breast development. She had no virilization or symptoms to suggest adrenal insufficiency. She endorsed pelvic fullness. Family history was negative for amenorrhea or fertility concerns.

Physical examination revealed a tall (height 187.3cm, 100th percentile) and lean body habitus. She has broad hands and long fingers. Pubertal assessment showed Tanner Stage V breast development and Tanner Stage V pubic hair. Prader score was 0. An examination under anesthesia demonstrated a normal appearance of the vagina, cervix, uterus and fallopian tubes.

Laboratory investigations included an elevated beta-HCG (93 IU/L, reference range <5 IU/L), elevated FSH (43 U/L), and elevated testosterone (3.8 nmol/L, reference range 0.5-2.0nmol/L). A pelvic MRI showed large bilateral adnexal masses with the left and right diameter measuring 9.4 cm and 8.3 cm respectively. Genetic testing identified a heterozygous pathogenic variant in POR gene responsible for P450 oxidoreductase deficiency (PORD), a rare form of congenital adrenal hyperplasia.

Pathology of the adnexal masses identified bilateral dysgerminomas arising in gonadoblastomas, with no discernible underlying gonadal tissue. There were no metastases.

Discussion: Despite progressive understanding of DSD and the increasing role of genetic testing, challenges in diagnosis persist. We suspect partial gonadal dysgenesis in this case given the presence of Mullerian structures and malignant gonads. We hypothesize that there was adequate function of dysgenetic gonads for full thelarche, before malignant transformation. The dysgerminomas then produced testosterone, accounting for elevated levels but minimal virilization. The identified heterozygous mutation for PORD is insufficient to explain her phenotype, however; we question if she has a secondary, unidentified compounding mutation. She has no clinical or biochemical features to suggest PORD.

This case highlights the challenges in diagnosing patients with 46 XY DSD, where 80% of causes of gonadal dysgenesis are unknown, and reinforces the value of a multi-disciplinary approach including genetic and endocrine expertise in diagnostic evaluation.

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