The Methylation Pattern of a Unique Bilateral Para-overian Adrenal Rest Tumor in a Girl With Nicotinamide Nucleotide Transhydrogenase Mutation

Clinical Presentation:
A 15-year-old girl, with homozygous G200S NNT-mutation followed for adrenal insufficiency reappeared to follow-up with severe virilization and elevated serum testosterone (28.3 nmol/l) and ACTH (1500 pmol/l). Pelvic MRI and Ultrasound demonstrated one sided paraovarian round tumor. Laparoscopic exploration revealed bilateral para ovarian mesosalpinx masses involving the serosa of the Fallopian tube, (3 and 1 cm in diameter). The testosterone level normalized within one day after surgical removal of those masses (0.2 nmol/l).

Results:
Histopathology demonstrated a pattern of adrenal rest tissue with strong intracellular positive staining for adrenal markers such as SF-1, calretinin, MART1 and inhibin. The staining for ovarian characteristic markers such as PAX 8 was negative. Studying mRNA extracted from the tissue by RT-PCR revealed the positive Gene expression of Cyp17a1, Cyp21a2 and Mc2rcDNA but not Pomc. We further profiled the epigenomic profile of the tumor using the Infinium Methylation EPIC array.

Conclusion:
This study exemplifies severe virilization that resulted from a unique and rare type of ART in ovarian related tissue. The laparoscopic surgical findings indicate that imaging techniques may be insufficient in identification of such rest tumors and call for laparoscopy when clinical findings are suggestive. Using histopathology markers cDNA studies and epigenomic profiling by methylation studies, our study shows for the first time that female ART originates from adrenal cells. The growth of a functional androgen producing “tumor” indicates that functional NNT protein is NOT required for androgen synthesis in contrast to glucocorticoids and that a zona reticularis similar tissue in ART is responsive to ACTH stimulation.