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Endocrine Abstracts (2024) 99 EP919 | DOI: 10.1530/endoabs.99.EP919

1Birmingham, Birmingham, United Kingdom; 2Würzburg, Würzburg, Germany; 3London, London, United Kingdom

Background: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing’s syndrome. Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess has never been studied before.

Methods: We investigated a woman with a large, heterogeneous 7 cm adrenal mass (with a radiologically normal contralateral adrenal) and adrenocorticotropic hormone (ACTH)-independent glucocorticoid and androgen excess, a presentation typically suggestive of adrenocortical carcinoma. We undertook detailed histopathological examination in addition to a comprehensive molecular analysis of the resected adrenal mass as well as of the patient and the parent’s leukocyte DNA.

Findings: Histopathological examination revealed macronodular adrenal hyperplasia without evidence of malignancy. Interval imaging 24 months after surgery persistently showed normal contralateral adrenal gland. At whole-exome sequencing of four representative nodules, we detected inactivating germline variants p.G46S and p.R269Dfs*7 in KDM1A; inactivating KDM1A variants have been described in 90% of PBMAH associated with ectopic expression of the gastric inhibitory polypeptide receptor (GIPR) leading to food-dependent Cushing syndrome. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA-sequencing on a representative nodule showed low/absent expression of KDM1A and a high expression of GIPR compared to an available dataset of 52 unilateral sporadic adenomas and 4 normal adrenal glands. Sanger sequencing confirmed germline KDMIA p.R269Dfs*7 variant in the father and KDM1A p.G46S variant in the mother. Clinical assessment of the parents showed no features of glucocorticoid or androgen excess.

Conclusion: We investigated the first case of primary unilateral macronodular adrenocortical hyperplasia (PUMAH) associated with severe Cushing’s syndrome and concomitant androgen excess and suggest pathogenic mechanisms involving KDM1A, but without features of food-dependent Cushing’s syndrome.

Volume 99

26th European Congress of Endocrinology

Stockholm, Sweden
11 May 2024 - 14 May 2024

European Society of Endocrinology 

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