Primary Unilateral Macronodular Adrenal Hyperplasia With Concomitant Glucocorticoid And Androgen Excess And KDM1A Inactivation.
Elhassan, Yasir S Appenzeller, Silke Landwehr, Laura-Sophie Lippert, Juliane Popat, Dillon Gilligan, Lorna C Abdi, Lida Goh, Edwina Diaz-Cano, Salvador Kircher, Stefan
Elhassan, Yasir S
Appenzeller, Silke
Landwehr, Laura-Sophie
Lippert, Juliane
Popat, Dillon
Gilligan, Lorna C
Abdi, Lida
Goh, Edwina
Diaz-Cano, Salvador
Kircher, Stefan
Citations
Altmetric:
Affiliation
Other Contributors
Publication date
2024-08-22
Subject
Collections
Research Projects
Organizational Units
Journal Issue
Abstract
Background: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and GIP-dependent Cushing's syndrome due to ectopic expression of the gastric inhibitory polypeptide receptor (GIPR) typically harbour inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied.
Methods: We investigated a woman with a large, heterogeneous adrenal mass and severe ACTH-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhoea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents.
Results: Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of four representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G>A:p.G46S and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA-sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared to 52 unilateral sporadic adenomas and four normal adrenal glands. LH Receptor (LHCGR) expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7; mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess.
Conclusions: We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.
Keywords: KDM1A; MC2R; Cushing’s syndrome; GIP receptor; PBMAH; PUMAH; adrenocortical tumour; androgen excess.
Citation
Elhassan YS, Appenzeller S, Landwehr LS, Lippert J, Popat D, Gilligan LC, Abdi L, Goh E, Diaz-Cano S, Kircher S, Gramlich S, Sutcliffe RP, Thangaratinam S, Chan LF, Fassnacht M, Arlt W, Ronchi CL. Primary Unilateral Macronodular Adrenal Hyperplasia With Concomitant Glucocorticoid And Androgen Excess And KDM1A Inactivation. Eur J Endocrinol. 2024 Aug 22:lvae106. doi: 10.1093/ejendo/lvae106. Epub ahead of print. PMID: 39171930.
Type
Article