Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
BACKGROUND: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor 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 adrenocorticotropic hormone-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 oligomenorrhea, 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 4 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 with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and 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.
Date Issued
2024-09
Date Acceptance
2024-08-20
Citation
European Journal of Endocrinology, 2024, 191 (3), pp.334-344
ISSN
0804-4643
Publisher
Oxford University Press
Start Page
334
End Page
344
Journal / Book Title
European Journal of Endocrinology
Volume
191
Issue
3
Copyright Statement
© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For
commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our
RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For
commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our
RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39171930
Subjects
Adrenal Glands
Adrenal Hyperplasia, Congenital
Adult
Androgens
Cushing Syndrome
Female
Glucocorticoids
Histone Demethylases
Humans
Pregnancy
adrenocortical tumor
androgen excess
Cushing's syndrome
GIP receptor
KDM1A
MC2R
PBMAH
PUMAH
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2024-08-22