Journal
FRONTIERS IN ENDOCRINOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2021.632543
Keywords
Cushing’ s syndrome; genetics; primary aldosteronism; adrenocortical hyperplasia; adrenocortical adenoma
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Funding
- Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA [Z01-HD008920]
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This review summarizes the genetic alterations that lead to the development of benign glucocorticoid and/or mineralocorticoid producing adrenocortical tumors and hyperplasias over the past two decades through advancements in genomics. It discusses the significance of intracellular calcium signaling and abnormal cyclic adenosine monophosphate-protein kinase A signaling in aldosterone and cortisol hypersecretion, identifying key causative defects in various genes. Additionally, it highlights the role of germline pathogenic variants in ARMC5 as a tumor suppressor in cortisol-producing primary bilateral macronodular adrenal hyperplasia.
The genetic alterations that cause the development of glucocorticoid and/or mineralocorticoid producing benign adrenocortical tumors and hyperplasias have largely been elucidated over the past two decades through advances in genomics. In benign aldosterone-producing adrenocortical tumors and hyperplasias, alteration of intracellular calcium signaling has been found to be significant in aldosterone hypersecretion, with causative defects including those in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. In benign cortisol-producing adrenocortical tumors and hyperplasias abnormal cyclic adenosine monophosphate-protein kinase A signaling has been found to play a central role in tumorigenesis, with pathogenic variants in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B being implicated. The role of this signaling pathway in the development of Cushing's syndrome and adrenocortical tumors was initially discovered through the study of the underlying genetic defects causing the rare multiple endocrine neoplasia syndromes McCune-Albright syndrome and Carney complex with subsequent identification of defects in genes affecting the cyclic adenosine monophosphate-protein kinase A pathway in sporadic tumors. Additionally, germline pathogenic variants in ARMC5, a putative tumor suppressor, were found to be a cause of cortisol-producing primary bilateral macronodular adrenal hyperplasia. This review describes the genetic causes of benign cortisol- and aldosterone-producing adrenocortical tumors.
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