Abstract
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.
Highlights
The discovery of the genetic drivers of adrenocortical tumorigenesis has been facilitated by advances in genomics over recent years and has provided new insights on the molecular pathogenesis of adrenocortical disease
Aberrant cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling was first associated with the development Cushing’s syndrome (CS) due to primary bimorphic adrenocortical disease (PBAD) in the rare tumor disorder McCune-Albright syndrome (MAS), which is caused by early embryonic postzygotic somatic activating defects in GNAS, the gene that encodes the a-subunit of the stimulatory G protein (Gsa) [2, 4]
Intravascular volume depletion causes activation of the reninangiotensin system with release of angiotensin II (AT-II) which binds to a G-protein coupled receptor (GPCR) on the adrenocortical zona glomerulosa cells, while increased potassium directly raises the production of aldosterone in adrenocortical zona glomerulosa cells, whose resting potential is set by potassium channel activity [10]
Summary
The discovery of the genetic drivers of adrenocortical tumorigenesis has been facilitated by advances in genomics over recent years and has provided new insights on the molecular pathogenesis of adrenocortical disease. Aberrant cAMP-PKA signaling was first associated with the development CS due to primary bimorphic adrenocortical disease (PBAD) in the rare tumor disorder McCune-Albright syndrome (MAS), which is caused by early embryonic postzygotic somatic activating defects in GNAS, the gene that encodes the a-subunit of the stimulatory G protein (Gsa) [2, 4]. Intravascular volume depletion causes activation of the reninangiotensin system with release of angiotensin II (AT-II) which binds to a G-protein coupled receptor (GPCR) on the adrenocortical zona glomerulosa cells, while increased potassium directly raises the production of aldosterone in adrenocortical zona glomerulosa cells, whose resting potential is set by potassium channel activity [10] These physiologic stimuli exert their effects through the generation of a cytoplasmic calcium signal through membrane depolarization with activation of voltage-gated calcium channels and increased intracellular calcium. Aldosterone acts on the mineralocorticoid receptor in the renal distal convoluted tubule, connecting tubule, and cortical collecting duct, amongst other tissues, with resulting increased renal sodium reabsorption and potassium excretion
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