Molecular Genetic and Genomic Alterations in Cushing's Syndrome and Primary Aldosteronism

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.

Keywords: Cushing’s syndrome; adrenocortical adenoma; adrenocortical hyperplasia; genetics; primary aldosteronism.

Figure 1

Prevalence of somatic driver pathogenic variants in aldosterone-producing adenomas. KCNJ5, potassium channel, inwardly rectifying, subfamily J, member 5; CACNA1D, calcium channel, voltage dependent, L-type, alpha-1D subunit; ATP1A1 ATPase, NA+/K+ transporting, alpha-1 polypeptide,; ATP2B3, ATPase, Ca(2+)-transporting, plasma membrane, 3; CACNA1H, calcium channel, voltage dependent, T-type, alpha-1H subunit; CTNNBI, catenin, beta-1.

Figure 2

Histologic Classification of Primary Aldosteronism.

Figure 3

Gene-based diagnostic algorithm for primary cortisol-producing adrenocortical hyperplasias. *APC, adenomatous polyposis coli gene; ARMC5, armadillo repeat-containing protein 5; c-PPNAD, CNC-associated primary pigmented nodular adrenocortical disease; CNC, Carney complex; FH, fumarate hydratase; GNAS, gene coding for the stimulatory subunit α of the G-protein (Gsα); i-MAD, isolated micronodular adrenocortical disease; i-PPNAD, isolated PPNAD; MAS, McCune–Albright syndrome; MEN1, multiple endocrine neoplasia type 1; PBAD, primary bimorphic adrenocortical disease; PBMAH, primary bilateral macronodular adrenocortical hyperplasia; PDE8B, phosphodiesterase 8B gene; PDE11A, phosphodiesterase 11A gene PPNAD, primary pigmented nodular adrenocortical disease; PRKACA, protein kinase, cAMP-dependent, catalytic, alpha; PRKAR1A, protein kinase, cAMP-dependent, regulatory, type I, α gene. *Adapted from Kamilaris CDC, Stratakis CA, Hannah-Shmouni F: Adrenocortical tumorigenesis: Lessons from genetics. Best Practice & Research Clinical Endocrinology & Metabolism 2020,34(3):101428.

Figure 4

Activation of cyclic AMP pathway through various genetic defects in adrenocortical tumors and hyperplasias. GNAS, gene coding for the stimulatory subunit α of the G-protein (Gsα); PDE8B, phosphodiesterase 8B gene; PDE11A, phosphodiesterase 11A gene; PRKACA, protein kinase, cAMP-dependent, catalytic, alpha; PRKAR1A, protein kinase, cAMP-dependent, regulatory, type I, α gene.