Molecular Basis of Primary Aldosteronism and Adrenal Cushing Syndrome

• Published in: Journal of the Endocrine Society Vol. 4; no. 9; p. bvaa075
• Main Authors: Vaduva, Patricia, Bonnet, Fideline, Bertherat, Jérôme
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.09.2020
• Subjects: Aldosterone; Corticosteroids; Cushing syndrome; Cyclic adenylic acid; Gene mutations; Genes; Genomics; Hyperaldosteronism; Mini-Reviews; Nervous system diseases; France; Texas; CTNNB1; cAMP; Cushing syndrome; primary aldosteronism
• ISSN: 2472-1972; 2472-1972
• DOI: 10.1210/jendso/bvaa075

Abstract This review reports the main molecular alterations leading to development of benign cortisol- and/or aldosterone-secreting adrenal tumors. Causes of adrenal Cushing syndrome can be divided in 2 groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly primary pigmented nodular adrenocortical disease, most of the time due to PRKAR1A germline-inactivating mutations, and primary bilateral macronodular adrenal hyperplasia that can be caused in some rare syndromic cases by germline-inactivating mutations of MEN1, APC, and FH and of ARMC5 in isolated forms. PRKACA somatic-activating mutations are the main alterations in unilateral cortisol-producing adenomas. In primary hyperaldosteronism (PA), familial forms were identified in 1% to 5% of cases: familial hyperaldosteronism type I (FH-I) due to a chimeric CYP11B1/CYP11B2 hybrid gene, FH-II due to CLCN-2 germline mutations, FH-III due to KCNJ5 germline mutations, FH-IV due to CACNA1H germline mutations and PA, and seizures and neurological abnormalities syndrome due to CACNA1D germline mutations. Several somatic mutations have been found in aldosterone-producing adenomas in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 genes. In addition to these genetic alterations, genome-wide approaches identified several new alterations in transcriptome, methylome, and miRnome studies, highlighting new pathways involved in steroid dysregulation.