Molecular Basis of Primary Aldosteronism and Adrenal Cushing Syndrome

Abstract

This review reports the main molecular alterations leading to development of benign cortisol and/or aldosterone secreting adrenal tumors. Causes of adrenal Cushing can be divided in two groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly Primary Pigmented Nodular Adrenocortical Disease (PPNAD), most of the time due to PRKAR1A germline inactivating mutations, and Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH), 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 (CPA). In primary hyperaldosteronism (PA), familial forms were identified in 1-5% 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, seizures and neurological abnormalities (PASNA) syndrome due to CACNA1D germline mutations. Several somatic mutations have been found in aldosterone producting adenomas (APAs) in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 genes.

Embryonic osteocalcin signaling determines lifelong adrenal steroidogenesis and homeostasis in the mouse

“…That we have been unable so far to identify individuals harboring a loss of function mutation in GPR158 through the screening of multiple databases is consistent with the notion that GPR158 seems intolerant to homozygous loss of function mutations (33). On the other hand, the fact that osteocalcin signaling in the adrenal gland regulates adrenal growth and steroidogenesis provides new molecular tools in the ongoing study aiming at elucidating the pathogenesis of the still poorly understood, pathological bilateral adrenal cell proliferation (34).…”

Síndrome de Cushing secundario a hiperplasia adrenal micronodular pigmentada primaria, revisión de caso

“…Dentro del síndrome de Cushing independiente de ACTH, los adenomas adrenales representan el 60% de los casos, el carcinoma adrenocortical el 35-40% y las hiperplasias nodulares < 2% 3 . En nuestro caso, al tratarse de un hipercortisolismo independiente de ACTH se esperaba la presencia de un adenoma adrenal, pero el resultado de la TC fue normal, por lo que se tuvieron que abordar causas menos frecuentes.…”

Transcriptomic Response Dynamics of Human Primary and Immortalized Adrenocortical Cells to Steroidogenic Stimuli

“…Primary adult adrenocortical cells were isolated from human adrenal glands removed from kidneys marked for transplant donation [22,30]. We characterized the timing of stimulation-induced gene expression responses by assaying five different post-stimulation time points (3,6,12,24, and 48 h), in triplicate. All replicates were highly correlated (average R ~0.97, Supplementary Figure S1 and Supplementary Table S2).…”

“…Additionally, there was also induction of CYP11B2, which encodes aldosterone synthase which carries out the last step of aldosterone synthesis [30]. While both ligands induced the expression of CYP11B1 and We characterized the timing of stimulation-induced gene expression responses by assaying five different post-stimulation time points (3,6,12,24, and 48 h), in triplicate. All replicates were highly correlated (average R~0.97, Supplementary Figure S1 and Table S2).…”

“…For example, primary aldosteronism is caused by the overproduction of aldosterone and leads to hypertension [ 3 , 4 , 5 ]. Likewise, overproduction of cortisol causes Cushing’s syndrome, which leads to severe metabolic disorders [ 6 ]. A detailed understanding of the regulation of steroidogenesis is imperative to harness these mechanisms for future treatments.…”