An Overview of the Heterogeneous Causes of Cushing Syndrome Resulting From Primary Macronodular Adrenal Hyperplasia (PMAH)

Abstract

Primary macronodular adrenal hyperplasia (PMAH) is considered a rare cause of adrenal Cushing syndrome, is pituitary ACTH-independent, generally results from bilateral adrenal macronodules (>1 cm), and is often associated with variable cortisol secretion, resulting in a heterogeneous clinical presentation. Recent advances in the molecular pathogenesis of PMAH have offered new insights into the comprehension of this heterogeneous and complex adrenal disorder. Different molecular mechanisms involving the actors of the cAMP/protein kinase A pathway have been implicated in the development of PMAH, including germline and/or somatic molecular defects such as hyperexpression of the G-protein aberrant receptors and pathogenic variants of MC2R, GNAS, PRKAR1A, and PDE11A. Nevertheless, since 2013, the ARMC5 gene is believed to be a major genetic cause of PMAH, accounting for more than 80% of the familial forms of PMAH and 30% of apparently sporadic cases, except in food-dependent Cushing syndrome in which ARMC5 is not involved. Recently, 2 independent groups have identified that the tumor suppressor gene KDM1A is responsible for PMAH associated specifically with food-dependent Cushing syndrome. Consequently, PMAH has been more frequently genetically associated than previously assumed. This review summarizes the most important aspects, including hormone secretion, clinical presentation, radiological imaging, and molecular mechanisms, involved in familial Cushing syndrome associated with PMAH.

Keywords: ARMC5; KDM1A; PMAH; macronodular adrenal hyperplasia.

Figure 1.

Major pathophysiological mechanisms in the development of PMAH. In normal adrenocortical cells, ACTH binds to MC2R, activating the Gs-protein, leading to activation of the cAMP/PKA signaling pathway, thereby culminating in adrenal steroidogenesis. In PMAH, various hormone receptors bind to their respective aberrant membrane receptors coupled to assorted G-proteins, thereby activating the AC-cAMP signaling pathways. The inactivating mutations of ARMC5 prevent its pro-apoptotic function and decreases steroidogenic enzyme expression that is probably involved in adrenal hyperplasia; however, this mechanism is unclear. Loss of KDM1A leads to persistent histone methylation, resulting in aberrant transcriptional activation. Abbreviations: AC, adenylate cyclase; AT1R, angiotensin-II receptor; AVPR, arginine vasopressin receptor; C, catalytic subunits; CREB, cAMP response element-binding protein; GIPR, gastric inhibitory polypeptide receptor; Gq/i, G-protein alpha subunit; Gs-protein, stimulatory G-protein; HTR, 5-hydroxytryptamine receptor, serotonin receptor; LHCGR, luteinizing hormone/choriogonadotropin receptor; MC2R, melanocortin 2 receptor; N, nucleus; PDE, phosphodiesterases; PKA, protein kinase A; PMAH, primary macronodular adrenal hyperplasia; R, regulatory subunits. Adapted with permission of Bioscientifica Limited, from Fragoso MC, Alencar GA, Lerario AM, Bourdeau I, Almeida MQ, Mendonca BB, et al. Genetics of primary macronodular adrenal hyperplasia. J Endocrinol. 2015;224(1):R31-R43.; permission conveyed through Copyright Clearance Center, Inc.

Figure 2.

Primary macronodular adrenal hyperplasia. Macroscopically (A), adrenal enlargement and the presence of yellowish nodules protruding from the glandular contours were observed. Under microscopy, it is possible to observe 60% of compact cells (B) and 30% of clear cells (C). Source: Primary macronodular adrenal hyperplasia patient archive at the HCFMUSP Suprarenal Unit.

Figure 3.

Imaging of 1 patient with familial PMAH, ARMC5 positive. (A) Abdominal CT image (precontrast phase) with nodules with over 20 HU. (B) Imaging of 18F-FDG-PET/CT, showing bilateral adrenal nodules with 18F-FDG standardized uptake higher than that in the liver. SUVmax was elevated in these adrenal masses, reaching levels (arrows) frequently observed in malignant and metastatic lesions (SUVmax > 3.1). Source: Primary macronodular adrenal hyperplasia patient archive at the HCFMUSP Suprarenal Unit.