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’s syndrome, pituitary ACTH-independent, generally due to 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/PKA 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, pathogenic variants of MC2R, GNAS, PRKAR1A and PDE11A. Nevertheless, since 2013, ARMC5 gene is believed to be a major genetic cause of PMAH, accounting for over 80% of the familial forms of PMAH and 30% of apparently sporadic cases, except in food-dependent Cushing’s syndrome in which ARMC5 is not involved. Recently, two independent groups have identified the tumor suppressor gene KDM1A responsible for PMAH associated specifically with food-dependent Cushing’s 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’s syndrome associated with PMAH.

Revisiting the Pathology of Bilateral Macronodular Adrenocortical Disease in Light of Recent Discoveries

“…In 2022, Vaczlavik et al [40] identi ed inactivating germline pathogenic variants in the lysine-speci c histone demethylase 1A gene (KDM1A) in BMAD patients diagnosed with food-dependent Cushing's syndrome and overexpression of the gastric inhibitory polypeptide receptor (GIP). Given that the authors detected no ARMC5 variations in those patients, such mutations appear to be mutually exclusive [40,41].…”

A Novel ARMC5 Germline Variant in Primary Macronodular Adrenal Hyperplasia Using Whole-Exome Sequencing

“…The ARMC5 gene was found to be the major genetic cause of PMAH and included nearly 80% of familial cases with PMAH and 30% of apparently sporadic forms [ 4 , 12 ]. ARMC5 has germline and somatic mutations, according to genetic analysis [ 7 ].…”

“…For instance, mutations in tumor suppressor genes, such as adenomatous polyposis coli gene ( APC ), menin ( MEN1 ), fumarate hydratase ( FH ), and armadillo repeat-containing protein 5 ( ARMC5 ), which later is detected in 20% to 50% of PMAH cases [ 8 ]. Recently, the other tumor suppressor gene, lysine (K)-specific demethylase 1A ( KDM1A) was identified in PMAH associated with food-dependent Cushing’s syndrome [ 9 , 10 , 11 , 12 ]. Furthermore, mutations in the ACTH receptor gene and guanine nucleotide-binding protein alpha-stimulating activity polypeptide ( GNAS ), cAMP-dependent protein kinase catalytic subunit alpha ( PRKACA ), phosphodiesterase 11A ( PDE11A ), and phosphodiesterase 8B ( PDE8B ) less frequently occurred in patients [ 8 ].…”

Cushing´s syndrome due to bilateral adrenal cortical disease: Bilateral macronodular adrenal cortical disease and bilateral micronodular adrenal cortical disease

“…These authors argue that more than one aberrant receptor is identified in each patient, rendering it difficult to select a specific receptor to be blocked (10) and that the use of aberrant receptor antagonists does not usually allow long-term control of hypercortisolism. Moreover, they are expensive and time-consuming tests (43). Nevertheless, the evaluation of the presence of aberrant receptors offers the possibility of using specific drugs to block the identified aberrant hormone receptors.…”