An Overview of the Heterogeneous Causes of Cushing's Syndrome due to Primary Macronodular Adrenal Hyperplasia (PMAH)

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.