LAUSR

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.