Primary bilateral macronodular adrenal hyperplasia: definitely a genetic disease

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is an adrenal cause of Cushing syndrome. Nowadays, a PBMAH diagnosis is more frequent than previously, as a result of progress in the diagnostic methods for adrenal incidentalomas, which are widely available. Although some rare syndromic forms of PBMAH are known to be of genetic origin, non-syndromic forms of PBMAH have only been recognized as a genetic disease in the past 10 years. Genomics studies have highlighted the molecular heterogeneity of PBMAH and identified molecular subgroups, allowing improved understanding of the clinical heterogeneity of this disease. Furthermore, the generation of these subgroups permitted the identification of new genes responsible for PBMAH. Constitutive inactivating variants in ARMC5 and KDM1A are responsible for the development of distinct forms of PBMAH. To date, pathogenic variants of ARMC5 are responsible for 20–25% of PBMAH, whereas germline KDM1A alterations have been identified in >90% of PBMAH causing food-dependent Cushing syndrome. The identification of pathogenic variants in ARMC5 and KDM1A demonstrated that PBMAH, despite mostly being diagnosed in adults aged 45–60 years, is a genetic disorder. This Review summarizes the important progress made in the past 10 years in understanding the genetics of PBMAH, which have led to a better understanding of the pathophysiology, opening new clinical perspectives. Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is an adrenal cause of Cushing syndrome. This Review outlines recent progress in understanding the genetics of PBMAH. Key points Primary bilateral macronodular adrenal hyperplasia (PBMAH) can be diagnosed after the investigation of clinical signs of cortisol excess or bilateral adrenal incidentalomas; multiple bilateral nodules of >1 cm are seen on imaging. Despite the presentation being apparently sporadic rather than familial, PBMAH is frequently of genetic origin. Biallelic ARMC5 inactivation is responsible for about 20% of PBMAH and is associated with more severe Cushing syndrome and a high number of macronodules on CT scan in the index patients, compared with other forms of PBMAH. Biallelic KDM1A inactivation induces a particular form of PBMAH called food-dependent Cushing syndrome that is molecularly characterized by ectopic expression of GIP receptor in adrenocortical cells. The discovery of ARMC5 and KDM1A genetic alterations in PBMAH enabled familial screening, which can reduce th