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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 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 the long-term consequences of cortisol dysregulation as a result of earlier

diagnosis.

ARMC5 and KDM1A genetic alterations are not observed in all patients with PBMAH, leading to the view that further research will identify other genetic causes of PBMAH.

The authors thank L. Bouys and E. Pasmant from Institut Cochin (Université Paris Cité, Inserm U1016, CNRS UMR8104, Paris, France) for helpful discussions. J.B.’s laboratory was supported by

the Agence Nationale de la Recherche (18-CE14-0008-01; ANR-21-CE14-0011-01) and the Fondation pour la Recherche Médicale (FRM EQU201903007854). M.C.F. and J.B. received funding from

FAPESP-ANR (#2015/50192-9). M.R. was supported by a grant from the Else Kröner-Fresenius Stiftung (2012_A103 and 2015_A228) and by the Deutsche Forschungsgemeinschaft (DFG, German Research

Foundation, Projektnummer 314061271-TRR 205). I.P.C. receives a fellowship from the Fondation pour la Recherche Médicale (SPF201809007096).

These authors contributed equally: Isadora P. Cavalcante, Annabel Berthon.

Université Paris Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France

Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, Brazil

Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universität München, München, Germany

Institute of Molecular Biology and Biotechnology, FORTH & ELPEN, Heraklion, Crete, Greece

Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

J.B., A.B., I.P.C. and B.R. contributed to all aspects of the article. M.C.F. researched data for the article, contributed to discussion of the content and reviewed and/or edited the

manuscript before submission. M.R. and C.A.S. contributed to discussion of the content and reviewed and/or edited the manuscript before submission.

J.B. has received grants to his institution from Novartis, HRA Pharma and Recordati, and personal honoraria for consulting, lectures and meeting attendance from Novartis, Corcept, HRA Pharma

and Recordati. C.A.S. holds patents on PRKAR1A, PDE11A and GPR101 function; he has also received support from ELPEN, Pfizer, Sandoz and Lundbeck pharmaceuticals. M.R. has received personal

honoraria for consulting, lectures and advisory board membership from Novartis, Recordati, HRA Pharma, Crinetics and Ipsen. The other authors declare no competing interests.

Nature Reviews Endocrinology thanks Carla Scaroni, who co-reviewed with Filippo Ceccato, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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