Endocrine Abstracts

Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is an adrenal cause of Cushing’s syndrome secondary to the development of bilateral benign adrenocortical macronodules responsible for variable levels of cortisol excess. The classic form causing overt-Cushing syndrome is rare, but mild form of the disease is nowadays more frequently diagnosed in patients with bilateral adrenal incidentalomas and Mild Autonomous Cortisol Secretion (MACS). Genomic studies identified molecular subgroups correlating with the clinical and morphological heterogeneity of PBMAH. ARMC5 was identified 11 years ago as a new tumor suppressor gene responsible for PBMAH and germline alterations are found in about 20 % of the patients (Assié G, N Engl J Med, 2013; Bouys L, Eur J Endocrinol, 2023). More recently germline KDM1A alterations have been identified in more than 90 % of PBMAH causing Food-Dependent Cushing (Vaczlavik A, Genetics in Medicine, 2022; Bouys L, Eur J Endocrinol, 2025). These translational advances clearly demonstrate that PBMAH is the result of a molecular oncogenic process. In the 2022 revision of the WHO classification of adrenocortical tumors the term Bilateral Macronodular Adrenal Disease (BMAD) is proposed to reflect that. The clinical heterogeneity of PBMAH correlates with the molecular classification of PBMAH. ARMC5 related PBMAH are more severe and with an equilibrated sex ratio. Treatment, especially surgery is more often done in these ARMC5 patients. KDM1A related PBMAH are associated with Food-Dependent Cushing and mostly observed in female. Adrenal enlargement can be asymmetric. Diagnosed KDM1A patients are almost always treated, mostly by surgery. The remaining PBMAH with no know genetic defect today are observed in 2 groups from the morphological point of view and present specific genomic profiles (Violon F, Endocr Pathol. 2024). Cushing syndrome is usually less severe and patients are less often treated, especially with surgery. The perspective for patients management of these progress will be discussed.