ESPE Yearbook of Paediatric Endocrinology

Brief summary: This narrative review summarizes the important progress made in the past 10 years in our understanding of the genetics of primary bilateral macronodular adrenal hyperplasia (PBMAH).

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is an adrenal cause of Cushing syndrome, attributed to the disrupted integrity of the adrenal cortex zonation that is important for steroidogenesis (1). Nowadays, the diagnosis of PBMAH is more frequent following the progress in the diagnostic methods for adrenal incidentalomas (2). The histologic milieu of PBMAH consists of adrenal enlargement with multiple bilateral benign adrenocortical nodules (diameter above 1 cm) that can result to cortisol excess independent of ACTH from the pituitary (adrenal Cushing syndrome) (3). PBMAH is diagnosed in adults, most often without any other personal or family history that would be suggestive of a genetic origin. However, the development of bilateral multiple benign adrenocortical tumours in the same patient suggests that predisposing genetic factors are important, while rare syndromic forms of PBMAH are known to be of genetic origin (4). Thus, in the past 10 years, non- syndromic forms of PBMAH have been recognized as a genetic disease (4). Genomics studies have highlighted the molecular heterogeneity of PBMAH and identified molecular subgroups, allowing improved understanding of the clinical heterogeneity of this disease (5). Constitutive inactivating variants in ARMC5 (20–25%) and KDM1A (>90%) of food dependent Cushing syndrome have demonstrated that PBMAH, despite mostly being diagnosed in adults aged 45–60 years, is a genetic disorder (6, 7).

This review summarizes the important progress made in the past 10 years, particularly the development of omics approaches and integrated genomics in understanding the genetics of PBMAH, which have led to a better understanding of the pathophysiology, opening new clinical perspectives. This important progress has translated into a better understanding of the physiopathology of the condition and has also highlighted factors and signaling pathways essential for the control of adrenocortical homeostasis. Still, the genetic cause (or causes) of the third molecular group of non-syndromic PBMAH that is not caused by ARMC5 or KDM1A remains to be determined. Considering the benefit for the index patient with PBMAH in identifying a genetic cause that could also favour the development of comorbidities, and that it could lead to early diagnosis of adrenal Cushing syndrome in family members, systematic genetic screening of PBMAH should now be considered.

References: 1. Lyraki, R. & Schedl, A. Adrenal cortex renewal in health and disease. Nat. Rev. Endocrinol. 2021; 17: 421–434. 2. Bengoa-Rojano N, Fernández-Argüeso M, Botella-Carretero JI, Pascual-Corrales E, Araujo-Castro M. Prevalence and phenotype of primary bilateral macronodular adrenal hyperplasia with autonomous cortisol secretion: a study of 98 patients. Rev Clin Esp (Barc). 2022; 222(8): 458–467. 3. Vassiliadi DA, Tsagarakis S. Diagnosis and management of primary bilateral macronodular adrenal hyperplasia. Endocr. Relat. Cancer. 2019; 26: R567–R581. 4. Bouys L, Chiodini I, Arlt W, Reincke M, Bertherat J. Update on primary bilateral macronodular adrenal hyperplasia (PBMAH). Endocrine. 2021 Mar;71(3):595–603. 5. Bonnet-Serrano F, Bertherat J. Genetics of tumors of the adrenal cortex. Endocr Relat Cancer. 2018; 25(3): R131–R152. 6. Tang P, Zhang J, Peng S, Yan X, Wang Y, Wang S, Zhang Y, Liu G, Xu J, Huang Y, Zhang D, Liu Q, Jiang J, Lan W. Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) patient with ARMC5 mutations. BMC Endocr Disord. 2023; 23(1): 77. 7. Vaczlavik A, Bouys L, Violon F, Giannone G, Jouinot A, Armignacco R, Cavalcante IP, Berthon A, Letouzé E, Vaduva P, Barat M, Bonnet F, Perlemoine K, Ribes C, Sibony M, North MO, Espiard S, Emy P, Haissaguerre M, Tauveron I, Guignat L, Groussin L, Dousset B, Reincke M, Fragoso MC, Stratakis CA, Pasmant E, Libé R, Assié G, Ragazzon B, Bertherat J. KDM1A inactivation causes hereditary food-dependent Cushing syndrome. Genet Med. 2022; 24(2): 374–383.