KDM1A pathogenic variants link epigenetic regulation to GIP-dependent primary bilateral macronodular adrenal...

Patients with primary bilateral macronodular adrenal hyperplasia, recently reclassified as bilateral macronodular adrenal disease (BMAD), have bilateral benign large adrenocortical nodules and variable cortisol excess. BMAD is considered a rare cause of overt Cushing's syndrome but a more frequent cause of bilateral adrenal incidentalomas. Initially considered a sporadic disease, the bilateral nature of the adrenal nodules and familial aggregation suggested a genetic origin. Indeed, genomic studies have improved our understanding of BMAD pathogenesis and identified several genetic events responsible for BMAD. As rare syndromic presentations were described, non-syndromic etiologies were also identified, suggesting distinct molecular backgrounds among BMAD cases. Firstly, germline heterozygous inactivating mutations of the ARMC5 gene, discovered in 2013, are now known to account for around 20-25% of sporadic cases and most familial cases. A second molecular group was later identified, characterized by germline heterozygous pathogenic variants and loss of heterozygosity of the lysine demethylase 1A gene (KDM1A, or LSD1) in familial and sporadic GIP-dependent BMAD, representing less than 5% of BMAD cases. Similarly to ARMC5, the stepwise inactivation of KDM1A, an epigenetic regulator gene, supports a tumor suppressor model of tumorigenesis. The latter, more heterogeneous, molecular group remains globally unelucidated, with the exception of reports of pathogenic variants in genes involved in the PKA and cAMP signaling pathways. In all cases, genetic counseling should be offered to identify affected members and to screen for BMAD.