This review reports the main molecular alterations leading to development of benign cortisol and/or aldosterone secreting adrenal tumors. Causes of adrenal Cushing can be divided in two groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly Primary Pigmented Nodular Adrenocortical Disease (PPNAD), most of the time due to PRKAR1A germline inactivating mutations, and Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH), that can be caused in some rare syndromic cases by germline inactivating mutations of MEN1, APC and FH and of ARMC5 in isolated forms. PRKACA somatic activating mutations are the main alterations in unilateral cortisol producing adenomas (CPA). In primary hyperaldosteronism (PA), familial forms were identified in 1-5% of cases: familial hyperaldosteronism type I (FH-I) due to a chimeric CYP11B1/CYP11B2 hybrid gene, FH-II due to CLCN-2 germline mutations, FH-III due to KCNJ5 germline mutations, FH-IV due to CACNA1H germline mutations and PA, seizures and neurological abnormalities (PASNA) syndrome due to CACNA1D germline mutations. Several somatic mutations have been found in aldosterone producting adenomas (APAs) in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 genes.

This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. Methods: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). Results: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10 -12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. Conclusion: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.