Heredity and cortisol regulation in bilateral macronodular adrenal hyperplasia.

Cushing’s syndrome is a challenging disease in which excess cortisol is secondary to diverse tumors with complex molecular mechanisms. The syndrome has been categorized as corticotropindependent or corticotropin-independent. Approximately 20% of cases — mainly cortisol-secreting unilateral adenomas or carcinomas — are considered corticotropin-independent. Cushing’s syndrome rarely (in <2% of cases) results from primary bilateral nodular hyperplasia (either corticotropin-independent macronodular adrenal hyperplasia or micronodular hyperplasia). Bilateral macronodular adrenal hyperplasia with subclinical cortisol secretion is more frequent; approximately 10% of incidentally detected adrenal lesions, which are seen in approximately 4% of adults, are bilateral.1 Despite suppressed levels of circulating corticotropin, excess cortisol is not autonomous in bilateral macronodular adrenal hyperplasia; it is frequently regulated by hormones that activate aberrant G-protein–coupled receptors in adrenocortical tissues (receptors for vasopressin, serotonin, glucose-dependent insulinotropic peptide, catecholamines, luteinizing hormone, human chorionic gonadotrophin, and others).1-4 Bilateral macronodular adrenal hyperplasia was initially considered sporadic, but familial autosomal dominant forms are now recognized.1 The presence of bilateral hyperplasia suggested a pathogenesis that involves either a somatic mutation in adrenal progenitor cells arising during embryogenesis in sporadic cases, or a germline mutation in familial forms.1,2 Bilateral macronodular adrenal hyperplasia occasionally occurs in carriers of mutations of multiple endocrine neoplasia type 1, familial adenomatous polyposis, and fumarate hydratase genes4; however, in most cases, the responsible gene has been unknown. In this issue of the Journal, Assié et al.5 identify several inactivating mutations of armadillo repeat containing 5 (ARMC5), which is located at 16p11.2, in 55% of the 33 patients in their study who had bilateral macronodular adrenal hyperplasia. In each macronodule examined, both alleles carried distinct ARMC5 mutations: a germline mutation and a distinct somatic mutation. In contrast, in internodular diffuse hyperplasia, only the germline mutation is detected. Previous transcriptome and genome hybridization studies showed that beyond a common event such as the occurrence of ectopic glucose-dependent insulinotropic peptide receptors in diffuse hyperplasia, several somatic genetic events occurred in the different macronodules6,7; the study by Assié et al. suggests that the second somatic ARMC5 mutation is important in the generation of larger nodules and in glucocorticoid excess. The study also indicates that bilateral macronodular adrenal hyperplasia is genetically determined more frequently than previously believed — approximately 50% of firstdegree relatives of patients with apparently sporadic cases of Cushing’s syndrome carried the same mutation and had unsuspected subclinical adrenal nodular hyperplasia. The function of ARMC5 is unknown, but Assié et al. show that it behaved as a tumor-suppressor gene, causing apoptosis and cell death when transfected into H295R adrenocortical carcinoma cells. Its inactivation decreased the expression of corticotropin receptor MC2R and steroidogenic enzymes, which are frequently reduced in bilateral macronodular adrenal hyperplasia, a pathologic condition in which each cell is rela-