Genetics of micronodular adrenal hyperplasia and Carney complex

Micronodular bilateral adrenal hyperplasia (MiBAH) is a rare cause of adrenal Cushing syndrome (CS). The investigations carried out on this disorder during the last two decades suggested that it could be divided into at least two entities: primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). The most common presentation of MiBAH is familial PPNAD as part of Carney complex (CNC) (cPPNAD). CNC, associated with multiple endocrine and non-endocrine neoplasias, was first described in 1985 in 40 patients, 10 of whom were familial cases. In 2000, we identified inactivating germline mutations of the PRKAR1A gene, encoding the regulatory subunit type 1α (RIα) of protein kinase A (PKA), in the majority of patients with CNC and PPNAD. PRKAR1A mutations causing CNC lead to increased PKA activity. Since then, additional genetic alterations in the cAMP/PKA signaling pathway leading to increased PKA activity have been described in association with MiBAH. This review summarizes older and recent findings on the genetics and pathophysiology of MiBAH, PPNAD, and related disorders.