Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome

Corticotropin-independent Cushing's syndrome occurs with adrenocortical tumors or hyperplasia. The authors report that germline duplications of PRKACA lead to bilateral adrenal hyperplasia, whereas somatic mutations lead to unilateral cortisol-producing adrenal adenomas. Endogenous hypercortisolism, referred to as Cushing's syndrome, is associated with substantial morbidity and mortality. 1 When Cushing's syndrome is severe, patients have catabolic symptoms such as muscle weakness, skin fragility, osteoporosis, and severe metabolic sequelae. 2 Hypersecretion of cortisol can be driven by an excess of pituitary or ectopic corticotropin or can be due to adrenocortical tumors or hyperplasias with corticotropin-independent cortisol production. Adrenal adenomas are common, with a prevalence of at least 3% among persons older than 50 years of age. 3 Whereas only a subset of these tumors is associated with overt Cushing's syndrome, some degree of cortisol excess is present, . . .