Cushing Syndrome Caused by Adrenocortical Tumors and Hyperplasias (Corticotropin- Independent Cushing Syndrome)

Abstract

Endogenous Cushing syndrome (CS) is caused by excess adrenal glucocorticoid secretion that is adrenocorticotropin (ACTH)-dependent or independent; ACTH-independent adrenocortical causes of CS account for up to 20% of CS in adults, and 15% in children over age 7 years. In younger children, ACTH-independent CS may account for as many as half of the CS cases. In both adults and children, adrenocortical lesions causing CS include the common, isolated and sporadic, solitary cortisol-producing adenoma, the rare adrenocortical cancer, and a spectrum of recently recognized, bilateral hyperplasias (bilateral adrenocortical hyperplasias, BAHs): micronodular adrenal disease and its pigmented variant, primary pigmented nodular adrenocortical disease are mostly genetic processes. Macronodular BAHs, ACTH-independent macronodular hyperplasia or massive macronodular adrenocortical disease are less frequently genetic and almost never present in children (except in McCune-Albright syndrome); they present often with atypical CS in middle-aged or elderly adults. The majority of benign adrenocortical tumors associated with CS are associated with defects of the cAMP signaling pathway, whereas adrenal cancer is linked to aberrant expression of growth factors and germline or somatic mutations of tumor suppressor genes such as TP53. Adrenalectomy is the preferred mode of treatment for all adrenocortical causes of CS.