Endocrine Abstracts

Primary adrenal Cushing syndrome is the result of cortisol hypersecretion mainly by adenomas and, rarely, by bilateral micronodular or macronodular adrenocortical hyperplasia. cAMP-dependent protein kinase A (PKA) signaling is the major activator of cortisol secretion in the adrenal cortex. Many adenomas and hyperplasias associated with primary hypercortisolism carry somatic or germline mutations of genes that constitute part of the cAMP–PKA pathway. We will discuss Cushing syndrome and its linkage to dysregulated cAMP–PKA signaling, with a focus on genetic findings in the past few years. In addition, we present the finding of germline inactivating mutations in ARMC5 that are associated with primary bilateral macronodular adrenocortical hyperplasia. This finding has implications for genetic counseling of affected patients; hitherto, most patients with this form of adrenal hyperplasia and Cushing syndrome were thought to have a sporadic and not a familial disorder. Other genetic syndromes including Li-Fraumeni, Beckwith Widemann, and Multiple Endocrine Neoplasia type 1 also are associated with familial Adrenal Cushing’s. In adrenal adenomas and PBMAH, a spectrum of tumour growth exists as a result of variable genetic defects. Many of the genetic factors that underlie the development of cortisol-producing lesions of the adrenal cortex have been identified. If germline mutations of the Carney complex gene PRKAR1A are present, patients develop PPNAD and cortisol hypersecretion in adolescence or early adulthood. If alterations of the cAMP–PKA pathway occur at the somatic level, cortisol-secreting adenomas form, at any age. However, active research is still attempting to understand why cAMP activation at different points in the pathway yields different phenotypes. Advances in knowledge in the past few years have identified novel treatment targets for cortisol excess in Cushing syndrome, and highlight the importance of genetic testing in this condition.