Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Neuroendocrinology 2010;92(suppl 1):6–10 DOI: 10.1159/000314215 Genetics of Cushing’s Syndrome Maria Yaneva   a, b Silvia Vandeva   a, b Sabina Zacharieva   a Adrian F. Daly   b Albert Beckers   b   a  Clinical Center of Endocrinology, Medical University, Sofia, Bulgaria; b  Department of Endocrinology, University of Liège, Liège, Belgium of MEN4, a rare MEN1-like syndrome due to mutation in the CDKN1B gene. Carney complex (CNC) due to PRKAR1A muta- tions in most cases is associated with CS, mainly as a cause of bilateral adrenal hyperplasia. The cAMP signaling path- way is affected in this setting. In recent times the involve- ment of genes such as PDE11A, PDE8B and others have ex- panded the spectrum of the genetic pathophysiology of CS. Copyright © 2010 S. Karger AG, Basel Introduction Cushing’s syndrome (CS) has been described for about a century and represents a classical syndrome in endocri- nology. Recent years have been marked by progress in elucidating the etiology and the pathogenesis of the dis- ease. In this short review, we summarize some of the mo- lecular genetic information of most relevance to the cau- sation of CS. Cushing’s Disease An ACTH-secreting pituitary adenoma (corticotropi- noma) is the commonest cause of CS, accounting for ap- proximately 75–80% of cases. A number of studies have examined the genetic alterations underlying sporadic corticotropinoma formation. Several changes in the pitu- itary-specific signaling pathways have been found. For instance, Morris et al. [1] found loss of expression of the Key Words Cushing’s disease  Cushing’s syndrome  Multiple endocrine neoplasia type 1  Carney complex  Familial isolated pituitary adenomas  Aryl hydrocarbon receptor-interacting protein Abstract Cushing’s syndrome (CS) is characterized by pathologically elevated free glucocorticoid levels. Endogenous hypercorti- solism is usually due to ACTH-secreting pituitary cortico- tropic adenomas and less often due to ectopic ACTH-secret- ing neuroendocrine neoplasms or ACTH-independent adre- nal cortisol hypersecretion. CS is a serious chronic disease leading to a several-fold increase in cardiovascular morbidi- ty and mortality. Multiple genetic alterations have been described in the setting of sporadic corticotropinoma for- mation. Changes in the expression profiles have been de- monstrated in growth factors and their receptors, cell-cycle regulators and in various genes related to hormonal gene transcription, synthesis and secretion. Sporadic adrenal ad- enomas and carcinomas may demonstrate dysfunction in genes such as TP53 among others. Cushing’s disease can be an inherited condition also. Multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenomas (FIPA) together account for 5% of pituitary adenomas. Cushing’s disease occurs infrequently in an inherited setting in both of these conditions. To date only 2 cases of Cushing’s disease have been described in association with mutations in AIP. One case of Cushing’s disease has been reported as part Published online: September 10, 2010 Albert Beckers Department of Endocrinology, CHU de Liège Domaine Universitaire du Sart-Tilman BE–4000 Liège (Belgium) Tel. +32 4 366 7083 or 8226, Fax +32 4 366 7261, E-Mail albert.beckers  @  chu.ulg.ac.be © 2010 S. Karger AG, Basel 0028–3835/10/0925–0006$26.00/0 Accessible online at: www.karger.com/nen