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Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias

Abstract

Adrenocortical causes of Cushing's syndrome include the following: common cortisol-producing adenomas, which are usually isolated (without associated tumors) and sporadic (without a family history); rare, but often clinically devastating, adrenocortical carcinomas; and a spectrum of adrenocorticotropin-independent, and almost always bilateral, hyperplasias, which are not rare, and are the most recently recognized cause. The majority of benign lesions of the adrenal cortex seem to be linked to abnormalities of the cyclic AMP signaling pathway, whereas cancer is linked to aberrant expression of insulin-like growth factor II, tumor protein p53 and related molecules. In this article, we propose a new clinical classification and nomenclature for the various forms of adrenocorticotropin-independent adrenocortical hyperplasias that is based on their histologic and genetic features. We also review the molecular genetics of adrenocortical tumors, including recent discoveries relating to the role of phosphodiesterase 11A. This is a timely Review because of recent advances in the clinical and molecular understanding of these diseases.

Key Points

  • Hyperplasias cause Cushing's syndrome more frequently than was previously thought, and they include an expanding list of diverse diseases

  • The WNT (wingless-type MMTV integration site family) pathway is an important molecular pathway involved in both adrenocortical development and tumor formation

  • Inhibin A and tumor protein p53 (the products of the INHA and TP53 genes, respectively) are involved in the formation of malignant adrenocortical tumors

  • An overactive cyclic AMP signaling pathway is involved in most adrenocortical hyperplasias and occasionally in sporadic adenomas

  • Insulin-like growth factor II mediates the most important signaling pathway in adrenal cancer

  • Genetic defects of phosphodiesterases might be a frequent cause of adrenal and, possibly, other tumors

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Figure 1: Macroscopic features of various adrenocortical lesions.
Figure 2: Microscopic features of various adrenocortical lesions following hematoxylin and eosin (H & E) staining.
Figure 3: Molecular pathways involved in adrenocortical hyperplasias and other adrenal tumors.

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Acknowledgements

This work was supported by the National Institute of Child Health and Human Development (NICHD), National Institutes for Health (NIH) intramural project Z01-HD-000642-04 to CA Stratakis and NICHD clinical protocols 95CH0059 and 00CH160. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Correspondence to Constantine A Stratakis.

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Stratakis, C., Boikos, S. Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias. Nat Rev Endocrinol 3, 748–757 (2007). https://doi.org/10.1038/ncpendmet0648

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