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  • Review Article
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A genetic and molecular update on adrenocortical causes of Cushing syndrome

Key Points

  • Germline alterations leading to aberrant cAMP-dependent protein kinase A (PKA) pathway activation can cause primary bilateral adrenal hyperplasia and Cushing syndrome

  • Cortisol-secreting adenomas can be caused by somatic mutations in genes encoding components of the cAMP–PKA pathway

  • Primary bilateral macronodular adrenal hyperplasia is frequently a genetic disorder caused by ARMC5 inactivating mutations

  • Intra-adrenal production of adrenocorticotropic hormone by steroidogenic cells contributes to dysregulated cortisol production in some types of adrenal hyperplasia, yielding potential new therapeutic targets for Cushing syndrome

Abstract

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) signalling is the major activator of cortisol secretion in the adrenal cortex. Many adenomas and hyperplasias associated with primary hypercortisolism carry somatic or germline mutations in genes that encode constituents of the cAMP–PKA pathway. In this Review, we discuss Cushing syndrome and its linkage to dysregulated cAMP–PKA signalling, with a focus on genetic findings in the past few years. In addition, we discuss the presence of germline inactivating mutations in ARMC5 in patients with primary bilateral macronodular adrenocortical hyperplasia. This finding has implications for genetic counselling 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.

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Figure 1: Ages of peak incidence of different causes of primary adrenal Cushing syndrome.
Figure 2: Development of adrenocortical lesions implicated in Cushing syndrome depends on the genetic aetiology.
Figure 3: Disruption of the cAMP–PKA signalling pathway in adrenocortical cells occurs in several endocrine disorders.

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Acknowledgements

This work was supported by the Intramural Research Program (IRP) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland 20892, USA.

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M.L. researched data and wrote the article. Both authors made substantial contribution to discussion of the content and reviewed and/or edited the manuscript before submission

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Correspondence to Constantine A. Stratakis.

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Lodish, M., Stratakis, C. A genetic and molecular update on adrenocortical causes of Cushing syndrome. Nat Rev Endocrinol 12, 255–262 (2016). https://doi.org/10.1038/nrendo.2016.24

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