Genetic Basis for PMAH Enables Earlier Diagnosis, Improves Management of Cushing Syndrome

Several research studies presented at ENDO 2021 have evaluated the molecular mechanisms underlying Cushing syndrome to facilitate earlier diagnosis and improve disease management.

The following article is part of our coverage of the Endocrine Society’s annual meeting (ENDO 2021) that is being held virtually from March 20-23, 2021. Endocrinology Advisor‘s staff will report on the top research in hormone science and clinical care. Check back for the latest news from ENDO 2021.


Recent molecular genetic investigations of primary macronodular adrenal hyperplasia (PMAH) provide new insights for future research on adrenal disorders, which enables earlier diagnosis to improve the management of Cushing syndrome, according to according to study data presented at ENDO 2021, held virtually from March 20 to 23, 2021.1-3

Research studies seek to understand the precise sequence of events and the molecular mechanisms underlying Cushing syndrome. Cortisol secretion has been shown to be regulated by the ectopic adrenocorticotropic hormone (ACTH).2

The regulation of cortisol production in PMAH, despite suppressed levels of ACTH of pituitary origin, is exceedingly complex. Molecular events have been proposed to explain enhanced cortisol secretion, increased cell proliferation, and nodule formation in PMAH.2

Recurrent mutations detected in corticotropinomas, particularly mutations of the USP8 gene, have been found in approximately 40% of all corticotropinomas and 10% of the USP48 gene.3 Both gene products play an important role in the process of protein degradation/recovery by ubiquitination/deubiquitination, in which they rescue distinct target proteins from lysosomal degradation.

Intracranial meningiomas were found in 43% of Brazilian PMAH-family members with germline ARMC5.2 ARMC5 inactivation was reportedly associated with a slowed process of dedifferentiation in adrenocortical cells, concomitant with reduced expression of MC2R and steroidogenic enzymes.

Researchers noted that MC2R and steroidogenic enzymes are also frequently reduced in PMAH. They added that the function of the ARMC5 protein was still unknown, but that its gene may belong to the tumor suppressor family.2

Overall, it was concluded that, “The identification of a genetic basis for PMAH permits earlier diagnosis and [can] improve the management of this heterogeneous adrenal disease.”

The definitive function of the ARMC5 protein remains unknown, but the findings herein suggest that its gene is classed in the tumor suppressor family. Contemporary molecular genetic studies of PMAH should be considered for future research on adrenal function.

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1. Di Dalmazi G. Adrenal somatic gene mutations causing cortisol excess. Presented at: ENDO 2021; March 20-23, 2021; Virtual. Session S34.

2. Fragoso MCBV. Inherited gene mutations causing primary macronodular adrenal hyperplasia in familial Cushing’s syndrome. Presented: at ENDO 2021; March 20-23, 2021; Virtual. Session S34.

3. Stalla GK. Pituitary gene mutations and Cushing disease. Presented: at ENDO 2021; March 20-23, 2021; Virtual. Session S34.