Pathogenesis of Cushing Disease

An Update on the Genetics of Corticotropinomas

Adriana Albani, MD; Luis G. Perez-Rivas, PhD; Martin Reincke, MD, PhD; Marily Theodoropoulou, PhD


Endocr Pract. 2018;24(10):907-914. 

In This Article

Abstract and Introduction


Objective: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically.

Methods: Literature review.

Results: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 (USP8) gene in almost half of Cushing disease tumors.

Conclusion: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease.