Somatic USP8 gene mutations are a common cause of pediatric cushing disease

Fabio R. Faucz, Amit Tirosh, Christina Tatsi, Annabel Berthon, Laura C. Hernández-Ramírez, Nikolaos Settas, Anna Angelousi, Ricardo Correa, Georgios Z. Papadakis, Prashant Chittiboina, Martha Quezado, Nathan D Pankratz, John Lane, Aggeliki Dimopoulos, James L. Mills, Maya Lodish, Constantine A. Stratakis

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Context: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed. Objective: We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas. Design and Methods: The USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations. Results: Five different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patientswith somaticmutationswere older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009). Conclusion: Somatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options.

Original languageEnglish (US)
Pages (from-to)2836-2843
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number8
StatePublished - Aug 1 2017

Bibliographical note

Funding Information:
This study was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (to C.A.S.).

Publisher Copyright:
© Copyright 2017 Endocrine Society.

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