Exploratory Study of the Association of Genetic Factors With Recovery of Adrenal Function in Cushing Disease

Matthew H Nguyen; Wei Zhang; Nathan Pankratz; John Lane; Prashant Chitiboina; Fabio R Faucz; James L Mills; Constantine A Stratakis; Christina Tatsi

doi:10.1210/jendso/bvad046

Exploratory Study of the Association of Genetic Factors With Recovery of Adrenal Function in Cushing Disease

J Endocr Soc. 2023 Apr 25;7(6):bvad046. doi: 10.1210/jendso/bvad046. eCollection 2023 May 5.

Authors

Matthew H Nguyen¹, Wei Zhang², Nathan Pankratz³, John Lane³, Prashant Chitiboina⁴, Fabio R Faucz⁵, James L Mills⁶, Constantine A Stratakis¹, Christina Tatsi¹

Affiliations

¹ Unit on Hypothalamic and Pituitary Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA.
² Academy of Mathematics and System Sciences, Chinese Academy of Sciences, Beijing 100045, China.
³ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55454, USA.
⁴ Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Epidemiology Branch, Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA.

Abstract

Successful treatment of endogenous Cushing disease (CD) is often followed by a period of adrenal insufficiency (AI). We performed an exploratory study on genetic factors potentially involved in the hypothalamic-pituitary-adrenal (HPA) axis recovery in patients with CD after remission. We identified 90 patients who achieved remission after surgery and had a minimum of 3 months follow-up. Variants in a selected panel of genes that were rare in the general population and predicted as damaging in silico were retrieved from whole exome sequencing analysis. We did not identify any variant with significant correlation with recovery time after adjusting for multiple comparisons. On gene-specific analysis the BAG1 gene showed a correlation with shorter duration of postsurgical AI, but both patients with BAG1 variants later experienced a recurrence. After excluding patients with recurrence, no statistical association was recorded. To conclude, we did not identify a strong genetic modifier of HPA recovery in this exploratory study.

Keywords: Cushing disease; HPA axis; adrenal insufficiency; genetics; pituitary.

Published by Oxford University Press on behalf of the Endocrine Society 2023.