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Eur J Clin Invest. 2015 Dec;45(12):1306-15. doi: 10.1111/eci.12554. Epub 2015 Nov 20.

Transient generalized glucocorticoid hypersensitivity.

Author information

1
Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece.
2
Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
3
Institute of Molecular Biology, Genetics and Biotechnology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
4
Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
5
Division of Hematology, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
6
First Pediatric Department, Aristotle University Medical School, Thessaloniki, Greece.
7
Saudi Diabetes Study Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Abstract

BACKGROUND:

Transient generalized glucocorticoid hypersensitivity is a rare disorder characterized by increased tissue sensitivity to glucocorticoids and compensatory hypo-activation of the hypothalamic-pituitary-adrenal axis. The condition itself and the underlying molecular mechanisms have not been elucidated.

OBJECTIVE:

To present the clinical manifestations, endocrinologic evaluation and transcriptomic profile in a patient with transient generalized glucocorticoid hypersensitivity.

DESIGN AND RESULTS:

A 9-year-old girl presented with an 8-month history of clinical manifestations suggestive of Cushing syndrome. Endocrinologic evaluation revealed undetectable 08:00 h ACTH (<1 pg/mL) and cortisol (0·025 μg/dL) concentrations, which remained decreased throughout the 24-h period and did not respond to stimulation with ovine CRH. The disease gradually resolved spontaneously over the ensuing 3 months. Sequencing of the human glucocorticoid receptor gene revealed no mutations or polymorphisms. Western blot analysis in peripheral blood mononuclear cells revealed equal protein expression of hGRα of the patient in the disease and postresolution phases compared with a control subject. Transcriptomic analysis in peripheral blood mononuclear cells in the disease and postresolution phases identified 903 differentially expressed genes. Of these, 106 genes were up-regulated and 797 were down-regulated in the disease compared with the resolution phase. Bioinformatics analysis on the differentially expressed gene networks revealed Nuclear Factor-κB as the predominant transcription factor influencing the expression of the majority of differentially expressed genes.

CONCLUSIONS:

Our findings indicate that a transient postreceptor defect, or a virus- or bacterium-encoded molecule, may have enhanced glucocorticoid signal transduction, leading to transient generalized glucocorticoid hypersensitivity and hypo-activation of the HPA axis.

KEYWORDS:

Glucocorticoid hypersensitivity; glucocorticoid receptor; glucocorticoid signalling; glucocorticoids; transcriptomics

PMID:
26479047
DOI:
10.1111/eci.12554
[Indexed for MEDLINE]

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