History

The first step in evaluating a patient with suspected alterations in tissue sensitivity to glucocorticoids is to obtain a complete personal and family history, with particular attention to evidence suggesting alterations in the activity of the HPA axis. In addition, any evidence suggesting possible CNS dysfunction, such as headaches, visual impairment, or seizures, should be noted. In female subjects, the regularity of menstrual cycles should be documented. In children and adolescents, growth and sexual maturation should be evaluated carefully.^[45]

Physical Examination

The physical examination should include an assessment for signs of hyperandrogenism, virilization, and glucocorticoid excess, as well as a complete neurologic examination. Arterial blood pressure should be recorded and preferably monitored over a 24-hour period.^[45]

Differential Diagnoses

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Auboeuf D, Honig A, Berget SM, O'Malley BW. Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science. 2002 Oct 11. 298(5592):416-9. [QxMD MEDLINE Link].
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Liu J, DeFranco DB. Protracted nuclear export of glucocorticoid receptor limits its turnover and does not require the exportin 1/CRM1-directed nuclear export pathway. Mol Endocrinol. 2000 Jan. 14(1):40-51. [QxMD MEDLINE Link].
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McMahon SK, Pretorius CJ, Ungerer JP, et al. Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1). J Clin Endocrinol Metab. 2010 Jan. 95(1):297-302. [QxMD MEDLINE Link].
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Media Gallery

(A) Schematic representation of the structure of the human glucocorticoid receptor (hGR) gene. Alternative splicing of the primary transcript gives rise to the 2 mRNA and protein isoforms, hGR-alpha and hGR-beta. (B) Functional domains of the hGR-alpha. The functional domains and subdomains are indicated beneath the linearized protein structures. AF, activation function; DBD, DNA-binding domain; LBD, ligand-binding domain; NLS, nuclear localization signal. (C) Enlargement of part of the DBD showing the amino acid sequence (single letter codes) of the 2 zinc fingers and the dimerization loop (in bold). The A to T mutation at position 458 that could produce a dimerization defective receptor is shown.
Nucleocytoplasmic shuttling of the glucocorticoid receptor. Upon binding to the ligand, the activated hGRα dissociates from heat shock proteins (HSPs) and translocates into the nucleus, where it homodimerizes and binds to glucocorticoid response elements (GREs) in the promoter region of target genes or interacts with other transcription factors (TFs), such as activator protein-1 (AP-1), nuclear factor-kappaκB (NF-kappaκB), and signal transducer and activator of transcription-5 (STAT5), ultimately modulating the transcriptional activity of, respectively, GRE- or TFRE-containing genes.
Location of the known mutations of the hGR gene causing primary generalized glucocorticoid resistance. DBD: DNA-binding domain. GR, glucocorticoid receptor; GREs, glucocorticoid response element; HSP, heat shock protein; LBD, ligand-binding domain; NTD, amino terminal domain; TF, transcription factor; TFRE, transcription factor response element.
Location of the identified mutations in the hGR gene causing Chrousos syndrome.

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Author

Nicolas Nicolaides, MD, PhD Fellow in Pediatric Endocrinology, First Department of Pediatrics, Aghia Sophia Children’s Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Tomoshige Kino, MD, PhD Staff Scientist, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health

Tomoshige Kino, MD, PhD is a member of the following medical societies: Endocrine Society

Disclosure: Nothing to disclose.

Evangelia Charmandari, MD, MSc, PhD, MRCP Associate Professor of Pediatric and Adolescent Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, Greece

Evangelia Charmandari, MD, MSc, PhD, MRCP is a member of the following medical societies: British Medical Association, Endocrine Society

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Society for Pediatric Research, Southern Society for Pediatric Research, Society for the Study of Reproduction, American Federation for Clinical Research, Pituitary Society

Disclosure: Nothing to disclose.

Chief Editor

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children's Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

Acknowledgements

Literary work of this article was funded by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, Maryland), the EU-European Social Fund, and the Greek Ministry of Development-General Secretariat of Research and Technology (Athens, Greece).

Sections Primary Generalized Glucocorticoid Resistance
Overview
Presentation
DDx
Workup
Treatment
Medication
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References

Primary Generalized Glucocorticoid Resistance Clinical Presentation

History

Physical Examination

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