Primary Generalized Glucocorticoid Resistance Differential Diagnoses

1. Kino T, Chrousos GP. Glucocorticoid effects on gene expression. Steckler T, Kalin NH , Reul JMHM, eds. Handbook of Stress and the Brain. Amsterdam: Elsevier; 2005. 5(1): 295–311.

2. Chrousos GP, Charmandari E, Kino T. Glucocorticoid action networks--an introduction to systems biology. J Clin Endocrinol Metab. 2004 Feb. 89(2):563-4. [QxMD MEDLINE Link].

3. Chrousos GP. The glucocorticoid receptor gene, longevity, and the complex disorders of Western societies. Am J Med. 2004 Aug 1. 117(3):204-7. [QxMD MEDLINE Link].

4. Galon J, Franchimont D, Hiroi N, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 2002 Jan. 16(1):61-71. [QxMD MEDLINE Link].

5. Zhou J, Cidlowski JA. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids. 2005 May-Jun. 70(5-7):407-17. [QxMD MEDLINE Link].

6. Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol. 2006 Dec. 102(1-5):11-21. [QxMD MEDLINE Link].

7. Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E. The human glucocorticoid receptor: molecular basis of biologic function. Steroids. 2010 Jan. 75(1):1-12. [QxMD MEDLINE Link].

8. Hollenberg SM, Weinberger C, Ong ES, et al. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985 Dec 19-1986 Jan 1. 318(6047):635-41. [QxMD MEDLINE Link].

9. Kino T, Manoli I, Kelkar S, Wang Y, Su YA, Chrousos GP. Glucocorticoid receptor (GR) beta has intrinsic, GRalpha-independent transcriptional activity. Biochem Biophys Res Commun. 2009 Apr 17. 381(4):671-5. [QxMD MEDLINE Link].

10. Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA. The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem. 1999 Sep 24. 274(39):27857-66. [QxMD MEDLINE Link].

11. Chrousos GP, Kino T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Sci STKE. 2005 Oct 4. 2005(304):pe48. [QxMD MEDLINE Link].

12. McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. 1999 Jun. 20(3):321-44. [QxMD MEDLINE Link].

13. McKenna NJ, O'Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell. 2002 Feb 22. 108(4):465-74. [QxMD MEDLINE Link].

14. 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].

15. Hittelman AB, Burakov D, Iniguez-Lluhi JA, Freedman LP, Garabedian MJ. Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. EMBO J. 1999 Oct 1. 18(19):5380-8. [QxMD MEDLINE Link].

16. 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].

17. Chrousos GP. Hormone resistance and hypersensitivity rtates. Chrousos GP, Olefsky JM, Samols E. (eds). Modern Endocrinology Series. Philadelphia, PA: Lippincott, Williams & Wilkins; 2002. 318(6047): 542.

18. Kino T, De Martino MU, Charmandari E, Mirani M, Chrousos GP. Tissue glucocorticoid resistance/hypersensitivity syndromes. J Steroid Biochem Mol Biol. 2003 Jun. 85(2-5):457-67. [QxMD MEDLINE Link].

19. Chrousos GP, Kino T. Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders. Ann N Y Acad Sci. 2009 Oct. 1179:153-66. [QxMD MEDLINE Link].

20. Chrousos GP, Vingerhoeds A, Brandon D, et al. Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. J Clin Invest. 1982 Jun. 69(6):1261-9. [QxMD MEDLINE Link]. [Full Text].

21. Chrousos GP, Detera-Wadleigh SD, Karl M. Syndromes of glucocorticoid resistance. Ann Intern Med. 1993 Dec 1. 119(11):1113-24. [QxMD MEDLINE Link].

22. Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab. 2008 May. 93(5):1563-72. [QxMD MEDLINE Link].

23. Nader N, Bachrach BE, Hurt DE, et al. A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain. J Clin Endocrinol Metab. 2010 May. 95(5):2281-5. [QxMD MEDLINE Link].

24. 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].

25. Tomlinson JW, Walker EA, Bujalska IJ, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004 Oct. 25(5):831-66. [QxMD MEDLINE Link].

26. Charmandari E, Kino T. Chrousos syndrome: a seminal report, a phylogenetic enigma and the clinical implications of glucocorticoid signalling changes. Eur J Clin Invest. 2010 Oct. 40(10):932-42. [QxMD MEDLINE Link].

27. Chrousos G. Q&A: primary generalized glucocorticoid resistance. BMC Med. 2011 Mar 23. 9:27. [QxMD MEDLINE Link].

28. Karl M, Lamberts SW, Koper JW, et al. Cushing's disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. Proc Assoc Am Physicians. 1996 Jul. 108(4):296-307. [QxMD MEDLINE Link].

29. Hurley DM, Accili D, Stratakis CA, et al. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 1991 Feb. 87(2):680-6. [QxMD MEDLINE Link].

30. Karl M, Lamberts SW, Detera-Wadleigh SD, et al. Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene. J Clin Endocrinol Metab. 1993 Mar. 76(3):683-9. [QxMD MEDLINE Link].

31. Malchoff DM, Brufsky A, Reardon G, et al. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 1993 May. 91(5):1918-25. [QxMD MEDLINE Link].

32. Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001 Nov. 86(11):5600-8. [QxMD MEDLINE Link].

33. Ruiz M, Lind U, Gafvels M, et al. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). 2001 Sep. 55(3):363-71. [QxMD MEDLINE Link].

34. Mendonca BB, Leite MV, de Castro M, et al. Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. J Clin Endocrinol Metab. 2002 Apr. 87(4):1805-9. [QxMD MEDLINE Link].

35. Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. 2002 Jun. 87(6):2658-67. [QxMD MEDLINE Link].

36. Charmandari E, Kino T, Souvatzoglou E, Vottero A, Bhattacharyya N, Chrousos GP. Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype. J Clin Endocrinol Metab. 2004 Apr. 89(4):1939-49. [QxMD MEDLINE Link].

37. Charmandari E, Raji A, Kino T, et al. A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: the importance of the C terminus of hGR LBD in conferring transactivational activity. J Clin Endocrinol Metab. 2005 Jun. 90(6):3696-705. [QxMD MEDLINE Link].

38. Charmandari E, Kino T, Ichijo T, Zachman K, Alatsatianos A, Chrousos GP. Functional characterization of the natural human glucocorticoid receptor (hGR) mutants hGRalphaR477H and hGRalphaG679S associated with generalized glucocorticoid resistance. J Clin Endocrinol Metab. 2006 Apr. 91(4):1535-43. [QxMD MEDLINE Link].

39. Charmandari E, Kino T, Ichijo T, et al. A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance. J Clin Endocrinol Metab. 2007 Oct. 92(10):3986-90. [QxMD MEDLINE Link].

40. Zhu HJ, Dai YF, Wang O, et al. Generalized glucocorticoid resistance accompanied with an adrenocortical adenoma and caused by a novel point mutation of human glucocorticoid receptor gene. Chin Med J (Engl). 2011 Feb. 124(4):551-5. [QxMD MEDLINE Link].

41. Roberts ML, Kino T, Nicolaides NC, et al. A novel point mutation in the DNA-binding domain (DBD) of the human glucocorticoid receptor causes primary generalized glucocorticoid resistance by disrupting the hydrophobic structure of its DBD. J Clin Endocrinol Metab. 2013 Apr. 98(4):E790-5. [QxMD MEDLINE Link].

42. Nicolaides NC, Roberts ML, Kino T, et al. A novel point mutation of the human glucocorticoid receptor gene causes primary generalized glucocorticoid resistance through impaired interaction with the LXXLL motif of the p160 coactivators: dissociation of the transactivating and transreppressive activities. J Clin Endocrinol Metab. 2014 May. 99(5):E902-7. [QxMD MEDLINE Link].

43. Nicolaides NC, Geer EB, Vlachakis D, et al. A novel mutation of the hGR gene causing Chrousos syndrome. Eur J Clin Invest. 2015 Aug. 45(8):782-91. [QxMD MEDLINE Link].

44. Nicolaides NC, Skyrla E, Vlachakis D, et al. Functional characterization of the hGRαT556I causing Chrousos syndrome. Eur J Clin Invest. 2016 Jan. 46(1):42-9. [QxMD MEDLINE Link].

45. Nicolaides NC, Charmandari E. Chrousos syndrome: from molecular pathogenesis to therapeutic management. Eur J Clin Invest. 2015 May. 45(5):504-14. [QxMD MEDLINE Link].

46. Vitellius G, Trabado S, Hoeffel C, et al. Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study. Eur J Endocrinol. 2018 Apr. 178 (4):411-23. [QxMD MEDLINE Link].

47. Nicolaides NC, Chrousos GP. Bilateral adrenal hyperplasia and NR3C1 mutations causing glucocorticoid resistance: Is there an association?. Eur J Endocrinol. 2018 Oct 12. 179 (5):C1-C4. [QxMD MEDLINE Link].

48. Nicolaides NC, Charmandari E. Primary generalized glucocorticoid resistance and hypersensitivity syndromes: a 2021 update. Int J Mol Sci. 2021 Oct 7. 22 (19):[QxMD MEDLINE Link]. [Full Text].

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

Disclosure: Nothing to disclose.

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.

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.

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.

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.

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).

• Print this section
• Print the entire contents of
• Print the entire contents of article