Primary Generalized Glucocorticoid Resistance: a case report

Primary glucocorticoid resistance (OMIM 615962) is a rare endocrinologic condition caused by resistance of the human glucocorticoid receptor (hGR) to glucocorticoids (GR) and characterised by general or partial insensitivity of target organs to GK. Compensatory activation of hypothalamic-pituitary-andrenal axis results in development of a various pathological conditions caused by overstimulation of adrenal glands. Clinical spectrum may range from asymptomatic cases to severe cases of mineralocorticoid and/or androgen excess. At present time, primary generalized glucocorticoid resistance has been exclusively associated with defects in the NR3C1 gene. Here, we present a case report of an adolescent patient with clinical presentation of glucocorticoid resistance confirmed by detailed endocrinologic evaluation but no confirmed mutations in the NR3C1 gene.

1. Vingerhoeds AC, Thijssen JH, Schwarz F. Spontaneous hypercortisolism without Cushing’s syndrome. J Clin Endocrinol Metab. 1976; 43(5):1128–33. doi: https://doi.org/10.1210/jcem-43-5-1128

2. Chrousos GP, Vingerhoeds A, Brandon D, et al. Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. J Clin Invest. 1982; 69(6):1261–9. doi: https://doi.org/10.1172/jci110565

3. 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. февраль 1991; 87(2):680–6. doi: https://doi.org/110.1172/JCI115046

4. Cook CH, Centner RL, Michaels SE. An acne grading method using photographic standards. Arch Dermatol. 1979 г.; 115(5):571–5

5. Scatchard G. The attractions of proteins for small molecules and ions. Ann N Y Acad Sci. 1 May 1949 г.; 51(4):660–72. doi: https://doi.org/10.1111/j.1749-6632.1949.tb27297.x

6. Dallman MF, Akana SF, Levin N, et al. Corticosteroids and the control of function in the hypothalamo-pituitary-adrenal (HPA) axis. Ann N Y Acad Sci. 1994; 746:22-31; discussion 31-32, 64–7

7. Nicolaides NC., KinoT., ChrousosG., et al. Primary Generalized Glucocorticoid Resistance or Chrousos Syndrome. In K.R. Feingold (Eds.) et. al. Endotext. MDText.com, Inc. 2017. Available from: http://www.ncbi.nlm.nih.gov/books/NBK278930

8. Nicolaides NC, Charmandari E. Chrousos syndrome: from molecular pathogenesis to therapeutic management. Eur J Clin Invest. 2015; 45(5):504–14. doi: https://doi.org/10.1111/eci.1242

9. Lamberts SW, Poldermans D, Zweens M, et al. Familial cortisol resistance: differential diagnostic and therapeutic aspects. J Clin Endocrinol Metab. 1986; 63(6):1328–33. doi: https://doi.org/10.1210/jcem-63-6-1328

10. 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; 108(4):296–307

11. Teplyuk NP, Dukhanin AS, Ogurtsov SI, et al. Effect of prednisolone on the exchange of second messengers in lymphocytes of patients with pemphigus vulgaris In: Materials XII Russian national congress «Person and medicine». Moscow, 18–22 April 2005. Moscow; 2005: 259. (in Russ)

12. Dukhanin AS, Teplyuk NP, Lepekhova AA, et al. Biochemical aspects of steroid resistance of autoimmune pemphigus // Russian Journal of Skin and Venereal Diseases. — 2014; 17; 3; 25–31. (in Russ). doi: https://doi.org/10.17816/dv36873

13. Huizenga NA, de Lange P, Koper JW, et al. Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene. J Clin Endocrinol Metab. 2000; 85(5):2076–81

14. Wochnik GM, Rüegg J, Abel GA, et al. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem. 2005; 280(6):4609–16. doi: https://doi.org/10.1074/jbc.M407498200

15. Matysiak M, Makosa B, Walczak A, Selmaj K. Patients with multiple sclerosis resisted to glucocorticoid therapy: abnormal expression of heat-shock protein 90 in glucocorticoid receptor complex. Mult Scler Houndmills Basingstoke Engl. 2008; 14(7):919–26. doi: https://doi.org/10.1177/1352458508090666

16. Ginsberg J, Labedz T, Brindley DN. Phosphorylation of heat shock protein-90 by TSH in FRTL-5 thyroid cells. Thyroid Off J Am Thyroid Assoc. 2006; 16(8):737–42. 26. doi: https://doi.org/10.1089/thy.2006.16.737

17. Cai R, Zhou W, Jiang L, et al. Association between thyroid function and serum cortisol in cortisol-producing adenoma patients. Endocrine. 2020. 69(1):196-203. doi: https://doi.org/10.3390/ijms22063131

18. Fekete C, Lechan RM. Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. Endocr Rev. 2014; 35(2):159-194. doi: https://doi.org/10.1210/er.2013-1087

19. Vitellius G, Lombes M. Genetics in endocrinology: Glucocorticoid resistance syndrome. Eur J Endocrinol. 2020 Feb 1; 182(2): R15-R27. doi: https://doi.org/10.1530/EJE-19-0811

20. Nicolaides NC., Charmandari E. Chrousos syndrome: from molecular pathogenesis to therapeutic management. European journal of clinical investigation. 2015. 45(5): 504–514. doi: https://doi.org/10.1111/eci.12426