Poster Presentation ESA-SRB 2023 in conjunction with ENSA

Familial partial glucocorticoid resistance syndrome (#316)

Sneha Krishna 1 , Adam Morton 1
  1. Mater Hospital Brisbane, South Brisbane, QLD, Australia

A 27-year-old male was referred with fatigue, arthralgia, and hypercortisolaemia. Morning serum cortisol levels were 933 and 952nmol/L (RR 140-640) on Siemens immunoassay and failed to suppress following 1mg dexamethasone (serum cortisol 518nmol/L; RR < 50). He denied symptoms of Cushing syndrome, alcohol excess, anxiety or depression, consumption of herbal or complimentary products, and was not aware of any family history of hirsutism, hypertension, or hypokalaemia. There were no features of Cushing syndrome on examination. He was normotensive with BP 110/70mmHg.

Further investigations revealed serum ACTH of 34ng/L (RR 10-50), 24-hour-urine free cortisol 280nmol/day (RR 10-165), urine cortisol:cortisone <1.0, and absence of assay interference when cortisol was checked by high performance liquid chromatography. Bone mineral densitometry, aldosterone, renin and dehydroepiandrosterone were normal. Early morning and late-night salivary cortisol confirmed intact diurnal rhythm of cortisol production.

It was discovered that the patient’s sister had been investigated for hirsutism and aggressive behaviour at age 17. Her serum cortisol levels were 843 and 826nmol/L fasting, and 201 nmol/L following 1mg overnight dexamethasone.

A diagnosis of familial partial glucocorticoid resistance syndrome was made. Genetic testing is pending.

Discussion

Familial glucocorticoid resistance was first described in 1976 as hypercortisolism without overt Cushing syndrome stigmata 1,2 It is caused by loss-of-function mutations of the glucocorticoid receptor, often in the NR3C1 gene, resulting in hypothalamic-pituitary axis hyperactivation via increased ACTH.1,3 It is a heterogenous condition with 33 index cases. It can manifest with hypertension (13/33), hirsutism (13/17), adrenal hyperplasia (13/33), and hypokalaemic alkalosis.1,4,5,6 Other causes of hypercortisolaemia are listed in Table 1.4,764ef1bed446e4-Screen+Shot+2023-08-30+at+8.44.25+pm.png

  1. Kino, T., & Chrousos, G. P. (2001). Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes. The Journal of endocrinology, 169(3), 437–445. https://doi.org/10.1677/joe.0.1690437
  2. Kino, T., De Martino, M. U., Charmandari, E., Mirani, M., & Chrousos, G. P. (2003). Tissue glucocorticoid resistance/hypersensitivity syndromes. The Journal of steroid biochemistry and molecular biology, 85(2-5), 457–467. https://doi.org/10.1016/s0960-0760(03)00218-8
  3. Shamim, W., Bakhai, A., Yousufuddin, M., & Coats, A. J. (2000). Increased urinary cortisol and androgen metabolites in a young female with hypertension: partial glucocorticoid resistance syndrome. Cardiology, 93(1-2), 131–132. https://doi.org/10.1159/000007015
  4. van Rossum, E. F., & Lamberts, S. W. (2006). Glucocorticoid resistance syndrome: A diagnostic and therapeutic approach. Best practice & research. Clinical endocrinology & metabolism, 20(4), 611–626. https://doi.org/10.1016/j.beem.2006.09.005
  5. Gossain, V. V., El-Rifai, M., Krishnan, P., & Bhavsar, B. (2018). Cushing's syndrome with no clinical stigmata - a variant of glucocorticoid resistance syndrome. Clinical diabetes and endocrinology, 4, 23. https://doi.org/10.1186/s40842-018-0072-5
  6. Vitellius, G., & Lombes, M. (2020). Genetics in endocrinology: Glucocorticoid resistance syndrome. European journal of endocrinology, 182(2), R15–R27. https://doi.org/10.1530/EJE-19-0811
  7. Sharma, S., Sabale, V., Satav, V. et al. (2021). Glucocorticoid resistance syndrome: let’s give it a thought. Afr J Urol 27(14). https://doi.org/10.1186/s12301-020-00112-y