Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study.

Abstract

BACKGROUND:

Recently discovered mutations of NR3C1 gene, encoding for the GR, in patients with glucocorticoid resistance and bilateral adrenal incidentalomas prompted us to investigate whether GR mutations might be associated with adrenal hyperplasia.

OBJECTIVE:

The multicenter French Clinical Research Program (Muta-GR) was set up to determine the prevalence of GR mutations and polymorphisms in patients harboring bilateral adrenal incidentalomas associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs.

RESULTS:

One hundred patients were included in whom NR3C1 sequencing revealed five original heterozygous GR mutations that impaired GR signaling in vitro. Mutated patients presented with mild glucocorticoid resistance defined as elevated urinary free cortisol (1.7 ± 0.7 vs 0.9 ± 0.8 upper limit of normal range, P = 0.006), incomplete 1 mg dexamethasone suppression test without suppressed 8-AM adrenocorticotrophin levels (30.9 ± 31.2 vs 16.2 ± 17.5 pg/mL) compared to the non-mutated patients. Potassium and aldosterone levels were lower in mutated patients (3.6 ± 0.2 vs 4.1 ± 0.5 mmol/L, P = 0.01, and 17.3 ± 9.9 vs 98.6 ± 115.4 pg/mL, P = 0.0011, respectively) without elevated renin levels, consistent with pseudohypermineralocorticism. Ex vivo characterization of mutated patients' fibroblasts demonstrated GR haploinsufficiency as revealed by below-normal glucocorticoid induction of FKBP5 gene expression. There was no association between GR polymorphisms and adrenal hyperplasia in this cohort, except an over-representation of BclI polymorphism.

CONCLUSION:

The 5% prevalence of heterozygous NR3C1 mutations discovered in our series is higher than initially thought and encourages GR mutation screening in patients with adrenal incidentalomas to unambiguously differentiate from Cushing's states and to optimize personalized follow-up.

• Authors: Géraldine Vitellius, Séverine Trabado, Christine Hoeffel, Jérôme Bouligand, Antoine Bennet, Frederic Castinetti, Bénédicte Decoudier, Anne Guiochon-Mantel, Marc Lombes, Brigitte Delemer, investigators of the MUTA-GR Study
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 178 Issue 4 Pg. 411-423 (Apr 2018) ISSN: 1479-683X [Electronic] England
• PMID: 29444898 (Publication Type: Journal Article, Multicenter Study)
• Copyright: © 2018 European Society of Endocrinology.

Chemical References

• NR3C1 protein, human
• Receptors, Glucocorticoid

Topics

• Adrenal Gland Neoplasms (diagnostic imaging, epidemiology, genetics)
• Aged
• Cells, Cultured
• Female
• Follow-Up Studies
• France (epidemiology)
• Humans
• Incidental Findings
• Male
• Middle Aged
• Mutation (genetics)
• Prevalence
• Receptors, Glucocorticoid (genetics)