Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study
| Autor: | Géraldine Vitellius, Séverine Trabado, Christine Hoeffel, Jérôme Bouligand, Antoine Bennet, Frederic Castinetti, Bénédicte Decoudier, Anne Guiochon-Mantel, Marc Lombes, Brigitte Delemer, F Amiot-Chapoutot, D Ancelle, F Bertoin, T Brue, P Caron, F Borson-Chazot, S Christin-Maitre, O Chabre, R Dessailloud, B Estour, H Grulet, F Illouz, N Jeandidier, V Kerlan, M Klein, A Penfornis, P Pierre, A Tabarin, P Touraine, M C Vantyghem, J Young |
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| Přispěvatelé: | Centre de Recherche en Sciences et Technologies de l'Information et de la Communication - EA 3804 (CRESTIC), Université de Reims Champagne-Ardenne (URCA) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism 03 medical and health sciences 0302 clinical medicine Endocrinology Glucocorticoid receptor Polymorphism (computer science) Internal medicine Renin–angiotensin system medicine business.industry General Medicine Hyperplasia medicine.disease 3. Good health 030104 developmental biology Dexamethasone suppression test Haploinsufficiency business Glucocorticoid Ex vivo medicine.drug |
| Zdroj: | European Journal of Endocrinology European Journal of Endocrinology, BioScientifica, 2018, 178 (4), pp.411-423. ⟨10.1530/EJE-17-1071⟩ |
| ISSN: | 0804-4643 1479-683X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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