24 results on '"Vitellius G"'
Search Results
2. Unilateral or bilateral adrenalectomy in PPNAD: six cases from a single family followed up over 40 years
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Vitellius, G., Donadille, B., Decoudier, B., Leroux, A., Deguelte, S., Barraud, S., Bertherat, J., and Delemer, B.
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- 2022
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3. Déficit hypophysaire combiné dans le cadre des mutations homozygotes du gène POMC
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Vitellius, G., Berot, A., Petit, J.M., Gatta Cherifi, B., Delemer, B., and Le Collen, L.
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- 2023
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4. Apport de l’imagerie fonctionnelle dans la prise en charge d’un patient porteur d’un macroadénome hypophysaire, d’un paragangliome, d’une tumeur rénale et d’un variant du gène SDHC
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Le Collen, L., Lussey-Lepoutre, C., Vitellius, G., Barraud, S., Lalire, P., Gimenez Roqueplo, A.P., and Delemer, B.
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- 2023
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5. Traitement chirurgical du complexe de Carney : surrénalectomie uni ou bilatérale ?
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Vitellius, G. and Delemer, B.
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- 2020
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6. Résistance généralisée aux glucocorticoïdes : une pathologie pas si rare d’expression variable
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Delemer, B., Vitellius, G., Trabado, S., and Lombes, M.
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- 2018
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7. Résultats du PHRC National muta-GR : prévalence des mutations NR3C1 dans l’hyperplasie bilatérale des surrénales
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Vitellius, G., Trabado, S., Bouligand, J., Hoeffel, C., Mantel, A. Guiochon, Delemer, B., and Lombes, M.
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- 2017
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8. Trois mutations originales du récepteur des glucocorticoïdes révélées par un incidentalome surrénalien
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Vitellius, G., Bouligand, J., Fagart, J., Castinetti, F., Mantel, A. Guiochon, Delemer, B., Trabado, S., and Lombès, M.
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- 2015
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9. Evaluation of the transition program at the University Hospital of Reims from 2015 to 2020.
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Chibane S, Berot A, Lukas-Croisier C, Dollez L, Barraud S, Delemer B, and Vitellius G
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- Humans, Female, Male, Young Adult, Adult, Adolescent, Program Evaluation, Follow-Up Studies, Child, France, Diabetes Mellitus, Type 1 therapy, Hospitals, University, Transition to Adult Care, Glycated Hemoglobin analysis
- Abstract
The transition of young type 1 diabetic (T1D) patients from pediatric to adult healthcare is a high-risk period of loss to follow-up. Since 2015, we have implemented a transition program, involving both pediatric and adult clinicians. The main objective was to evaluate the number of patients who had succeeded this transition program at 1 year. We found that 86% of patients underwent the complete transition program. However, adverse outcomes occurred in 19.1% of patients at 1 year but decreased to 2.9% after 3 years. In 63% of patients their HbA1c level had deteriorated 1 year after the transition day and this level stabilized at around 8% in the following 2 and 3 years. In patients who had improved HbA1c levels the body mass index was lower (P = 0.03) and they lived alone (P = 0.04). Although our program seemed to allow a better follow-up than previously described, this study highlights the importance of further supporting this transition period., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)
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- 2024
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10. Correction: Artifactual hypoglycemia revealing an acrosyndrome: better believe in the glucose sensor.
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Taieb L, Ly TS, Francois M, Toquet S, Vitellius G, and Delemer B
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- 2024
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11. Artifactual hypoglycemia revealing an acrosyndrome: better believe in the glucose sensor.
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Taieb L, Ly TS, Francois M, Toquet S, Vitellius G, and Delemer B
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- 2024
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12. Medullary Thyroid Cancer: Epidemiology and Characteristics According to Data From the Marne-Ardennes Register 1975-2018.
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Caillé S, Debreuve-Theresette A, Vitellius G, Deguelte S, La Manna L, and Zalzali M
- Abstract
Context: Medullary thyroid cancer (MTC) is a rare disease., Objective: The main objective of our study was to analyze the incidence evolution of MTC with a follow-up of more than 40 years. Further, a descriptive and survival analysis was performed according to the Kaplan-Meier analysis., Design Setting and Patients: This is a retrospective epidemiological study using data from the Marne-Ardennes registry from 1975 to 2018. Two hundred sixty patients with MTC were included., Main Outcome Measures: The incidence was calculated in the territory of the register (Marne and Ardennes departments of France) and standardized on the demographic structure of France. Patient and tumor characteristics were described. An analysis in a subgroup comparing hereditary and sporadic forms was performed. An analysis of survival was performed., Results: The standardized incidence shows an increasing trend over time. The incidence increased significantly from 0.41 to 0.57/100 000 person-years between 1986 and 1996 and 2008 and 2018. The MTC was hereditary in 21.2% of cases. The sex ratio (males:females) was 0.73. The average age at diagnosis was 53 years. Ninety-seven patients (37.3%) were N1, 26 (10%) were M1, and 56 (21.5%) developed metastases during the follow-up. Complete remission was obtained in 58.5% of patients. The disease was refractory for 18.1% of patients. The 5-year survival rate was 88.4%. Sporadic cases had a poorer prognosis than hereditary MTC., Conclusion: Our study demonstrates a moderate increase in the incidence of MTC between 1975 and 2018. The prognosis remains worse for sporadic MTC than for hereditary MTC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2024
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13. [Predictive factors of complications in abdominal sequelae surgery of weight loss, after bariatric surgery in non-smokers].
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Delecroix Q, Jayyosi L, Loron G, Vitellius G, Raimond E, and François C
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- Humans, Retrospective Studies, Non-Smokers, Postoperative Complications surgery, Weight Loss, Bariatric Surgery adverse effects, Plastic Surgery Procedures, Abdominoplasty adverse effects, Obesity, Morbid surgery
- Abstract
The goal of this work was to find the main predictive factors of postoperative complications, other than smoking, after abdominoplasty or bodylift concerning sequelae of post-bariatric weight loss., Patients and Method: A retrospective monocentric study, including abdominoplasties or bodylift, after bariatric surgery was carried out between 01/01/2016 and 12/31/2019. The following were excluded: active smokers, non-bariatric patients and/or patients who had already had an abdominoplasty or body lift and/or who had undergone combined surgery., Results: 105 patients were included (73 bodylifts, 32 abdominoplasties). 68% presented at least one complication. The majority of them only resulted in an extension of local care. The serious complication rate was 2.9%. The risk factors for complications were: a young subject (P=0.014), greater weight loss (P=0.03), longer delay between bariatric surgery and plastic surgery (P=0.0002), performing a bodylift versus an abdominoplasty (P<0.01), gastric banding (P=0.029). Conversely, the bypass appeared to be a factor limiting post-sequelae complications of weight loss (P=0.041). The predictive complication model from the multivariate study concludes that the type of plastic surgery and preoperative BMI play a major role in the risk of complications., Conclusion: Surgery for abdominal weight loss sequelae presents frequent but generally benign complications. Preoperative patient information must therefore be adapted according to initial obesity and the extent of weight loss., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
- Published
- 2023
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14. Efficacy and Safety of Osilodrostat in Paraneoplastic Cushing Syndrome: A Real-World Multicenter Study in France.
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Dormoy A, Haissaguerre M, Vitellius G, Do Cao C, Geslot A, Drui D, Lasolle H, Vieira-Pinto O, Salenave S, François M, Puerto M, Boullay HD, Mayer A, Rod A, Laurent C, Chanson P, Reznik Y, Castinetti F, Chabre O, Baudin E, Raverot G, Tabarin A, and Young J
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- Humans, Prospective Studies, Retrospective Studies, Adrenocorticotropic Hormone, Hydrocortisone therapeutic use, Cushing Syndrome drug therapy, Adrenal Insufficiency
- Abstract
Context: Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS)., Objective: This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS., Methods: A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11)., Results: In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P < .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 × ULN [1.1-144] to 0.22 × ULN [0.12-0.66]; P < .01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h-UFC from 11.8 × ULN (0.3-247) to 0.43 × ULN (0.33-2.4) (P < .01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients., Conclusion: Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2023
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15. The mineralocorticoid receptor modulates timing and location of genomic binding by glucocorticoid receptor in response to synthetic glucocorticoids in keratinocytes.
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Carceller-Zazo E, Sevilla LM, Pons-Alonso O, Chiner-Oms Á, Amazit L, An Vu T, Vitellius G, Viengchareun S, Comas I, Jaszczyszyn Y, Abella M, Alegre-Martí A, Estébanez-Perpiñá E, Lombès M, and Pérez P
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- Animals, Mice, Glucocorticoids pharmacology, Glucocorticoids metabolism, Kinetics, Keratinocytes metabolism, Mice, Knockout, Genomics, Receptors, Glucocorticoid metabolism, Receptors, Mineralocorticoid genetics, Receptors, Mineralocorticoid metabolism
- Abstract
Glucocorticoids (GCs) exert potent antiproliferative and anti-inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in classical and non-classical targets including keratinocytes. Using knockout mice, we previously demonstrated that GR and MR exert essential nonoverlapping functions in skin homeostasis. These closely related receptors may homo- or heterodimerize to regulate transcription, and theoretically bind identical GC-response elements (GRE). We assessed the contribution of MR to GR genomic binding and the transcriptional response to the synthetic GC dexamethasone (Dex) using control (CO) and MR knockout (MR
EKO ) keratinocytes. GR chromatin immunoprecipitation (ChIP)-seq identified peaks common and unique to both genotypes upon Dex treatment (1 h). GREs, AP-1, TEAD, and p53 motifs were enriched in CO and MREKO peaks. However, GR genomic binding was 35% reduced in MREKO , with significantly decreased GRE enrichment, and reduced nuclear GR. Surface plasmon resonance determined steady state affinity constants, suggesting preferred dimer formation as MR-MR > GR-MR ~ GR-GR; however, kinetic studies demonstrated that GR-containing dimers had the longest lifetimes. Despite GR-binding differences, RNA-seq identified largely similar subsets of differentially expressed genes in both genotypes upon Dex treatment (3 h). However, time-course experiments showed gene-dependent differences in the magnitude of expression, which correlated with earlier and more pronounced GR binding to GRE sites unique to CO including near Nr3c1. Our data show that endogenous MR has an impact on the kinetics and differential genomic binding of GR, affecting the time-course, specificity, and magnitude of GC transcriptional responses in keratinocytes., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)- Published
- 2023
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16. Characteristics of newly diagnosed type 1 diabetes in paediatric and adult population from Reims University Hospital, France from 1997 to 2019.
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Berot A, Gitton A, Diallo AM, Rahim A, Lukas C, Souchon PF, Salmon AS, François M, Ly S, Vitellius G, Decoudier B, Sulmont V, Delemer B, and Barraud S
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- Adult, Child, Child, Preschool, Hospitals, Humans, Incidence, Retrospective Studies, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 epidemiology, Diabetic Ketoacidosis diagnosis, Diabetic Ketoacidosis epidemiology, Diabetic Ketoacidosis etiology, Ketosis
- Abstract
French health insurance data showed that the incidence of type 1 diabetes mellitus (T1DM) in children increased over the years to 2015. The objective of our study was to assess the evolution of the number of incident cases of paediatric and adult type 1 diabetes in our institution, and to describe their clinical presentation and its evolution. All patients with T1DM managed at diagnosis at Reims University Hospital between 1997 and 2019 were included. The clinical and biological data were extracted from the Champagne-Ardenne Diabetes Network database. Included were 847 patients with a median age of 10.3 years. Diagnosis was established in 71% of cases before 15 years, 7.4% after 35 years. The number of newly diagnosed cases was 3.6-times higher in 2019 compared to 1997. Ketoacidosis, the frequency of which decreased with age (P < 0.0001), revealed diabetes in a total of 32% of cases and in 46% of children under 5 years. It was more severe in children than in adults (P = 0.03), and its frequency increased over the study period. Hypotrophy was found in 23% of children under 15 years of age, and was more pronounced before 5 years of age, with no improvement over time. We saw an increase in the frequency of obesity or overweight among adults. Our study showed an increase in incident cases of diabetes in our hospital that continued over time for both children and adults. Clinical features at diagnosis deteriorated during this period for those under 15 years of age with an increase in ketoacidosis frequency., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
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- 2022
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17. Three cases of thyroiditis after COVID-19 RNA-vaccine.
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Brès F, Joyeux MA, Delemer B, Vitellius G, and Barraud S
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- COVID-19 Vaccines adverse effects, Humans, RNA, 2019-nCoV Vaccine mRNA-1273 adverse effects, COVID-19 prevention & control, Graves Disease, Thyroiditis etiology
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- 2022
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18. Contraception use and knowledge related to pregnancy in diabetic women.
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Feutry L, Barbe C, Marquet-Dupont A, Fèvre A, Lukas-Croisier C, Vitellius G, Delemer B, and Barraud S
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- Adult, Contraception methods, Contraceptive Agents, Female, Humans, Pregnancy, Young Adult, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2 epidemiology, Pregnancy in Diabetics epidemiology
- Abstract
Background: Diabetes mellitus prevalence is increasing among women of child-bearing age. Diabetic pregnancy is associated with major maternal and fetal risks, and these can be reduced by preconception care. Pregnancy can be planned using appropriate effective contraception. The objective of this study was to assess diabetic patients' knowledge about pregnancy and to describe their contraceptive use., Study Design: An observational study was conducted from February to July 2020 at Reims University Hospital, France. Inclusion criteria were: women aged 18 to 40years, with type 1 (T1D) or type 2 diabetes (T2D). Patients filled out a survey about contraceptive use and knowledge regarding diabetic pregnancy and data were completed from medical records., Results: Eighty-nine T1D and 33 T2D patients were included, with mean ages of 27.9±6.3 and 32.6±4.6years, respectively. Seventy-five percent reported that they had been informed about pregnancy-related risks and 67% about the need to plan pregnancy. The preconception HbA1c target was known by 33% of patients. Appropriate knowledge about pregnancy was greater in T1D patients (65.9%, versus 36.4% in T2D patients; P=0.003). The rate of patients using an effective contraceptive method was 66.4%. Fifteen percent patients for whom contraception was recommended reported having no contraceptive method; 12.5% of contraception users were using a contraindicated method., Conclusion: A large majority of diabetic women were aware of pregnancy-related risks and the importance of pregnancy planning, but there are still gaps, especially in T2D patients. We need to improve our practices by providing more information and better access to appropriate effective contraception., Gov Number: NCT04350879., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
- Published
- 2022
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19. GENETICS IN ENDOCRINOLOGY: Glucocorticoid resistance syndrome
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Vitellius G and Lombes M
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- Adrenocorticotropic Hormone blood, Adrenocorticotropic Hormone genetics, Glucocorticoids blood, Glucocorticoids genetics, Humans, Hydrocortisone blood, Hydrocortisone genetics, Metabolism, Inborn Errors blood, Receptors, Glucocorticoid blood, Receptors, Glucocorticoid genetics, Metabolism, Inborn Errors diagnosis, Metabolism, Inborn Errors genetics, Receptors, Glucocorticoid deficiency
- Abstract
Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients presenting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to increased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11βHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier metabolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resistant patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients., (© 2020 European Society of Endocrinology)
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- 2020
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20. Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 in Glucocorticoid-Resistant Patients.
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Vitellius G, Delemer B, Caron P, Chabre O, Bouligand J, Pussard E, Trabado S, and Lombes M
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- Adult, Aged, Cell Line, Tumor, Dexamethasone administration & dosage, Female, HEK293 Cells, Humans, Loss of Function Mutation, Male, Middle Aged, Mineralocorticoid Excess Syndrome, Apparent genetics, Mineralocorticoid Excess Syndrome, Apparent metabolism, Promoter Regions, Genetic, RNA, Messenger metabolism, Receptors, Glucocorticoid agonists, Receptors, Glucocorticoid genetics, Signal Transduction, Mineralocorticoid Excess Syndrome, Apparent, 11-beta-Hydroxysteroid Dehydrogenase Type 2 metabolism, Gene Expression Regulation, Receptors, Glucocorticoid metabolism
- Abstract
Context: Six patients carrying heterozygous loss-of-function mutations of glucocorticoid (GC) receptor (GR) presented with hypercortisolism, associated with low kalemia, low plasma renin, and aldosterone levels, with or without hypertension, suggesting a pseudohypermineralocorticism whose mechanisms remain unclear. We hypothesize that an impaired activity of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; encoded by the HSD11B2 gene), catalyzing cortisol (F) inactivation, may account for an inappropriate activation of a renal mineralocorticoid signaling pathway in these GC-resistant patients., Objective: We aim at studying the GR-mediated regulation of HSD11B2., Design: The HSD11B2 promoter was subcloned and luciferase reporter assays evaluated GR-dependent HSD11B2 regulation, and 11β-HSD2 expression/activity was studied in human breast cancer MCF7 cells, endogenously expressing this enzyme., Results: Transfection assays revealed that GR transactivated the long (2.1-kbp) HSD11B2 promoter construct, whereas a defective 501H GR mutant was unable to stimulate luciferase activity. GR-mediated transactivation of the HSD11B2 gene was inhibited by the GR antagonist RU486. A threefold increase in HSD11B2 mRNA levels was observed after dexamethasone (DXM) treatment of MCF7 cells, inhibited by RU486 or by actinomycin, supporting a GR-dependent transcription. Chromatin immunoprecipitation further demonstrated a DXM-dependent GR recruitment onto the HSD11B2 promoter. 11β-HSD2 activity, evaluated by the cortisone/F ratio, quantified by liquid chromatography/tandem mass spectrometry, was 10-fold higher in the supernatant of DXM-treated cells than controls, consistent with a GR-dependent stimulation of 11β-HSD2 catalytic activity., Conclusion: Collectively, we demonstrate that 11β-HSD2 expression and activity are transcriptionally regulated by GR. In the context of GR haploinsufficiency, these findings provide evidence that defective GR signaling may account for apparent mineralocorticoid excess in GC-resistant patients., (Copyright © 2019 Endocrine Society.)
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- 2019
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21. Functional Characterization of Glucocorticoid Receptor Variants Is Required to Avoid Misinterpretation of NGS Data.
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Foussier L, Vitellius G, Bouligand J, Amazit L, Bouvattier C, Young J, Trabado S, and Lombès M
- Abstract
Recent advances in genetic analysis technologies such as next-generation sequencing (NGS) have considerably increased the incidental discovery of genetic abnormalities. Six heterozygous missense mutations of the human glucocorticoid receptor (GR; encoded by the NR3C1 gene) have been identified in the context of genetic screening of endocrine pathologies. GR, a nuclear receptor, hormone-induced transcription factor, is involved in many physiological processes. Nevertheless, the pathogenic significance of incidentally discovered mutations remains obscure. The aim of this work was to characterize these variants by evaluating their functional impact on GR signaling. Six original GR variants, located in exon 2, led to amino acid substitutions of the N -terminal domain of GR (F65V, M86V, A229T, A304E, N374S, and R386Q), excluding mainly the activation function tau core 1 domain, the potential site of functional interaction with transcriptional coregulators. Transient cotransfection in HEK293T cells of mutated GR-expressing vectors and a luciferase reporter established dose-response curves for dexamethasone. This excluded any major transactivation abnormality of the mutated GRs (ligand concentration leading to 50% maximal transactivation capacity ≈ 0.2 nM), with maximal transactivation capacity identical to that of the wild-type (WT) GR and without modification of the potentiation of transcriptional coactivator steroid receptor coactivator 2 except in N374S. Moreover, protein expression of mutated GRs and their cytonuclear translocation studied by immunocytochemistry were almost unchanged compared with WT GR. These results underline the silent nature of these missense GR variants and call for cautious interpretation of the discovery of genetic incidentalomas by NGS in the absence of detailed characterization in order to appropriately assess their functional impact on a particular signaling pathway.
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- 2019
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22. Pathophysiology of Glucocorticoid Signaling.
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Vitellius G, Trabado S, Bouligand J, Delemer B, and Lombès M
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- Cushing Syndrome genetics, Genetic Predisposition to Disease, Humans, Hypothalamo-Hypophyseal System physiology, Mutation, Pituitary-Adrenal System physiology, Polymorphism, Genetic, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Signal Transduction genetics, Glucocorticoids metabolism, Metabolism, Inborn Errors genetics, Metabolism, Inborn Errors metabolism, Receptors, Glucocorticoid deficiency
- Abstract
Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9β) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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23. Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study.
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Vitellius G, Trabado S, Hoeffel C, Bouligand J, Bennet A, Castinetti F, Decoudier B, Guiochon-Mantel A, Lombes M, and Delemer B
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- Adrenal Gland Neoplasms epidemiology, Aged, Cells, Cultured, Female, Follow-Up Studies, France epidemiology, Humans, Male, Middle Aged, Prevalence, Adrenal Gland Neoplasms diagnostic imaging, Adrenal Gland Neoplasms genetics, Incidental Findings, Mutation genetics, Receptors, Glucocorticoid genetics
- 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., (© 2018 European Society of Endocrinology.)
- Published
- 2018
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24. Three Novel Heterozygous Point Mutations of NR3C1 Causing Glucocorticoid Resistance.
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Vitellius G, Fagart J, Delemer B, Amazit L, Ramos N, Bouligand J, Le Billan F, Castinetti F, Guiochon-Mantel A, Trabado S, and Lombès M
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- Adrenal Gland Neoplasms drug therapy, Adult, Animals, Binding Sites, COS Cells, Cell Nucleus metabolism, Chlorocebus aethiops, Cushing Syndrome genetics, Cytoplasm metabolism, DNA, Neoplasm metabolism, Dexamethasone pharmacology, Female, HEK293 Cells, Humans, Male, Middle Aged, Models, Molecular, Mutation, Missense, Protein Structure, Secondary, Protein Transport, Receptors, Glucocorticoid metabolism, Adrenal Gland Neoplasms genetics, Drug Resistance, Neoplasm, Glucocorticoids pharmacology, Point Mutation, Receptors, Glucocorticoid chemistry, Receptors, Glucocorticoid genetics
- Abstract
Generalized glucocorticoid resistance is associated with glucocorticoid receptor (GR; NR3C1) mutations. Three novel heterozygous missense NR3C1 mutations (R477S, Y478C, and L672P) were identified in patients presenting with adrenal incidentalomas, glucocorticoid excess without Cushing syndrome. Dexamethasone (DXM) binding studies demonstrated that the affinity of GRR477S and GRY478C mutants, located in the DNA-binding domain (DBD) of GR, was similar to wild-type GR (Kd = 2-3 nM). In contrast, GRL672P mutant, located in the ligand-binding domain (LBD) of GR, was unable to bind glucocorticoids and was more sensitive to protein degradation. GR subcellular distribution revealed a marked decrease in DXM-induced nuclear translocation of GRR477S and GRY478C mutants, whereas GRL672P remained exclusively cytoplasmic. Chromatin immunoprecipitation demonstrated impaired recruitment of DBD mutants onto the regulatory sequence of FKBP5. Transactivation assays disclosed the lack of transcriptional activity of GRR477S and GRL672P , whereas GRY478C had a reduced transactivation capacity. Three-dimensional modeling indicated that R477S lost two essential hydrogen bonds with DNA, Y478C resulted in altered interaction with surrounding amino-acids, destabilizing DBD, whereas L672P altered the H8 helix folding, leading to unstructured LBD. This study identifies novel NR3C1 mutations with their molecular consequences on altered GR signaling and suggests that genetic screening of NR3C1 should be conducted in patients with subclinical hypercorticism., (© 2016 WILEY PERIODICALS, INC.)
- Published
- 2016
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