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      Analysis of BCLI, N363S and ER22/23EK Polymorphisms of the Glucocorticoid Receptor Gene in Adrenal Incidentalomas

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          Abstract

          Context

          Patients with adrenal incidentalomas (AI) may experience detrimental consequences due to a minimal cortisol excess sustained by adrenal adenoma. SNPs of the glucocorticoid receptor gene ( NR3C1) modulate individual sensitivity to glucocorticoids and may interfere with the clinical presentation.

          Objective

          To compare the frequency of N363S, ER22/23EK and BclI SNPs in patients with AI with the general population and to evaluate whether these SNPs are linked to consequences of cortisol excess.

          Setting

          Multicentric, retrospective analysis of patients referred from 2010 to 2014 to 4 centers (Orbassano, Milano, Messina [Italy] and Zagreb [Croatia]).

          Patients

          411 patients with AI; 153 males and 258 females and 186 from blood donors.

          Main outcomes measures

          All patients and controls were genotyped for BclI, N363S and ER22/23EK and SNPs frequency was associated with clinical and hormonal features.

          Results

          SNP frequency was: SNP frequency was: N363S 5.4% (MAF 0.027), BclI 54.7% (MAF 0.328), ER22/23EK 4.4% (MAF 0.022), without any significant difference between patients and controls. N363S was more frequent in hypertensive patients (p = 0.03) and was associated with hypertension (p = 0.015) in patients with suppressed cortisol after the 1-mg DST.

          Conclusions

          Our results demonstrate that SNPs of the glucocorticoid receptor gene do not play a pathogenetic role for AI. The impact of any single SNP on the phenotypic expression of minimal cortisol excess is limited and their analysis does not provide additional data that may be exploited for patient management.

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          Most cited references30

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          Clinical practice. The incidentally discovered adrenal mass.

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            The clinically inapparent adrenal mass: update in diagnosis and management.

            Clinically inapparent adrenal masses are incidentally detected after imaging studies conducted for reasons other than the evaluation of the adrenal glands. They have frequently been referred to as adrenal incidentalomas. In preparation for a National Institutes of Health State-of-the-Science Conference on this topic, extensive literature research, including Medline, BIOSIS, and Embase between 1966 and July 2002, as well as references of published metaanalyses and selected review articles identified more than 5400 citations. Based on 699 articles that were retrieved for further examination, we provide a comprehensive update of the diagnostic and therapeutic approaches focusing on endocrine and radiological features as well as surgical options. In addition, we present recent developments in the discovery of tumor markers, endocrine testing for subclinical disease including autonomous glucocorticoid hypersecretion and silent pheochromocytoma, novel imaging techniques, and minimally invasive surgery. Based on the statements of the conference, the available literature, and ongoing studies, our aim is to provide practical recommendations for the management of this common entity and to highlight areas for future studies and research.
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              AME position statement on adrenal incidentaloma.

              To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 September 2016
                2016
                : 11
                : 9
                : e0162437
                Affiliations
                [1 ]Internal Medicine 1, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Italy
                [2 ]Unit of Endocrinology and Metabolic Diseases, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milano Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
                [3 ]Endocrine Unit, Department of Clinical and Experimental Medicine, University of Messina, Policlinico G. Martino Hospital, Messina, Italy
                [4 ]Department of Endocrinology, University Hospital Zagreb, Zagreb, Croatia
                [5 ]Statistical Unit, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga, Hospital, Orbassano, Italy
                [6 ]Medical Genetics, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Italy
                University of Birmingham, UNITED KINGDOM
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MT received research grants and speaker honoraria from HRA Pharma. GR received grants from Novartis and Shire. SC received grants from Novartis, Ipsen, Italfarmaco, Pfizer and Eli Lilly. The other Authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: GR MT IC.

                • Data curation: PPerotti.

                • Formal analysis: PBerchialla PPerotti DG.

                • Funding acquisition: GR MT.

                • Investigation: SP AP VM AC DK SC PPaccotti.

                • Methodology: GR DG MDM PBerchialla.

                • Supervision: PBeck-Peccoz MDM.

                • Writing – original draft: GR MT.

                • Writing – review & editing: GR SP IC DK SC.

                Article
                PONE-D-16-16833
                10.1371/journal.pone.0162437
                5029814
                27649075
                4e651640-3f45-4c10-9530-5f77a37ca0c6
                © 2016 Reimondo et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 April 2016
                : 23 August 2016
                Page count
                Figures: 0, Tables: 7, Pages: 11
                Funding
                Funded by: Università degli Studi di Torino (IT)
                Award ID: Ricerca Locale 2013 and 2014
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100006692, Università degli Studi di Torino;
                Award ID: Ricerca Locale 2013 and 2014
                Award Recipient :
                The study was supported by grants from the University of Turin (Ricerca Locale 2013 and 2014) to GR and MT. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Hormones
                Lipid Hormones
                Hydrocortisone
                Biology and Life Sciences
                Biochemistry
                Hormones
                Steroid Hormones
                Hydrocortisone
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Hypertension
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Adenomas
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
                Variant Genotypes
                Medicine and Health Sciences
                Endocrinology
                Endocrine Disorders
                Diabetes Mellitus
                Medicine and Health Sciences
                Metabolic Disorders
                Diabetes Mellitus
                Biology and Life Sciences
                Biochemistry
                Lipids
                Cholesterol
                Biology and Life Sciences
                Anatomy
                Bone
                Bone Density
                Medicine and Health Sciences
                Anatomy
                Bone
                Bone Density
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Bone
                Bone Density
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Bone
                Bone Density
                Medicine and Health Sciences
                Health Care
                Patients
                Custom metadata
                Due to legal restrictions, access to data is limited. For researchers who meet the criteria for access to confidential data, all relevant data are available upon request from Internal Medicine 1, San Luigi Gonzaga Hospital, Orbassano, Italy. Data requests can be sent to the corresponding author of the paper.

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