{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:44:23Z","timestamp":1790837063064,"version":"4.1.0"},"reference-count":70,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,3,23]],"date-time":"2015-03-23T00:00:00Z","timestamp":1427068800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"The European Union (European Social Fund \u2013 ESF) and Greek national funds through the Operational Program \u201cEducation and Lifelong Learning\u201d of the National Strategic Reference Framework (NSRF) \u2013 Research Funding Program: THALIS \u2013University of Athens","award":["377204"],"award-info":[{"award-number":["377204"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Primary Generalized Glucocorticoid Resistance or Chrousos syndrome is a rare genetic condition characterized by end\u2010organ insensitivity to glucocorticoids owing to inactivating mutations of the\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>\n                        3C1\n                      <\/jats:italic>\n                      gene.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      We conducted a systematic review of the published, peer\u2010reviewed medical literature using\n                      <jats:styled-content style=\"fixed-case\">MEDLINE<\/jats:styled-content>\n                      (1975 through November 2014) to identify original articles and reviews on this topic. The search terms included \u2018primary generalized glucocorticoid resistance\u2019, \u2018Chrousos syndrome\u2019, \u2018glucocorticoid receptor gene\u2019 and \u2018glucocorticoid receptor mutations\u2019.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Only a few cases of Chrousos syndrome have been described to date, ranging from asymptomatic to severe forms of mineralocorticoid and\/or androgen excess. All reported cases have been associated with point mutations or deletions in the\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>\n                        3C1\n                      <\/jats:italic>\n                      gene. The tremendous progress of molecular biology has enabled us to apply standard methods to investigate the molecular mechanisms of action of the mutant glucocorticoid receptors (GRs). We and others have identified and functionally characterized novel mutations causing Chrousos syndrome, while structural biology has enabled us to have a better understanding of how conformational changes of the receptor cause glucocorticoid resistance. In this review, we also present our results of the functional characterization of two recently described mutations, and we discuss the diagnostic approaches and therapeutic management of patients with Chrousos syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Although Chrousos syndrome is a rare condition, many clinical cases remain unrecognized for a long time. We recommend determination of the 24\u2010h urinary free cortisol excretion and sequencing of the\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>\n                        3C1\n                      <\/jats:italic>\n                      gene in patients with hyperandrogenism and\/or hypertension of unknown origin.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/eci.12426","type":"journal-article","created":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T01:13:25Z","timestamp":1424913205000},"page":"504-514","source":"Crossref","is-referenced-by-count":61,"title":["Chrousos syndrome: from molecular pathogenesis to therapeutic management"],"prefix":"10.1111","volume":"45","author":[{"given":"Nicolas C.","family":"Nicolaides","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Metabolism and Diabetes First Department of Pediatrics University of Athens Medical School \u2018Aghia Sophia\u2019 Children's Hospital Athens Greece"},{"name":"Division of Endocrinology and Metabolism Clinical Research Center Biomedical Research Foundation of the Academy of Athens Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Charmandari","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism and Diabetes First Department of Pediatrics University of Athens Medical School \u2018Aghia Sophia\u2019 Children's Hospital Athens Greece"},{"name":"Division of Endocrinology and Metabolism Clinical Research Center Biomedical Research Foundation of the Academy of Athens Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,3,23]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12464"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000362736"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2009.106"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1992.03480090092034"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.67.040403.120816"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199505183322008"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0278-5846(85)90187-3"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4899-2064-5_13"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000181089"},{"key":"e_1_2_13_11_1","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1210\/jcem.84.5.5631","article-title":"Clinical review 104: adrenocorticotropin (ACTH)\u2010 and non\u2010ACTH\u2010mediated regulation of the adrenal cortex: neural and immune inputs","volume":"84","author":"Bornstein SR","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/10253890701292119"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-032026"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/stke.3042005pe48"},{"key":"e_1_2_13_15_1","first-page":"295","volume-title":"Handbook of Stress and the Brain","author":"Kino T","year":"2005"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra050541"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2009.09.002"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1123348"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2005.02.006"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117943"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2004-0112"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.12.4319-4330.2003"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.02.110"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-009-0098-z"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.544072"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.07.013"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010014\u20108900\u20109"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R110.179325"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.03.025"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0328com"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022289"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-0245com"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01151-12"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-216382"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2005.11.012"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-012-1155-2"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2012.01129.x"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026499604848"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0507572102"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0502-473"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400775"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-08798-6_6"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61684-0"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2013.183"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1159\/000330759"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2003337"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1159\/000342505"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6823-14-71"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2010.02336.x"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0040"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-9-27"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110565"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-119-11-199312010-00009"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2463"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-1003"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.6.2036"},{"key":"e_1_2_13_57_1","first-page":"296","article-title":"Cushing's disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant\u2010negative glucocorticoid receptor mutation","volume":"108","author":"Karl M","year":"1996","journal-title":"Proc Assoc Am Physicians"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115046"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.76.3.683"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116410"},{"key":"e_1_2_13_61_1","doi-asserted-by":"crossref","first-page":"5600","DOI":"10.1210\/jcem.86.11.8017","article-title":"Pathologic human GR mutant has a transdominant negative effect on the wild\u2010type GR by inhibiting its translocation into the nucleus: importance of the ligand\u2010binding domain for intracellular GR trafficking","volume":"86","author":"Kino T","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_2_13_62_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2001.01323.x"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.4.8379"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.6.8520"},{"key":"e_1_2_13_65_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-030450"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-1920"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-1893"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-2830"},{"key":"e_1_2_13_69_1","first-page":"551","article-title":"Generalized glucocorticoid resistance accompanied with an adrenocortical adenoma and caused by a novel point mutation of human glucocorticoid receptor gene","volume":"124","author":"Zhu HJ","year":"2011","journal-title":"Chin Med J (Engl)"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3549"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-3005"}],"container-title":["European Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Feci.12426","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.12426","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T01:53:55Z","timestamp":1696298035000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/eci.12426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,23]]},"references-count":70,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,5]]}},"alternative-id":["10.1111\/eci.12426"],"URL":"https:\/\/doi.org\/10.1111\/eci.12426","archive":["Portico"],"relation":{},"ISSN":["0014-2972","1365-2362"],"issn-type":[{"value":"0014-2972","type":"print"},{"value":"1365-2362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,23]]}}}