Primary Generalized Glucocorticoid Resistance Syndrome

Tomoshige Kino; Nicolas C. Nicolaides; Evangelia Charmandari; George P. Chrousos

Primary Generalized Glucocorticoid Resistance Syndrome

Review

In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.

2024 May 19.

Authors

Tomoshige Kino¹, Nicolas C. Nicolaides², Evangelia Charmandari², George P. Chrousos²

Book Editors

Kenneth R Feingold¹, Bradley Anawalt², Marc R Blackman³, Alison Boyce⁴, George Chrousos⁵, Emiliano Corpas⁶, Wouter W de Herder⁷, Ketan Dhatariya⁸, Kathleen Dungan⁹, Johannes Hofland¹⁰, Sanjay Kalra¹¹, Gregory Kaltsas¹², Nitin Kapoor¹³, Christian Koch¹⁴, Peter Kopp¹⁵, Márta Korbonits¹⁶, Christopher S Kovacs¹⁷, Wendy Kuohung¹⁸, Blandine Laferrère¹⁹, Miles Levy²⁰, Elizabeth A McGee²¹, Robert McLachlan²², Maria New²³, Jonathan Purnell²⁴, Rakesh Sahay²⁵, Amy S Shah²⁶, Frederick Singer²⁷, Mark A Sperling²⁸, Constantine A Stratakis²⁹, Dace L Trence³⁰, Don P Wilson³¹

Affiliations

¹ Division of Internal Medicine, Katta General Hospital, Miyagi 989-0225, Japan
² Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children's Hospital, Athens, 11527, Greece. Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou tou Efessiou Street, Athens, 11527, Greece

Book Affiliations

¹ Professor of Medicine Emeritus, University of California, San Francisco, CA
² Chief of Medicine at the University of Washington Medical Center and Professor and Vice Chair of the Department of Medicine, University of Washington
³ Sr. Physician Scientist, Washington DC VA Medical Center; Professor of Medicine & Rehabilitation Medicine, Georgetown University; Clinical Professor of Medicine, Biochemistry and Molecular Medicine, George Washington University; and Professor of Medicine (Part-time), Johns Hopkins University
⁴ Pediatric Endocrinologist and Associate Research Physician in the Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health
⁵ Professor of Pediatrics and Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
⁶ M.D. Ph.D in Gerontology. Honorary Professor of Medicine, Universidad de Alcalá, Madrid. Consultant in Endocrinology, Hospital HLA Guadalajara (Spain).
⁷ Professor of Endocrine Oncology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
⁸ Consultant in Diabetes, Endocrinology and General Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust and University of East Anglia, Norwich, UK.
⁹ Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Ohio State University
¹⁰ Consultant Endocrinologist, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
¹¹ Consultant Endocrinologist, Department of Endocrinology, Bharti Hospital, Karnal, India
¹² Professor of General Medicine-Endocrinology, 1st Department of Propaedeutic Medicine, National and Kapodistrian University of Athens, Athens, Greece
¹³ Professor of Endocrinology, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College & Hospital, Vellore, Tamil Nadu, India, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Australia.
¹⁴ Professor, The University of Tennessee Health Science Center, Memphis, Tennessee
¹⁵ Professor of Medicine and Chief of the Division of Endocrinology, Diabetology and Metabolism, University of Lausanne, Switzerland
¹⁶ Professor of Endocrinology and Metabolism, Centre Lead for Endocrinology and Deputy Institute Director, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, England
¹⁷ University Research Professor and Professor of Medicine (Endocrinology and Metabolism), Obstetrics & Gynecology, and BioMedical Sciences, at Memorial University of Newfoundland in St. John’s, Newfoundland, Canada.
¹⁸ Director of the Division of Reproductive Endocrinology at Boston Medical Center and an Associate Professor of Obstetrics and Gynecology at the Boston University School of Medicine
¹⁹ Professor of Medicine, New York Nutrition Obesity Research Center, Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
²⁰ Consultant endocrinologist at University Hospitals of Leicester and Honorary Associate Professor at Leicester University
²¹ Professor of Obstetrics and Gynecology at the University of Vermont and Director of the Division of Reproductive Endocrinology and Infertility. Burlington, Vermont
²² Director of Clinical Research, Hudson Institute of Medical Research; Consultant Endocrinologist, Monash Medical Centre, Melbourne, Australia
²³ Professor of Pediatrics, Professor of Genetics and Genomic Sciences, and Chief of the Adrenal Steroid Disorders Program, Icahn School of Medicine, Mount Sinai School of Medicine, New York, NY
²⁴ Professor of Medicine, Knight Cardiovascular Institute and the Division of Endocrinology, and Associate Director, Bob and Charlee Moore Institute for Nutrition and Wellness, Oregon Health and Science University, Portland, OR
²⁵ Professor and Head of Department of Endocrinology, Osmania Medical College and Osmania General Hospital, Hyderabad, India.
²⁶ Professor of Pediatrics, The University of Cincinnati, Department of Pediatrics and Cincinnati Children’s Hospital Medical Center, Division of Endocrinology, Cincinnati, OH, USA
²⁷ Director of the Endocrine/Bone Disease Program, Saint Johns Cancer Institute at Saint John’s Health Center, Santa Monica, CA; Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles, CA
²⁸ Professorial Lecturer, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, NY. Emeritus Professor and Chair, Department of Pediatrics, University of Pittsburgh.
²⁹ CSO, ELPEN, Inc. & Director, Research Institute, Athens, Greece & Senior Investigator, Human Genetics & Precision Medicine, FORTH (ITE), Heraklion, Greece. Emeritus Scientific Director & Senior Investigator, NICHD, NIH, Bethesda, MD, USA
³⁰ Professor of Medicine, Emeritus, University of Washington, Seattle, WA
³¹ Endowed Chair, Cardiovascular Health and Risk Prevention, Pediatric Endocrinology and Diabetes, Cook Children's Medical Center, Fort Worth, TX

PMID: 25905168
Bookshelf ID: NBK278930

Excerpt

Primary generalized glucocorticoid resistance syndrome is a rare genetic disorder characterized by resistance of entire tissues to glucocorticoids. Affected subjects demonstrate elevation of serum cortisol without Cushingoid manifestations, as the hypothalamic-pituitary-adrenal (HPA) axis is upregulated to compensate for the reduced action of this steroid in local tissues. Instead, these patients develop hypertension and/or signs of hyperandrogenism, because hyper-secreted adrenocorticotropic hormone (ACTH) stimulates production of adrenal mineralocorticoids and/or androgens in addition to the glucocorticoid cortisol. At the molecular level, this syndrome is caused by inactivating mutations in the NR3C1 gene that encodes the human glucocorticoid receptor (hGR) protein. Biochemical, molecular and structural exploration on pathologic mutant receptors revealed a variety of functional defects, such as reduced affinity to glucocorticoids or target DNA, inability to transactivate glucocorticoid-responsive genes, and slowing of the cytoplasmic to nuclear translocation. The clinical spectrum of this syndrome is thus broad, ranging from asymptomatic to severe cases of mineralocorticoid and/or androgen excess depending on the severity of genetic defects and resulting dysfunction of the mutated receptors. When this syndrome is suspected, a detailed personal and family history should be obtained. Physical examination should include an assessment for signs of mineralocorticoid and/or androgen excess. In neonates and young children, severe hypoglycemia and loss of consciousness due to reduced actions of glucocorticoids in the liver may be present as initial manifestations in addition to hypertension and/or genital abnormalities. Suspected subjects should undergo a detailed endocrinologic evaluation with particular emphasis on the measurement of diurnal serum cortisol and plasma ACTH concentrations and determination of the 24-hour urinary free cortisol excretion to identify upregulation of the HPA axis with preservation of the normal circadian rhythmicity. The diagnosis of this syndrome should be confirmed by sequencing of the NR3C1 gene including exon/intron junctions and subsequent validation of functional defects of the mutated receptors. Treatment involves administration of high doses of mineralocorticoid activity-sparing pure glucocorticoids like dexamethasone, which stimulate the mutant and/or the wild-type hGR, and suppress the endogenous secretion of ACTH and adrenal steroids in the affected subjects. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

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