Primary Generalized Glucocorticoid Resistance Differential Diagnoses

  • Author: Evangelia Charmandari, MD, MRCP, MSc; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Jul 27, 2010
 
 

Differential Diagnoses

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Contributor Information and Disclosures
Author

Evangelia Charmandari, MD, MRCP, MSc  Pediatric and Adolescent Endocrinologist, Senior Investigator, Division of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, Greece

Evangelia Charmandari, MD, MRCP, MSc is a member of the following medical societies: British Medical Association and Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Tomoshige Kino, MD, PhD  Staff Scientist, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health

Tomoshige Kino, MD, PhD is a member of the following medical societies: Endocrine Society

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London)  Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Thomas A Wilson, MD  Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD  Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Literary work of this article was funded by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, Maryland), the EU-European Social Fund, and the Greek Ministry of Development-General Secretariat of Research and Technology (Athens, Greece).

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Schematic representation of the structure of the human glucocorticoid receptor (hGR) gene. Alternative splicing of the primary transcript gives rise to the 2 mRNA and protein isoforms, hGRα and hGRβ.
Functional domains of human glucocorticoid receptor (hGR)α. The functional domains and subdomains are indicated beneath the linearized protein structures. AF = Activation function; DBD = DNA-binding domain; LBD = Ligand-binding domain; NLS = Nuclear localization signal.
Nucleocytoplasmic shuttling of the glucocorticoid receptor. Upon binding to the ligand, the activated human glucocorticoid receptor (hGR)α dissociates from heat shock proteins (hsps) and translocates into the nucleus, where it homodimerizes and binds to glucocorticoid response elements (GREs) in the promoter region of target genes. TF = Transcription factor; TFRE = Transcription factor response element.
Schematic representation of the interaction of activation function (AF)-1 and AF-2 of human glucocorticoid receptor (hGR)α with coactivators. DRIP/TRAP = Vitamin D receptor-interacting protein/thyroid hormone receptor-associated protein; GREs = Glucocorticoid response elements; SWI/SNF = Switching/sucrose nonfermenting.
Location of the known mutations of the glucocorticoid receptor (hGR) gene (upper panel) and protein (lower panel). DBD = DNA-binding domain; NTD = Amino terminal domain; LBD = Ligand-binding domain.
Crystal structure of the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR)α. Stereotactic conformation of the agonist (left) and antagonist (right) form of the LBD of hGRα. The yellow arrows indicate the position of helix 12, which is critical for the formation of activation function (AF)-2 surface that allows interaction with activators.
Location of the known mutations of human glucocorticoid receptor(hGR)α in the agonist (upper panel) and antagonist (lower panel) form of the LBD of hGRα. Helices are indicated in red and are underlined, whereas β-sheets are indicated in green. Two mutations (I559 and V571A) are located within H5, whereas 4 mutations (V729I, F737L, I747M, and L773P) are located within or close to helices 11 and 12. The ligand-binding pocket is formed by helices 3, 5, 11, and 12. Upon ligand-binding, the receptor undergoes major conformational changes that alter the position of helix 11 and helix 12 and generate an interaction surface that allows coactivators to bind to the LBD through their LXXLL motifs. Helix 12 plays a critical role in the formation of both the ligand-binding pocket and the activation function (AF)-2 surface that facilitates interaction with coactivators. The fact that most hGRα mutations are clustered around helix 5, helix 11, and helix 12 indicates that these helices play an important role in glucocorticoid signal transduction.
Alterations in the hypothalamic-pituitary-adrenal (HPA) axis in primary generalized glucocorticoid resistance. The impaired glucocorticoid feedback inhibition at the hypothalamic and anterior pituitary levels results in increased secretion of corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH), adrenal hyperplasia, and increased secretion of adrenal steroids with mineralocorticoid and/or androgenic activity. AVP = Arginine vasopressin; DOC = Deoxycorticosterone.
Table. Mutations of the Human Glucocorticoid Receptor Gene Causing Primary Generalized Glucocorticoid Resistance
Mutation Position Molecular Mechanisms Genotype Phenotype
cDNAAmino Acid
1922 (A → T)641 (D → V)Transactivation ↓



Affinity for ligand ↓ (x3)



Nuclear translocation: 22 min



Abnormal interaction with GRIP1



HomozygousHypertension, hypokalemic alkalosis
4 bp deletion in exon-intron 6hGRα number: 50% of control,



inactivation of the affected allele



HeterozygousHirsutism,



male-pattern hair loss, menstrual irregularities



2185 (G → A)729 (V → I)Transactivation ↓,



affinity for ligand ↓ (x2),



nuclear translocation: 120 min,



abnormal interaction with GRIP1



HomozygousPrecocious puberty,



hyperandrogenism



1676 (T → A)559 (I → N)Transactivation ↓, decrease in hGR binding sites,



transdominance (+), nuclear translocation: 180 min, abnormal interaction with GRIP1



HeterozygousHypertension,



oligospermia, infertility



1430 (G → A)477 (R → H)Transactivation ↓, no DNA binding,



nuclear translocation: 20 min



HeterozygousHirsutism,



fatigue, hypertension



2035 (G → A)679 (G → S)Transactivation ↓, affinity for ligand ↓ (x2),



nuclear translocation: 30 min, abnormal interaction with GRIP1



HeterozygousHirsutism, fatigue, hypertension
1712 (T → C)571 (V → A)Transactivation ↓, affinity for ligand ↓ (x6),



nuclear translocation: 25 min, abnormal interaction with GRIP1



HomozygousAmbiguous genitalia, hypertension,



hypokalemia, hyperandrogenism



2241 (T → G)747 (I → M)Transactivation ↓, transdominance (+), affinity for ligand ↓ (x2), nuclear translocation ↓,



abnormal interaction with GRIP1



HeterozygousCystic acne, hirsutism, oligo-amenorrhea
2318 (T → C)773 (L → P)Transactivation ↓, transdominance (+), affinity for ligand ↓ (x2.6),



nuclear translocation: 30 min, abnormal interaction with GRIP1



HeterozygousFatigue, anxiety, acne, hirsutism, hypertension
2209 (T → C)737 (F → L)Transactivation ↓, transdominance (time-dependent) (+), affinity for ligand ↓ (x1.5), nuclear translocation: 180 min, abnormal interaction with GRIP1HeterozygousHypertension, hypokalemia
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