title: Transient generalized glucocorticoid hypersensitivity.
abstract: BACKGROUND
  Transient generalized glucocorticoid hypersensitivity is a rare disorder characterized by increased tissue sensitivity to glucocorticoids and compensatory hypo-activation of the hypothalamic-pituitary-adrenal axis. The condition itself and the underlying molecular mechanisms have not been elucidated.
  
  
  OBJECTIVE
  To present the clinical manifestations, endocrinologic evaluation and transcriptomic profile in a patient with transient generalized glucocorticoid hypersensitivity.
  
  
  RESULTS
  A 9-year-old girl presented with an 8-month history of clinical manifestations suggestive of Cushing syndrome. Endocrinologic evaluation revealed undetectable 08:00 h ACTH (<1 pg/mL) and cortisol (0·025 μg/dL) concentrations, which remained decreased throughout the 24-h period and did not respond to stimulation with ovine CRH. The disease gradually resolved spontaneously over the ensuing 3 months. Sequencing of the human glucocorticoid receptor gene revealed no mutations or polymorphisms. Western blot analysis in peripheral blood mononuclear cells revealed equal protein expression of hGRα of the patient in the disease and postresolution phases compared with a control subject. Transcriptomic analysis in peripheral blood mononuclear cells in the disease and postresolution phases identified 903 differentially expressed genes. Of these, 106 genes were up-regulated and 797 were down-regulated in the disease compared with the resolution phase. Bioinformatics analysis on the differentially expressed gene networks revealed Nuclear Factor-κB as the predominant transcription factor influencing the expression of the majority of differentially expressed genes.
  
  
  CONCLUSIONS
  Our findings indicate that a transient postreceptor defect, or a virus- or bacterium-encoded molecule, may have enhanced glucocorticoid signal transduction, leading to transient generalized glucocorticoid hypersensitivity and hypo-activation of the HPA axis.
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece.|Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Nicolas C
authors.initials: NC
authors.lastname: Nicolaides
authors.affiliation: Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Agaristi
authors.initials: A
authors.lastname: Lamprokostopoulou
authors.affiliation: Institute of Molecular Biology, Genetics and Biotechnology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Polyzos
authors.affiliation: Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
authors.affiliation: Division of Hematology, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Katsantoni
authors.affiliation: First Pediatric Department, Aristotle University Medical School, Thessaloniki, Greece.
authors.forename: Panagiota
authors.initials: P
authors.lastname: Triantafyllou
authors.affiliation: First Pediatric Department, Aristotle University Medical School, Thessaloniki, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Christophoridis
authors.affiliation: First Pediatric Department, Aristotle University Medical School, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Katzos
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Dracopoulou
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece.
authors.forename: Amalia
authors.initials: A
authors.lastname: Sertedaki
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece.|Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.|Saudi Diabetes Study Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece.|Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Charmandari
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000172:deficiency; D002648:Child; D005260:Female; D005938:Glucocorticoids / Q000235:genetics*; D006801:Humans; D006854:Hydrocortisone / Q000172:deficiency; D006967:Hypersensitivity / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012075:Remission, Spontaneous
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone
keywords: Glucocorticoid hypersensitivity; glucocorticoid receptor; glucocorticoid signalling; glucocorticoids; transcriptomics