title: Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1).
abstract: BACKGROUND
  Glucocorticoid resistance is a rare genetic condition characterized by reduced sensitivity to cortisol signaling and subsequent hyperactivation of the hypothalamic-pituitary-adrenal axis.
  
  
  OBJECTIVE
  The objective was to confirm the diagnosis of glucocorticoid resistance in the patient, to determine the degree of suppression of cortisol and ACTH levels in response to dexamethasone, and to determine the underlying genetic abnormality and functional consequences of the mutation.
  
  
  METHODS
  The patient presented on the first day of life with profound hypoglycemia. Initial cortisol levels were appropriately elevated; however, the patient was found to have persistently elevated levels of both cortisol and ACTH. The baby developed a tanned appearance and severe hypertension and fatigued easily with feeding. Serial oral dexamethasone suppression tests were performed with doses escalating from 0.125 mg to 12 mg dexamethasone given at 2300 h. Sequencing of the glucocorticoid receptor gene was performed along with functional studies of the glucocorticoid receptor. GH secretion was assessed with an arginine glucagon stimulation test.
  
  
  RESULTS
  Cortisol and ACTH levels did not suppress with doses of up to 12 mg dexamethasone. A 2-bp deletion was found at amino acid position 773 of the glucocorticoid receptor ligand binding domain. A complete lack of dexamethasone binding and in vitro biological effect was demonstrated. GH stimulation testing was consistent with GH deficiency.
  
  
  CONCLUSIONS
  The homozygous mutation in the ligand-binding domain of the glucocorticoid receptor gene resulted in a functionally inactive glucocorticoid receptor and apparent complete glucocorticoid resistance with biochemical GH deficiency.
authors.affiliation: Department of Endocrinology and Diabetes, Royal Children's Hospital, Brisbane, Herston, Queensland 4029, Australia. sarah_mcmahon@health.qld.gov.au
authors.forename: Sarah K
authors.initials: SK
authors.lastname: McMahon
authors.forename: Carel J
authors.initials: CJ
authors.lastname: Pretorius
authors.forename: Jacobus P J
authors.initials: JP
authors.lastname: Ungerer
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Salmon
authors.forename: Louise S
authors.initials: LS
authors.lastname: Conwell
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pearen
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Batch
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004351:Drug Resistance / Q000235:genetics*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006130:Growth Disorders / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D006720:Homozygote; D019382:Human Growth Hormone / Q000172:deficiency*; D006801:Humans; D007231:Infant, Newborn; D008024:Ligands; D008297:Male; D009154:Mutation / Q000502:physiology; D015997:Neonatal Screening; D010290:Parents; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid; D019382:Human Growth Hormone