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)

McMahon, Sarah K., Pretorius, Carel J., Ungerer, Jacobus P. J., Salmon, Nathaniel J., Conwell, Louise S., Pearen, Michael A. and Batch, Jennifer A. (2010) 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). Journal of Clinical Endocrinology and Metabolism, 95 1: 297-302. doi:10.1210/jc.2009-1003


Author McMahon, Sarah K.
Pretorius, Carel J.
Ungerer, Jacobus P. J.
Salmon, Nathaniel J.
Conwell, Louise S.
Pearen, Michael A.
Batch, Jennifer A.
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)
Journal name Journal of Clinical Endocrinology and Metabolism   Check publisher's open access policy
ISSN 0021-972X
1945-7197
2150-5810
Publication date 2010-01
Year available 2009
Sub-type Article (original research)
DOI 10.1210/jc.2009-1003
Volume 95
Issue 1
Start page 297
End page 302
Total pages 6
Place of publication Chevy Chase, United States
Publisher The Endocrine Society
Collection year 2011
Language eng
Formatted abstract
Context: 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.
Patient and 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: CortisolandACTHlevels did not suppress with doses ofupto 12mgdexamethasone.A2-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.
Conclusion: 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. Copyright © 2010 by The Endocrine Society.
Keyword Primary cortisol resistance
Point mutation
GR
Phenotype
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online: Nov 20, 2009 Published under heading: Brief Report

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 24 Jan 2010, 00:03:01 EST