Authors: Nicolas C Nicolaides, M.D., Tomoshige Kino, M.D., Ph.D., George Chrousos, MD, MACE, MACP, FRCP, and Evangelia Charmandari, M.D.
Abstract: Primary Generalized Glucocorticoid Resistance or Chrousos Syndrome is a rare endocrinologic condition, which affects almost all tissues, and is characterized by resistance of tissues to glucocorticoids. The clinical spectrum of Chrousos syndrome is broad, ranging from asymptomatic cases to severe cases of mineralocorticoid and/or androgen excess. At the molecular level, Chrousos syndrome has been associated with defects in the NR3C1 gene that encodes the human glucocorticoid receptor (hGR). We and others have applied molecular and structural biology methods to investigate the molecular mechanisms of action of the mutant hGRs. We demonstrated that the defective hGRs impair several steps of glucocorticoid signaling cascade depending on the position of the NR3C1 gene defect. In clinical practice, when Chrousos syndrome is suspected, a detailed personal and family history should be obtained, while physical examination should include an assessment for signs of mineralocorticoid and/or androgen excess. Suspected patients should then undergo a detailed endocrinologic evaluation with particular emphasis on the measurement of serum cortisol concentrations and determination of the 24-hour urinary free cortisol (UFC) excretion on 2 or 3 consecutive days. Affected subjects demonstrate resistance of the HPA axis to dexamethasone suppression, which may vary depending on the severity of the condition. The diagnosis of Chrousos syndrome is confirmed by sequencing of the coding region of the NR3C1 gene, including the intron/exon junctions. Treatment of Chrousos syndrome involves administration of high doses of mineralocorticoid-sparing synthetic glucocorticoids, which activate the mutant and/or wild-type hGRα, and suppress the endogenous secretion of ACTH in affected subjects. For complete coverage of this and related areas in Endocrinology, visit our free web-books, www.endotext.org and www.thyroidmanager.org.
