Background: Primary Generalized Glucocorticoid Resistance or Chrousos syndrome is a rare genetic condition characterized by end-organ insensitivity to glucocorticoids owing to inactivating mutations of the NR3C1 gene.
Materials and methods: We conducted a systematic review of the published, peer-reviewed medical literature using MEDLINE (1975 through November 2014) to identify original articles and reviews on this topic. The search terms included 'primary generalized glucocorticoid resistance', 'Chrousos syndrome', 'glucocorticoid receptor gene' and 'glucocorticoid receptor mutations'.
Results: Only a few cases of Chrousos syndrome have been described to date, ranging from asymptomatic to severe forms of mineralocorticoid and/or androgen excess. All reported cases have been associated with point mutations or deletions in the NR3C1 gene. The tremendous progress of molecular biology has enabled us to apply standard methods to investigate the molecular mechanisms of action of the mutant glucocorticoid receptors (GRs). We and others have identified and functionally characterized novel mutations causing Chrousos syndrome, while structural biology has enabled us to have a better understanding of how conformational changes of the receptor cause glucocorticoid resistance. In this review, we also present our results of the functional characterization of two recently described mutations, and we discuss the diagnostic approaches and therapeutic management of patients with Chrousos syndrome.
Conclusions: Although Chrousos syndrome is a rare condition, many clinical cases remain unrecognized for a long time. We recommend determination of the 24-h urinary free cortisol excretion and sequencing of the NR3C1 gene in patients with hyperandrogenism and/or hypertension of unknown origin.
Keywords: Glucocorticoid receptor; NR3C1 mutations; glucocorticoid resistance; glucocorticoid signalling; glucocorticoids.
© 2015 Stichting European Society for Clinical Investigation Journal Foundation.