Primary Generalized Familial and Sporadic Glucocorticoid Resistance (Chrousos Syndrome) and Hypersensitivity

The human glucocorticoid receptor (hGR) is a ubiquitously expressed intracellular, ligand-dependent transcription factor, which mediates the action of glucocorticoids and influences physiologic functions essential for life. Alterations in the molecular mechanisms of hGR action modify glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the pathophysiology, molecular mechanisms, and clinical aspects of primary generalized familial and sporadic glucocorticoid resistance (PGGR or Chrousos syndrome) and hypersensitivity (PGGH). The molecular basis of Chrousos syndrome and PGGH has been ascribed to mutations in the hGR gene, which alter tissue sensitivity to glucocorticoids. The stochastic nature of glucocorticoid signaling pathways in association with the variable effect that hGR gene mutations/polymorphisms might have on glucocorticoid signal transduction indicates that alterations in hGR action may have important implications for many critical biological processes, such as the behavioral and physiologic responses to stress, intermediary metabolism, the immune and inflammatory reaction, as well as growth, development, and reproduction.