Generalized glucocorticoid resistance

Generalized glucocorticoid resistance, also called Chrousos syndrome, is an extraordinarily rare genetic disorder that can run in families or be sporadic. It is characterized by partial or generalized target-tissue insensitivity to glucocorticoids. Genetic defects in the NR3C1 gene, which encodes the glucocorticoid receptor, can cause sporadic cases, or the condition can be inherited in an autosomal recessive or dominant manner. Defective receptors in the hypothalamus and pituitary impair negative feedback and lead to excess secretion of ACTH, CRH and vasopressin. The clinical spectrum runs from no symptoms to hypertension, low potassium, alkalosis and androgen excess, and the most common symptom is fatigue. Diagnosis rests on raised urinary free cortisol without signs of Cushing syndrome, confirmed by receptor assays and gene sequencing. Treatment uses high doses of mineralocorticoid-sparing synthetic glucocorticoids such as dexamethasone to reduce ACTH secretion.