(p. 837) Glucocorticoid resistance—a defect of the glucocorticoid receptor 

The first case of glucocorticoid resistance was reported in 1976 by Vingerhoeds et al. (1). The patient was suffering from hypercortisolism with none of the tissue effects of Cushing’s disease. Further evaluation revealed that the ligand-binding affinity of the glucocorticoid receptor (GR) was diminished. His son and nephew were mildly affected and their GR also showed a reduced hormone affinity, although this was to a lesser extent. Later, the GR gene of the index patient was sequenced and showed a homozygous mutation at position 2054, yielding a valine for aspartic acid substitution at amino acid residue 641 (2). The other two family members appeared to be heterozygous carriers of the same mutation, which can explain their milder clinical picture. Since then, other patients with mutations in the GR gene leading to the syndrome of generalized glucocorticoid resistance have been described (Table 5.8.1) (18).

Familial glucocorticoid resistance is a rare disease, characterized by reduced cortisol action at the tissue level, which is compensated for by elevation of ACTH levels, resulting in an increase of adrenal steroids (glucocorticoids, androgens, mineralocorticoids) (18). It is rather unfamiliar and may confuse clinicians, since the signs and symptoms can be nonspecific. This syndrome has an autosomal recessive or dominant mode of inheritance.