Glucocorticoid Resistance Syndrome in 2 Patients With Diverse Genotype

Glucocorticoid resistance syndrome (GRS) is caused by inactivating pathogenic variants in the glucocorticoid receptor gene NR3C1. Reduced glucocorticoid receptor signaling leads to decreased tissue sensitivity to cortisol and resultant biochemical hypercortisolism without the classic clinical features of Cushing syndrome. Patients variably present with signs and symptoms of mineralocorticoid and androgen excess from ACTH overstimulation of the adrenal cortex. Neuropsychiatric symptoms, such as anxiety, depression, anorexia, and insomnia, have also been reported and may be related to CRH excess. Due to the broad clinical spectrum and genetic heterogeneity of the disorder, it remains a diagnostic and treatment challenge. In this report, we describe 2 cases of GRS that highlight the genetic diversity of the condition. Both patients had prominent neuropsychiatric symptoms. While 1 patient had no identifiable variant in the glucocorticoid receptor gene, the other was found to have a novel NR3C1 variant. Low-dose dexamethasone treatment led to clinical improvement in the patient with negative genetic testing, and the second patient continues to be monitored.