A Novel Pathogenic Variant in the N-Terminal Domain of the Glucocorticoid Receptor, Causing Glucocorticoid Resistance

Generalized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations in the NR3C1 gene coding the human glucocorticoid receptor (hGR). Most of the pathogenic hGR variants are identified in the ligand-binding domain (LBD). However, we report a new case associated with a novel NR3C1 pathogenic variant in the N-terminal domain (NTD) of the hGR.

The index case was an Italian 31-year-old woman with a history of chronic fatigue, anxiety, hirsutism, irregular menstrual cycles, and infertility, but no clinical manifestations suggestive of Cushing's syndrome. Standard clinical methods were used to assess the patient's hypothalamic-pituitary-adrenal axis. Molecular analysis of the NR3C1 gene was performed by Sanger sequencing. In addition, we perform an extensive survey of all clinical pathogenic variants modifying the whole sequence of the NR3C1 gene.

Endocrinologic evaluation revealed elevated serum cortisol, plasma adrenocorticotropic hormone, and androstenedione concentration and increased urinary free cortisol excretion. Morning serum cortisol levels remained elevated and were not suppressed during a 2-day, 2-mg dexamethasone suppression test. The identification of the novel p.(Glu123Ter) NR3C1 variant confirmed the diagnosis of glucocorticoid resistance.

Our findings improve the understanding of NR3C1 mutational spectrum in patients affected by glucocorticoid resistance syndrome and contribute to precise diagnosis and genetic counseling.