A novel pathogenic variant of the glucocorticoid receptor gene, causing generalized glucocorticoid resistance: a case report and review of the literature.

Purpose: Generalized glucocorticoid resistance (GGCR) is caused by variants in the NR3C1 gene, which encodes the human glucocorticoid receptor (hGR). To date, 39 pathogenic variants of NR3C1 have been reported, primarily in the ligand-binding domain (LBD). This study presents a novel case of the NR3C1 variant located in the N-terminal domain (NTD) of hGR, highlighting its clinical and molecular significance in glucocorticoid resistance.

Case presentation: The patient was a 21-year-old woman presenting with chronic fatigue, irregular menstrual cycles, and osteopenia, though without any clinical signs of Cushing's syndrome. She underwent a standard evaluation of the hypothalamic-pituitary-adrenal (HPA) axis. Endocrinological tests revealed elevated levels of ACTH, morning serum cortisol, aldosterone, DHEAS, 11-deoxycortisol, pregnenolone, and corticosterone, as well as increased urinary-free cortisol excretion. The low-dose dexamethasone suppression test (LDDST) showed suppression of cortisol levels. Molecular analysis via Whole Exome Sequencing (WES) identified a novel heterozygous pathogenic variant, c.220 C > T (p.Gln74Ter), in the NR3C1 gene. This confirmed the diagnosis of glucocorticoid resistance syndrome.

Conclusion: This case contributes to expanding the mutational spectrum of NR3C1 in glucocorticoid resistance syndrome, supporting more accurate diagnosis and genetic counseling for affected individuals.