NR3C1 – Glucocorticoid Resistance

Glucocorticoid resistance (Chrousos syndrome) is characterized by impaired cortisol signaling, leading to variable biochemical hypercortisolism with minimal Cushingoid features. Pathogenic variants in NR3C1 disrupt ligand binding and transcriptional activation of the glucocorticoid receptor (GR), resulting in hypertrophic adrenal feedback and clinical manifestations ranging from neonatal hypoglycemia to adult infertility and adrenal adenomas.

Several case reports have established the genetic spectrum of NR3C1-related resistance. A neonate with complete generalized resistance harbored a homozygous 2-bp deletion in helix 12 of the ligand-binding domain, resulting in loss of dexamethasone binding and profound GH deficiency (PMID:19933394). A 31-year-old woman with infertility and partial resistance carried a heterozygous c.2140G>A (p.Arg714Gln) missense variant with maintained circadian cortisol rhythm but failed dexamethasone suppression (PMID:29510671). A reversible syndrome was described in a patient with an adrenal adenoma and heterozygous c.1706G>A (p.Arg569Gln), showing impaired nuclear translocation and reduced ligand affinity that normalized at supraphysiologic cortisol levels (PMID:38584335).

In a multicenter French cohort of 100 patients with bilateral adrenal incidentalomas and hypertension or mild hypercortisolism, heterozygous GR mutations were identified in 5% of cases, including five original missense variants; notably c.1430G>A (p.Arg477His) was recurrent and impaired FKBP5 induction in patient fibroblasts (PMID:29444898).

Inheritance is predominantly autosomal dominant with variable expressivity; family studies are limited, and segregation beyond probands is rare (PMID:29510671). No robust segregation of affected relatives has been documented to date.

Functional assays across variants demonstrate a loss-of-function mechanism: complete absence of receptor binding and transactivation for the neonatal deletion, reduced cortisol affinity and transcriptional activation for p.Arg714Gln and p.Arg569Gln, and haploinsufficiency in fibroblast models for p.Arg477His. Structural modeling supports disrupted helix H12 conformation and impaired coactivator interaction, concordant with clinical resistance phenotypes.

Collectively, moderate genetic evidence from eight unrelated probands and consistent functional concordance support a Moderate ClinGen classification for NR3C1–glucocorticoid resistance. This association underpins diagnostic sequencing, enables personalized surveillance of adrenal pathology, and informs therapeutic strategies targeting receptor sensitivity.

References

• The Journal of clinical endocrinology and metabolism • 2010 • Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene PMID:19933394
• BMC medical genetics • 2018 • An unexpected, mild phenotype of glucocorticoid resistance associated with glucocorticoid receptor gene mutation case report and review of the literature PMID:29510671
• European journal of endocrinology • 2024 • A novel mutation in the NR3C1 gene associated with reversible glucocorticoid resistance PMID:38584335
• European journal of endocrinology • 2018 • Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study PMID:29444898

Evidence Based Scoring (AI generated)