Glucocorticoid Resistance Syndrome: A Systematic Review of the Genotypes, Phenotypes, and Their Relationships.

OBJECTIVE

Generalized glucocorticoid residestance syndrome is a rare disorder caused by mutations in NR3C1. We aimed to systematically characterize its clinical, biochemical, and genetic features and quantitatively evaluate their inter-relationships.

METHODS

We conducted a systematic literature review, identifying 67 cases from 33 published reports, and included 4 unreported cases from Peking Union Medical College Hospital.

RESULTS

In total, 71 cases from 43 unrelated families were analyzed, encompassing 39 distinct NR3C1 mutations. The most frequent clinical manifestations were symptoms of androgen excess (43.3%), followed by mineralocorticoid excess (38.8%) and glucocorticoid deficiency (14.9%). Elevated post-low-dose dexamethasone suppression test cortisol was the predominant hormonal abnormality (97.8%). Adrenal computed tomography revealed hyperplasia or adenomas in 68.8% of evaluated patients. Compared with heterozygotes, those with homozygous/compound heterozygous mutations presented earlier (19.9 vs 35.5 year old, P = .007), with markedly higher prevalence of hypertension/hypokalemia (90.9% vs 28.6%, odds ratio 25.00 [95% confidence interval 2.95 -211.61], P < .001) and higher cortisol (3.20 [1.19, 2.63] vs 1.40 [0.59, 1.20] × upper limit of normal [ULN], P = .002), adrenocorticotropic hormone (4.81 [1.71, 13.00] vs 1.04 [1.00, 1.76] × ULN, P = .001), and testosterone levels (1.84 [1.34, 2.79] vs 0.89 [0.55, 1.77] × ULN, P = .047). Sensitivity analyses restricted to probands confirmed these associations. Clinical manifestations correlated with elevated cortisol, and lower renin was observed in patients with hypertension/hypokalemia.

CONCLUSION

This study provided the most comprehensive quantitative synthesis to date of glucocorticoid resistance syndrome, highlighting genotype-phenotype correlations and advancing understanding of its clinical and hormonal spectrum.