Glucocorticoid resistance syndrome: A systematic review of the genotypes, phenotypes, and their relationships.

Abstract

Objectives: Generalized glucocorticoid resistance 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 interrelationships.

Methods: We conducted a systematic literature review, identifying 67 cases from 33 published reports, and included four 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-LDDST cortisol was the predominant hormonal abnormality (97.8%). Adrenal CT 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 years old, P = 0.007), with markedly higher prevalence of hypertension/hypokalemia (90.9% vs. 28.6%, OR 25.00 [95% CI 2.95 -211.61], P < 0.001) and higher cortisol (3.20 [1.19, 2.63] vs. 1.40 [0.59, 1.20] × ULN, P = 0.002), ACTH (4.81 [1.71, 13.00] vs. 1.04 [1.00, 1.76] × ULN, P = 0.001), and testosterone levels (1.84 [1.34, 2.79] vs. 0.89 [0.55, 1.77] × ULN, P = 0.047). 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.