Significant Prevalence of Mutations in Incidentally Discovered Bilateral Adrenal Hyperplasia: Results of the French MUTA-GR Study

Background: Recently discovered mutations of gene, encoding for the GR, in patients with glucocorticoid resistance and bilateral adrenal incidentalomas prompted us to investigate whether GR mutations might be associated with adrenal hyperplasia.

Objective: The multicenter French Clinical Research Program (Muta-GR) was set up to determine the prevalence of GR mutations and polymorphisms in patients harboring bilateral adrenal incidentalomas associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs.

Results: One hundred patients were included in whom sequencing revealed five original heterozygous GR mutations that impaired GR signaling . Mutated patients presented with mild glucocorticoid resistance defined as elevated urinary free cortisol (1.7 ± 0.7 vs 0.9 ± 0.8 upper limit of normal range,  = 0.006), incomplete 1 mg dexamethasone suppression test without suppressed 8-AM adrenocorticotrophin levels (30.9 ± 31.2 vs 16.2 ± 17.5 pg/mL) compared to the non-mutated patients. Potassium and aldosterone levels were lower in mutated patients (3.6 ± 0.2 vs 4.1 ± 0.5 mmol/L,  = 0.01, and 17.3 ± 9.9 vs 98.6 ± 115.4 pg/mL,  = 0.0011, respectively) without elevated renin levels, consistent with pseudohypermineralocorticism. characterization of mutated patients' fibroblasts demonstrated GR haploinsufficiency as revealed by below-normal glucocorticoid induction of gene expression. There was no association between GR polymorphisms and adrenal hyperplasia in this cohort, except an over-representation of polymorphism.

Conclusion: The 5% prevalence of heterozygous mutations discovered in our series is higher than initially thought and encourages GR mutation screening in patients with adrenal incidentalomas to unambiguously differentiate from Cushing's states and to optimize personalized follow-up.