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Updated: Jun 3, 2025
A Novel Method: Super-selective Adrenal Venous Sampling
Published on: September 15, 2017
PDE11A Is a Phenotype Modulator of Primary Bilateral Macronodular Adrenal Hyperplasia: Results of a 334-Patient
Patricia Vaduva1, Lucas Bouys1,2, Anne Jouinot1
1Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris 75014, France.
Context:
Primary bilateral macronodular adrenal hyperplasia (PBMAH), the most common cause of Cushing syndrome due to bilateral nodules, is a heterogeneous disease at the clinical, hormonal, and morphological levels. ARMC5-inactivating pathogenic variants are causative of PBMAH, and rare variants of PDE11A have been associated with PBMAH.
Objective:
The aim of this study, on a large cohort of individuals with PBMAH from Europe and America, was to study the ARMC5 and PDE11A genotype to determine the genotype/phenotype correlation and to investigate the hypothesis that PDE11A could be a modifying gene of the adrenal phenotype.
Methods:
Leukocyte DNA of 354 PBMAH index cases was sequenced for ARMC5 and PDE11A genes by next-generation sequencing. Phenotypic characteristics of 334 of these patients were analyzed to study the genotype/phenotype correlations.
Results:
Seven out of 16 PDE11A variants were considered damaging according to in silico predictions: 6 missense variants (p.Tyr727Cys, p.Met623Arg, p.Tyr658Cys, p.Ag867Trp, p.Asn298Ser, p.Glu840Lys) and 1 stop-gain variant (p.Arg307Ter). In the cohort, 11.4% of patients had one of these variants and 19.2% had ARMC5-pathogenic variants. There was no statistically significant difference in the distribution of PDE11A-damaging variants according to ARMC5 status (P = .83; OR = 0.79; 95% CI, 0.26-2.03) nor in the distribution of ARMC5 pathogenic variants according to PDE11A status (P = .83; OR = 0.81; 95% CI, 0.27-2.04). Patients with PDE11A-damaging variants had lower urinary free cortisol (0.7 vs 1.25 upper limit of normal; P = .0002), midnight plasma cortisol (157.81 vs 222.19 nmol/L, P = .016), and number of adrenal nodules (3.46 vs 4.74; P = .048) compared to PDE11A wild-type patients. Patients with ARMC5-pathogenic variants had a more severe phenotype with more frequent comorbidities and were more often treated by adrenalectomy (60%).
Conclusion:
PDE11A appears to be a modulator of PBMAH phenotype, damaging variants being associated with an attenuated form. This may contribute to the heterogeneity of PBMAH and could affect patient management.
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