Endocrine Abstracts

Introduction

Primary bilateral macronodular adrenal hyperplasia (PBMAH), the most common cause of adrenal Cushing’s syndrome due to bilateral adrenal tumors, is an heterogenous disease with various clinical, hormonal and morphological characteristics. ARMC5 inactivating mutations is the most frequent genetic cause of PBMAH and variants of PDE11A4 have been associated with the disease. In order to better understand the heterogeneity of PBMAH, this study was undertaken to determine whether PDE11A4 variants might be associated with a specific phenotype.

Methods

Leukocyte DNA of 354 index cases of PBMAH were sequenced for ARMC5 and PDE114A by NGS (Ion Torrent). The frequency of variants was established in this cohort and the phenotypic characteristics were analysed in order to determine the genotype/phenotype correlations. Were considered pathogenic: PDE11A4 variants with altered enzymatic function; ARMC5 nonsense, frame shift and rare missense variants predicted deleterious in silico.

Results

ARMC5 mutations were present in 76 patients (21.5%) and pathogenic variants of PDE11A4 in 65 patients (18.4%), with a similar frequency regardless of ARMC5 status. Phenotype was more severe in ARMC5 mutated patients compared to ARMC5 wild type, with a higher 24-hour urinary free cortisol, expressed as a multiple of the upper standard range (UFC) (2.04 vs 0.99, P = 0.005) and midnight plasma cortisol (MPC) (328.06 vs 187.24 nmol/l, P = 0.003), larger adrenals (122.7 vs 91.31 mm, P = 4.87e – 05) and higher number of nodules as determined on CT-scan (10.25 vs 3.44, P = 8.62e – 07). There were six PDE11A4 pathogenic variants (p.R804H, p.R867G, p.M878V, p.D609N, p.Y727C, p.R307X). Patients with these variants had a less severe phenotype, with a lower MPC (162.17 vs 222.91 nmol/l, P = 0.015) and fewer adrenal nodules (3.45 vs 4.75, P = 0.015) in comparison with the PDE11A4 wild type group. Regarding the initial management, 50% of patients with pathogenic variants of PDE11A4 were abstaining from treatment, 37% were treated by adrenalectomy and 10.9% were treated medically. This phenotypic modulation of the PDE11A4 was confirmed in ARMC5 mutated patients: patients with pathogenic variants of PDE11A4 (n = 13), had lower UFC (1.1 vs 2.25, P = 0.014), smaller adrenal glands (90 mm vs 127 mm, P = 0.008) and a lower number of nodules (6 vs 10.94, P = 0.03) compared to the PDE11A4 wild type group.

Conclusion

This association of PDE11A4 variants with a less severe PBMAH phenotype regardless of ARMC5 status suggests that PDE11A4 is a modulator of PBMAH development. The mechanisms of this modulation remain to be determined and will help to better describe the heterogeneity of PBMAH and to elucidate its pathophysiology.