Prevalence and clinical features of armadillo repeat-containing 5 mutations carriers in a single center cohort of patients with bilateral adrenal incidentalomas

Objective: We aimed to evaluate the prevalence of armadillo repeat-containing 5 (ARMC5) genetic defects in our cohort of bilateral adrenal incidentaloma (BAI) patients and to evaluate the possible existence of genotype-phenotype correlations. Design: Cross-sectional study. Setting: Tertiary care center. Participants: 72 BAI patients. Main Outcome Measure(s): The following data have been collected: morning adrenocorticotropic hormone (ACTH) concentrations; cortisol levels after 1 mg overnight dexamethasone suppression test (F-1mgDST); urinary free cortisol (UFC) levels; diameter of the adrenal masses; and the association with overweight/obesity, arterial hypertension, diabetes mellitus, dyslipidemia, cardiovascular events, unrelated neoplasia, osteoporosis, thyroid nodular disease, and primary hyperparathyroidism. A search for ARMC5 germline and somatic pathogenic variants was performed in all patients and in the adrenal tissue of patients operated on, respectively. Results: The prevalence of germline ARMC5 pathogenic variants among patients with mild autonomous cortisol secretion (MACS+, defined as F1mgDST > 1.8 mu g/dL) was 18.8%. No germline pathogenic variants were detected in patients without MACS. Moreover, somatic ARMC5 pathogenic variants were also found in the adrenal tissue of six patients without germline ARMC5 variants. The F-1mgDST levels >5 mu g/dL predicted with a poor sensitivity but a 90.5% specificity in identifying the presence of ARMC5 germline pathogenic variants. We did not find any clinical parameter predictive of the ARMC5 mutation presence. Conclusions: In MACS+ BAI patients, germline ARMC5 gene pathogenic variants are frequent. Further studies are needed to elucidate the pathophysiological role of somatic ARMC5 pathogenic variants on adrenal tumor development in otherwise wild-type (WT) patients.

Automated summary

This study aimed to evaluate the prevalence of ARMC5 genetic defects in patients with bilateral adrenal incidentaloma (BAI) and explore the possible genotype-phenotype correlations. The results showed that the prevalence of germline ARMC5 pathogenic variants was 18.8% in BAI patients with mild autonomous cortisol secretion (MACS+). Somatic ARMC5 pathogenic variants were also found in adrenal tissue of patients without germline ARMC5 variants, indicating their involvement in adrenal tumor development.