Genetics and clinical characteristics of Korean patients with bilateral macronodular adrenocortical disease

Bilateral macronodular adrenocortical disease (BMAD) is a rare disorder characterized by bilateral adrenocortical nodules and variable cortisol excess. ARMC5 is a well-established genetic driver of BMAD, but data in East Asian populations are limited. We investigated the prevalence of pathogenic variants and genotype-phenotype correlations in Korean patients with BMAD.

A total of 69 patients with BMAD were retrospectively enrolled at Seoul National University Hospital (2009-2023). Whole-exome sequencing was performed for 35 patients. Clinical, biochemical, and imaging data were analyzed. Serum steroid profiling was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify 18 adrenal-derived steroids.

The mean age of the cohort was 66.4 years, and 58% were male. Most had mild autonomous cortisol secretion (79.7%), and 15.9% had overt Cushing syndrome. Among the 35 patients who underwent genetic testing, 22.9% harbored pathogenic/likely pathogenic (P/LP) variants in ARMC5. P/LP ARMC5 variant carriers had lower BMI (25.0 vs 27.4 kg/m2), larger maximal tumor diameter (4.1 vs 2.7 cm), and greater total adrenal volume (19.8 vs 15.3 cm3). LC-MS/MS profiling revealed that P/LP ARMC5 carriers had significantly higher cortisol (153.1 vs 100.6 ng/mL), corticosterone (16.5 vs 1.3 ng/mL), and 18-hydroxycortisol concentrations (1.66 vs .66 ng/mL) (P < .05).

This study in a Korean cohort with BMAD showed that P/LP ARMC5 variants were present in 22.9% of the genetically investigated patients and were associated with more severe radiological and steroidogenic features. These findings underscore the importance of closely monitoring patients with BMAD who carry ARMC5 P/LP variants.