Key result
In Korean patients with BMAD, 22.9% had P/LP ARMC5 variants, associated with larger tumor size and significantly higher cortisol levels (153.1 vs 100.6 ng/mL).
Why the study?
ARMC5 is an established genetic driver of bilateral macronodular adrenocortical disease, but data in East Asian populations were limited.
Are pathogenic ARMC5 variants associated with specific clinical, radiological, and steroidogenic phenotypes in Korean patients with bilateral macronodular adrenocortical disease?
Are pathogenic ARMC5 variants associated with specific clinical, radiological, and steroidogenic phenotypes in Korean patients with bilateral macronodular adrenocortical disease?
In Korean patients with bilateral macronodular adrenocortical disease, pathogenic ARMC5 variants are present in about 23% of cases and correlate with more severe radiological and steroidogenic features.
ARMC5 screening may aid risk stratification in BMAD; extends prior associations to Korean patients but should not yet change practice.
Objective 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. Methods 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. Results 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 0.66 ng/mL) (P<0.05). Conclusion 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.
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Park et al. (2026) studied this question. In Korean patients with BMAD, 22.9% had P/LP ARMC5 variants, associated with larger tumor size and significantly higher cortisol levels (153.1 vs 100.6 ng/mL).
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