# Primary Bilateral Macronodular Adrenocortical Disease With Concomitant Cushing Syndrome and Primary Aldosteronism Harboring Distinct ARMC5 Mutations in Individual Nodules

## TL;DR

A case study shows that different adrenal nodules in a rare adrenal disease can have unique genetic mutations, leading to varied hormone production.

## Contribution

This case is the first to demonstrate intraglandular genetic heterogeneity in adrenal nodules through nodule-specific ARMC5 mutation analysis.

## Key findings

- Distinct ARMC5 mutations were identified in individual adrenal nodules.
- The disease presented with both cortisol and aldosterone overproduction.
- Genetic heterogeneity suggests independent clonal origins for different nodules.

## Abstract

Primary bilateral macronodular adrenocortical disease is an uncommon adrenal disorder characterized by bilateral adrenal enlargement with multiple nodules and autonomous steroid hormone production. Although genetic alterations involving ARMC5 have been implicated in its development, individual nodules within the same adrenal gland often show considerable variability in size, morphology, and hormonal activity, and detailed genetic evaluation of each nodule has rarely been performed. We report the case of a 58-year-old man with a long-standing history of hypertension who was found to have bilateral adrenal nodules on imaging studies. Endocrinological evaluation revealed primary aldosteronism with lateralized aldosterone secretion from the left adrenal gland, along with autonomous cortisol secretion from both adrenal glands. The patient underwent laparoscopic left adrenalectomy. Gross and histopathological examination demonstrated multiple macronodular lesions without evidence of malignancy. Genetic analyses conducted separately on individual nodules identified different ARMC5 mutations in each nodule examined, indicating intraglandular genetic heterogeneity. This case illustrates that distinct adrenal nodules within primary bilateral macronodular adrenal disease can arise from genetically independent clonal events. The concomitant presence of cortisol and aldosterone overproduction further underscores the functional diversity of this condition. Careful histopathological sampling combined with nodule-specific molecular analysis may provide important insights into the pathogenesis and biological heterogeneity of this disease.