Genetic background and management outcomes in primary bilateral macronodular adrenal hyperplasia: Implications for diagnosis and treatment—A retrospective cohort study

Objective Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing syndrome. Recent evidence, particularly the 2023 European Society of Endocrinology guidelines, clinically classifies cortisol excess into overt Cushing syndrome and mild autonomous cortisol secretion. Germline mutations in the Armadillo repeat-containing 5 (ARMC5) gene have been identified in 20%–55% of patients with PBMAH. This study aimed to describe the clinical, radiological, and biochemical characteristics of PBMAH; classify cortisol secretion according to updated guidelines; and evaluate surgical and conservative treatment outcomes. Methods This retrospective cohort study included 58 patients with bilateral adrenal macronodules who underwent ARMC5 genetic testing at a tertiary center between 2023 and 2025. Clinical, imaging, laboratory, and genetic data were collected. Mild autonomous cortisol secretion was defined according to the 2023 European guidelines as a post–dexamethasone suppression test cortisol level >1.8 μg/dL in the absence of overt Cushing syndrome features. Postoperative and follow-up data, including hormonal assessments and remission criteria, were recorded. Results A total of 58 patients were included; 14 (23.7%) were male, and the mean age was 57.7 years (39–73). Four patients (6.9%) with overt Cushing syndrome carried germline ARMC5 mutations, three of whom belonged to the same family, supporting an autosomal dominant pattern of inheritance. Among them, 34 patients with mild autonomous cortisol secretion and 20 patients with nonfunctional PBMAH were managed conservatively. Unilateral laparoscopic adrenalectomy was performed in five patients, all of whom achieved biochemical and clinical remission during follow-up (median, 14 months). No postoperative adrenal insufficiency or persistent hypercortisolism was observed. Conclusion PBMAH demonstrates a broad clinical spectrum, ranging from nonfunctional disease to overt Cushing syndrome. The updated classification of cortisol secretion (mild autonomous cortisol secretion vs. overt Cushing syndrome) improves clinical stratification and supports treatment decision-making. ARMC5 genetic analysis contributes to diagnostic confirmation, facilitates cascade family screening, and enables identification of asymptomatic carriers. Unilateral adrenalectomy is effective in patients with overt Cushing syndrome, whereas surveillance is appropriate for those with mild autonomous cortisol secretion or nonfunctional PBMAH.