Mild Autonomous Cortisol Secretion in Context of Bilateral Macronodular Adrenocortical Disease due to ARMC5 Mutation: A Rare Familial Case

Introduction Bilateral macronodular adrenocortical disease (BMAD) is an uncommon cause of endogenous Cushing syndrome, often diagnosed through bilateral adrenal incidentalomas without clinical manifestations of hypercortisolism. Mutations in the armadillo repeat-containing 5 ( ARMC5 ) gene represent one of the causes of this disease, frequently correlating to a more severe phenotype. After diagnosis, it is essential to establish a proper management strategy and offer genetic screening to first‐degree family members if a genetic cause is identified. Clinical Cases Presentation Patient A, a 61‐year‐old woman, underwent abdominal computed tomography (CT) in 2013 following right hemicolectomy. Imaging revealed bilateral adrenal nodules (largest: right 32 mm and left 31 mm). She had no evidence of clinical features suggestive of endocrine dysfunction, and work‐up was consistent with mild autonomous cortisol secretion (MACS) with associated lumbar spine osteopenia. Patient B, her 66‐year‐old brother, underwent abdominal imaging in 2017 for macroscopic hematuria, revealing bilateral nodular adrenal enlargement (largest: right 23 mm and left 31 mm). He showed no clinical features indicative of endocrine dysfunction, with further evaluation consistent with MACS and no cortisol‐associated comorbidities. Aberrant hormone receptor testing was negative. Genetic analysis confirmed the presence of the same pathogenic ARMC5 variant [c.1855C > T p.(Arg619 ∗ )] in both individuals. A conservative approach with periodic monitoring was adopted following multidisciplinary discussion. Over the follow‐up, Patient B remained stable, while Patient A exhibited clinical and radiological progression, warranting reconsideration of adrenalectomy. Conclusion Cortisol secretion in the context of BMAD associated with ARMC5 mutations represents a diagnostic challenge due to its dynamic nature and insidious presentation. This familial case adds to the few reported ones and illustrates the variable expression and clinical courses of this condition, even in relatives with the same acknowledged etiology. Its management requires a multidisciplinary and individualized approach, considering disease severity and adrenalectomy risks. Regular surveillance and genetic counseling remain crucial to enable early detection of carriers and guide timely therapeutic decisions.