Case Report: a family presenting with β-adrenergic/vasopressin-responsive bilateral macronodular adrenal disease with an ARMC5 mutation treated with metyrapone monotherapy for more than 5 years.

Bilateral macronodular adrenal disease (BMAD), also referred to as primary bilateral macronodular adrenal hyperplasia (PBMAH), represents a rare etiology of subclinical or overt Cushing's syndrome (CS), characterized by the presence of multiple large nodules in both adrenal glands. Although historically considered a sporadic condition, familial cases of BMAD have become increasingly recognized in recent years. As early surgical intervention is typically chosen for these familial cases, evidence on the long-term effectiveness of conservative medical therapy remains scarce. Here, we report a Japanese parent-child pair with subclinical and overt CS with genetically confirmed BMAD in which both individuals harbored ARMC5 mutations and exhibited aberrant hormone responses and were managed with long-term metyrapone monotherapy. In both cases, sustained biochemical control of adrenocortical hyperfunction was achieved in more than 5 years. One patient developed progressive hypokalemia, eventually leading to unilateral adrenalectomy. These findings suggest that metyrapone monotherapy serves as an effective noninvasive treatment strategy for select familial BMAD patients, although close monitoring is warranted for potential complications.