The enigma unfolds: ARMC5-associated primary bilateral macronodular adrenal hyperplasia in a young man

Abstract

Background: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome. Germline pathogenic ARMC5 variants are among the most well-established genetic causes and are associated with variable penetrance and clinical expression. Diagnosis of PBMAH can be difficult and challenging for clinicians. We report a young man with severe Cushing syndrome due to PBMAH associated with an ARMC5 splice-site variant.

Case summary: A 30-year-old man was referred to our department for evaluation of resistant hypertension along with bilateral adrenal enlargement. On background history, he reported progressive weight gain for 7 years, fatigue, and daytime somnolence. Examination revealed a plethoric rounded face, dorsocervical pad of fat, acanthosis nigricans, multiple skin tags, central obesity and wide deep violaceous striae, without bruising or proximal muscle weakness. His body mass index was 34.1 kg/m², and his blood pressure was 160/100 mmHg. On biochemical evaluation, he had newly diagnosed diabetes and ACTH-independent hypercortisolism, characterized by elevated 24-hour urinary free cortisol and late-night salivary cortisol, failure to suppress cortisol on low-dose dexamethasone testing, and suppressed plasma ACTH. CT scan of abdomen demonstrated bilateral adrenal enlargement with nodular thickening involving the adrenal bodies and limbs. Laparoscopic bilateral adrenalectomy was performed, with histopathology confirming bilateral macronodular adrenal hyperplasia. Next-generation sequencing identified a novel heterozygous germline ARMC5 c.476-1G>A 3′ splice-site variant, classified as likely pathogenic and consistent with autosomal-dominant PBMAH type 2. Following surgery, hypercortisolism resolved with rapid normalization of blood pressure and glycemia. He subsequently required glucocorticoid and mineralocorticoid replacement.

Conclusions: PBMAH should be considered in a patient with ACTH-independent Cushing syndrome and bilateral nodular adrenal enlargement. Bilateral adrenalectomy can achieve definitive control of hypercortisolism and reverse its metabolic complications. Identification of a germline ARMC5 variant establishes a potential hereditary etiology and highlights the importance of genetic counseling and family screening.

[J Assoc Clin Endocrinol Diabetol Bangladesh, 2026;5(Suppl 1): S51]