Cushing syndrome due to bilateral macronodular adrenocortical disease

Cushing syndrome due to bilateral macronodular adrenocortical disease (BMAD), also known as ACTH-independent macronodular adrenal hyperplasia (AIMAH) or primary bilateral macronodular adrenal hyperplasia (PBMAH), is a rare cause of Cushing syndrome characterized by the bilateral enlargement of the adrenal glands with multiple large nodules (greater than 1 cm) that autonomously produce excess cortisol. Unlike the more common forms of Cushing syndrome, this condition is independent of pituitary ACTH stimulation. The excess cortisol affects multiple body systems, leading to characteristic features including central obesity, moon face, skin thinning with easy bruising, purple striae, proximal muscle weakness, hypertension, glucose intolerance or diabetes mellitus, osteoporosis, and mood disturbances. Some patients may have subclinical hypercortisolism for years before overt Cushing syndrome develops. The disease typically presents in adulthood, most commonly between the fifth and sixth decades of life. In many cases, the adrenal nodules express aberrant (ectopic or eutopic) hormone receptors — such as receptors for gastric inhibitory polypeptide (GIP), vasopressin, catecholamines, serotonin, or luteinizing hormone — which can drive cortisol production in response to stimuli that would not normally affect the adrenal glands. Germline inactivating mutations in the ARMC5 gene have been identified as a major genetic cause, found in approximately 25-50% of apparently sporadic cases and in familial forms. Mutations in other genes, including KDM1A and potentially others, have also been implicated. Treatment depends on the severity of hypercortisolism. Bilateral adrenalectomy is the definitive treatment for patients with overt Cushing syndrome, though it necessitates lifelong glucocorticoid and mineralocorticoid replacement therapy. In cases where aberrant receptor expression is identified, targeted medical therapy (such as beta-blockers for catecholamine-dependent cases) may be attempted. Unilateral adrenalectomy of the larger gland may be considered in select cases to reduce cortisol excess while preserving some adrenal function. Medical therapies used in other forms of Cushing syndrome, such as steroidogenesis inhibitors (ketoconazole, metyrapone, osilodrostat), may also be employed to control hypercortisolism. Genetic counseling is recommended, particularly when ARMC5 mutations are identified, given the autosomal dominant inheritance pattern with variable expressivity.

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