Cushing syndrome (CS) is characterized by elevated plasma cortisol levels resulting from exogenous exposure or endogenous overproduction. Common manifestations include moon face, central obesity, proximal myopathy, striae, hirsutism, and impaired glucose tolerance. Cushing disease (CD), a subset of Cushing syndrome, results from corticotropin (ACTH)-secreting pituitary adenomas. We report a case of recurrent CS, initially presenting with adrenal nodules and later diagnosed as CD. This case illustrates the diagnostic challenges of CD and highlights the importance of identifying the primary etiology of CS to guide appropriate treatment.

The patient initially presented with CS and normal ACTH levels. Imaging studies revealed bilateral adrenal adenomas with left predominance, while pituitary MRI reported negative result, which led to left adrenalectomy. Two years later, recurrent CS with markedly elevated ACTH was diagnosed, and further MRI and IPSS confirmed CD. Literature review suggests the presentation compatible with ACTH-dependent macronodular adrenal hyperplasia (MAH), a form of CD characterized by chronic ACTH stimulation causing adrenal hyperplasia and autonomous cortisol production.

This autonomous secretion of cortisol suppresses ACTH, resulting in relatively low ACTH levels, a phenomenon referred to as “auto-suppression.” We postulate that a tiny, undetectable ACTH-secreting pituitary microadenoma initially stimulated adrenal growth and cortisol secretion in the present case. Adrenalectomy removed the source of auto-suppression, and led to pituitary tumor progression and recurrence. As up to 23% of CD patients have normal pituitary MRI findings, IPSS remains the gold standard of diagnosing CD. However, due to limited availability, procedural risks and costs of IPSS, shared decision-making is essential.

Adrenal tumors with laterality, such as MAH, can be initial presentation of CD. Therefore, identifying the primary cause of CS is essential. When clinical findings and test results are inconsistent, differential diagnosis should be reconsidered. A negative pituitary MRI does not exclude CD, and IPSS remains the most valuable diagnostic tool in challenging cases.