Depression and metabolic crisis masked Cushing's syndrome for years.

A body in metabolic strain

A 51-year-old man carried a five-year history of hypertension and diabetes mellitus. Despite treatment with multiple medications, including nifedipine, irbesartan, metformin, and repaglinide, his conditions remained a significant burden. He did not regularly monitor his glucose levels, and for years, the underlying driver of his metabolic instability remained unidentified.

In the two weeks leading up to his clinical evaluation, his condition shifted. He presented with new symptoms of fatigue and abdominal distension. Upon physical examination, clinicians observed prominent violaceous abdominal striae—deep purple stretch marks—along with cutaneous atrophy and telangiectasias, visible signs of a body under intense hormonal stress.

Atypical presentations

While the patient’s primary complaints were physical, the medical literature notes that this specific type of adrenal disease can manifest with atypical presentations, including depression. These psychiatric and metabolic disturbances are often the first signs of a rare etiology of Cushing’s syndrome: adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH).

The adrenal evidence

Initial imaging and biochemical tests began to reveal the source of the patient's symptoms. Adrenal MRI showed bilateral adrenal enlargement, and dexamethasone suppression tests were positive, indicating that his body was producing an autonomous excess of cortisol. Further testing at a second hospital confirmed severe hypercortisolism with a 24-hour urinary free cortisol of 836 µg and an ACTH level suppressed to less than 5.00 pg/mL.

His blood work also showed hypokalemia, with serum potassium dropping to 3.2 mmol/L. For five months, the patient attempted medical therapy, but the treatment failed to provide significant symptomatic improvement. He was eventually admitted to the Department of Endocrinology and Metabolism at the First Affiliated Hospital of Anhui Medical University for a definitive workup.

The genetic thread

Genetic analysis identified the root cause of the patient’s illness: a heterozygous pathogenic variant in the ARMC5 gene (c.2692C>T, p.Arg898Trp). ARMC5 is a tumor suppressor gene; when it malfunctions, it can trigger a "two-hit" model of tumorigenesis, leading to the growth of large nodules on the adrenal glands that pump out cortisol regardless of the body’s actual needs.

Family screening revealed that the patient’s father carried the exact same genetic variant but remained entirely asymptomatic. This highlighted a hallmark of ARMC5 mutations: incomplete penetrance, where the genetic "label" exists, but the clinical disease may or may not manifest until a second biological "hit" occurs.

Outcome and persistent disease

The patient underwent a laparoscopic right adrenalectomy to remove the most heavily affected gland. While his serum cortisol levels dropped by 48% four weeks after surgery, they did not return to normal range. His ACTH remained suppressed, and follow-up imaging at six months showed that the remaining left adrenal gland had progressed toward a cystic morphology.

The case illustrates that for carriers of this genetic mutation, surgery is often a cytoreductive measure rather than a complete cure. The patient reported a marked enhancement in his quality of life after the procedure, but the discovery of the ARMC5 variant indicated he would require lifelong surveillance of his remaining adrenal gland to monitor for the recurrence of hypercortisolism.