Cushing’s Disease in a Patient with MEN 2B Syndrome

A 28-year-old male presented with arterial hypertension and type 2 diabetes mellitus, gradually developing over the last 18 months. Both hypertension and diabetes were inadequately controlled with maximal daily doses of perindopril, amlodipine, metformin, and dapagliflozin. His previous photograph taken 5 years ago showed a lean male with marfanoid features and bumpy lips (Figure A). Current physical examination disclosed increased blood pressure (148/92 mmHg), a body mass index of 28.2 kg/m², facial plethora, and a “buffalo hump” (Figure B). Endocrinological evaluation was carried out in order to make the diagnosis of secondary hypertension and secondary diabetes mellitus. Increased 24-hour urinary metanephrine (16,880 nmol/24 hours, normal < 1300) and normetanephrine (10,273 nmol/24 hours, normal < 2800) were found, which were highly suggestive of pheochromocytoma. Moreover, the diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing’s disease was made: ACTH 10.1 pmol/L (normal 2.2-13.3), serum cortisol following 1 mg dexamethasone suppression test of 701 nmol/L, and 24-hour urinary-free cortisol of 4754 nmol/24 hours (normal 72-325). Due to previously evident marfanoid features and suspicion of pheochromocytoma, multiple endocrine neoplasia type 2B (MEN 2B) syndrome was suspected. Increased serum calcitonin (1649 ng/L, normal <18.2) and serum carcinoembryonic antigen (162 ng/L, normal <5) were suggestive of medullary thyroid carcinoma.

Fludeoxyglucose positron-emission tomography showed a metabolically inactive tumor mass in the right thyroid lobe and metabolically active bilateral adrenal masses, along with a metabolically active lymph node conglomerate, in the right upper abdomen. His colon was profoundly dilated, measuring 10 cm with no clinical or radiographical signs of mechanical intestinal obstruction, suggestive of Hirschprung’s disease, which is highly prevalent in MEN2B syndrome. Pituitary magnetic resonance imaging was normal. Genetic testing confirmed M918T RET mutation consistent with MEN2B syndrome. Total thyroidectomy was performed followed by single-stage total colectomy and radical bilateral adrenalectomy with lymph node metastasectomy. Histopathology was consistent with medullary thyroid carcinoma and metastatic pheochromocytoma, whereas pheochromocytoma tissue showed positive immunostaining for ACTH. Postoperatively, his serum calcitonin and carcinoembryonic antigen levels remained increased, whereas urinary free cortisol and cateholamines normalized with a consequent remission of hypertension and diabetes.

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-Ivan Kruljac, MD, PhD^a, Nina Dabelić, MD, PhD^b, Domagoj Marjan, MD^c, Kristina Blaslov, MD, PhD^a, Božidar Perić, MD^a, Gorana Mirošević, MD, PhD^a, Davor Vagić, MD, PhD, (Professor of Medicine)^d,e, Milan Vrkljan, MD, PhD, (Professor of Medicine)^a,e