Pheochromocytomas, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease

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Abstract
Pheochromocytoma is a feature of two disorders with an autosomal dominant pattern of inheritance -- multiple endocrine neoplasia type 2 (MEN-2) (with medullary thyroid carcinoma and hyperparathyroidism) and von Hippel-Lindau disease (with angioma of the retina, hemangioblastoma of the central nervous system, renal-cell carcinoma, pancreatic cysts, and epididymal cystadenoma). The frequency of these syndromes in patients with pheochromocytoma is not known. In an unselected group of patients with pheochromocytoma, we performed pentagastrin tests, parathyroid hormone assays, computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, ophthalmoscopy, CT imaging of the abdomen, and ultrasonography of the testes. We also screened members of families with MEN-2 or von Hippel-Lindau disease for pheochromocytoma by measuring plasma and urine catecholamines and plasma chromogranin A and by performing abdominal ultrasonography, CT and MRI, and metaiodobenzylguanidine scintigraphy. Nineteen of 82 unselected patients with pheochromocytomas (23 percent) were carriers of familial disorders; 19 percent had von Hippel-Lindau disease and 4 percent had MEN-2. Prospectively, in 36 of 79 subjects at risk for pheochromocytoma (46 percent), 42 unsuspected pheochromocytomas were found. Overall, there were 130 patients with 185 pheochromocytomas; 43 had von Hippel-Lindau disease, 24 had MEN-2, and 63 had sporadic tumors. The patients with familial and those with sporadic pheochromocytomas differed in mean age at diagnosis (32 vs. 46 years, P<0.001), multifocal localization (55 vs. 8 percent, P<0.001), and cancer (0 vs. 11 percent, P = 0.005); but not in the frequency of extraadrenal tumors (24 vs. 16 percent). Thirty-eight percent of carriers of von Hippel-Lindau disease and 24 percent of carriers of MEN-2 had pheochromocytoma as the only manifestation of their syndrome. All patients with pheochromocytomas should be screened for MEN-2 and von Hippel-Lindau disease to avert further morbidity and mortality in the patients and their families. All patients in families with MEN-2 or von Hippel-Lindau disease should be screened for pheochromocytoma, even if they are asymptomatic.