Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: Comparison with sporadic pheochromocytoma gives insight intonatural history of pheochromocytoma

Purpose: Families with von Hippel-Lindau disease have variable risk of pheo chromocytoma. Patients with von Hippel-Lindau disease and pheochromocytoma identified by screening can have no characteristic signs or symptoms. Famil ies with von Hippel-Lindau disease were screened and followed to describe t he natural history of von Hippel-Lindau pheochromocytoma, and to correlate these findings with von Hippel-Lindau germline mutation. Materials and Methods: Between 1988 and 1997, 246 individuals with von Hipp el-Lindau disease were identified (von Hippel-Lindau group). Between August 1990 and June 1997, 26 consecutive patients with sporadic pheochromocytoma were evaluated (sporadic group). Results: A total of 64 patients with von Hippel-Lindau disease had manifest ations of pheochromocytoma, including 33 newly diagnosed during screening a t the National Institutes of Health and 31 previously treated (93 adrenal a nd 13 extra-adrenal pheochromocytomas). Germline von Hippel-Lindau gene mis sense mutation was associated with extra-adrenal pheochromocytoma, younger age at presentation and the only patient with metastases. Of the 33 newly d iagnosed patients with von Hippel-Lindau disease 4 had pheochromocytoma 2 t imes (37 pheochromocytomas) during followup. Of these pheochromocytomas 35% (13 of 37) were associated with no symptoms, normal blood pressure and nor mal catecholamine testing. Comparison of urinary catecholamines in the von Hippel-Lindau and sporadic groups demonstrated increased epinephrine, metan ephrines and vanillylmandelic acid in the sporadic group. Analysis of urina ry catecholamine excretion in the von Hippel-Lindau and sporadic groups tog ether demonstrated a correlation between tumor size, and urinary metanephri nes, vanillylmandelic acid, norepinephrine, epinephrine and dopamine. In 12 patients without signs or symptoms of pheochromocytoma 17 newly diagnosed pheochromocytomas were followed for a median of 34.5 months without morbidi ty. Median tumor doubling time was 17 months. Conclusions: Von Hippel-Lindau gene missense mutation correlated with the r isk of pheochromocytoma in patients with von Hippel-Lindau disease. These f indings support a von Hippel-Lindau disease clinical classification, wherei n some families are at high risk for manifestations of pheochromocytoma. Vo n Hippel-Lindau disease pheochromocytomas identified by screening were smal ler and less functional than sporadic pheochromocytomas.