Pheochromocytoma in von Hippel-Lindau disease and neurofibromatosis type 1

Clinical and genetic understanding of chromaffin tumors has been greatly enhanced in the last few years. Although some pheochromocytoma genes may still be unknown, the role of RET, VHL, SDHB, SDHD and NF1 genes is unequivocal and phenotypes are also being better characterized. The loss of function of VHL and NF1 genes can lead to a variety of tumors including phechromocytoma and their mechanism of action is under intensive investigation. Many different mutations are responsible for VHL gene inactivation but only missense mutations have been described so far in families with pheochromocytoma. Because of its large size extensive mutation analysis of the NF1 gene has seldom been performed, and mutations have only been identified in about 15% of patients. Several point mutations have been found in exon 31. Differences in pheochromocytoma phenotype in VHL or NF1 are not very pronounced, but it may be of some interest to consider the two groups separately. In VHL, pheochromocytoma has an earlier onset than in sporadic forms, it is often multiple, and malignancy is less frequent. The mean age of diagnosis is 28 years, the youngest patient being 5 years old. In NF1 patients pheochromocytoma phenotype is similar to sporadic forms. The mean age of pheochromocytoma onset is 42 years; 84% of patients have solitary adrenal tumors, 9.6% have bilateral adrenal disease and 6.1% have ectopic pheochromocytomas; malignant pheochromocytomas were identified in 11.5% of the cases. The group of pheochromocytoma susceptibility genes includes, along with the tumor suppressor genes VHL and NF1, the proto-oncogene RET and the genes encoding succinate dehydrogenase subunit D and succinate dehydrogenase subunit B. Whether there is a common pathway among these different genes is still a matter of debate.