Pheochromocytoma and NF1

Abstract

Pheochromocytoma and neurofibromatosis type 1 (NF1) are rarely observed in the same patient. However, pheochromocytoma represents a substantial manifestation of NF1 and occurs in about 3 % of affected individuals. In general, pheochromocytomas occur sporadically although they are a classic feature of numerous familial cancer syndromes. Neurofibromatosis type 1 is the oldest of the known inherited pheochromocytoma-associated syndromes which also include multiple endocrine neoplasia type 2 (MEN2), von Hippel–Lindau disease (VHL), the pheochromocytoma/paraganglioma syndromes type 1–4 (PGL1–4), and the familial pheochromocytoma syndromes. Interestingly, NF1-associated pheochromocytomas share many features with sporadic pheochromocytomas such as the mean age at diagnosis, the frequency of malignant transformation, and the extra-adrenal and bilateral tumor growth. NF1 germline mutation analysis in patients with NF1 and pheochromocytoma is time-consuming and remains a considerable challenge and hence has rarely been performed. More than 80 % of the mutations are either nonsense or frameshift mutations while 10 % are deletions or duplications affecting the length of one to >50 exons. A clustering within distinct areas of the NF1 gene is not evident. It is important to note that to date no case with pheochromocytoma and a NF1 germline mutation has been reported that did not show typical lesions of NF1. Therefore, for clinical and scientific studies, mutation analysis of the NF1 gene is not indicated. Why pheochromocytomas due to NF1 germline mutations grow only in selected NF1 patients has still to be elucidated.