Skin neurofibromas are the most common tumors of patients with neurofibromatosis type 1 (NF1), yet we know very little about how they develop. We propose to study a subset of NF1 patients that are prone to early onset and large numbers of skin neurofibromas. These patients carry a deletion of the NF1 gene and about 15 adjacent genes of unknown function. We propose that deletion of one of these adjacent genes favors the development of skin neurofibromas, and possibly also plexiform neurofibromas and malignant tumors. Studying patients with NF1 deletions holds the key to identifying this unknown adjacent gene and understanding how it promotes tumor growth. We propose to evaluate many patients with deletions and determine when and what kind of tumors and other clinical features they have. This may result in a recommendation for increased clinical surveillance for tumors and cancers that would benefit this group of patients. We will look for specific genetic changes in skin neurofibromas of patients with NF1 deletions to provide insight into how they develop. We have identified one adjacent gene that is good candidate for promoting tumor growth. This gene will be analyzed in detail. One problem in identifying a tumor-promoting gene adjacent to NF1 is the lack of a map and DNA sequence of the region. This also hampers identification and analysis of new data that suggests there is a second NF1-like gene adjacent to the functional NF1 gene. We propose to employ new and powerful technology from the Human Genome Project to confirm or disprove the presence of an NF1-like gene. If present, this gene may contribute in some unknown way to making the disease more or less severe. Therefore, identifying NPL and the possible NF1-like gene will help us understand how neurofibromas form and grow, which is necessary to plan ways to slow or halt their growth.