Neurofibromatosis type 1 (NF1) is a common (approximately 85,000 Americans) genetic disorder of dysregulated cell growth. Affected people develop multiple (tens, hundreds, or thousands) of soft fleshy tumors called neurofibromas. People with NF1 also develop malignant cancers. There are limited therapies and no cures for NF1. At this time it is essentially impossible to predict the severity of the disorder. With few exceptions, neither mutation testing of the involved gene (NF1) nor the severity of other affected family members help in estimating the clinical course of the condition. In this study we study the wide variability in severity seen in families with NF1. In our translational approach, we quantitatively evaluate families with NF1 using a variety of methods (magnetic resonance imaging (MRI), skin and eye photography, physical exam). We plan to correlate differences in these measurements with differences in the expression of genes, as determined by a microarray. The ultimate goal is to identify genes associated with severity. Differences in these genes (such as single nucleotide polymorphisms (SNPs)) may be useful in predicting the severity of the disorder. Gene products associated with severity may also be useful therapeutic targets. I joined NHGRI at the end of November 2004. The IRB approved the project in April 2005 and recruitment started shortly thereafter. By the end of fiscal 2005, we had evaluated 4 families with NF1, and had 5 more families scheduled to visit by the end of November 2005. A complementary project using a large previously-banked NF1 pedigree from Coriell Cell Repositories (Camden, NJ) is also underway. We are currently developing another project with Dr. Brigitte Widemann of NCI to investigate the growth and biology of neurofibromas. This project, the result of a 2005 Bench-to-Bedside Award, is in anticipation of a clinical trial of a novel agent to control neurofibroma growth.