Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1

Overview

This study will explore the growth of dermal neurofibromas (skin tumors) in patients with neurofibromatosis type 1 (NF1). Investigators will try to learn: 1) how fast (or slow) these benign tumors grow in NF1, 2) how often new tumors appear and 3) what genes are involved in the growth of the tumors. Men and women between 20 and 50 years of age diagnosed with NF1 and their biological parents are eligible for this study. Patients with NF1 are evaluated at the NIH Clinical Center with the following tests and procedures: * Medical examination and drawing of family tree. * Photos of the back, abdomen and thigh in order to count the number of skin tumors. * Photos of the skin taken with a special camera (Primos camera) that takes very detailed pictures of a small area of skin. * Photos of the skin taken with a dermatoscope, which takes very detailed pictures of a small area of skin under high magnification. * Biopsy of at least one skin tumor and biopsy of a small piece of normal skin. * Blood sample collection for genetic testing of the gene NF1 and to establish a cell line. * Other medical tests (e.g., x-rays or MRI) if needed. Patients and their families will also have a genetic counseling session and an opportunity to ask questions about neurofibromatosis type 1. Patients return to the NIH after 3, 6, 12, 18 and 24 months for follow-up photographs and possibly blood samples. Biological parents of patients provide a blood sample for genetic testing.

This protocol results from a funded 2005 Bench-to-Bedside Award and explores the genetic basis of disease severity in neurofibromatosis type 1 (NF1) and the evaluation of three methods to measure disease progression of dermal neurofibromas. NF1 is a common multisystem genetic disorder associated with the development of benign and malignant tumors, primarily of the nervous system. NF1 is 100% penetrant and features variable expressivity and limited phenotype/genotype correlation. No standard treatment other than surgery exists for most NF1-associated tumors. Many aspects of the natural history of NF1-associated tumors are not fully characterized and require investigation to assess the effects of potential new treatments, in future clinical trials. The development of medical treatments for NF1-associated tumors is an important goal given their morbidity and the lack of non-surgical treatment options. The ability to predict the ultimate severity of disease would have a significant impact on the management and treatment of individuals with NF1. Sorafenib (BAY 43-9006) is a novel, orally bioavailable agent that targets downstream effectors in the Ras signaling pathway (a key dysregulated pathway in NF1). It has thus a strong scientific rationale for evaluation in NF1 related tumors. Dermal neurofibromas occur in nearly every individual with NF1, and are a significant cosmetic problem and a major cause of morbidity. This protocol will 1) quantify the growth of dermal neurofibromas in NF1 with 3 different imaging modalities 2) use an innovative gene expression method to identify genetic modifiers of dermal neurofibroma burden, and 3) evaluate dermal neurofibromas and normal skin for the presence of targets of sorafenib. Successful validation of reliable quantitative imaging methods of dermal neurofibroma growth is a logical prerequisite to subsequent clinical trials with medical treatments, which will evaluate the effect of new agents on the growth rate of dermal neurofibromas. Identification of genetic modifiers may permit prediction of ultimate tumor burden. Evaluation of targets of new agents in dermal neurofibromas will allow for more rationale drug development for NF1. Given the paucity of protocols for adults with NF1 and dermal neurofibromas, this study will likely generate great interest among affected individuals and have rapid accrual.