Neurofibromatosis Type 1: A Common Familial Cancer Syndrome

Neurofibromatosis type 1 (NF1) is one of the most common dominantly inherited neurogenetic disorders, affecting about 1 in every 4000 individuals worldwide. It is fully penetrant by the age of five. The condition is characterized by multiple caf�-au-lait spots, benign neurofibromas, and Lisch nodules (1 ). Other clinical manifestations include abnormalities of the cardiovascular, gastrointestinal, renal, and endocrine systems; major orthopedic problems; facial and body disfigurement; and cognitive deficit and malignancy, with tumors of the peripheral nerve sheath and central nervous system (CNS). About one-quarter of NF1 patients develop one or more of these clinical complications, demonstrating the significant morbidity and mortality associated with this disorder. However, the clinical expression varies greatly from one patient to another, between families, and even within a given family carrying the same underlying gene lesion. The establishment of diagnostic criteria for NF1 (2 ) has potentiated the clinical diagnosis of NF1 in most patients. Neurofibromas are a hallmark feature of NF1. Each neurofibroma is composed of Schwann cells (60%–80%), fibroblasts, perineurial cells, axons, and mast cells. The cellular sources of the various neurofibroma-associated mitogens, the occurrence of specific receptors for each of these factors, and their functional role in tumor development remain unclear. Indeed, the characterization of novel tumor growth-promoting factors and their receptors in both benign and malignant cancers may help to define potential treatment strategies for NF1.