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From the Departments of Neurology and Pediatrics (Dr. Packer) and Radiology (Neuroradiology) (Dr. Vezina), Children’s National Medical Center, George Washington University, Washington, DC; Department of Neurology (Dr. Gutmann), Washington University School of Medicine, and Neurofibromatosis Program, St. Louis Children’s Hospital, St. Louis, MO; Department of Neurology (Dr. Rubenstein), Mount Sinai School of Medicine, and National Neurofibromatosis Foundation (Dr. Small), New York, NY; Department of Pediatrics (Dr. Viskochil), University of Utah, Salt Lake City; Department of Radiology (Neuroradiology) (Dr. Zimmerman), Children’s Hospital of Philadelphia and University of Pennsylvania; and Harvard–Partners Center for Genetics and Genomics (Dr. Korf), Massachusetts General Hospital, Boston.
Address correspondence and reprint requests to Dr. Roger J. Packer, Center for Neuroscience and Behavioral Medicine, Department of Neurology, Children’s National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010; e-mail: rpacker{at}cnmc.org
Neurofibromatosis type 1 (NF1) is one of the most common neurogenetic diseases affecting adults and children. Neurofibromas are one of the most common of the protean manifestations of NF1. Plexiform neurofibromas, which will frequently cause cosmetic abnormalities, pain, and neurologic deficits, are composed of "neoplastic" Schwann cells accompanied by other participating cellular and noncellular components. There is increasing evidence that loss of NF1 expression in neoplastic Schwann cells is associated with elevated levels of activated RAS, supporting the notion that the NF1 gene product, neurofibromin, acts as a growth regulator by inhibiting ras growth-promoting activity. In addition, there is increasing evidence that other cooperating events, which may be under cytokine modulation, are important for neurofibroma development and growth. Treatment of plexiform neurofibromas has been empiric, with surgery being the primary option for those with progressive lesions causing a major degree of morbidity. The efficacy of alternative treatment approaches, including the use of antihistamines, maturation agents, and antiangiogenic drugs, has been questionable. More recently, biologic-based therapeutic approaches, using drugs that target the molecular genetic underpinnings of plexiform neurofibromas or cytokines believed important in tumor growth, have been initiated. Evaluation of such trials is hindered by the unpredictable natural history of plexiform neurofibromas and difficulties in determining objective response in tumors that are notoriously large and irregular in shape. Innovative neuroimaging techniques and the incorporation of quality-of-life scales may be helpful in evaluation of therapeutic interventions. The ability to design more rational therapies for NF1-associated neurofibromas is heavily predicated on an improved understanding of the molecular and cellular biology of the cells involved in neurofibroma formation and growth.
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