The neurofibromatosis type 1 gene and its protein product, neurofibromin.

Von Recklinghausen neurofibromatosis, or neurofibromatosis type 1 (NFI), affects approximately 1 in 3500 individuals of all ethnic backgrounds. It is inherited as an autosomal dominant disease and is manifested clinically by abnormalities that predominantly affect tissues which derive from the neural crest (Riccardi, 1981,199l; Riccardi and Eichner, 1986). Affected individuals are often noted to have multiple cafeau-lait spots during the first year of life. These pigmented birthmarks contain melanocytes harboring macromelanosomes, but have noclinical significance other than as a diagnostic clue. Similarly, another important clinical feature, the presence of Lisch nodules of the iris, has no associated morbidity. However, these hamartomas appear during childhood and are eventually present in close to 100% of affected adults. Neurofibromas, which give the disease its name and usually make their appearance just before or during adolescence, are benign cutaneous tumors consisting of Schwann cells, fibroblasts, and other cellular elements. They increase in size and number with age, but at an unpredictable rate. More deeply placed neurofibromas, called plexiform lesions, usually appear in childhood and can lead to significant complications due to associated overgrowth of nearby tissues. Furthermore, such plexiform lesions have a modest but significant risk of degenerating into malignant neurofibrosarcoma, a highly invasive soft tissue tumor that is frequently fatal. This potential, plus the risk of optic glioma (which affects 2%-S% of all individuals with NFI) justifies placing this disease on the list of familial cancer syndromes (Bader, 1986). Other features of NFI arevariable but can be significant in a given patient. Approximately half of affected individuals have at least some degree of learning disability, and a small percentage have frank mental retardation (Riccardi, 1981). Seizures are present in about 5% of individuals, and megalencephaly is a typical finding. The diagnosis is usually not difficult to make in an adolescent or adult, but can occasionally present difficulties in a very young child. NFI is characterized by extreme variability, even among individuals within the same family who carry the same mutation. Approximately two-thirds of individuals with NFI lead relatively normal lives, with occasional interruptions for surgical management of their disease, often to remove neurofibromas that are causing cosmetic or physical distress. About one-third of individuals suffer a severe complication sometime during their lifetime. NFI has occasionally been erroneously referred to as “the elephant man disease”; while the gross facial distortion and other deformities present in Joseph Merrick, the Elephant Man, in some ways resemble the most severe end of the spectrum of NFI, subsequent evaluation of Merrick’s skeleton indicates that he probably had another disorder known as Proteus syndrome (Tibbles and Cohen, 1986).