Models for inherited susceptibility to cancer in the nervous system: a molecular-genetic approach to neurofibromatosis.

Neurofibromatosis (NF) is one of the most frequent and clinically important Mendelian disorders in man, with an incidence of 1 in 3,000. While different organ systems and cell types can be affected in NF, the most common abnormalities are in cells of neural crest origin. Two distinct forms of NF have been described: 'peripheral' or von Recklinghausen NF (VRNF) and 'central' or bilateral acoustic NF (BANF). VRNF is characterized clinically by hyperpigmented patches of skin and multiple tumors of the peripheral and central nervous system, which can cause disfigurement, paralysis, blindness and death. In comparison, BANF is characterized by the bilateral occurrence of acoustic neurinomas (Schwann cell-derived tumors of the 8th cranial nerve) and increased susceptibility to certain other nervous system tumors, including meningiomas and gliomas. These tumors can lead to deafness and other serious neurological morbidity and mortality within the first few decades of life. The primary biochemical defects in both forms of NF is not yet known, but is of great fundamental interest in view of the potential role of these genes in controlling proliferation and differentiation of neural crest cells. Here we discuss different molecular-genetic approaches towards identifying these defective genes. In particular, our studies on tumors associated with BANF have specifically implicated chromosome 22 as the location of the gene defect causing this serious neurological disorder. The identification and characterization of the NF genes, based on their chromosomal localizations, will have profound implications for diagnosis and treatment of these diseases and might yield significant insights into mechanisms controlling development and differentiation of the human nervous system.