To identify genetic determinants of human cancer, cancer families and genetic disorders predisposing to neoplasia are studied in an interdisciplinary approach to gain insights into human carcinogenesis. Study of 40 patients with neurofibromatosis 2 (NF2) confirmed that posterior subcapsular lens opacities (cataracts) are a frequent and early feature of the disorder. Evaluation of the clinical or genetic findings present in 23 of our patients prior to NF2 diagnosis suggested that this disorder should be considered in young people who do not meet the diagnostic criteria for neurofibromatosis I (NFI) but have cutaneous neurofibromas or central nervous system tumors and cataracts at a young age. Of course all first degree relatives of affected individuals should also be evaluated for NF2. We have observed marked interfamily differences in the clinical expression of NF2 based on average age at diagnosis and at death. The three groups comprise one family with mild NF2 (bilateral acoustic neuromas), one family with severe NF2 (extensive meningiomatosis of brain and spinal cord) and seven families with moderate NF2 (bilateral acoustic neuromas plus meningiomas). Linkage analysis in our NF2 families with chromosome 22 DNA markers is continuing. From comparisons of ratios of head circumference to height in normal individuals, persons with the Nevoid Basal Cell Carcinoma syndrome and persons with NF1, we concluded that NFI is a true macrocephaly syndrome. Finally, specimens were obtained from 33 families with a variety of different cancer diagnoses that are components of the Li-Fraumeni syndrome for evaluation by PCR of DNA from the p53 gene.
