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Abstract

Neurofibromatosis 1 (NF1) exhibits extreme clinical variability. This variability greatly increases the burden for affected families. The relationship of genetic factors to variable expressivity in NF1 is poorly understood. To improve understanding of NF1,1 studied relationships between several disease features in individuals and among affected relatives. My studies used clinical information on 4731 NF1 patients from three independent databases: the National NF Foundation International Database, the NF Institute Database and a population-based registry of NF1 patients in north-west England. My initial studies found associations between several pairs of features in affected probands and between the occurrence of individual features in affected parents and children. This establishes that some patients are more likely than others to develop particular NF1 features. Furthermore, the results of my logistic regressive models are consistent with grouping 9 of the features into three sets of associated features: 1) cafeau- lait spots, intertriginous freckling and Lisch nodules; 2 ) cutaneous, subcutaneous and plexiform neurofibromas; and 3) macrocephaly, optic glioma and other neoplasms. Also, the occurrence of Unidentified Bright Objects on magnetic resonance imaging in young (