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Analysis of variable expressivity in neurofibromatosis 1 Szudek, Jacek


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 (<21 years) NF1 patients was associated with other expressed diagnostic features. Clinical features within a group may share pathogenic mechanisms that differ, at least in part, from those underlying features in other groups. I found no local associations between the presence of cutaneous neurofibromas, plexiform neurofibromas, and cafe-au-lait spots in each of ten divisions of the body surface in NF1 patients. However, the correlation among relatives in the number of body segments affected with one or more lesions was positive and significant for all three features. The developments of cutaneous neurofibromas, plexiform neurofibromas, and cafe-au-lait spots in NF1 patients are each spatialy independent but influenced by familial factors. Familial aggregation patterns of NF1 features among various classes of affected relatives were used to examine familial aggregation in greater detail. Using multivariate analyses, statistically significant associations among different classes of relatives were found for several features. Three distinct patterns were observed among the associations for familial features: 1) Lisch nodules and cafe-au-lait spots had greater associations between 1st degree relatives than between 2 n d degree relatives; 2) Subcutaneous neurofibromas, plexiform neurofibromas, cafe-au-lait spots, and intertriginous freckling had greater associations between sibs than between parents and children; and 3) Head circumference and stature had similar associations for all affected relatives. These familial patterns suggest that unlinked modifying genes, the normal NF1 allele, and the mutant NF1 allele may all be involved in the development of particular clinical features of NF1, but that the relative contributions vary for different features. The results presented in this thesis suggest that genetic factors are involved in phenotypic variability in NFL These findings also provide specific clues to pathogenesis of NF1 features that can be tested in molecular studies. The methods of biostatistical analysis developed as part of this thesis can be applied to the study of other complex disorders.

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