Neurofibromatosis type 1 (NF1) is a common genetic disorder with a high degree of variability of clinical expression, including skeletal abnormalities in over 1/3 of patients. These osseous manifestations are unpredictable, and the pathogenesis, natural history and clinical outcome remain relatively obscure. I propose to test the hypothesis that NF1 is a constitutional disorder of bone with generalized osseous abnormalities by addressing 3 Specific Aims. The first Specific Aim is to determine the differences in bone health variables between NF1 individuals and individuals without NF1, and between NF1 individuals with and without osseous abnormalities. Bone-health measurements from imaging modalities [dual energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT)], and biochemical markers of bone metabolism including urinary pyridinium cross-links will be used to test the hypothesis that there are subtle bone abnormalities in NF1 compared to the general population. The second Specific Aim is to determine genotype-phenotype correlations of the NF1 gene and osseous abnormalities. High-throughput DNA sequencing will be used to determine if a specific mutation class contributes to the NF1 osseous phenotype. In addition, a cohort of NF1 families will be recruited to assess osseous phenotypes through sib-pair and parent-child analyses, including NF1 haplotype analysis. The third Specific Aim is to assess health status and health-related quality of life (HRQL) in children and adolescents with NF1 and scoliosis. Utilizing a 1:3 case-control design through a multi-center collaborative network, HRQL measures from a battery of questionnaire instruments between NF1 individuals with and without scoliosis will be obtained and analyzed. The principal investigator has developed an interdisciplinary plan utilizing mentors, a scientific advisory committee, didactic courses and resources at the University of Utah, General Clinical Research Center in order to become an independent researcher.
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