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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS052500-05
Application #
7590458
Study Section
NST-2 Subcommittee (NST)
Program Officer
Morris, Jill A
Project Start
2005-08-16
Project End
2011-10-17
Budget Start
2009-04-01
Budget End
2011-10-17
Support Year
5
Fiscal Year
2009
Total Cost
$176,094
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Larson, A Noelle; Ledonio, Charles Gerald T; Brearley, Ann M et al. (2018) Predictive Value and Interrater Reliability of Radiographic Factors in Neurofibromatosis Patients With Dystrophic Scoliosis. Spine Deform 6:560-567
Mitchell, Sheri; Siegel, Dawn H; Shieh, Joseph T C et al. (2012) Candidate locus analysis for PHACE syndrome. Am J Med Genet A 158A:1363-7
Johnson, Barbara A; Macwilliams, Bruce; Carey, John C et al. (2012) Lower extremity strength and hopping and jumping ground reaction forces in children with neurofibromatosis type 1. Hum Mov Sci 31:247-54
Wang, Weixi; Nyman, Jeffry S; Ono, Koichiro et al. (2011) Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I. Hum Mol Genet 20:3910-24
Kossler, Nadine; Stricker, Sigmar; Rodelsperger, Christian et al. (2011) Neurofibromin (Nf1) is required for skeletal muscle development. Hum Mol Genet 20:2697-709
Stevenson, David A; Yan, Jincheng; He, Yongzheng et al. (2011) Multiple increased osteoclast functions in individuals with neurofibromatosis type 1. Am J Med Genet A 155A:1050-9
Stevenson, D A; Schwarz, E L; Carey, J C et al. (2011) Bone resorption in syndromes of the Ras/MAPK pathway. Clin Genet 80:566-73
Stevenson, David A; Viskochil, David H; Carey, John C et al. (2011) Pediatric 25-hydroxyvitamin D concentrations in neurofibromatosis type 1. J Pediatr Endocrinol Metab 24:169-74
Johnson, Barbara A; MacWilliams, Bruce A; Carey, John C et al. (2010) Motor proficiency in children with neurofibromatosis type 1. Pediatr Phys Ther 22:344-8
Muram-Zborovski, Talia M; Stevenson, David A; Viskochil, David H et al. (2010) SPRED 1 mutations in a neurofibromatosis clinic. J Child Neurol 25:1203-9

Showing the most recent 10 out of 25 publications