This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Neurofibromatosis type 1 (NF1) is a common genetic disorder with good potential for insight into biological processes. It is classically characterized as a neurocutaneous disorder, but osseous and spinal abnormalities are clearly associated with NF1. Skeletal abnormalities associated with NF1 include long bone dysplasia (2-5%), sphenoid wing dysplasia (3-7%), and spinal abnormalities (10-33%). These complications are not well understood and rarely emphasized, even though as high as 38% have been reported to have osseous manifestations. The management of tibial pseudarthrosis and dystrophic scoliosis presents a significant challenge to practitioners. As yet, there is no easy explanation for the mesodermally derived osseous defects in NF1. Neurofibromin, the NF1 gene product, has tumor suppressor aspects through its interactions with ras, and may interact with other biochemical pathways involved in bone metabolism. Questions regarding pathogenesis, natural history, burden of morbidity, and clinical outcome remain unanswered. If generalized skeletal abnormalities exist in NF1 then some patients may be predisposed to develop localized defects. We theorize that there is a subtle primary disorder of bone in NF1 that predisposes NF1 individuals to the development of local, more severe osseous defects. Generalized osseous findings in NF1 include short stature and macrocephaly. Many of the localized osseous findings in NF1 (vertebral wedging and scalloping, rib-penciling, osteopenia and poor bone healing in long bone bowing with pseudarthrosis, localized overgrowth, and multiple cystic areas of bone in some patients) appear randomly, supporting this hypothesis. We hypothesize that there are generalized bone abnormalities with decreased bone health indexes in patients with NF1 compared to the general population. We also hypothesize that there is a phenotype-genotype correlation in NF1 patients with osseous defects. We will address these hypotheses with two corresponding specific aims.
Specific aim #1 : Describe the bone health of children with neurofibromatosis type 1 (NF1) using peripheral quantitative computerized tomography (pQCT), dual energy X-ray absorptiometry (DXA), and urinary pyridinium crosslinks.
Specific aim #2 : Describe the genotype-phenotype relationships of NF1 and osseous defects using mutation screening of the NF1 gene and clinical phenotyping.
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