NEUROFIBROMATOSIS SCREENING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 1型神经纤维瘤病(NF1)是一种常见的遗传性疾病，具有很好的生物过程研究潜力。它的经典特征是一种神经皮肤病，但骨骼和脊柱的异常显然与NF1有关。与NF1相关的骨骼异常包括长骨发育不良(2-5%)、蝶骨发育不良(3-7%)和脊柱异常(10-33%)。这些并发症没有得到很好的了解，也很少被强调，尽管据报道高达38%的并发症有骨质的表现。胫骨假关节和营养不良性脊柱侧弯的治疗对从业者来说是一个巨大的挑战。到目前为止，对于NF1中胚层来源的骨缺陷还没有简单的解释。NF1基因产物神经纤维蛋白通过与ras的相互作用具有肿瘤抑制作用，并可能与参与骨代谢的其他生化途径相互作用。关于发病机制、自然病史、发病负担和临床结果的问题仍未得到回答。 如果NF1存在全身性骨骼异常，那么一些患者可能倾向于发生局限性缺陷。我们推测，NF1存在一种微妙的原发骨质紊乱，使NF1个体易于发生局部的、更严重的骨缺陷。NF1的全身骨性表现包括身材矮小和大头畸形。NF1的许多局限性骨性表现(椎体楔形和扇形、肋骨束状、骨量减少和长骨弯曲合并假关节愈合不良、局限性过度生长和一些患者的多发性骨囊性区域)随机出现，支持这一假说。 我们假设，与普通人群相比，NF1患者存在全身性骨异常，骨健康指数降低。我们还假设NF1患者的骨缺陷与表型-基因相关。 我们将用两个相应的具体目标来解决这些假设。 具体目标#1：使用外周定量计算机断层扫描(PQCT)、双能X射线吸收测量仪(DXA)和尿吡啶交联剂描述1型神经纤维瘤病(NF1)儿童的骨健康状况。 具体目的#2：通过NF1基因突变筛查和临床表型分析，描述NF1和骨缺陷的基因-表型关系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.