SKELETAL PHENOTYPING AND MUTATION SCREENING IN NEUROFIBROMATOSIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。1型神经纤维瘤病（NF 1）是一种常见的遗传性疾病，具有很好的潜力，了解生物过程。它的典型特征是神经皮肤疾病，但骨和脊柱异常明显与NF 1相关。与NF 1相关的颅骨异常包括长骨发育不良（2-5%）、蝶骨翼发育不良（3-7%）和脊柱异常（10-33%）。这些并发症并没有得到很好的理解，也很少强调，尽管据报道高达38%的并发症有骨性表现。胫骨假关节和营养不良性脊柱侧凸的治疗对医生来说是一个巨大的挑战。到目前为止，还没有简单的解释中胚层来源的骨缺损的NF 1。神经纤维蛋白，NF 1基因产物，通过与ras相互作用具有肿瘤抑制作用，并可能与骨代谢中涉及的其他生化途径相互作用。关于发病机制、自然史、发病负担和临床结局的问题仍然没有答案。 如果NF 1存在全身骨骼异常，则一些患者可能倾向于发展局部缺陷。我们的理论是，有一个微妙的原发性疾病的骨在NF 1，倾向于NF 1个人发展的地方，更严重的骨缺损。NF 1的全身骨性表现包括身材矮小和大头畸形。NF 1中的许多局部骨质发现（椎骨楔形和扇形、肋骨弯曲、骨质减少和长骨弯曲伴假关节、局部过度生长和一些患者中的多个骨囊性区域中的骨愈合不良）随机出现，支持这一假设。 我们假设与一般人群相比，NF 1患者存在全身性骨异常和骨健康指数降低。我们还假设，有一个表型-基因型相关性在NF 1患者骨缺损。 我们将通过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线吸收测定法（DXA）和尿吡啶交联法描述1型神经纤维瘤病（NF 1）儿童的骨健康状况。 具体目标2：通过NF 1基因突变筛查和临床表型分析，描述NF 1和骨缺损的基因型-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.