SKELETAL PHENOTYPING AND MUTATION SCREENING IN NEUROFIBROMATOSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。1型神经纤维瘤病（NF1）是一种常见的遗传疾病，具有良好的潜在洞察生物学过程。它的典型特征是神经皮肤疾病，但骨和脊柱异常明显与NF1相关。与NF1相关的骨骼异常包括长骨发育不良（2-5%）、鸡翅发育不良（3-7%）和脊柱异常（10-33%）。这些并发症并没有得到很好的理解，也很少被重视，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管理提出了一个显着的挑战从业者。到目前为止，对于NF1中胚层来源的骨缺损还没有一个简单的解释。NF1基因产物神经纤维蛋白通过与ras的相互作用具有抑瘤作用，并可能与骨代谢的其他生化途径相互作用。关于发病机制、自然史、发病负担和临床结果的问题仍未得到解答。如果NF1存在全身性骨骼异常，那么一些患者可能倾向于发展局部缺陷。我们推测NF1中存在一种微妙的原发性骨疾病，使NF1个体容易发展为局部更严重的骨缺陷。NF1的广泛性骨骼表现包括身材矮小和大头畸形。NF1的许多局部骨骼表现（假性关节伴长骨弯曲的椎体楔入和扇形、肋骨削尖、骨质减少和骨愈合不良、部分患者的局部过度生长和多个骨囊区）随机出现，支持了这一假设。我们假设与一般人群相比，NF1患者存在全身性骨异常和骨健康指数下降。我们还假设NF1骨性缺损患者存在表型-基因型相关性。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线吸收仪（DXA）和尿吡呤交联来描述1型神经纤维瘤病（NF1）儿童的骨骼健康状况。具体目标#2：利用NF1基因的突变筛选和临床表型，描述NF1基因型-表型与骨缺陷的关系。

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.