Clinical, Pathophysiologic and Therapeutic Studies

骨骼发育不良（SD）是一组异质性的软骨和骨疾病超过370 感染率约为2000分之一该项目旨在定义临床，遗传，产前，病理， 这些疾病的分子和病理生理特征，以帮助了解其原因， 为患者和家属提供更好的信息和临床护理。具体目标包括： 1.为了改进SD的表征：使用收集的大量病例，我们将 继续我们长期以来的努力，以改善临床，遗传，放射学的定义， SD的形态异质性和变异性。我们将定义新的疾病，并改善 肢端发育不良、弯曲骨发育不良和胸-喉-骨盆发育不良的定义。我们将测试 假设屈伸MRI研究测量脑脊液和静脉血流量将有助于 定义ACH患者的手术需求，这是目前存在争议的领域。 2.为了定义SD的产前表现并改善产前诊断：许多SD， 无论是致命性的还是非致命性的，都有证据表明胎儿期骨骼异常。我们假设 通过使用2D和3D产前超声（乌茨），然后将结果与胎儿或胎儿的年龄相关联， 新生儿X线检查结果将导致乌茨参数的产前诊断，这些 紊乱我们将客观地确定乌茨参数，最好地预测死亡率在立即新生儿 在不同的骨软骨发育不良中建立短指畸形的产前超声测量， 并确定一组常见疾病组的区别超声特征， 弯曲骨发育不良。 3.确定SD中表型-基因型相关性：比较临床表型与 分子和生物化学缺陷使我们能够确定疾病的表型变异范围， 连接病理生理相关的疾病，并揭示异质性。由于他们的频率和兴趣 在其潜在的致病途径中，该项目的项目组选择研究短肋 多指（趾）畸形和窒息性胸廓发育不良、短肢畸形和常染色体隐性遗传 成骨不全II型和III型。我们还将继续进行上一周期开始的研究，包括 定义ACH和软骨发育不全（HCH）的特征（有和无FGFR 3突变），以及 有和没有TGF-1突变的Engelmann病。我们进一步提出检验假设， Burton发育不良和一些未分类的弯曲骨发育不良的病例是由于 串珠素基因我们将检验这一假设，即椎间盘发育不全（DSD）是由突变引起的 在Pax 1基因中。

The skeletal dysplasias (SDs) are a heterogeneous group of over 370 disorders of cartilage and bone affecting about 1 in 2,000. This project is aimed at defining the clinical, genetic, prenatal, pathologic, molecular, and pathophysiologic.features of these disorders to assist in understanding their causes and provide better information and clinical care to patients and families. Specific aims include: 1. To improve the characterization of the SDs: Using the large number of cases collected, we will continue our long-standing effort to improve the definition of the clinical, genetic, radiographic, and morphologic heterogeneity and variability of the SDs. We will define novel disorders, and improve the definition of the acrodysplasias, bent bone dysplasias, and thoraco-laryngo-pelvic dysplasia. We will test the hypothesis that flexion-extension MRI studies with measurements of cerebrospinal and venous flow will aid n defining the need for surgery in patients with ACH, an area of current controversy. 2. To define the prenatal presentation of the SDs and improve prenatal diagnosis: Many of the SDs, both lethal and nonlethal, have evidence of skeletal abnormalities in the prenatal period. We hypothesize that by employing 2D and 3D prenatal ultrasound (UTZ) and then correlating the findings to the fetal or newborn radiographic findings will lead to improved UTZ parameters for the prenatal diagnosis of these disorders. We will objectively determine UTZ parameters that best predict lethality in the immediate neonatal period, establish prenatal ultrasound measurements for brachydactyly in distinct osteochondrodysplasias, and determine differentiating ultrasound features for one group of commonly occurring group of disorders, the bent bone dysplasias. 3. To determine phenotype-genotype correlations in the SDs: Comparing the clinical phenotype with molecular and biochemical defects has allowed us to define the range of phenotypic variability of disorders, link pathophysiologically related disorders, and uncover heterogeneity. Due to their frequency and interest in their underlying pathogenic pathways, the program project team has chosen to study the short-rib polydactyly disorders and asphyxiating thoracic dysplasia, the brachyolmias, and autosomal recessive osteogenesis imperfecta types II and III. We will also continue studies begun in the previous cycle, including defining the characteristics of ACH and hypochondroplasia (HCH) with and without mutations in FGFR3, and Engelmann disease with and without TGF-_1 mutations. We further propose to test the hypothesis that Burton dysplasia and some of the cases of unclassified bent bone dysplasias are due to mutations in the perlecan gene. We will test the hypothesis that diaphanospondylodysostosis (DSD) is caused by mutations in the Pax1 gene.