Clinical, Pathophysiologic and Therapeutic Studies

骨骼发育不良是一组异质性的370多种软骨和骨骼疾病。 每2000人中就有1人受到影响。这个项目的目的是定义临床，遗传，产前，病理， 分子和病理生理学。这些疾病的特征，以帮助了解其原因和 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.为了改善病症的特征：利用收集到的大量病例，我们将 继续我们长期的努力，以改善临床、遗传、放射学和 SDS的形态异质性和变异性。我们将定义新的障碍，并改善 肢端发育不良、弯曲性骨发育不良、胸喉盆发育不良的定义。我们将测试 假设屈曲-伸展MRI检查结合脑脊液和静脉血流的测量将有助于 N定义急性脑出血患者的手术需求，这是目前存在争议的一个领域。 2.明确抑郁症的产前表现，提高产前诊断水平：许多抑郁症， 无论是致命的还是非致命的，都有产前骨骼异常的证据。我们假设 通过使用2D和3D产前超声(UTZ)，然后将结果与胎儿或 新生儿X光检查结果将导致改善UTZ参数用于产前诊断这些疾病 精神错乱。我们将客观地确定最能预测新生儿立即死亡的UTZ参数 时期，建立不同骨软骨发育不良的短指畸形的产前超声测量， 并确定一组常见疾病的鉴别超声特征， 弯曲的骨发育不良。 3.在抑郁自评量表中确定表型-基因相关性：比较临床表型和 分子和生化缺陷使我们能够定义疾病的表型变异范围， 链接与病理生理相关的疾病，并发现异质性。由于他们的频率和兴趣 在他们潜在的致病途径中，项目团队选择了研究短肋 多指畸形和窒息胸廓发育不良、短指畸形和常染色体隐性遗传 成骨不完全III型和III型。我们还将继续前一个周期开始的研究，包括 明确伴有和不伴有FGFR3突变的ACH和软骨发育不良(HCH)的特征，以及 伴和不伴转化生长因子-1突变的Engelmann病。我们进一步建议检验假设 Burton发育不良和一些未分类的弯曲性骨发育不良病例是由于 Perlecan基因。我们将检验这样一种假设，即脱发脊椎病(DSD)是由突变引起的 在Pax1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.