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 i nclude: 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.
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