The skeletal dysplasias (SDs) are a heterogeneous group of over 370 disorders of cartilage and boneaffecting 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 andprovide 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 willcontinue our long-standing effort to improve the definition of the clinical, genetic, radiographic, andmorphologic heterogeneity and variability of the SDs. We will define novel disorders, and improve thedefinition of the acrodysplasias, bent bone dysplasias, and thoraco-laryngo-pelvic dysplasia. We will test thehypothesis that flexion-extension MRI studies with measurements of cerebrospinal and venous flow will aidn 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 hypothesizethat by employing 2D and 3D prenatal ultrasound (UTZ) and then correlating the findings to the fetal ornewborn radiographic findings will lead to improved UTZ parameters for the prenatal diagnosis of thesedisorders. We will objectively determine UTZ parameters that best predict lethality in the immediate neonatalperiod, 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 withmolecular 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 interestin their underlying pathogenic pathways, the program project team has chosen to study the short-ribpolydactyly disorders and asphyxiating thoracic dysplasia, the brachyolmias, and autosomal recessiveosteogenesis imperfecta types II and III. We will also continue studies begun in the previous cycle, includingdefining the characteristics of ACH and hypochondroplasia (HCH) with and without mutations in FGFR3, andEngelmann disease with and without TGF-_1 mutations. We further propose to test the hypothesis thatBurton dysplasia and some of the cases of unclassified bent bone dysplasias are due to mutations in theperlecan gene. We will test the hypothesis that diaphanospondylodysostosis (DSD) is caused by mutationsin the Pax1 gene.
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