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INTRODUCTION

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Definitions

  1. Amelia: absence of a limb or limbs.

  2. Dysostosis: disorder of individual bones, singly or in combination; the lesions are local and nonprogressive.

  3. Hemimelia: absence of a longitudinal segment of a limb, such as radial hypoplasia or aplasia.

  4. Micromelia: shortening of the entire limb.

  5. Osteochondrodysplasia: results from abnormal growth and development of bone and/or cartilage; the lesions are generalized and progressive.

  6. Phocomelia: hypoplasia of the limbs, with hands and feet attached to the shoulder and hips.

  7. Polydactyly: presence of more than 5 digits.

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The human skeleton (from the Greek word skeletos, dried up) is a complex organ that consists of 206 bones. It has multiple embryonic origins and serves many key functions, including mechanical support for movement, protection of vital organs, and a reservoir of blood and minerals.1 Fetal skeletal dysplasias are a heterogeneous group of disorders that result in abnormalities in the size and shape of various segments of the skeleton due to intrinsic derangement of the growth, development, and/or differentiation. Nearly 300 disorders are included in this entity; most of them are heritable diseases.2 Although most of the diseases are rare, skeletal dysplasia as an entity is common. There are two classes of skeletal dysplasia: osteochondrodysplasia and dysostosis.2 Osteochondrodysplasia results from abnormal growth and development of bone and/or cartilage; the lesions are generalized and progressive. Examples include achondroplasia and osteogenesis imperfecta. In contrast, dysostosis is the disorder of individual bones, singly or in combination; the lesions are local and nonprogressive. Poly/syndactyly and craniosynostoses are representative diseases. Previously, it was thought that the two were different in that osteochondrodysplasia was considered a genetic disorder, whereas dysostosis was an accidental derangement during embryonic development (unrelated to genes).2 However, it is now known that both are caused by genetic abnormalities. Responsible genes for skeletal dysplasia have been identified in more than 150 diseases mainly through positional cloning.2 In recent years, major advances have been made in identifying mutations associated with chondrodysplasias. This chapter reviews progress that has been made in this field, the birth prevalence and classification of skeletal dysplasias, and provides an approach to the diagnosis of these conditions in utero.

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MOLECULAR GENETIC BASIS OF THE CHONDRODYSPLASIAS

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The process of skeletal formation and growth includes the differentiation of mesenchymal cells to form cartilage for future bone endochondral ossification. The growth of the long bones occurs through differentiation of chondrocytes in the growth plates and intramembranous ossification.3,4 Disruption in any of these processes results in skeletal abnormalities.5 Although a wide range of phenotypes has been described in osteochondrodysplasias, recent advances in the understanding of the molecular basis of skeletal dysplasias indicate that a spectrum of phenotypes share a similar genetic basis.6,7 Although the familial tendency of chondrodysplasias has been known for many years, the molecular basis for a number of conditions has only recently been clarified (Table 19-1).8...

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