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INTRODUCTION

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Skeletal dysplasias represent a complex set of disorders that affect bone and/or cartilage, and typical clinical manifestations include short stature and orthopedic complications. Skeletal manifestations are common among this group of disorders; however, findings in other tissues may also be clinically relevant and can help establish the underlying diagnosis. Skeletal features can be diverse but are generally divided into the osteodysplasias (eg, osteogenesis imperfecta), chondrodysplasias (eg, achondroplasia), or dysostoses (eg, spondylocostal dysostosis). Determining the genetic basis of skeletal dysplasias is not only important for counseling and defining recurrence risk, but also for guiding pharmacologic and surgical management. In this chapter, we will review the pathogenesis and epidemiology of this set of disorders and describe clinically relevant skeletal dysplasias in which treatments or medical interventions are available.

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PATHOGENESIS AND EPIDEMIOLOGY

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With the advent of novel genetic testing strategies, such as whole-exome sequencing (WES), the underlying etiologies of skeletal dysplasias are increasingly being identified. There are currently over 400 disorders in the Online Mendelian Inheritance in Man (OMIM) database (www.omim.org) with skeletal features and greater than 500 genes implicated in the pathogenesis of these disorders. Although each disorder itself is rare, together they are estimated to be present in roughly 1 in 4000 live births.

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The human skeleton consists of 206 bones, and although important functions include mechanical support and protection, the skeleton is also involved in linear growth, endocrine regulation, mineral release, sound conductance, and blood cell development. During intrauterine development, skeletal elements are patterned from mesenchymal cells that differentiate into chondrocytes with subsequent mineralization of cartilage. Later, there is an invasion of vascular elements and inclusion of osteoprogenitor cells. The primary ossification center is formed, typically in the midshaft of the developing bone, and creates the cortex. At the end of the developing bone, a second ossification center forms and results in the cartilaginous growth plate between the 2 ossification centers.

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A number of naming conventions exist for skeletal dysplasias; most rely on the location and radiologic findings of implicated skeletal elements. Dysostoses result in malformations from abnormal embryologic bone development and patterning. They can include the formation of abnormal bones, such as polydactyly, or the lack of bone formation, such as skeletal truncation defects. Primary abnormalities of bone or bone metabolism typically result in disorders of bone density. Chondrodysplasias involve defects in both cartilage and the resulting bone and are characterized by short stature. In addition, the naming of disorders is often based on specific skeletal features. For example, spondylometaphyseal dysplasias are characterized by the involvement of both the spine (spondylo) and long-bone metaphyses. Other naming conventions rely on classifying skeletal dysplasias by specific genes and pathways that are affected, for example, the COL2A1-related disorders, which have overlapping features that range in severity from the perinatal lethal disorder achondrogenesis type II to Stickler syndrome at the mildest end of the spectrum of disorders caused by ...

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