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Skeletal dysplasias are heritable disorders of bone caused by abnormal development, growth, and maintenance of the human skeleton. They are a heterogeneous group of conditions that vary significantly in clinical severity, ranging from conditions that almost always cause death in utero or soon after to birth, to conditions resulting in short stature and chronic health complications that are not generally life limiting. This chapter presents an approach to the diagnosis and management of the skeletal dysplasias that commonly present in the neonatal period.
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The overall birth prevalence of all types of skeletal dysplasias is estimated to be 2–3 per 10,000 births.1,2 The 2010 revision of the Nosology and Classification of Genetic Skeletal Disorders recognized 456 different conditions and classified them into different groups by their clinical and radiographic features and molecular pathogenesis.3 Skeletal dysplasias classified as lethal (those that result in death in utero or early neonatal death) make up about 50%. The most common groups of disorders are osteogenesis imperfecta (various types), disorders related to fibroblast growth factor receptor 3 (FGFR3) disorders (thanatophoric dysplasia and achondroplasia are most common), and type II collagenopathies (achondrogenesis is most common) (see further sections for descriptions of these disorders).1 Achondroplasia is the most common cause of disproportionate short stature that is not associated with in utero or early neonatal death. The prevalence of achondroplasia has been estimated at 0.36–0.6 per 10,000 live births (1/27,780–1/16,670 live births).4
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Identification of the genes responsible for many of the skeletal dysplasias has led to better understanding of the underlying pathogenesis and emerging treatments of these disorders.
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Defects in Local Regulation of Cartilage Growth
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Defects in local regulation of cartilage growth include disorders caused by abnormalities in growth factors and their receptors. FGFR3 plays a role in the negative regulation of bone growth by inhibiting cell growth in cartilaginous growth plates. Almost all cases of achondroplasia are caused by 1 of 2 specific gain-of-function mutations in the FGFR3 gene, which result in upregulation of the FGFR3 pathway. The lethal thanatophoric dysplasias (type I and II) are caused by different mutations in the FGFR3 gene.
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Defects in Structural Proteins of Cartilage
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Defects of structural cartilage proteins such as collagen type I, II, IX, X, and XI and extracellular matrix proteins such as COMP (cartilage oligometric matrix protein) result in various different forms of skeletal dysplasias. Mutations in the gene encoding collagen type II cause the group of disorders known collectively as the type II collagenopathies, which comprise achondrogenesis type II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita (SEDC), Kneist dysplasia, and Stickler syndrome.
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Defects in Cartilage Metabolic Pathways
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Defects of enzymes, ion channels, and transporters essential for cartilage metabolism and homeostasis have been ...