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Connective tissue provides form, strength, and support to different parts of the body. It also serves as a medium for cellular transport as well as storage and exchange of nutrients. It is made up of dozens of proteins constituting either the extracellular fibers, amorphous matrix called ground substance, or the cellular network. The most abundant extracellular fibers are composed of the protein collagen, which is also the most abundant protein found in the human body. Pathogenic variants in genes encoding the collagen proteins cause diseases such as Ehlers-Danlos syndrome, Stickler syndrome, and osteogenesis imperfecta. Other extracellular fibers consist of an amorphous protein called elastin, which is ensheathed in strong microfibrils composed of the protein fibrillin. Pathogenic variants in the gene encoding fibrillin-1 are associated with Marfan syndrome.

Connective tissue disorders are a group of disorders that affect the proteins that make up the connective tissue matrix such as collagens, proteoglycans, elastins, fibrillins, and laminins. Several hundred different heritable disorders of connective tissue have been described. Most of these recognizable disorders are caused by pathogenic variants in single genes and segregate as an autosomal dominant, autosomal recessive, or X-linked trait. Diagnosis of these disorders can be clinically challenging because of overlapping symptoms and the broad spectrum of physical findings. Identification of key clinical features will help guide diagnosis toward a specific disorder. It is imperative for a pediatrician to be cognizant of the signs and symptoms of connective tissue disorders. Management of many of these conditions needs to be initiated in early years of life as some of the main complications from these disorders are progressive and early management can lead to a better prognosis. Well-known connective tissue disorders such as Ehlers-Danlos syndrome (EDS), Marfan syndrome, Loeys-Dietz syndrome, and Stickler syndrome will be presented in this chapter.



There are numerous connective tissue disorders related to defects in collagen and its other extracellular matrix proteins such as elastin, proteoglycans, and macromolecular proteins. There are different types of collagen, and these proteins are multimeric, occurring as trimers with a central triple helical orientation. All types of collagen are synthesized first as precursor molecules of procollagen, which are then modified by specific proteases to form the subunits of extracellular fibrils. Collagenopathies result from alterations in the structure and function of collagens I, II, III, IV, V, VI, VII, IX, X, XI, and XVII and the enzymes lysyl hydroxylase and type I procollagen N-proteinase involved in the posttranslational modification of collagens. EDS is a molecularly heterogeneous disorder, as defects in different types of collagen, particularly types I, III, and V, and several extracellular matrix proteins, such as tenascin and lysyl hydroxylase, have been implicated in its pathogenesis and form the basis of the 1997 Villefranche classification of EDS (Table 180-1). Procollagen genes COL2A1 and COL11A1/A2 are expressed in the eye and cartilage, and defects in these ...

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