Selected Heritable Disorders of Connective Tissue and Disability (2022) / Chapter Skim
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2 Overview of Hereditary Disorders of Connective Tissue
2 Overview of Hereditary Disorders of Connective Tissue
Pages 25-46
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From page 25... ...
. Specialized connective tissues include bone, cartilage, ligaments, tendons, and adipose tissue (fat)
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From page 26... ...
The 2002 volume Connective Tissue and Its Heritable Disorders, edited by Royce and Steinmann, includes 26 chapters, many of which subsume multiple distinct diagnoses (for example, Chapter 23 includes the skeletal dysplasias, of which there are now more than 450 well-delineated forms) (Mortier et al., 2019)
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As a result of the Human Genome Project and ready access to rapid genomic sequencing, new language has been adopted to describe the changes observed in human DNA; such changes are now referred to as "variants." The classification of sequence variations has been standardized according to guidelines published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (Richards et al., 2015)
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Three basic types of fiber make up connective tissue: collagenous fibers, predominantly type I collagen that provides tensile strength to loose and dense connective tissues (RicardBlum, 2011) ; thin reticular fibers, composed of type III collagen that forms cross-links to generate a supportive mesh for tissues (Hayakawa et al., 1990)
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. In contrast with other connective tissues, bone ECM is mineralized, giving it strength and rigidity to sustain mechanical forces (Weatherholt et al., 2012)
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Like other connective tissue structures, it serves as a medium for transmitting forces, particularly those that come from muscle, and it is composed of cells, ground substance, and fibers that form a three-dimensional network. Fibroblasts and fibrocytes are the major cell types in fascia, which is composed predominantly of type I and III collagens, and proteoglycans and glycoproteins contribute to the formation of the ground substance.
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From page 31... ...
While all connective tissues have the general types of ECM proteins (e.g., collagens, elastin, fibrillin) in common, their modifying genes, ECM organization, and differential gene expression contribute to variation in their function and in their presentation and phenotype in patients.
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. These examples highlight that expression of an abnormal or decreased amount of protein in connective tissues that rely on a functional protein produces phenotypes that affect individuals in multiple organ systems.
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Once that suspicion has been entertained, clinical algorithms and diagnostic criteria can help provide a specific diagnosis. For most of the HDCTs, once a clinical diagnosis has been suspected or established, it can be confirmed through molecular genetic testing.
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. Indeed, patients report experiencing denial among health care providers, as well as family members, as to the reality of their lived experience of certain manifestations of the disorders, such as pain, fatigue, and mild cognitive impairment, sometimes described as "brain fog," as well as limited treatment options (Clark, 2021; Langhinrichsen-Rohling et al., 2021; Palomo-Toucedo et al., 2020)
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Nevertheless, the natural history of HDCTs as a general group demonstrates several commonalities, including the disorders' multisystem nature and potential secondary impairments. Multiple connective tissues can work synchronously to form such structures as joints, where two bones make contact.
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For many HDCTs, a patient's disease severity, manifestations, and clinical course may be adversely affected by specific environmental factors. In addition, physical and mental demands related to school or work may precipitate or exacerbate secondary impairments,
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Recognizing the presence of these conditions and taking action to address them, even in the absence of confirmatory genetic testing, can mitigate their effects on the functional status and quality of life of individuals with HDCTs. DISEASE STATE MANAGEMENT Central to minimizing the impact of HDCTs on function is a coordinated multidisciplinary management strategy (Miklovic and Sieg, 2021; Mittal et al., 2021)
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2-4. Because HDCTs can cause a wide variety of physical and mental secondary impairments involving multiple organ systems, affected individuals often are referred to a succession of different specialists, resulting in delayed diagnosis of the underlying HDCT.
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2-10. The severity of HDCTs is linked to the severity of affected indi viduals' physical and mental secondary impairments, including the combined effects of multiple impairments, as well as the frequency, severity, and predictability of their fluctuations.
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American Journal of Medical Genetics. Part C: Seminars in Medical Genetics 187(4)
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American Journal of Medical Genetics Part C: Seminars in Medical Genetics 175(1)
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American Journal of Medical Genetics Part C: Seminars in Medical Genetics 187(4)
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American Journal of Medical Genetics Part A 179(12)
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American Journal of Medical Genetics Part A 173(2)
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From page 45... ...
American Journal of Medical Genetics Part C: Seminars in Medical Genetics 175(1)
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