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Selected Heritable Disorders of Connective Tissue and Disability (2022)

Chapter:5 Heritable Disorders of Connective Tissue and Effects on Function

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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page138
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page139
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page140
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page142
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page143
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page145
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page146
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page147
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page149
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page150
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page151
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page152
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page153
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page154
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page155
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page156
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page157
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page158
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page159
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page160
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page161
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page162
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page163
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page164
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page166
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page167
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page169
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Page171
Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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Suggested Citation:"5 Heritable Disorders of Connective Tissue and Effects on Function." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Heritable Disorders of Connective Tissue and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26431.
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5 Heritable Disorders of Connective Tissue and Effects on Function As discussed in previous chapters, heritable disorders of connective tissue (HDCTs) manifest as physical and mental secondary impairments, potentially in many different body systems. The severity of the disease pro- cess varies among individuals and relates to the type, number, and severity of the secondary impairments, as well as the combined effects of multiple “less severe” impairments. As described in Chapter 1, the International Classification of Functioning, Disability and Health (ICF) model of disability identifies three domains of functioning: (1) body function and structure (i.e., physiological functions of the body, including psychological functions, and functioning of body structures); (2) activities (i.e., actions or tasks); and (3) participation (i.e., performance of tasks in a societal context, such as school or work (WHO, 2001). “Impairments” are deficits in body function and structure; “limita- tions” refer to deficits in completing activities; and “restrictions” refer to reductions in participation (WHO, 2001). Personal and environmental fac- tors act on the ICF domains to either enhance or diminish an individual’s activity and participation. Some effects of HDCTs, and in some cases their treatment, manifest as impairments in body structures and physical and psychological func- tions, with resulting activity limitations and restrictions on participation. The impairments associated with HDCTs affect mental (e.g., cognitive, psychosocial, emotional) functioning as well as physical functioning. 125

126 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE Moreover, these areas of functioning interact such that impairments in one area (e.g., physical) may precipitate or exacerbate impairments in one or more of the others (cognitive, psychosocial, and/or emotional). Chronic pain, for example, is reported to have a bidirectional relation- ship with depression (Vadivelu et al., 2017), and an association between gastrointestinal and psychological disorders has also been reported (Stasi et al., 2017). Similarly, physical conditions such as pain and fatigue can adversely affect cognitive functioning (Higgins et al., 2018; Moriarty et al., 2011; Vadivelu et al., 2017). This chapter first describes the relationship between secondary im- pairments associated with HDCTs and functioning, and then provides an overview of the potential effects on global (full-body); physical; vision, hearing, and speech; and mental functioning. The chapter also reviews se- lected listings from the U.S. Social Security Administration’s (SSA’s) Listing of Impairments that may be particularly applicable to individuals with specific HDCTs. SECONDARY IMPAIRMENTS The statement of task for this study asks the committee “to describe to the degree possible” the “secondary impairments that result from either the [selected HDCTs] or their treatments (if applicable).” As defined in Chapter 1, the committee understands “secondary impairments” to mean physical and mental manifestations (medical diagnoses, syndromes, or health conditions) that are associated with and may also result from an HDCT, although they may occur independently in individuals without an HDCT. Annex Tables 5-3–5-12 at the end of this chapter present selected manifestations (organized by body system) and some of the HDCTs with which they are associated, as well as common diagnostic techniques and potential treatments. The number, type, and severity of the secondary impairments experi- enced by an individual with an HDCT drive the person’s functioning and potential disability. Annex Tables 5-13–5-16 summarize the potential im- plications of secondary impairments for global functioning; physical func- tioning; vision, hearing, and speech functioning; and mental functioning in individuals with HDCTs. The tables list physical and mental activities the

EFFECTS ON FUNCTION 127 committee determined to be of particular interest to SSA,1 the potential rea- sons for limitations in those activities for individuals with HDCTs, selected measures for assessing function in the relevant areas, and selected assistive technologies and reasonable accommodations that could help mitigate the effects of the impairment(s) on an individual’s ability to work, participate in school, and the like. The assessment measures are categorized primarily as performance-based or self-reported. Performance-based measures require that the individual being assessed perform a set of physical or mental activi- ties or tasks so that his or her ability to execute them can be ascertained. Self-reported (or proxy-reported) measures require the individual being as- sessed or a third party to complete a questionnaire asking about symptoms (e.g., pain, fatigue, anxiety) or the individual’s ability to perform a specific set of mental or physical tasks. Patient-reported outcome or experience measures, questionnaires regarding activities of daily living (ADLs) and instrumental activities of daily living (IADLs), and some types of psycho- logical tests are examples of such measures. The medical tables (Annex Tables 5-3–5-12) and the function tables (Annex Tables 5-13–5-16) in this chapter can be used together to under- stand how secondary impairments associated with different HDCTs may affect an individual’s functioning in various areas. The “potential reasons” column in the function tables provides information and cross-references that allow the reader to identify the relevant medical tables (e.g., musculo- skeletal, neurological), which include information about specific diagnoses. As discussed in the final section of the chapter, the secondary impair- ments identified in the medical tables can also serve as an interface with 1 SSA classifies jobs as sedentary, light, medium, heavy, and very heavy based on the level of physical exertion requirements of the work (CFR § 416.967). Annex Table 5-1 provides the definitions for each level of work. When a person applies for disability benefits, SSA collects information about the applicant’s physical and mental impairment(s) and functioning from a variety of sources, including the applicant, medical providers, employers, teachers, and other third parties with knowledge of the applicant. Information collected about physical functioning includes information about such activities as sitting, standing, walking, lifting, carrying, reaching, handling large objects, writing, typing, handling small objects, and low work (stooping, kneeling, crouching, crawling) (SSA, 2020). Information is collected as well about the applicant’s ability to perform various daily activities, such as dressing, bathing, self-feeding, and using the toilet, as well as preparing meals, doing house- and yardwork, get- ting around, shopping, and the like. SSA also must consider information about the physical and mental demands of different jobs, such as the amount of time an employee is required to stand or walk and whether a job requires driving, using a keyboard, or reaching overhead (SSA, n.d.-a). The physical; vision, hearing, and speech; and mental activities addressed in this chapter (Annex Table 5-2) are those the committee determined to be most relevant to SSA based on the information SSA collects about applicants and the information the U.S. Bureau of Labor Statistics collects about the physical and mental demands of jobs for inclusion in the Occupational Information System, which is being developed to serve as the main source of occupational information for SSA’s disability adjudication process (SSA, 2022).

128 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE existing SSA listings. For example, some individuals with HDCTs applying for SSA disability benefits might qualify at the listing level step in the de- termination process on the basis of the secondary impairment(s) they are experiencing rather than the HDCT itself. ENVIRONMENTAL FACTORS AND FUNCTIONING Environmental factors can adversely affect functioning in some people. Environmental factors that can impair an individual’s functioning include extreme heat and cold; noise; vibration; wetness; humidity; and atmo- spheric conditions that can affect the respiratory system, nervous system, eyes, or skin (e.g., scents, allergens, fumes, noxious odors, dusts, mists, gases, and poor ventilation) (BLS, 2020). SSA recognizes this and takes an individual’s environmental restrictions into account. “A nonexertional impairment is one which is medically determinable and causes a nonexer- tional limitation of function or an environmental restriction” (SSR 85-15, emphasis added; SSA, n.d.-f). Accordingly, SSA takes into account the rela- tive availability of jobs that would not expose an affected individual to the relevant environmental factors. For example, a restriction on exposure to excessive amounts of noise, vibration, or dust would have little effect “because most job environments do not involve great noise, [vibration, or] amounts of dust” (SSA, n.d.-f). But “where an individual can tolerate very little noise, [vibration, or] dust, …the impact on the ability to work would be considerable because very few job environments are entirely free of [such] irritants…” (SSA, n.d.-f). Environmental factors can significantly affect functioning in some in- dividuals with HDCTs. For example, patients with the Ehlers-Danlos syn- dromes (EDS) and hypermobility spectrum disorders (HSD) are at increased risk of mast cell activation disease (MCAD), a condition that can be trig- gered by environmental substances (Frieri, 2018). Humidity and changes in atmospheric pressure appear to have a negative effect on functioning in EDS/HSD patients, which causes psychosocial distress (Palomo-Toucedo et al., 2020). There may be a number of reasons for this effect on functioning. First, patients with EDS/HSD have lowered cold and heat pain thresholds (Di Stefano et al., 2016). In addition, migraine, known to be more com- mon in patients with either Marfan syndrome (MFS) (von Kodolitsch et al., 2019) or EDS/HSD (Puledda et al., 2015) relative to the general population, are triggered by environmental substances and weather changes (Marmura, 2018). Furthermore, cardiovascular autonomic dysfunction in EDS/HSD patients appears to have environmental triggers (Hakim et al., 2017b), and changes in temperature and barometric pressure can exacerbate joint problems and symptoms of dysautonomia and affect intracranial pressure (Herbowski, 2017, 2019; Palomo-Toucedo et al., 2020). Likewise, sound,

EFFECTS ON FUNCTION 129 odors, light, and foods can trigger or exacerbate manifestations in individu- als with EDS/HSD (Syx et al., 2017). GLOBAL FUNCTIONING Chronic pain, chronic fatigue, and a type of cognitive dysfunction or mild cognitive impairment sometimes referred to as “brain fog” are some of the most common and potentially disabling manifestations of EDS/HSD, especially hypermobile EDS (hEDS)/HSD (Arnold et al., 2015; Chopra et al., 2017; Ocon, 2013; Raj et al., 2018; Rombaut et al., 2011; Ross et al., 2013; Sacheti et al., 1997; Voermans et al., 2010a; Wells et al., 2020). Chronic pain and fatigue are also common among individuals with MFS (Nelson et al., 2015b; Peters et al., 2001; Ratiu et al., 2018). This section begins with a discussion of the effect of chronic pain and chronic fatigue on global functioning and selected measures for assessing their severity. It then reviews the roles of two global modulators of function (orthostatic intolerance and MCAD) in individuals with EDS/HSD, particu- larly hEDS/HSD. The section concludes with a discussion of two categories of measures for assessment of global functioning. Chronic Pain Pain can be characterized in two broad ways. The first is by its cause. Neuropathic pain is caused by damage to or irritation of the nerves them- selves. Nociceptive pain is caused by stimulation of pain receptors, which send signals to the brain leading to the experience of pain. Depending on the location of the pain receptors, nociceptive pain may be somatic (surface of the body or musculoskeletal system) or visceral (stemming from pain receptors within the body cavity). Nociplastic pain arises from altered no- ciception in the absence of damage to the somatosensory system or stimu- lation of pain receptors in response to an assault (IASP, 2021). Most EDS/ HSD patients experience all three types of pain. Pain also may be classified by its duration. Typically, acute pain is a time-limited response to an injury (e.g., pulled muscle, broken bone) or warning of potential injury (e.g., from a hot stove or sharp object). Chronic pain has been defined as “persistent or recurrent pain lasting longer than 3 months” (Treede et al., 2015; WHO, 2021). Breakthrough pain occurs when an episode of acute pain “breaks through” otherwise well-controlled chronic pain. Everyone experiences acute pain from time to time. While estimates indicate that 20 percent of individuals worldwide experience chronic pain (Treede et al., 2015), studies have found that 80–100 percent of individuals with EDS, especially hEDS/HSD, and MFS experience chronic pain (Chopra

130 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE et al., 2017; Nelson et al., 2015a; Peters et al., 2001; Ratiu et al., 2018; Rombaut et al., 2011; Speed et al., 2017; Voermans et al., 2010a). The International Classification of Diseases, Eleventh Edition (ICD- 11) (WHO, 2021) identifies seven categories of chronic pain, five of which are most relevant to individuals with HDCTs such as EDS/HSD and MFS: (1) chronic primary pain, (2) chronic secondary musculoskeletal pain (Voermans et al., 2010a), (3) chronic secondary visceral pain (Fikree et al., 2017), (4) chronic neuropathic pain (Camerota et al., 2011; Rombaut et al., 2015), and (5) chronic secondary headache or orofacial pain (Mitakides and Tinkle, 2017). Individuals with EDS/HSD may also appear to be more predisposed to chronic postsurgical or posttraumatic pain (Chopra et al., 2017; Voermans et al., 2010a), perhaps because of increased difficulty with healing. The seventh pain category, chronic cancer-related pain, does not apply to pain secondary to an HDCT. Potential Reasons Individuals with hEDS/HSD may experience neuropathic or nociceptive pain (Camerota et al., 2011; Rombaut et al., 2015; Voermans et al., 2010a), and some individuals also experience central sensitization, stemming from “a generalized hyperexcitability of central nociceptive pathways” (Rombaut et al., 2015, p. 1126). Pain is most frequently reported in the neck, shoul- ders, hips, and legs (Voermans et al., 2010a). Chronic pain and hypersensitivity are explained by peripheral and central sensitization. Persistent nociceptive input from musculoskeletal and visceral sources can lead to peripheral and central sensitization, which often perpetuates chronic pain through processes involving neuroplasticity (Ji et al., 2018; Matsuda et al., 2019). In response to persistent nociceptive signaling from peripheral sensitized tissue, a number of synapse-to-nucleus messengers are recruited. As peripheral sensitization persists, it leads to central sensitization. Peripheral sensitization is accompanied by a reduction in threshold and increase in magnitude of response at the peripheral end of sensory nerve fibers (Gangadharan and Kuner, 2013). Chemical inflamma- tory mediators (e.g., mast cells, platelets, neutrophils, basophils, endothelial cells) are released by nociceptors and non-neuronal tissue. This release of inflammatory mediators can exacerbate local connective tissue dysfunction and local tissue damage (Chiu et al., 2012). Furthermore, since histamine is a key mediator in neurogenic inflammation (Rosa and Fantozzi, 2013), the prevalent comorbidity of MCAD with HCDTs suggests that neurogenic inflammation may contribute to the link between peripheral or central sen- sitization and connective tissue involvement in HDCTs. Under normal circumstances, the spinal cord sends modulatory signals to suppress pain signals. When a constant barrage of pain signals reaches

EFFECTS ON FUNCTION 131 the spinal cord, it causes sensitization of the dorsal horn cells; as a result, the central nervous system (CNS) switches from suppressing signals to en- hancing its response to stimuli. The persistent barrage of pain signals to and increased modulatory signals from the CNS lead to central sensitization. Central sensitization explains why chronic pain persists and even increases. Pain may be caused by secondary impairments in virtually every body system, including musculoskeletal disorders, such as joint subluxations or dislocations and myofascial disorders (see Annex Table 5-3); neurologi- cal disorders, such as neuropathies, and nerve compression disorders (see Annex Tables 5-3 and 5-4); gastrointestinal disorders, such as gastroen- teritis, mast cell disorders, and inflammatory bowel disease (see Annex Table 5-8); and genitourinary disorders, such as chronic pelvic pain and dysmenorrhea (see Annex Table 5-10). MCAD (see Annex Table 5-7) con- tributes to pain through the role of mast cells in neurogenic inflammation, which causes pain as well as itching (Gupta and Harvima, 2018), and in immune-mediated disorders that cause pain (see, e.g., Annex Tables 5-4 and 5-8). In addition, individuals with chronic pain have a higher risk of developing symptoms of anxiety or depression, and individuals with anxi- ety or depression are more likely to experience chronic or intensified pain (Anxiety & Depression Association of America, 2021; Harvard Health Publishing, 2017; Vadivelu et al., 2017). Poor sleep quality, experienced by many individuals with EDS/HSD, also contributes to the experience of pain (Voermans et al., 2010a). Interventions Management of chronic pain depends on the type of pain (nocicep- tive, neuropathic, or nociplastic) and its location. Notably, individuals with HDCTs may experience multiple root causes of pain and related loss of function, necessitating a comprehensive approach to their evaluation and treatment. Treatment often is multimodal, involving physical therapy, occupational therapy, medication, psychological interventions, surgical co- management, good sleep hygiene, education, and taking care of one’s over- all health. Although analgesics and other treatments (e.g., braces) may be used to mitigate pain and improve functionality, it is important to identify and address the root cause(s) of the pain and, when applicable, implement preventive measures to reduce the risk of recurrence (Chopra, 2020). For example, pain caused by a dislocation would be treated by fixing the dis- location (underlying cause), potentially treating the acute pain with anal- gesics until it had resolved, and prescribing physical therapy and exercises to reduce the risk of another dislocation. Although anti-inflammatory and nerve pain medications may be used to treat pain, opioids typically are not helpful for individuals with EDS/HSD and may exacerbate other symptoms,

132 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE such as those associated with certain gastrointestinal disorders and MCAD (Chopra, 2020). Use or overuse of steroids can lead to increased instability in joints, as well as increased risk for glaucoma and cataracts (Liu et al., 2103). Selected Assessment Measures Because the experience of pain differs from individual to individual, the gold standard of pain assessment is self-report. Annex Table 5-13 (on global functioning) includes a list of several common self-reported pain measures. Effects on Functioning Chronic pain in particular can adversely affect individuals’ functioning. Voermans and colleagues (2010a) found that pain severity among individu- als with EDS/HSD was independently related to functional impairment. Children with chronic pain may experience significant adverse effects on participation in academic, athletic, and social activities (Rabin et al., 2017). Pain can interfere with all types of physical activities that may be involved in work or school, including such sedentary activities as sitting at a desk, writing, or working on a computer. Chronic pain also has an effect on cognitive functioning, including such areas as long-term memory, selective attention, processing speed, and executive functioning (Berryman et al., 2013, 2014; Khera and Rangasamy, 2021; Lee et al., 2010; Ratiu et al., 2018). Chronic Fatigue Chronic fatigue has been defined as persistent or recurrent tiredness or exhaustion that typically persists for 6 months or more, cannot be ex- plained by other diagnoses, does not result from ongoing exertion, is not alleviated by rest or sleep, and prevents patients from carrying out normal activities (Hakim et al., 2017a). EDS/HSD has long been associated with a high prevalence of chronic fatigue, which, together with pain, is an impor- tant determinant of impaired health-related quality of life in this condition (Ritelli et al., 2020; Rombaut et al., 2010). It has been estimated that more than 75 percent of patients with EDS/HSD suffer from severe fatigue, which appears to be more common in hEDS/HSD than in the classic type of EDS (Ritelli et al., 2020; Voermans et al., 2010b). Fatigue in patients with hEDS/ HSD is different from tiredness and has several symptoms that overlap with a condition called myalgic encephalomyelitis (ME), or chronic fatigue syndrome (CFS) (ME/CFS) (Hakim et al., 2017a). Chronic fatigue may be a major presenting symptom of hEDS/HSD, and an appropriate diagnostic

EFFECTS ON FUNCTION 133 workup should distinguish between hEDS/HSD and ME/CFS (Hakim et al., 2017a). Fatigue also has been reported in as many as 89 percent of individuals with MFS (Bathen et al., 2014; Peters et al., 2001; van Dijk et al., 2008). Potential Reasons Common causes of fatigue in patients with EDS/HSD include the following: • Ligament laxity. People with EDS/HSD have ligament laxity, or loose ligaments, which can require muscles, including those in the proprioceptive system responsible for balance, to work harder to compensate for the laxity and joint instability. People with ligament laxity resulting from EDS/HSD may experience postural instabil- ity and rely on muscles to maintain postural control (Galli et al., 2011). However, these muscles are affected by weak connective tissue, resulting in extra work for them to maintain posture, and this excess demand on muscles can cause fatigue. • Dysautonomia. Many people with EDS/HSD experience orthostatic intolerance (described later in this chapter), or dysautonomia (dys- function of the autonomic nervous system that controls involuntary bodily functions). Patients with secondary dysautonomia—that is, dysautonomia associated with a disease such as EDS/HSD—may experience a variety of symptoms including fatigue, balance prob- lems, mild cognitive impairment, weakness, and exercise intoler- ance (De Wandele et al., 2016). Postural orthostatic tachycardia syndrome (POTS; discussed in the section on orthostatic intoler- ance) is one form of dysautonomia, as is pure autonomic fail- ure, which is characterized by tiredness, dizziness, and fainting (Cleveland Clinic, 2020). • Medication. Some medications, such as benzodiazepines and an- tidepressants, have sedative side effects that can contribute to fa- tigue (Voermans et al., 2010b). People with EDS/HSD are often prescribed multiple medications for pain, MCAD, POTS, or other forms of dysautonomia, and some or all of these medications can contribute to lethargy, which adds to fatigue. • Nonrestorative sleep. People with EDS/HSD and dysautonomia experience either decreased parasympathetic tone or an excessively high sympathetic activity that essentially keeps one’s brain active when sleeping. These patients often present with nonrestorative sleep that may be the result of pain, nocturnal tachycardia, or

134 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE sleep-disordered breathing (sleep apnea) (Hakim et al., 2017a; Ritelli et al., 2020). • Nutritional. Gastrointestinal issues, including bowel dysfunction, are common in EDS/HSD (Fikree et al., 2017; Ritelli et al., 2020). They vary from slowing of intestinal motility to chronic nausea, constipation, and/or diarrhea. Malabsorption and poor nutritional status can result in nutritional deficiencies, including low iron stor- age levels that may result in decreased blood oxygen levels with concomitant fatigue. • Physical deconditioning. Chronic pain, poor physical activity, and exercise intolerance can result in fatigue upon exertion (Hakim et al., 2017a; Ritelli et al., 2020). Other manifestations of EDS/HSD associated with chronic fatigue in- clude chronic pain, anxiety and depression, nocturnal micturition (possibly contributing to nonrestorative sleep), and headaches and migraines (Hakim et al., 2017a; Ritelli et al., 2020). Interventions Treatment of the fatigue associated with EDS/HSD is multimodal and may require a team of health care experts. Medications, such as antidepres- sants, pain medications, anti-anxiety drugs, sleep aids, and medications for orthostatic intolerance, may be used to address the underlying causes of the fatigue. Nutritional supplements and dietary modification, preferably based on recommendations from a dietician, may help with nutritional deficiencies. Lifestyle modifications, such as rest and relaxation techniques and good sleep hygiene, can also help alleviate some aspects of fatigue. Graded exercise therapy may be appropriate for some patients with joint hypermobility. Relaxation techniques (e.g., yoga, mindfulness, progressive muscle relaxation), other exercise regimens, physical therapy, and planned management of daily activities are also important therapeutic approaches to fatigue, but all of them must be tailored to the individual patient’s needs. Finally, cognitive-behavioral therapy may be beneficial for encouraging ex- ercise and adherence to the lifestyle modifications necessary to control the underlying causes of the fatigue, including anxiety, depression, and chronic pain (Hakim et al., 2017a). In some more severe cases, assistive devices, such as wheelchairs and reachers, may be necessary. One important aspect of chronic fatigue associated with HDCTs is that it is often unpredictable. Patients report that they may be functioning well one day and completely unable to perform job-related activities and ADLs the next. This variability in performance capability may lead to frequent absences from work and difficulty in maintaining employment.

EFFECTS ON FUNCTION 135 Selected Assessment Measures Assessment of chronic fatigue is based on self-reports, and a number of self-report instruments are available to provide a consistent measure of the impact and severity of fatigue. These instruments include the Brief Fatigue Inventory, the Fatigue Impact Scale, the Fatigue Severity Scale, the Fatigue Symptom Inventory, the Multidimensional Assessment of Fatigue scale, and the Multidimensional Fatigue Symptom Inventory. It must be noted, however, that these instruments are used most often in research and are not typically used in the clinical setting. The Wood Mental Fatigue Inventory is one instrument that can be used in the clinic to assess the cognitive symptoms of fatigue (Hakim et al., 2017a). The CRESTA Fatigue Clinic booklet (Newcastle upon Tyne Hospitals: NHS Foundation Trust, 2020), developed by the UK National Health Service Foundation Trust, uses a patient-oriented approach to help patients identify what daily tasks and activities result in fatigue and how often, and encourages them to keep an activity log. Such self-report measures may assist both the patient and clinician in developing an exercise program and a symptom management plan to minimize fatigue on an ongoing basis. Effects on Functioning Chronic fatigue associated with HDCTs can result in a number of func- tional impairments that affect daily activities; the more severe the fatigue, the greater is the impairment (Voermans et al., 2010b). These impairments can include an inability to remain upright for even short periods of time, difficulty with concentration (De Wandele et al., 2016), difficulty in mov- ing from standing to sitting and back to standing, and decreased executive functioning resulting from poor sleep; planning and sequencing, memory, and attention may also be affected (Capuron et al., 2006; Dobbs et al., 2001; Joyce et al., 1996; Ratiu et al., 2018). Many patients with EDS/HSD rest or sleep during the day as a result of their fatigue, which can impact social functioning, work, and other activities (Voermans et al., 2010b). The inability to remain upright or standing in particular can negatively affect the performance of many normal activities for both children and adults. In one study, parents of children aged 4–12 years reported that their children were unable to “keep up with peers” because of fatigue and other factors (Warnink-Kavelaars et al., 2019). Fatigue also can prevent people with EDS/HSD from working at jobs that are physically demanding (De Baets et al., 2021). One study found that fatigue was the major reason people with hEDS did not work (De Baets et al., 2021). And a Norwegian study of in- dividuals with MFS found severe fatigue to be “significantly associated with low work participation” (Velvin et al., 2015; see also Bathen et al., 2014).

136 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE Orthostatic Intolerance2 Orthostatic intolerance refers to a condition in which individuals de- velop symptoms upon assuming and maintaining upright posture, with symptoms improving (although not necessarily resolving completely) after they return to a recumbent position (Low et al., 2009). Symptoms, many of which overlap with those of EDS/HSD, include rapid heart rate (tachycar- dia) or palpitations, feeling faint or fainting, lightheadedness or dizziness upon standing, vertigo, blurred vision, weakness, fatigue, pain, headaches, anxiety, exercise intolerance, difficulty regulating body temperature, sensi- tivity to auditory or visual stimuli, nutrient imbalance, and cognitive dif- ficulties (Goodman, 2018; Rich et al., 2020). Hemodynamic abnormalities in orthostatic intolerance can include classical or delayed orthostatic hypotension, neurally mediated hypoten- sion, and POTS (Freeman et al., 2011; Goldstein et al., 2002; Low et al., 2009; Rosen and Cryer, 1982; Schondorf and Low, 1993; Sheldon et al., 2015; Stewart et al., 2018). Classical orthostatic hypotension, common in particular in older adults, is defined by a sustained blood pressure reduc- tion of at least 20 mm Hg systolic or 10 mm Hg diastolic during the first 3 min after assuming an upright posture (Freeman et al., 2011). POTS is increasingly being recognized as a common form of orthostatic intolerance in individuals with EDS/HSD, and is diagnosed (1) in the absence of ortho- static hypotension in the first 3 minutes of standing or tilt testing, and (2) upon an increase in heart rate of ≥ 30 beats per minute (bpm) in adults (≥ 40 bpm in those under age 20 years) in the first 10 minutes after going from recumbent to standing or passive upright tilt; a heart rate of > 120 bpm dur- ing the first 10 minutes upright may be an additional criterion (Roma et al., 2018; Rowe, 2022). Inappropriate sinus tachycardia, which has symptoms similar to those of POTS, is characterized by a sinus rhythm with a heart rate greater than 100 bpm at rest (Sheldon et al., 2015). Neurally mediated hypotension, which occurs in both adults and children, is a reflex form of hypotension, and is defined by at least a 25 mm Hg reduction in systolic blood pressure, often accompanied by a relative slowing of the heart rate at the time of presyncope or hypotension (Rowe, 2022). The true prevalence of orthostatic intolerance in EDS/HSD is not known. In clinical studies, however, 41–100 percent of people with joint hypermobility or EDS have reported orthostatic symptoms on a regular basis (Rowe, 2022). 2 This section draws heavily on a paper by Peter Rowe (2022) commissioned by the com- mittee (see Appendix B).

EFFECTS ON FUNCTION 137 Potential Reasons Orthostatic intolerance results primarily from two physiological changes in response to upright posture: (1) a reduction in cerebral blood flow, and (2) an exaggerated compensatory adrenergic response to the re- duction in cerebral blood flow (Low et al., 2009). Other potential causes of orthostatic intolerance in persons with HDCTs include the development of autoantibodies to adrenergic receptors and rarely Chiari I malformation (Hakim et al., 2017b). The reduction in cerebral blood flow may result from excessive gravitational pooling of blood, low blood volume, and an increased sympathetic nervous system and adrenal catecholamine response (Rowe, 2022). Increased peripheral pooling of blood or decreased vaso- constriction is affected by the duration of quiet upright posture, increased compliance of the blood vessel wall in response to hydrostatic pressure, the presence of venous varicosities, obstruction of venous return, and vasodi- lating substances. Low blood volume occurs with a variety of conditions of orthostatic intolerance, including POTS and ME/CFS (Hurwitz et al., 2009; Okamoto et al., 2012; Streeten and Bell, 1998). Low blood volume has been associated with lower renin:aldosterone ratios and lower levels of antidiuretic hormone (Okamoto et al., 2012; Wyller et al., 2010). Physical inactivity can result in reductions in plasma volume, thereby aggravating symptoms of orthostatic intolerance and interfering with daily function (Rowe, 2022). Interventions Management of orthostatic intolerance requires a comprehensive care program beginning with nonpharmacologic interventions. These interven- tions include (1) avoiding conditions that increase dependent pooling of blood, such as prolonged standing or sitting; (2) improving venous return to the heart by using the muscle pump of the lower limbs, such as by cross- ing the legs while standing or shifting weight from one leg to the other and using compression garments; (3) avoiding depletion of salt and water and other causes of low blood volume; and (4) avoiding increasing catechol- amines beyond their baseline levels (which may be elevated) by minimizing stress and in some patients reducing caffeine consumption (Rowe et al., 2017). Further care focuses on managing migraine headaches; allergies; mast cell activation syndrome; anxiety; depression; menstrual dysfunc- tion; and areas of biomechanical dysfunction, which can be managed with physical therapy or osteopathic manual therapy, as well as occupational therapy and environmental modifications (Levine et al., 2021; Rowe, 2016). Individuals with POTS and fatigue may need to lie down during the day to avoid flares of their condition.

138 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE Most individuals with more than a minor degree of functional impair- ment from orthostatic intolerance will need medication. Pharmacologic treatments, such as low-dose beta blockers, fludrocortisone, or midodrine, may ameliorate some of the effects of the condition. Those with neutrally mediated hypotension (NMH) may benefit from selective serotonin reup- take inhibitors. Adolescent girls and women may benefit from hormone therapy (Rowe, 2022, citing Boehm et al., 1997). And individuals with POTS with fatigue and tachycardia may be treated with ivabradine (Rowe, 2022). Assessment Clinical assessment of orthostatic intolerance is based on two main tests—standing tests and head-up tilt tests. There is no gold standard for such assessments, and techniques for these tests vary (Rowe, 2022). The impact of orthostatic intolerance on overall function is best assessed with self-reported health-related quality of life questionnaires, such as the SF-36, Euro QOL, or PROMIS measures in adults (Cook et al., 2012; EuroQol Group, 1990; Ware and Sherbourne, 1992) and the age-specific Functional Disability Inventory of Pediatric Quality of Life (PedsQL) for children (Varni et al., 2001). Brief self-reported measures of general or cognitive fatigue include the PedsQL Mutidimensional Fatigue Inventory (MFI), the Wood Mental Fatigue Inventory, and the Fatigue Severity Scale, among oth- ers. The SF-36 physical functioning scale can distinguish between diseased and nondiseased individuals. However, it is less useful for ascertaining the degree of disability in individual patients (van Campen et al., 2020). This may be the case for those with EDS/HSD, as function can be affected not just by orthostatic intolerance and fatigue but also by joint stability and pain. Effects on Functioning The symptoms of orthostatic intolerance and ME/CFS and their sever- ity can be unpredictable. They are influenced by the level of activity or degree of orthostatic and other physiologic stressors in the preceding days, which can provoke postexertional malaise (PEM). PEM denotes an exac- erbation of any of a variety of symptoms—fatigue, lightheadedness, cogni- tive dysfunction, headache, sensitivity to sensory stimuli, and generalized pain—after people have increased their usually tolerated physical, cognitive, or orthostatic stress (Rowe, 2022). In a study by Ross and colleagues (2013), 96 percent of patients with POTS self-reported cognitive deficits, referred to as “brain fog.” Blurred or double vision can impact reading, driving, and mobility, and acute

EFFECTS ON FUNCTION 139 sensitivity to smells, temperatures, sounds, and lights can affect socializa- tion, child care, bathing, and participation in such activities as grocery shopping and doctor’s appointments (Rich et al., 2020). A consistent finding among people with orthostatic intolerance is exacerbation of symptoms in the morning (Rich et al., 2020). Mast Cell Activation Disease Mast cells reside throughout the connective tissues, but tend to cluster in the skin and at the epithelial borders of the gastrointestinal, respiratory, and urogenital tracts, which interact with the external world. Mast cells have a variety of functions, including phagocytosis, antigen presentation, cytokine and chemokine production, and the release of vasoactive substances; they also play a role in local tissue homeostasis (tissue repair, angiogenesis) and coordination of immune responses to numerous pathogens (Seneviratne et al., 2017). MCAD is an immune syndrome that can be localized; localized mast cell disorders include, for example, rhinitis, hypersensitivity gastro- enteritis, asthma, and urticaria. Systemic mast cell activation, called mast cell activation syndrome, presents with symptoms involving two or more organ systems (skin: urticaria [hives], angioedema [swelling under the skin], and flushing; gastrointestinal: nausea, vomiting, diarrhea, and abdominal cramping; cardiovascular: hypotensive syncope [fainting] or near syncope and tachycardia; respiratory: wheezing; naso-ocular: conjunctival injection, pruritus [itching], and nasal congestion) (Akin, 2017). Mast cell activation syndrome can result from abnormal production of progenitor mast cells with genetic mutations or mast cell activation events triggered by comorbid disorders (Akin, 2017). The former etiology reflects clonal mast cell disorders with a neoplastic gain of function leading to production of abnormal mast cells; an example of this type of disorder is systemic mastocytosis. The latter etiology reflects mast cell activation that is disproportionate to that required to protect the body from the perceived assault (Akin, 2017). This second form of mast cell activation syndrome, termed nonclonal or secondary mast cell activation syndrome, is the more prevalent and reflects inappropriate activation of the cells to stimuli that otherwise would be tolerated if the individual were in a nonreactive state (Akin, 2017; Hamilton, 2018). Mast cell dysregulation appears to play a role in EDS/HSD, as well as neuropathies and hypersensitivity syndromes, both immediate and delayed (Seneviratne et al., 2017). Co-occurrence of MCAD and EDS, particularly hEDS/HSD, has been linked to primary immunodeficiency disorders in these patients (Brock et al., 2021). In a study of 974 patients attending an allergy/immunology clinic, Brock and colleagues (2021) sought to identify those with the diagnostic codes for immunoglobulin deficiency, MCAD, and

140 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE hEDS/HSD. They found that 46 percent of the 974 patients had MCAD but no codes for immunoglobulin deficiency or hEDS/HSD, 10 percent had a diagnosis of both MCAD and hEDS/HSD, and 19 percent had a diagnosis of all three disorders. The authors point out that HDCTs may increase sus- ceptibility to aberrant mast cell activation (Brock et al., 2021). Potential Reasons Mast cells are closely associated with the epithelium of internal organs and the endothelium lining blood vessels and the lymphatic system and play a central role in the detection of and response to tissue injury. As described by Brock and colleagues (2021), mast cells are activated by factors derived from injured connective tissue, as well as activated inflammatory cascades. Following detection of danger or inflammatory signals, mast cells use an ar- ray of pathogen receptors to determine the nature of the impending danger, which may include infectious agents, toxins, and physical insults. Mast cells are thereby primed to release their cache of chemical mediators to recruit and activate other components of the innate and adaptive immune systems, as well as release chemicals that play a role in regulating angiogenesis, tissue remodeling, and wound healing (Brock et al., 2021). Interventions Treatment for MCAD is typically based on the etiology of mast cell reactivity, clonal versus nonclonal MCAD, triggers of mast cell activation events, and symptoms (see Annex Table 5-7). Therapy starts with identi- fication and avoidance of triggers, such as foods, physical environmental factors, and medications. The latter category of triggers is important in the setting of pain management and surgeries, since several antibiotics, anesthetic agents, and pain relievers, including opioids and nonsteroidal anti-inflammatory agents, are known to be direct mast cell secretagogues. Patients with mast cell activation syndrome should receive premedica- tion recommendations and treatment recommendations for anaphylaxis. Premedication and treatment recommendations consist of histamine and leukotriene blockade, as well as mast cell membrane–stabilizing compounds, such as ketotifen and cromolyn (Hamilton, 2018; Weiler et al., 2019). In addition to medications and foods, patients with EDS/HSD and comorbid MCAD need to identify and reduce exposure to nonimmunologic triggers, such as chemicals, stress, pollen, heat/cold, and exercise (Seneviratne et al., 2017). For patients with more recalcitrant MCAD, desensitization therapy may be appropriate, as well as use of nonsteroidal immunosuppressants and some biologic therapies, including omalizumab and possibly supple- mental gamma globulin (Molderings et al., 2016; Seneviratne et al., 2017).

EFFECTS ON FUNCTION 141 Glucocorticoid therapy is not recommended for patients with both EDS/ HSD and MCAD (Seneviratne et al., 2017). Regular exercise to the patient’s usual limit of tolerance is recommended; however, strenuous exercise may trigger a mast cell activation flare (Seneviratne et al., 2017). Assessment Three criteria have been proposed for diagnosing mast cell activation syndrome: (1) typical signs and symptoms of mast cell mediator release (affecting at least two organ systems); (2) specific symptoms in six organ systems (skin, cardiovascular, gastrointestinal, respiratory, naso-ocular, and anaphalyxis); and (3) objective evidence of mast cell–derived mediator release or chronically activated mast cells, typically obtained with labora- tory testing (Seneviratne et al., 2017). Elevated serum tryptase is often used in the diagnosis of mast cell activation syndrome, although symptoms of MCAD may occur without elevated tryptase. Annex Table 5-7 summarizes common methods used to diagnose MCAD. Effects on Functioning Patients with MCAD and EDS/HSD may experience fatigue and mal- aise. Both physical and psychological stress can activate mast cells. Pain is a common characteristic of MCAD that can be treated with nonsteroidal anti-inflammatory drugs, although their use needs to be tailored to the individual patient. Among the many symptoms of MCAD that may affect function are urticaria, angioedema, asthma, neurocognitive impairment, throat swelling, diarrhea, and cramping (Seneviratne et al., 2017). Full-Body Functioning One of the challenges of assessment of functioning, especially as it relates to SSA disability determinations, is capturing the full effect of an in- dividual’s impairment(s) on daily activities (see NASEM, 2019). This is par- ticularly true when a person has multiple impairments that individually do not rise to the level of severity required by SSA but collectively may do so. Given that individuals with HDCTs typically experience secondary impair- ments in multiple body systems, it is important to assess the collective effect of all their physical and mental impairments on their ability to function in daily life, including at work and in school. In addition, as discussed previ- ously, some frequently experienced conditions, such as chronic pain, fatigue, mild cognitive impairment, anxiety, and depression, can affect individuals’ overall functioning. As described in Chapter 1, SSA’s disability determina- tion process for children includes a concept called functional equivalence.

142 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE The technique for determining functional equivalence is a “whole child” approach that “accounts for all of the effects of a child’s impairments singly and in combination—the interactive and cumulative effects of the impairments—because it starts with a consideration of actual functioning in all settings” (SSA, 2009). This approach is particularly well suited to evaluating the combined effects on functioning of the many and varied im- pairments that often manifest in HDCTs and other multisystem disorders. Potential Reasons Annex Table 5-13 lists some of the potential reasons for limitations in full-body functioning among individuals with HDCTs. These include pain; weakness; fatigue; deconditioning; joint instability throughout the body; dysautonomia, including POTS; balance dysfunction; and cardiovascular, respiratory, and gastrointestinal impairments. Assessment A number of performance-based and self-reported measures for as- sessing overall physical functioning are included in Annex Table 5-13. The Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) is an established performance-based measure for assessing gross and fine motor function in children and young adults (ages 4–21) (Bruininks and Bruininks, 2005). BOT-2 comprises eight subtests: fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, running speed and agility, upper-limb coordination, and strength (Bruininks and Bruininks, 2005). A small Swedish study of children aged 8–16 years found that children with joint hypermobility scored lower on the BOT-2 balance subtest compared with the control group (Schubert-Hjalmarsson et al., 2012). The Bruininks Motor Ability Test (BMAT) is an adaptation of the BOT-2 for adults aged 40 and older (Bruininks and Bruininks, 2012). BMAT subtests include fine motor integration, manual dexterity, coordi- nation, balance and mobility, and strength and flexibility (Bruininks and Bruininks, 2012). A small study of healthy adults aged 65–92 living in the community in Australia found scores on the fine motor integration and manual dexterity subtests of BMAT to be predictive of the participants’ level of activity and participation as assessed on several measures, while scores on the coordination, balance, and mobility subtests were not (Seaton and Brown, 2018). Similar research using validated measures for working- age adults would be informative. Other performance-based assessments that provide information about individuals’ overall physical functioning include functional capacity evaluation (Chen, 2007; Fore et al., 2015; Genovese and Galper, 2009; Jahn et al., 2004; Kuijer et al., 2012; Soer et

EFFECTS ON FUNCTION 143 al., 2008) and exercise testing that includes assessment of aerobic capacity and neuromuscular performance (Liguori and American College of Sports Medicine, 2021). The Composite Autonomic Symptom Score-31 (COMPASS-31) is a 31- item self-report questionnaire about individuals’ experience of symptoms related to dysautonomia (Sletten et al., 2012). A study aimed at differen- tiating severity groups among individuals with hEDS/HSD using a set of validated self-report questionnaires found that COMPASS-31 accurately differentiated individuals with more from those with less severely involved hEDS/HSD (Copetti et al., 2019). Selected Assistive Technologies and Relevant Accommodations The assistive technologies and accommodations that are relevant to individuals with limitations in full-body functioning will depend on the specific impairments or conditions that are affecting their physical function- ing. Annex Tables 5-14 (physical functioning) and 5-15 (vision, hearing, and speech functioning) list selected assistive technologies and reasonable accommodations for specific areas of physical functioning. Work-Related Functioning, Activities of Daily Living, and Instrumental Activities of Daily Living Potential Reasons Potential reasons for limitations in work activities, ADLs, and IADLs are listed in Annex Table 5-13 and are similar to those for full-body functioning. Assessment A number of measures can be used to perform an integrated assessment of overall physical and mental functioning (see NASEM, 2019, Chapter 4). Five such measures that provide information on work-related function- ing are the Work Disability Functional Assessment Battery (WD-FAB), the Work Ability Index (WAI), the Sheehan Disability Scale (SDS), the Social and Occupational Functioning Assessment Scale (SOFAS), and the Mental Illness Research, Education, and Clinical Center version of the Global Assessment of Functioning scale (MIRECC GAF). WD-FAB is a computerized self-report measure designed to assess work- related functioning in two domains: physical and mental health (Brandt and Smalligan, 2019; Meterko et al., 2019). WD-FAB consists of eight scales: basic mobility, upper-body function, fine motor function, community

144 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE mobility, resilience and sociability, self-regulation, communication and cog- nition, and mood and emotions (Marfeo et al., 2019). Content relating to physical functioning includes such activities as sitting, standing, walking, and using a wheelchair/device to move around, as well as driving; using transportation; and pushing, pulling, lifting, and carrying (Marfeo et al., 2019). Content related to mental functioning includes cognitive function- ing; communication; and management of mood, emotions, and behaviors (Marfeo et al., 2019). The WAI is a seven-item self-report questionnaire designed to measure the work capacity of individuals in an occupational health clinic environ- ment (Ilmarinen, 2007; NASEM, 2019; Tuomi et al., 1998, p. 90). It asks respondents about their “current work ability compared with the lifetime best,” their “work ability in relation to the demands of the job,” the “num- ber of current diseases diagnosed by a physician,” their “estimated work impairment due to diseases,” the amount of “sick leave during the past year (12 months),” their “own prognosis of work ability 2 years from now,” and “mental resources” (Ilmarinen, 2007). The responses are used to calculate a score categorizing the individual’s work capability as poor, moderate, good, or excellent. The WAI can be used to predict early retirement, work disabil- ity, absence due to sickness, and mortality relatively well (NASEM, 2019). It also can be used to identify individuals who need supportive intervention (Adel et al., 2019). Repeated administration of the WAI over time may be particularly informative. The SDS is a five-item self-report questionnaire designed to measure the effect of symptoms due to a physical or mental health condition on an individual’s functioning in three areas: work or school, social life, and family life or home responsibilities (Sheehan, 1983). It can be used to as- sess change in functioning over time and has been shown to be sensitive to treatment effects in a selected group of mental health conditions, including anxiety disorders and depression (Sheehan and Sheehan, 2008). The SOFAS provides a rating of social and occupational functioning on a scale from 0 to 100: lower scores indicate lower functioning (Rybarczyk, 2011). In contrast to the Global Assessment of Functioning scale, the SOFAS focuses on functioning independent of the severity of the person’s psychological symptoms, and it includes impairments caused by physical as well as mental disorders (Rybarczyk, 2011). The MIRECC GAF measures occupational, social, and psychological functioning separately on three different subscales—occupational, social, and symptom—that use ratings of 0 to 100, with lower scores indicating worse functioning and greater symptom burden (Niv et al., 2007). ADLs and IADLs are tasks typically performed by individuals in the course of everyday life. ADLs include such basic self-care tasks as “personal care and hygiene, dressing, feeding, continence management, and mobility”

EFFECTS ON FUNCTION 145 (NASEM, 2019, p. 77). IADLs are “more complex tasks related to indepen- dent living in the community, such as navigating transportation options and shopping, preparing meals, managing one’s household, managing finances and medications, communicating with others, and providing companion- ship and mental support” (NASEM, 2019, p. 77). ADLs and IADLs can be assessed through self report, third-party report (e.g., caretaker, fam- ily member), direct observation, and/or specific assessment measures, a number of which are listed in Annex Table 5-13. The assessment of ADLs and IADLs and their relevance to work disability are discussed in detail in Functional Assessment for Adults with Disability (NASEM, 2019, pp. 76–82). Although information about individuals’ ability to perform ADLs and IADLs may help inform determinations about their ability to work, there is no evidence to support a direct correlation between ADL and IADL assessments and the ability to perform work (NASEM, 2019). Selected Assistive Technologies and Relevant Accommodations Annex Table 5-13 lists a number of assistive technologies and ac- commodations that may improve individuals’ ability to perform ADLs and IADLs, as well as work-related functioning. These include devices to improve mobility, reachers, built-up handles on home or work tools, and reorganization of or modifications to the home and workplace. The specific types of devices and accommodations needed depend on individuals’ spe- cific impairments and the activities affected. PHYSICAL FUNCTIONING The physical activities addressed in Annex Tables 5-2 and 5-14 are sitting, standing, walking, strenuous physical activity, lifting (floor to waist and overhead), carrying (which usually requires the ability to stand, lift, and walk), pushing or pulling, reaching, overhead reaching, at or below the shoulder reaching, gross manipulation, fine manipulation, foot and leg controls, climbing (which may include stairs, ramps, ladders, scaffold- ing, ropes, etc.), and low work (including stooping, crouching, kneeling, crawling, or lying on the ground). As previously mentioned, the committee identified these activities as most relevant to SSA based on the information SSA collects about applicants and the information the U.S. Bureau of Labor and Statistics collects about the physical demands of jobs for inclusion in the Occupational Information System. The committee added “strenuous physical activity” to the list and modified the grouping of some of the other activities on the basis of their functional similarities or dissimilarities. Annex Table 5-2 provides definitions of the various physical activities along with explanations for deviations from the definitions of relevant physical

146 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE job demands provided in the ORS [Occupational Requirements Survey] Collection Manual (BLS, 2020). Potential Reasons The committee identified seven potential reasons for limitations in any of the physical activities listed above: (1) pain, (2) joint instability, (3) weak- ness, (4) balance dysfunction, (5) fatigue and deconditioning, (6) neuro- logical compromise, and (7) orthostatic intolerance and dysautonomia (see Annex Table 5-14). The specific activities affected depend on the location of the pain, the affected joints, weakness, and/or neurological compromise experienced by the individual. For example, instability in the cervical or lumbar spine, pelvis, and knees, as well as weakness and balance dysfunc- tion affecting the trunk, can limit an individual’s ability to sit, especially uninterrupted for prolonged periods of time. Instability in the cervical or upper-extremity joints and weakness in the arms and hands can limit an individual’s ability to perform activities requiring fine manipulation, including keyboarding. Gross and fine manipulation may also be affected by coordination deficits. In addition to the effects of musculoskeletal and neurological impairments, such activities as walking and strenuous physi- cal activity can be limited by cardiac and/or respiratory dysfunction and exercise intolerance. Recovery from major aortic surgery can take up to a year depending on extent of aortic replacement, further restricting partici- pation during that time. Cardiac and aortic dysfunction also can restrict an individual’s ability to lift objects from floor to waist or overhead. Physical activity guidelines and restrictions for individuals with MFS and related disorders must be tailored to the specific person. However, general guidelines include avoidance of intense isometric exercise, such as occurs when straining to lift a heavy weight; contact sports that can lead to blows to the head; activities that involve rapid acceleration and decelera- tion over short distances (sprinting); activities that involve rapid changes in pressure (e.g., scuba diving); and exercise to the point of exhaustion (Paris and Brigham and Women’s Hospital, 2008; Marfan Foundation, 2017). Metabolic equivalent of task (MET), or simply metabolic equivalent, is a physiological measure expressing the energy cost (or calories expended) of physical activities as a multiple of resting energy consumption. Generally, it is recommended that individuals with MFS and related disorders keep the intensity of their physical activity in the low to moderate range (i.e., < 6 METs) (Marfan Foundation, 2017). The physical activity guidelines from The Marfan Foundation (2017, p. 3) include a table of common physical and recreational activities that fall into light (< 3 METs), moderate (3–6 METs), and vigorous (> 6 METs) categories of intensity. Also included is a table of competitive sports and athletic activities organized by risk of

EFFECTS ON FUNCTION 147 contact and intensity (Marfan Foundation, 2017, p. 7). The mental and physical health benefits of exercise are well known, but it is important to tailor the type and intensity of physical activity to the specific needs of indi- viduals with HDCTs. Especially for children and adolescents, the benefits of physical activities often extend beyond the physical. Participation in sponta- neous and organized physical activities, from playing tag and climbing trees to engaging in contact sports, gymnastics, and dance, is often the center of social interaction and central to the psychosocial and emotional well-being of many children and adolescents. Research on the relative benefits versus risks of participation in common physical activities is therefore important to better inform disease management in these age groups. Maintaining a static position uninterrupted, such as sitting (especially the prolonged sitting often required to perform sedentary work or par- ticipate in a classroom) or standing for a prolonged period of time can be particularly problematic for individuals with HDCTs. Weak connective tissue and limited functionality of primary stabilizers (ligaments and ten- dons) can limit the ability to be erect in sitting or standing or for travel, and POTS can limit the ability to stand for extended periods. Jobs that might be considered sedentary but require an employee to move frequently between a seated and standing position may also be difficult for individuals with orthostatic intolerance. The freedom to move about and change posi- tion as needed (e.g., sitting to standing, walking in place) is important for these individuals to maintain function and reduce impairment. Conditions such as POTS, discussed earlier, can limit an individual’s ability to remain in a seated position for even a few minutes or to function effectively while sitting or standing because of mild cognitive impairment. Individuals with EDS/HSD and other HDCTs may be unable to perform repetitive motions, including the fine manipulations, writing, and, in some cases, keyboarding that are often integral to sedentary work and school activities, over an extended period of time. It is important to remember that the performance of a specific physi- cal activity rarely if ever occurs independently of other physical activities. Annex Table 5-14 notes some of the overlaps among physical activities. Also, as previously mentioned, the committee includes lying down on the ground under “low work,” along with stooping, crouching, kneeling, and crawling. This contrasts with the collection of occupational data on “sit- ting,” which includes “active lying down. For example, a mechanic lying on a dolly working underneath a vehicle is sitting” (BLS, 2020, p. 112). Although lying on a raised surface (e.g., a bed) may be grouped with sitting, sitting is distinct from lying down on the ground (e.g., lying on a dolly un- derneath a vehicle). From a functional perspective, lying on the ground has more in common with other low work activities in that it includes the need to get up and down from the ground and potentially squirming around to

148 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE do work while on the ground. These are difficult tasks that are equivalent to the other low work activities. Assessment Annex Table 5-14 lists performance-based and self-reported outcome measures that provide information relevant to an individual’s ability to perform specific physical activities. Because of the importance of matching an individual’s functional capacities to specific job requirements, a func- tional capacity evaluation is advised for individuals with hEDS/HSD (De Baets et al., 2021). Alternatively, specific function testing performed by a trained clinician (e.g., physical therapist, occupational therapist, exercise physiologist), directed at an individual’s ability to perform the activities of interest, provides information about the person’s ability to sustain those activities for the length of time required to perform a specific job or partici- pate in classroom or other activities. When extrapolating from the testing environment to the workplace or school, it is important to remember that environmental conditions can affect individuals’ symptoms and functioning. Performance at work and school, where physical, cognitive, and emotional stressors are often greater than in the testing environment, may be affected in ways not observed during testing. Selected Assistive Technologies and Relevant Accommodations Annex Table 5-14 lists a variety of assistive technologies and accommo- dations that can assist individuals in performing specific physical activities. Braces and other supports can assist with sitting, and allowing students or employees to alternate between sitting and other positions and to take rest breaks as needed can help them participate successfully in school and work. Specialized pencil/pen grips and alternative keyboards may facilitate handwriting and keyboarding. Students may benefit from a number of other school-based accommodations as well (SchoolToolkit, 2022), which can be formalized in a 504 plan or individualized education program. The use of certain assistive devices, in particular mobility devices to assist with stand- ing and walking, including wheelchairs, can be very stressful for upper- extremity joints and may interfere with those activities requiring use of the upper extremities (e.g., lifting or carrying while using crutches). Similarly, ambulation devices that allow one to move well on a level or sloped surface may not be usable for climbing or ascending steep inclines.

EFFECTS ON FUNCTION 149 VISION, HEARING, AND SPEECH FUNCTIONING To a greater or lesser extent, vision, hearing, and speech functions may be affected in people with HDCTs (see Annex Tables 5-11 and 5-15). Vision Near visual acuity is defined as “clarity of vision at approximately 20 inches or less, as when working with small objects or reading small print” (BLS, 2020, p. 154). Close work, such as reading, writing, computer use, and manipulation of small objects, requires not only near visual acuity but also the ability of the eyes to work together as a team (binocular vi- sion). When one’s eyes do not work together because of accommodative or vergence dysfunction, one’s ability to perform tasks requiring near vision (close work) may be impaired even when vision is normal in each eye inde- pendently (monocular vision). Difficulties performing close work can affect performance in school, recreational activities (sports, riding a bicycle), and jobs requiring close work. Far visual acuity is defined as “clarity of vision at a distance of 20 feet or more, involving the ability to distinguish features of a person or objects at a distance” (BLS, 2020, p. 154). Peripheral vision refers to “what is seen above, below, to the left or right by the eye while staring straight ahead” (BLS, 2020, p. 154). Such tasks as driving, reading a blackboard, or partici- pating in certain sports require far visual acuity. Driving and participating in certain sports are examples of tasks that also require peripheral vision. Potential Reasons A number of potential reasons for limitations in near and far visual acuity and peripheral vision are listed in Annex Table 5-15. They range from uncorrected refractive error to lens dislocation, retinal detachment or scarring, and cataract formation. Assessment Assessment of near and far visual acuity is performed using eye charts (e.g., Snellen, Bailey-Lovie) at a distance and handheld charts, respectively. Convergence (the ability of the eyes to work together) is assessed through orthoptic evaluation. One test of convergence asks the subject to main- tain focus on a near target at a fixed distance while passing progressively stronger base-out prisms in front of one eye until the person experiences double vision or the examiner sees one of the eyes drift outward. Peripheral vision is assessed using kinetic or semiautomated kinetic perimetry to create

150 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE maps of an individual’s visual field. Functional Assessment for Adults with Disabilities includes a more detailed discussion of visual functioning and assessment (NASEM, 2019, pp. 128-133). Selected Assistive Technologies and Relevant Accommodations Assistive technologies for individuals with vision impairments include low-vision devices (refractive lenses), over-the-counter reading glasses to help with accommodative insufficiency, and base-in prism glasses to help with double vision during near work when impairment is related to conver- gence insufficiency. Other interventions include auditory replacements for vision tasks, glare-reducing equipment, orientation and mobility training (for impaired far and peripheral vision), and such modifications as sitting closer to the blackboard/screen in a classroom. Hearing Hearing is defined as the “ability to hear, understand, and distinguish speech and/or other sounds” (BLS, 2020, p. 149). Hearing is typically needed for jobs and schooling requiring communication, one-on-one and in group settings, in person or through video conferencing. It also is needed when a job requires use of a telephone or similar device, such as a radio, walkie-talkie, intercom, or public address system, or the ability to hear such sounds as machinery alarms and equipment sounds (BLS, 2020). Potential Reasons Hearing loss generally is classified as sensorineural, conductive, or a mix of the two, all of which may be seen in individuals with EDS/HSD, MFS, and Loeys-Dietz syndrome (LDS). People with EDS/HSD also may experience tinnitus, which refers to hearing sounds (e.g., ringing, clicking) in the absence of a corresponding external noise. Some people with tinnitus experience a muffling or distortion of external sounds (Møller, 2007). Assessment Performance-based measures for assessing hearing include pure tone audiometry (McBride et al., 1994; Yueh et al., 2003), speech recognition in noise testing (Giguère et al., 2008; Laroche et al., 2003), and internet- and telephone-based screening (Smits et al., 2004; Watson et al., 2012). Self-reported outcome measures for individuals with hearing impairments include the Hearing Handicap Inventory for Adults (Newman et al., 1990) and the Speech, Spatial, and Qualities of Hearing Scale (Gatehouse and

EFFECTS ON FUNCTION 151 Noble, 2004). Assessment of hearing impairments and their effects on indi- viduals’ functioning are discussed in Functional Assessment for Adults with Disabilities (NASEM, 2019, pp. 133–143). Selected Assistive Technologies and Relevant Accommodations A 2017 National Academies report provides an analysis of selected assistive technologies and devices, including products and technologies pertaining to hearing (NASEM, 2017). Such technologies include hearing aids, personal sound amplification products, remote microphone hearing assistive technology, captioning, and telecommunications relay services. Environmental modifications (e.g., to improve acoustics) are also helpful. Speech Speech is defined as the expression or exchange of “ideas by means of the spoken word to impart oral information…accurately, loudly, or quickly” (BLS, 2020, p. 149). Although functional communication need not involve speech (but may involve, for example, alternative expressive modali- ties, nonverbal interactions, written language, and social communication), speech is necessary for certain jobs and is important if children are to be able to participate fully in school, including interaction with their peers. Language is another component of functional communication. Whereas speech comprises the physical processes of forming word sounds to convey a message, language is defined as the use of words, grammar rules, and the like to construct the content of the message. Potential Reasons Many factors contribute to communication, including the skills of the individual and the communication partner(s), as well as environmental conditions (e.g., background noise). With respect to the individual, “physi- cal factors specific to communication (articulation accuracy, speaking rate, voice quality, loudness, fluency, effort, and fatigue) affect the intelligibility and comprehensibility of speech production” (NASEM, 2019, p. 144). Functional speech among individuals with HDCTs may be affected by tem- poromandibular joint dysfunction, laryngeal dysfunction, oral and dental pain, and vocal fatigue. Individuals with EDS/HSD may experience “pain- less dysphonia, fluctuating hoarseness, weak voice, dysphagia, recurrent epi- sodes of laryngospasm, and subglottic stenosis” (Chohan et al., 2021, citing Arulanandam et al., 2017). Dysphonia among individuals with EDS/HSD may be attributable, at least in part, to “laxity, hypotonia, discoordination or decreased movement of the vocal cords, as well as reduced mobility of

152 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE the cricoarytenoid joint” (Chohan et al., 2021, citing Arulanandam et al., 2017; Castori et al., 2010; Hunter et al., 1998). Individuals with cervical medullary syndrome and Chiari malformation may also experience dysar- thria (Henderson et al., 2019). With respect to language, “mental factors specific to communication at the individual level (receptive, expressive, and pragmatic language skills) affect message comprehension” (NASEM, 2019, p. 144). For example, difficulties with word finding, experienced by some individuals with mild cognitive impairment, affect language. Assessment Annex Table 5-15 lists a selection of measures of speech function, in- cluding measures of intelligibility, dysarthria, and apraxia, as well as several communication scales. A more complete discussion of speech functioning in the context of work, along with assessment measures, is included in Functional Assessment for Adults with Disabilities (NASEM, 2019, pp. 143–157). Selected Assistive Technologies and Relevant Accommodations A number of technologies can assist individuals with functional com- munication when speech is impaired. Personal voice amplification devices may be used to increase the volume of one’s natural speech, and a wide vari- ety of augmentative and alternative communication devices can replace oral communication if necessary (see NASEM, 2017, Chapter 6). Environmental modifications may help as well. For example, dry or dusty environments can exacerbate speech difficulties among individuals with EDS/HSD. MENTAL FUNCTIONING The committee focused on the mental activities included in Annex Table 5-16 because they are areas of mental functioning of particular interest to SSA for adults and children aged 3–18 years. The following mental activities are found in Paragraph B of SSA’s Listing of Impairments for mental dis- orders (SSA, n.d.-c, n.d.-d): understand, remember, and apply information; concentrate, persist, or maintain pace; problem solve; interact with others; and adapt or manage oneself. Annex Table 5-2 provides definitions for each of these areas of mental functioning. Difficulties in these areas can affect quality of life in individuals with HDCTs. A study of executive functioning and quality of life in adults with MFS found that “mental fatigue, commitment, instructions, problem solving, prospective memory, impulsivity, and flexibility” were all reliable predictors

EFFECTS ON FUNCTION 153 of satisfaction with quality of life (Ratiu et al., 2018). Cognitive dysfunc- tion also has been reported in patient populations with conditions associ- ated with HDCTs, including POTS (Raj et al., 2018; Ross et al., 2013; Wells et al., 2020) and CFS (Ocon, 2013). Such patients often complain of “brain fog,” a type of cognitive dysfunction involving mild cognitive impairment. Patient-reported descriptors of “brain fog” include forgetful- ness, difficulty thinking, difficulty focusing, feeling cloudy, difficulty find- ing the right words/communicating, mental fatigue, slowness, mind going blank, feeling “spacey,” and difficulty processing what others say (Ross et al., 2013). Individuals reporting “brain fog” have shown mild to moderate cognitive impairment (Raj et al., 2018). Specific deficits have been found in short-term and working memory, selective attention, cognitive process- ing, reaction times, and executive functioning, although specific results vary among studies (Arnold et al., 2015; Ocon, 2013; Wells et al., 2020). Chapman (2020) reports effects on verbal recall and ability to do basic math, as well as short-term memory and concentration; word choice and language may also be affected. Ross and colleagues (2013) found that 96 percent of respondents (aged 14–29) with POTS reported “brain fog,” with 67 percent experiencing it daily. The majority of respondents said their symptoms adversely affected “their ability to complete schoolwork (86%), be productive at work (80%), and participate in social activities (67%).” These findings are consistent with other reports that individuals with “brain fog” “often complain of an inability to perform day-to-day tasks, organize thoughts, or hold a conver- sation,” as well as difficulty with focus, learning and retaining information, and maintaining employment (Chapman, 2020). A recent review of literature on the psychological burden associ- ated with EDS/HSD found the highest prevalence for “language disor- ders (63.2%), attention-deficit/hyperactivity disorder (ADHD) (52.4%), anxiety (51.2%), learning disabilities (42.4%), and depression (30.2%),” although there often is great variability among studies in the prevalence reported (Kennedy et al., 2022). The reported prevalence for depression, for example, ranged from 11.1 to 30.2 percent, while that for anxiety ranged from 9.0 to 51.2 percent (Kennedy et al., 2022). Anxiety can manifest as feeling nervous, restless, or tense; worry; brooding—trouble concentrating or thinking about anything except the present worry; anticipatory anxiety; a sense of dread; task avoidance; and irritability, as well as physical symp- toms (Mayo Clinic, 2022a; NLM, 2020). Depressive episodes manifest in symptoms (sadness, irritability, and emptiness; loss of pleasure or interest in activities) that persist for most of the day, almost every day, for at least 2 weeks (WHO, 2022). Other symptoms may include trouble concentrat- ing, a feeling of excessive guilt or low self-worth, and hopelessness, in ad- dition to physical symptoms (Mayo Clinic, 2022b; WHO, 2022). Anxiety

154 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE and depression, which may coexist, can significantly interfere with daily activities, including participation in school and work; personal and social activities; and relationships with family, friends, teachers, coworkers, and others (Mayo Clinic 2022b; WHO, 2022). Potential Reasons Importantly, both physical and psychiatric conditions contribute to decrements in mental functioning. Chronic pain, fatigue, cognitive impair- ments, depression, mood disorders, anxiety, and impulsivity, individually and collectively, can affect mental functioning in the areas identified (see Annex Table 5-16). Impaired cerebral blood flow associated with POTS (Ross et al., 2013; Wells et al., 2020); chronic inflammatory processes, which may disrupt the normal neuroimmune communication that is important to learning and memory (Mackay, 2015); and fatigue and poor sleep quality (Ross et al., 2013) may play a role in the cognitive dysfunction experienced by patients. Orthostatic and cognitive stressors, such as prolonged standing and pro- longed concentration, have been reported to trigger or worsen cognitive dysfunction (Ocon, 2013; Ross et al., 2013), although some patients have reported that symptoms continue even after they return to a supine posi- tion, and others have reported that cognitive stressors (e.g., prolonged con- centration) trigger symptoms while they are lying down (Ross et al., 2013). Research on the effects of anxiety and depression on work and school performance in populations without HDCTs shows that both conditions can adversely affect performance (Beck et al. 2019; Jaycox et al., 2009; Mazzone et al., 2007; Plaisier et al., 2010), although depression may have a larger effect than anxiety (Plaisier et al., 2010). Plaisier and colleagues (2010) found that the risk of absenteeism and decreased work performance was greater among individuals who had more severe anxiety and depres- sion. Beck and colleagues (2019) also found a relationship between pro- ductivity loss and severity of depression based on PHQ-9 scores, with even minor levels of depression being associated with decreased work function. In another study, teenagers with versus those without depression reported significantly greater impairment in academic, peer, and family functioning and physical health-related quality of life, as well as more days of impair- ment (Jaycox et al., 2009). Anxiety also adversely affects school perfor- mance and is associated with impaired memory and cognitive functions (Mazzone et al., 2007). Anxiety may interfere as well with the development of social skills, social life, and overall well-being (Mazzone et al., 2007).

EFFECTS ON FUNCTION 155 Assessment Annex Table 5-16 lists a variety of psychological and neuropsycho- logical measures for assessing individuals’ functioning in each of the areas of interest. More generally, as discussed in the section on work-related functioning, ADLs, and IADLs, the SDS has been widely used to assess the effects of symptoms of different mental health conditions on an individual’s functioning at work or in school, in social life, and in family or home responsibilities (Sheehan, 1983). In addition, the WD-FAB is designed to assess cognitive functioning; communication; and management of mood, emotions, and behaviors relevant to work (Marfeo et al., 2019). Selected Assistive Technologies and Relevant Accommodations Annex Table 5-16 lists a number of accommodations that may sup- port or improve individuals’ mental functioning in the specified areas. Providing short, step-by-step instructions and breaking work tasks down into sequential steps is helpful, along with providing a written summary of the steps or recording them for playback by the individual as needed. Arranging for work to be performed in a quiet area without distractions and allowing individuals to sit or stand at will and take breaks as needed can also improve functioning. HERITABLE DISORDERS OF CONNECTIVE TISSUE AND THE U.S. SOCIAL SECURITY ADMINISTRATION’S LISTING OF IMPAIRMENTS The statement of task for this study asked the committee to “identify [for the selected HDCTs] non-exertional physical limitations (e.g., balanc- ing or using the upper extremities for fine or gross movements) and mental limitations (e.g., cognitive or behavioral) that are equivalent in severity to the standard represented in the listings (i.e., that would prevent any gain- ful activity) but are not captured by currently existing listings and are not currently reflected in SSA’s disability grid rules.” For SSA, nonexertional limitations occur when “limitations and restric- tions imposed by [an individual’s] impairment(s) and related symptoms, such as pain, affect only [their] ability to meet the demands of jobs other than the strength demands.”3 Examples include “difficulty functioning be- cause [one is] nervous, anxious, or depressed”; “difficulty maintaining attention or concentrating”; “difficulty understanding or remembering de- tailed instructions”; “difficulty in seeing or hearing”; “difficulty tolerating 3 20 CFR 404.1569a.

156 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE some physical feature(s) of certain work settings, e.g., one cannot tolerate dust or fumes”; and “difficulty performing the manipulative or postural functions of some work such as reaching, handling, stooping, climbing, crawling, or crouching.”4 It is clear from the variety of physical and mental secondary impair- ments throughout all body systems, related symptoms (e.g., pain, fatigue), and potential environmental triggers experienced by individuals with HDCTs that they can experience nonexertional limitations in any of the above areas. In some cases, the limitations may be sufficiently severe as to preclude the individual’s participation in any gainful activity. In other cases, the combined effects of an individual’s qualifying physical and/or mental secondary impair- ments may limit function sufficiently to preclude participation in work “in an ordinary work setting, on a regular and continuing basis, and for 8 hours a day, 5 days a week, or an equivalent work schedule” (SSA, 2021) or, for children, to cause “marked and severe functional limitations.”5 Some individuals with HDCTs may qualify for SSA disability benefits at the listing-level step in the determination process on the basis of the second- ary impairment(s) they are experiencing, rather than the HDCT itself. With the exception of MFS, which is identified under the cardiovascular listing 4.10 (aneurysm of aorta or major branches), HDCTs are not currently specified in the listings; for both adults and children, SSA disability claims related to HDCTs are evaluated under listings for the affected body system. Annex Table 5-17 includes some of the listings that may apply to certain individuals with HDCTs, as well as notes indicating special considerations. Examples of musculoskeletal SSA listings that could apply directly to some applicants with an HDCT include 1.15 Disorders of the skeletal spine resulting in compromise of a nerve root(s); 1.16 Lumbar spinal stenosis resulting in compromise of the cauda equina; 1.17 Reconstructive surgery or surgical arthrodesis of a major weight- bearing joint; 1.18 Abnormality of a major joint(s) in any extremity; and 1.21 Soft tissue injury or abnormality under continuing surgical man- agement (see SSA, n.d.-b). Joint and soft-tissue injury or abnormalities and pain are very com- mon in individuals with HDCTs and hypermobility, resulting in significant functional limitations. It is important to note that certain abnormalities 4 20 CFR 404.1569a. 520 CFR 416.906.

EFFECTS ON FUNCTION 157 may not be seen on standard imaging, necessitating the use of specialized imaging (e.g., flexion or extension imaging; magnetic resonance imaging [MRI], potentially upright, if tolerated; dynamic or soft-tissue imaging). In addition, as discussed previously, individuals with versus those with- out HDCTs are more likely to have poor outcomes with major surgery, especially if their HCDT was not previously recognized or taken into ac- count in performing the surgery and providing aftercare. Wound healing is slow in many HDCTs, and wound dehiscence may occur despite excellent surgical and postoperative care. Some patients are unable to engage fully in postoperative therapy because of such HDCT-associated problems as fatigue, orthostatic intolerance, MCAD, depression, mild cognitive impair- ment, gastrointestinal disorders, or other musculoskeletal issues, which may further comprise surgical outcomes. As a result, surgical intervention, especially repeated surgery, for soft-tissue injuries or abnormalities may be contraindicated in some people with HDCTs even if it would be standard treatment for someone without an HDCT. The absence of surgery therefore need not imply that the person’s functional limitations are any less severe. Further, individuals with significant upper-extremity involvement may not be candidates for assistive technology to aid mobility because they would not be able to use it effectively and therefore may not have been prescribed such a device. Listings in other body systems that may apply directly to some indi- viduals with HDCTs include 2.02 Loss of central visual acuity; 2.03 Contraction of the visual field in the better eye (meeting the specified criteria); 2.04 Loss of visual efficiency, or visual impairment, in the better eye (meeting the specified criteria); 3.03 Asthma; 3.07 Bronchiectasis; 3.14 Respiratory failure; 4.10 Aneurysm of aorta or major branches; 5.08 Weight loss due to any digestive disorder (meeting the speci- fied criteria); 11.08 Spinal cord disorders; 12.04 Depressive, bipolar and related disorders; 12.06 Anxiety and obsessive-compulsive disorders; and 14.09 Inflammatory arthritis (SSA, n.d.-b). The relationship between HDCTs and immune system dysfunction is a subject of ongoing research. It is clear that immune system dysfunction (e.g., MCAD) mediates HDCT-related secondary impairments in multiple

158 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE body systems. Criteria in two of the listings for immune system disorders are especially relevant to the multisystem presentation and symptoms of HDCTs. The specific disorders listed—systemic lupus erythematosus and Sjogren’s syndrome—are central to each set of criteria but are not common to HDCTs. The criteria listed for these disorders include A. Involvement of two or more organs/body systems, with: 1. One of the organs/body systems involved to at least a moderate level of severity; and 2. At least two of the constitutional symptoms or signs (severe fatigue, fever, malaise, or involuntary weight loss). OR B. Repeated manifestations of [the listed disorder], with at least two of the constitutional symptoms or signs (severe fatigue, fever, mal- aise, or involuntary weight loss) and one of the following at the marked level: 1. Limitation of activities of daily living. 2. Limitation in maintaining social functioning. 3. Limitation in completing tasks in a timely manner due to de- ficiencies in concentration, persistence, or pace. (SSA, n.d.-b, 14.02, 14.10) Given that individuals with HDCTs typically experience physical and mental secondary impairments in multiple body systems, it is important to assess the collective effect of all their physical and mental impairments on their ability to function in daily life, including at work and in school. This is particularly true when a person has multiple impairments that individu- ally do not rise to the level of severity required by SSA but collectively may do so. The concept of functional equivalence used by SSA in some disabil- ity determinations in children is particularly well suited to evaluating the combined effects on an applicant’s functioning of the many and varied im- pairments that often manifest in HDCTs and other multisystem disorders. FINDINGS AND CONCLUSIONS Findings 5-1. The number, type, and severity of the physical and mental secondary impairments experienced by an individual with a heritable disorder of connective tissue (HDCT) drive the person’s functioning and potential disability. 5-2. Environmental factors (e.g., temperature extremes, noise, vibration, atmospheric conditions, inhaled or skin irritants) can have signifi- cant adverse effects on function for some individuals with HDCTs.

EFFECTS ON FUNCTION 159 5-3. Both physical and mental conditions can precipitate or exacerbate decrements in physical and mental functioning in individuals with HDCTs. 5-4. Chronic pain, chronic fatigue, and mild cognitive impairment are some of the most common and potentially disabling manifestations of the Ehlers-Danlos syndromes (EDS), especially hypermobile EDS (hEDS), hypermobility spectrum disorders (HSD), and Marfan syn- drome (MFS). 5-5. A complex relationship exists among pain, fatigue, postural ortho- static tachycardia syndrome, and mast cell activation disease. 5-6. Pain can interfere with all types of physical activities that may be entailed in work or school, including sedentary activities. Pain also has an effect on cognitive functioning. 5-7. Fatigue associated with EDS/HSD and MFS can result in a number of physical and mental functional impairments that affect daily activities, including participation in work and physical activities. 5-8. Mild cognitive impairment can adversely affect participation in school, work, and social activities. 5-9. A challenge in assessment of functioning is capturing the full ef- fect of individuals’ impairments on their daily activities, including at work and in school. This is particularly true when a person has multiple impairments. 5-10. Numerous validated performance-based and self-reported measures are available for assessing physical and mental functioning, includ- ing several that can be used to perform an integrated assessment of an individual’s overall physical and mental functioning. 5-11. Performance of a specific physical activity rarely if ever occurs in- dependently of other physical activities. 5-12. Performance at work and in school, where physical, cognitive, and emotional stressors are often greater than in the testing environ- ment, may be affected in ways not observed during testing. 5-13. Physical activity guidelines and restrictions for individuals with HDCTs need to be tailored to the specific person. 5-14. General physical activity guidelines exist for people with MFS and related disorders, such as avoidance of intense isometric exercise, contact sports that can lead to blows to the head, activities that involve rapid acceleration and deceleration over short distances (sprinting) or rapid changes in pressure (e.g., scuba diving), and exercise to the point of exhaustion. 5-15. Depending on a person’s underlying impairment(s), assistive tech- nologies and relevant accommodations can improve physical and mental functioning in some cases.

160 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 5-16. Some of the listings in SSA’s Listing of Impairments—Adult Listings include severity criteria for some of the secondary impairments that may be experienced by individuals with HDCTs such as MFS, EDS, and related disorders. 5-17. Individuals with HDCTs may experience significant variability in their physical and/or mental secondary impairments from day to day or even within a single day. This variability is often unpredict- able and may limit the ability to sustain gainful employment. Conclusions 5-1. Given that individuals with HDCTs typically experience physical and mental secondary impairments in multiple body systems, it is important to assess the collective effect of all their physical and mental impairments on their ability to function in daily life, includ- ing at work and in school. 5-2. Accurately assessing the full effect of an individual’s impairment(s) is especially important for SSA disability determinations. This is particularly true when a person has multiple impairments that in- dividually do not rise to the level of severity required by SSA but collectively may do so. The concept of functional equivalence used by SSA in some disability determinations in children is particularly well suited to evaluating the combined effects on an applicant’s functioning of the many and varied impairments that often manifest in HDCTs and other multisystem disorders. 5-3. Because of the importance of matching an individual’s functional ca- pacities to specific job requirements, functional capacity evaluation or specific function testing, performed by a trained clinician and directed at an individual’s ability to perform the activities of inter- est, is suggested to provide information about the person’s ability to sustain those activities for the length of time required to perform a specific job or participate in classroom or other activities. 5-4. When extrapolating from the testing environment to the workplace or school, it is important to take into account specific environ- mental conditions that can affect the individual’s symptoms and functioning. 5-5. Some of SSA’s Listing of Impairments—Adult Listings apply directly to secondary impairments experienced by individuals with HDCT syndromes and could be used to evaluate disability in those indi- viduals. Other listings, with some modification, could apply to in- dividuals with certain secondary impairments associated with their HDCTs.

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EFFECTS ON FUNCTION 195 ANNEX TABLE 5-1 Levels of Work Based on Physical Exertion Requirements Level of Work Definition Sedentary Sedentary work involves “lifting no more than 10 pounds at a time and occasionally lifting or carrying articles like docket files, ledgers, and small tools” (SSA, n.d.-e). Although a sedentary job is defined as one that involves sitting, a certain amount of walking and standing is often necessary in carrying out job duties. Jobs are sedentary if walking and standing are required occasionally and other sedentary criteria are met. By its very nature, work performed primarily in a seated position entails no significant stooping. Most unskilled sedentary jobs require good use of the hands and fingers for repetitive hand-finger actions. “Occasionally” means occurring from very little up to one-third of the time. Since being on one’s feet is required “occasionally” at the sedentary level of exertion, periods of standing or walking should generally total no more than about 2 hours of an 8-hour workday, and sitting should generally total approximately 6 hours of an 8-hour workday. Work processes in specific jobs will dictate how often and how long a person will need to be on his or her feet to obtain or return small articles. (SSA, n.d.-e; see also CFR § 416.967) Light Light work involves lifting no more than 20 pounds at a time with frequent lifting or carrying of objects weighing up to 10 pounds. Even though the weight lifted in a particular light job may be very little, a job is in this category when it requires a good deal of walking or standing— the primary difference between sedentary and most light jobs. A job is also in this category when it involves sitting most of the time but with some pushing and pulling of arm-hand or leg-foot controls, which require greater exertion than in sedentary work; e.g., mattress sewing machine operator, motor-grader operator, and road-roller operator (skilled and semiskilled jobs in these particular instances). Relatively few unskilled light jobs are performed in a seated position. “Frequent” means occurring from one-third to two-thirds of the time. Since frequent lifting or carrying requires being on one’s feet up to two-thirds of a workday, the full range of light work requires standing or walking, off and on, for a total of approximately 6 hours of an 8-hour workday. Sitting may occur intermittently during the remaining time. The lifting requirement for the majority of light jobs can be accomplished with occasional, rather than frequent, stooping. Many unskilled light jobs are performed primarily in one location, with the ability to stand being more critical than the ability to walk. They require use of arms and hands to graspcontinued and to hold and turn objects, and they generally do not require use of the fingers for fine activities to the extent required in much sedentary work. (SSA, n.d.-e; see also CFR § 416.967) continued

196 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE ANNEX TABLE 5-1 Continued Level of Work Definition Medium Medium work involves lifting no more than 50 pounds at a time with frequent lifting or carrying of objects weighing up to 25 pounds. A full range of medium work requires standing or walking, off and on, for a total of approximately 6 hours in an 8-hour workday in order to meet the requirements of frequent lifting or carrying objects weighing up to 25 pounds. As in light work, sitting may occur intermittently during the remaining time. Use of the arms and hands is necessary to grasp, hold, and turn objects, as opposed to the finer activities in much sedentary work, which require precision use of the fingers as well as use of the hands and arms. The considerable lifting required for the full range of medium work usually requires frequent bending-stooping. (Stooping is a type of bending in which a person bends his or her body downward and forward by bending the spine at the waist.) Flexibility of the knees as well as the torso is important for this activity. (Crouching is bending both the legs and spine in order to bend the body downward and forward.) However, there are relatively few occupations in the national economy which require exertion in terms of weights that must be lifted at time (or involve equivalent exertion in pushing and pulling), but are performed primarily in a sitting position, e.g., taxi driver, bus driver, and tank-truck driver (semi- skilled jobs). In most medium jobs, being on one’s feet for most of the workday is critical. Being able to do frequent lifting or carrying of objects weighing up to 25 pounds is often more critical than being able to lift up to 50 pounds at a time. (SSA, n.d.-e; see also CFR § 416.967) Heavy “Heavy work involves lifting no more than 100 pounds at a time with frequent lifting or carrying of objects weighing up to 50 pounds” (CFR § 416.967). Very heavy “Very heavy work involves lifting objects weighing more than 100 pounds at a time with frequent lifting or carrying of objects weighing 50 pounds or more” (CFR § 416.967). SOURCES: SSA, n.d.-e; CFR § 416.967.

EFFECTS ON FUNCTION 197 ANNEX TABLE 5-2 Physical Activities; Vision, Hearing, and Speech; and Mental Activities Activity Definition Physical Activities Sitting For the purpose of collecting occupational data, the U.S. Bureau of Labor Statistics considers sitting to be present when any of the following conditions exists: • Workers remain in a seated position. This includes active sitting. For example, bicyclists sit but push/pull with their feet/legs. • Workers are lying down. This includes active lying down. For example, a mechanic lying on a dolly working underneath a vehicle is sitting. • Workers may choose between sitting and standing for a given task. For example, office workers can choose a standing desk. (BLS, 2020, p. 112) From a functional perspective, however, sitting as a physical activity involves resting one’s lower body (buttocks) on a seat or the ground, while maintaining one’s upper body (torso, neck, head) in an upright position. In addition to strong neck, shoulder, and core muscles, sitting requires balance and good proprioception. Although lying on a raised surface (e.g., a bed) may be grouped with sitting, sitting is distinct from lying down on the ground (e.g., lying on a dolly underneath a vehicle), which this report groups under low work. Standing For the purpose of collecting occupational data, the Occupational Requirements Survey distinguishes only between sitting (as defined previously) and standing/walking defined as “whenever workers are not sitting or lying down,” including “time spent stooping, crawling, kneeling, crouching, or climbing” (BLS, 2020, p. 112). In other words, “a worker is always either sitting or standing/walking” (BLS, 2020, p. 112). From a functional perspective, standing is distinct from walking, which in turn is distinct from low work (stooping, crawling, kneeling, crouching), or climbing. For the purpose of this report, standing is defined as being “in an upright position with all of [one’s] weight on [one’s] feet” (Stand, n.d.). Walking Moving along on foot or advancing by steps, with one foot always on the ground. Distance (long or short) and surface type (uneven, rough) can affect an individual’s ability to walk. Strenuous Strenuous physical activity captures activities that require exertion and physical activity stamina—for example, running, jumping, swimming, throwing, catching, and the like. It potentially includes all other physical activities, in addition to running and other impact activities. Lifting (floor Use of upper and/or lower extremities to raise or lower an object from to waist and one level to another, including upward pulling (BLS, 2020, p. 118). overhead) Carrying “Transporting an object, usually by holding it in the hands or arms, or wearing it on the body, usually around the waist or upper torso” (BLS, 2020, p. 118). Carrying usually also requires the ability to stand, lift, and walk. continued

198 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE ANNEX TABLE 5-2 Continued Activity Definition Pushing/pulling Use of upper and/or lower extremities to exert force upon an object so that the object moves away from or toward the origin of the force (BLS, 2020, p. 125). Reaching “Extending the hand(s) and arm(s) in any direction, requiring the straightening and extending of the arm(s) and elbow(s) and the engagement of the shoulder(s)” (BLS, 2020, p. 130). Reaching may require standing. Overhead Extending the arm(s) with the hand(s) higher than the head and (1) reaching the elbow is bent and the angle at the shoulders is about 90 degrees or more or (2) the elbow is extended and the angle at the shoulder is about 120 degrees or more (BLS, 2020, p. 130). Overhead reaching requires neck extension and may require standing. At/below Reaching that does not meet the threshold for overhead reaching the shoulder described above (BLS, 2020, p. 130). reaching At/below the shoulder reaching may require standing. Gross Gross manipulation involves “seizing, holding, grasping, turning, or manipulation otherwise working with the hand(s). Fingers are involved only to the extent that they are an extension of the hand to hold or operate an object or tool, such as hammer” (BLS, 2020, p. 187). It includes handling of large objects. Fine Fine manipulation involves “touching, picking, pinching, or otherwise manipulation working primarily with fingers rather than with the whole hand or arm” (BLS, 2020, p. 133). It includes writing, typing, or handling small objects (fingering). Foot/leg Refers to the “use of one or both feet or legs to move controls on controls machinery or equipment. Controls include, but are not limited to, pedals, buttons, levers, and cranks” (BLS, 2020, p. 133). Climbing “The act of ascending or descending stairs, ramps, ladders, ropes or scaffolding and similar structures using feet, legs, hands, and/or arms” (BLS, 2020, p. 142).

EFFECTS ON FUNCTION 199 ANNEX TABLE 5-2 Continued Activity Definition Low work Low work is a group of activities that includes stooping, crouching, kneeling, crawling, and lying on the ground. Stooping is the act of “bending the body forward and down while bending the spine at the waist 45 degrees or more either over something below waist level or down towards an object on or near the ground” (BLS, 2020, p. 193). Must be performed standing. Crouching is “bending the body downward and forward by bending the legs and spine” (BLS, 2020, p. 138). Kneeling is “bending the legs at the knees to come to rest on the knee or knees” (BLS, 2020, p. 139). Crawling is “moving about on hands and knees or hands and feet” (BLS, 2020, p. 139). Lying on the ground includes the need to get down and up from the ground (e.g., lying down on a trolley on the ground). Clustering the low work activities is appropriate because one generally has to be able to stoop, crouch, and kneel to be able to crawl. There might be an occasion when someone only has to kneel momentarily (e.g., to lift a child) that might be less difficult for some people, but most of the difficulties are shared among these activities. From a functional perspective, lying on the ground has more in common with other low work activities in that it includes the need to get up and down from the ground and potentially squirming around to do work while on the ground. These are difficult tasks that are equivalent to the other low work activities. Vision, Hearing, and Speaking Activities Near visual “Clarity of vision at approximately 20 inches or less, as when working acuity with small objects or reading small print” (BLS, 2020, p. 154), including the use of a computer in support of a critical job function, regardless of distance. Far visual acuity “Clarity of vision at a distance of 20 feet or more, involving the ability to distinguish features of a person or objects at a distance” (BLS, 2020, p. 154). Peripheral “What is seen above, below, to the left or right by the eye while staring vision straight ahead” (BLS, 2020, p. 154). Hearing “Ability to hear, understand, and distinguish speech and/or other sounds” (BLS, 2020, p. 149). Includes hearing in-person one-on-one and group or conference communication; telephones and similar devices, such as radios, walkie-talkies, intercoms, and public address systems; and other such sounds as machinery alarms and equipment sounds. Passing a hearing test may be required for certain jobs. continued

200 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE ANNEX TABLE 5-2 Continued Activity Definition Speaking “Expressing or exchanging ideas by means of the spoken word to impart oral information to clients or the public and to convey detailed spoken instructions to other workers accurately, loudly, or quickly” (BLS, 2020, p. 149). Mental Activities Understand, The abilities to learn, recall, and use (apply) information (SSA, n.d.-c, remember, n.d.-d). and apply information Concentrate, The abilities to focus attention on work/school activities and stay on persist, or task at a sustained rate (SSA, n.d.-c, n.d.-d). maintain pace Problem solve “Analyze issues and make decisions that have a moderate to significant level of difficulty (e.g., the full extent of issues may not be readily apparent and requires independent judgment and research or investigation). The defining characteristics of problem solving are that there is no obvious, immediate solution to a problem or issue, and the worker must identify and weigh alternatives to arrive at a solution” (BLS, 2020, p. 99). Interact with The abilities to relate to and work with supervisors, coworkers, the others public, teachers, peers, and others—for example, cooperating with others; asking for help when needed; handling conflicts with others; stating [one’s] point of view; initiating or sustaining conversation; understanding and responding to social cues (physical, verbal, emotional); responding to requests, suggestions, criticism, correction, and challenges; and keeping social interactions free of excessive irritability, sensitivity, argumentativeness, or suspiciousness. (SSA, n.d.-c; see also SSA, n.d.-d) Adapt or The abilities to “regulate emotions, control behavior, and maintain well- manage oneself being” in a work or school setting—for example, responding to demands; adapting to changes; managing [one’s] psychologically based symptoms; distinguishing between acceptable and unacceptable work performance; setting realistic goals; making plans for [oneself] independently of others; maintaining personal hygiene and [appropriate attire]; and being aware of normal hazards and taking appropriate precautions. (SSA, n.d.-c; see also SSA, n.d.-d) SOURCES: BLS, 2020; SSA, n.d.-c, n.d.-d.

ANNEX TABLE 5-3 Selected Musculoskeletal Manifestations Associated with Heritable Disorders of Connective Tissue HDCTs Manifestations (Selected) Common Diagnostic Techniques Potential Treatments Subluxations and Patella • Hypermobile • Physical exam • Physical therapya dislocations EDS (hEDS)/ • X-ray for dislocation and risk • Self-administered interventionsb HSD factors; imaging might not • Medications (oral and topical) • EDS (many detect subluxation • Surgical intervention other • Advanced imaging (e.g., MRI, • Orthoses (e.g., braces, splints), subtypes) CT) assistive devices (e.g., crutches, • MFS wheelchair); custom orthoses may be important • Environmental modifications Shoulder • hEDS/HSD • Physical exam • Physical therapya • Classical • X-ray for dislocation; imaging • Self-administered interventionsb EDS (cEDS) might not detect subluxation • Occupational therapyc • MFS • Advanced imaging • Medications (oral and topical) • Surgical intervention • Orthoses, compression clothing • Environmental modifications Hip • hEDS/HSD • Physical exam • Physical therapya • MFS • X-ray for dislocation; imaging • Self-administered interventionsb might not detect subluxation • Medications (oral and topical) • Advanced imaging • Compression clothing, assistive devices (e.g., crutches, wheelchair); less often orthoses • Surgical intervention • Environmental modifications continued 201

ANNEX TABLE 5-3 Continued 202 HDCTs Manifestations (Selected) Common Diagnostic Techniques Potential Treatments Ankle/subtalar joint • HSD • Physical exam • Medications (oral) • EDS (all • X-ray • Physical therapya types) • Advanced imaging • Self-administered interventionsb • MFS • Orthoses, assistive devices • Surgical intervention • Environmental modifications Temporomandibular • hEDS/HSD • Physical exam • Liquid diet joint (TMJ) • EDS (many • Advanced imaging • Physical therapya other • Self-administered interventionsb subtypes) • Speech therapy • Surgical intervention • Medications (oral, topical, injected) • Dental appliance • Psychological support for pain or stress management; cognitive behavioral therapy (CBT) training for patients • Botox injections (muscles of mastication; use extreme caution if injecting cervical muscles due to likelihood of cervical instability)

Rib • hEDS/HSD • Physical exam (Imaging • Physical therapya • EDS (other often cannot pick up subtle • Self-administered interventionsb subtypes) malalignments.) • Medications (oral and topical) • Orthoses, straps, compression garments, etc. • Breathing arts, such as yoga, tai chi, Pilates • Environmental modifications Other common joints • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Self-administered interventionsb subtypes) • Occupational therapyc • Orthoses, compression clothing, assistive devices • Environmental modifications continued 203

ANNEX TABLE 5-3 Continued 204 HDCTs Manifestations (Selected) Common Diagnostic Techniques Potential Treatments Instability Cervical • HSD • Gentle cervical traction for • Physical therapya (Mechanical • EDS (all diagnostic purposes only cervical traction may be used for types) • Physical exam for ligamentous diagnostic purposes, but there is a • LDS laxity (e.g., Sharp-Purser, alar precaution/contraindication in its ligament, Aspinall, etc.) use for treatment.) • Physical exam for cervical • Self-administered interventionsb myelopathy (e.g., Hoffmann, • Medications (oral and topical); Babinski, grip-release tests) topicals for trigger points • Testing should also address • Pilates contributing factors, such • Speech therapy (for swallowing as weakness or poor motor disorders) control of deep neck flexors • Rigid cervical stabilization braces (craniocervical flexion test with • Surgical intervention pressure biofeedback) and • Environmental modifications proprioceptive deficits (joint • Occupational therapyc position error with laser). Lumbar and sacroiliac • HSD • Physical exam • Mechanical lumbar traction is a • EDS (all • Testing should also address precaution/contraindication, even if types) contributing factors, such as radicular signs are present. weakness or poor motor control • Self-administered interventionsb of stabilizing muscles. • Pilates, tai chi, some forms of yoga • Orthoses, compression clothing, etc. • Surgical intervention • Medications (oral and topical) • Environmental modifications • Occupational therapyc

Costochondritis • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Other tests to rule out other • Self-administered interventionsb subtypes) conditions • Medications (oral, topical, injectable) • Orthoses, compression clothing, etc. • Environmental modifications • Occupational therapyc Hand/finger instability • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Self-administered interventionsb subtypes) • Occupational therapyc • Environmental modifications • Orthoses, splints, compression clothing, etc. • Medications (oral and topical) Pain Joint pain • hEDS/HSD • Physical exam • Medications (oral, topical, • EDS (other • Advanced imaging injectable) subtypes) • Evaluation for presence of • Physical therapya • MFS immune-mediated arthropathy • Self-administered interventionsb (see Annex Table 5-7 • Occupational therapyc [immunologic table]) • Orthoses, splints, compression clothing, assistive devices, etc. • Environmental modifications continued 205

ANNEX TABLE 5-3 Continued 206 HDCTs Manifestations (Selected) Common Diagnostic Techniques Potential Treatments Chronic pain syndrome • All • Physical exam • Physical therapya • Self-administered interventionsb • Occupational therapyc • Mind–body arts, such as yoga, Pilates, tai chi • Psychological support for pain management; CBT training for patients • Mast cell activation disease (MCAD) management • Postural orthostatic tachycardia syndrome (POTS) management • Orthoses, compression clothing, etc. Spinal pain (including, • hEDS/HSD • Physical exam • Medications (oral, topical, but not limited to, • EDS (other • Advanced imaging injectable) instability, muscle subtypes) • Evaluation for neurological • Physical therapya spasm, nerve • MFS complications • Self-administered interventionsb compression, facet • Occupational therapyc joint syndromes) • Orthoses, braces, compression clothing, assistive devices, etc. • Environmental modifications

Headache • hEDS/HSD • Physical exam (looking for • Physical therapya; precaution with • EDS (other contributing factors, as well as mechanical traction, especially subtypes) pain generators) when cervical instability present, • Advanced imaging only if though traction may be used for suspicion of serious spinal diagnostic purposes pathology is present • Self-administered interventionsb • Medications (oral, topical, injectable) • Neck braces if neck is unstable • Botox injections (Use caution when injecting muscles providing stability, especially in the neck. Those who are not knowledgeable about EDS should avoid doing Botox injections into cervical muscles in EDS.) Tendon and Tendon abnormalities • hEDS/HSD • Physical exam • Physical therapya ligament • EDS (other • Advanced imaging • Self-administered interventionsb disorders subtypes) • Orthoses, compression clothing, etc. • Occupational therapyc • Medications (oral and topical) Plantar fasciitis • All • Physical exam • Physical therapya • Advanced imaging • Self-administered interventionsb • Orthoses, compression clothing, etc; custom orthoses may be important continued 207

ANNEX TABLE 5-3 Continued 208 HDCTs Manifestations (Selected) Common Diagnostic Techniques Potential Treatments Cartilage Meniscus tears • All • Advanced imaging • Physical therapya disorders • CT arthrogram • Self-administered interventionsb • Physical exam • Orthoses, compression clothing, etc. • Surgical intervention Hip labrum tears, • All • Advanced imaging • Physical therapya “snapping hip • CT arthrogram • Self-administered interventionsb syndrome,” hip • Physical exam • Surgical intervention impingement • Orthoses, compression clothing, assistive devices, mobility devices Shoulder labrum tears • hEDS/HSD • Advanced imaging • Physical therapya • EDS (other • CT arthrogram • Self-administered interventionsb subtypes) • Physical exam • Surgical intervention • Orthoses, compression clothing, etc. Triangular • hEDS/HSD • Physical exam • Physical therapya fibrocartilage complex • EDS (other • Advanced imaging • Self-administered interventionsb subtypes) • Occupational therapyc • Orthoses

Myofascial Muscle spasms/trigger • hEDS/HSD • Physical exam • Physical therapya disorders points • EDS (other • Self-administered interventionsb subtypes) • Occupational therapyc • Massage therapy • Movement art, such as Pilates, yoga, tai chi • Orthoses, splints, compression clothing, etc. • Botox injections (Use caution when injecting muscles providing stability, especially in the neck. Those who are not knowledgeable about EDS should avoid doing Botox injections into cervical muscles in EDS.) Myofascial restriction • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Self-administered interventionsb subtypes) • Massage therapy • Orthoses, compression clothing, etc. • Movement art, such as yoga, tai chi, qigong TMJ myofascial pain • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Self-administered interventionsb subtypes) • Dental appliance • Speech therapy • Psychological support for pain management Chronic pelvic pain • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Internal EMG • Self-administered interventionsb subtypes) • Advanced imaging • Orthoses, compression clothing, • Advanced diagnostic testing etc. • Psychological support continued 209

ANNEX TABLE 5-3 Continued 210 HDCTs Manifestations (Selected) Common Diagnostic Techniques Potential Treatments Nerve Thoracic outlet • hEDS/HSD • Physical exam • Physical therapya compression syndrome • EDS (other • X-ray (1st rib) • Self-administered interventionsb disorders subtypes) • Arteriogram • Medications (oral and topical) • Electrodiagnostic testing • Movement arts that involve diaphragmatic breathing: yoga, tai chi, qigong • Surgical intervention Carpal tunnel • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Electrodiagnostic testing • Self-administered interventionsb subtypes) • Occupational therapyc • Medications (oral and topical) • Orthoses, compression clothing, etc. • Surgical intervention Cubital tunnel • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Electrodiagnostic testing • Self-administered interventionsb subtypes) • Occupational therapyc • Orthoses, compression clothing, etc. • Medications (oral and topical) • Surgical intervention Sciatica • hEDS/HSD • Physical exam • Physical therapya • EDS (other • Electrodiagnostic testing • Self-administered interventionsb subtypes) • Advanced imaging to rule out • Medications (oral) spinal source • Orthoses, compression clothing, etc.

Morton’s neuroma • MFS • Physical exam • Orthoses; custom orthoses may be • hEDS/HSD • Advanced imaging important • LDS • Physical therapya • Self-administered interventionsb • Medications (oral) • Injections • Surgical intervention Scoliosis • MFS • Physical exam • Physical therapya • LDS • Advanced imaging • Bracing • CCA • Surgical intervention Joint • MFS • Physical exam • Physical therapya contractures • CCA • Occupational therapyc • Botox injections • Bracing • Surgical release NOTES: CCA = congenital contractural arachnodactyly; CT = computed tomography; EDS = Ehlers-Danlos syndromes; EMG = electromyogram; HDCT = heritable disorder of connective tissue; HSD = hypermobility spectrum disorders; LDS = Loeys-Dietz syndrome; MFS = Marfan syndrome. aPhysical therapy includes, but is not limited to, the following interventions: • Education about posture, body mechanics, ergonomics, joint protection, trigger point management, pain self-management (pain neuroscience, physiological quiet- ing, biofeedback, self-care), POTS self-care, MCAS self-care • Neuromuscular reeducation: proprioception, motor control, stabilization, balance; may include forms of movement biofeedback; also includes breathing retraining • Exercise, including range of motion, strengthening, muscle/fascia stretching, cardiovascular exercise; includes named exercise approaches, such as Pilates, tai chi, and yoga, if instructed by someone knowledgeable about EDS; also includes POTS-specific prescribed exercise • Recommending, training, and/or fitting for braces, splints, orthotics, assistive devices, taping, compression clothing • Gait training with or without assistive devices, particularly for lumbar and lower extremity conditions • Physical modalities should not be the core of clinic management but may be helpful to permit active interventions. Modalities include heat/ice, transcutaneous electric nerve stimulation, with less evidence for ultrasound, laser, infrared, and shock wave. Cervical and lumbar traction are a precaution in hypermobility, so should only be used with caution. 211

ANNEX TABLE 5-3 Continued 212 • In addition to physical therapy, manual therapy approaches may be performed by a variety of professionals and include, but are not limited to, massage, soft-tissue mobilization, myofascial release, joint mobilizations (mobilizations are a precaution, and manipulations are contraindicated except by experts in manual therapy for EDS), acupuncture, dry needling, and other named manual therapy approaches (e.g., “Mobilization with Movement,” “Visceral Mobilization,” or “Strain Counter- strain”; many other terms are used). bSelf-administered interventions with guidance from a health care provider include, but are not limited to, the following interventions: • Posture, joint protection principles, ergonomic modifications • Exercise (including all types that could be recommended/instructed by a physical therapist, occupational therapist, or other qualified health care provider, including Pilates, tai chi, qigong, some forms of yoga, and breathing exercises) • Physical modalities, such as ice, heat, transcutaneous electric nerve stimulation (TENS). • Over-the-counter topicals (e.g., diclofenac cream, lidocaine spray, menthol spray/cream, salicylate, CBD, capsaicin) and oral analgesics (e.g., acetaminophen, ibuprofen). • Using splints, braces, orthoses, compression clothing, assistive devices, taping, etc. • Self-management of trigger points through exercise, self-manual therapy, topicals, etc. • Pain self-management using principles of pain neuroscience, physiological quieting, biofeedback, pacing cOccupational therapy includes, but is not limited to, the following interventions: • Adapting of person, tasks, and environment to increase function and decrease pain • Education about posture, body mechanics, ergonomics, joint protection, trigger point management, pain self-management (pain neuroscience, physiological quiet- ing, biofeedback, self-care) • Neuromuscular reeducation: proprioception, motor control, stabilization, including breathing retraining and, possibly, forms of movement biofeedback • Exercise: including range of motion, strengthening, muscle/fascia stretching, cardiovascular exercise • Recommending, training, fabrication, and/or fitting for braces, splints, assistive devices, taping, compression clothing • Manual therapy: massage, soft-tissue mobilization, myofascial release, joint mobilizations/manipulations (manipulations and, to a lesser degree, mobilizations are a precaution), dry needling (where allowed), and other named manual therapy approaches (e.g., “Mobilization with Movement,” or “Strain Counterstrain”; many terms are used) • Physical modalities should not be the core of clinical management, but may be helpful to permit active interventions. These modalities include heat/ice and transcu- taneous electroneural stimulation, with less evidence for ultrasound, laser, infrared, and shock wave. • Cognitive retraining • Work retraining SOURCES: Barrett et al., 2021; Bier et al., 2018; Blanpied et al., 2017; Butts et al., 2017; Carpal tunnel syndrome, 2019; Celletti et al., 2021; Clinical guidance to optimize work participation after injury or illness, 2021; Daley et al., 2021; De Baets et al., 2021; Enseki et al., 2014; Erickson et al., 2019; Exercise for knee injury prevention, 2018; Finucane et al., 2020; George et al., 2021; JOSPT infographic, 2021; Kareha et al., 2021; Knee ligament sprain guidelines, 2017; Lin et al., 2020; Logerstedt et al., 2017; Logerstedt et al., 2018; Martin et al., 2021; Minhas, 2021; Oliveira et al., 2018a; Palmer et al., 2021; Physical therapy after an ankle sprain, 2021; Price et al., 2020; Reischl et al., 2020; Reychler et al., 2021; Røe, 2014; Steinberg et al., 2021; van Rossom et al., 2018; Wallis et al., 2021; Willy et al., 2019.

ANNEX TABLE 5-4 Selected Neurologic Manifestations Associated with Heritable Disorders of Connective Tissue HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments Cranial disorders Migraines • hEDS/HSD • Clinical • Medications • EDS (other • Evaluation for postural • Environmental modifications subtypes, orthostatic tachycardia (e.g., avoid known triggers, unspecified) syndrome (POTS) and such as foods, smoke, smells, • MFS mast cell activation stress) • LDS disease • Physical therapy • Occupational therapy • Psychological support for pain management; cognitive behavioral therapy training Empty sella turcica • EDS (subtypes • Advanced imaging • Medications syndrome unspecified) Delayed cognitive • EDS (subtypes • Clinical • Occupational therapy development unspecified) Craniosynostosis • EDS (subtypes • Advanced imaging • Surgical intervention unspecified) Intracranial venous • EDS (subtypes • Advanced imaging • Surgical intervention stenosis unspecified) Eagle syndrome • hEDS/HSD • Advanced imaging • Surgical intervention • EDS (other • Clinical subtypes unspecified 213 continued

ANNEX TABLE 5-4 Continued 214 HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments Intracranial pressure Intracranial • hEDS/HSD • Advanced imaging • Medications changes hypertension • EDS (other • Intracranial pressure • Physical therapy subtypes monitoring • Occupational therapy unspecified) • Environmental modifications • MFS • Surgical intervention • LDS Intracranial hypotension • Advanced imaging • Medications • Intracranial pressure • Physical therapy monitoring • Occupational therapy • Environmental modifications • Autologous blood patch • Surgical intervention Chiari malformation • hEDS/HSD • MRI (brain, upright • Medications • EDS (other cervical, thoracic spine) • Physical therapy subtypes • Surgical decompression unspecified) • MFS • LDS Spinal disorders Atlanto-occipital • hEDS/HSD • Advanced imaging • Medications instability • EDS (other • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • MFS • Surgical intervention • LDS

Atlanto-axial instability • hEDS/HSD • Advanced imaging • Medications • EDS (other • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • MFS • Surgical intervention • LDS Basilar invagination • EDS (subtypes • Advanced imaging • Medications unspecified) • Physical therapy • MFS • Occupational therapy • LDS • Environmental modifications • Surgical intervention Spontaneous CSF leak • hEDS/HSD • Advanced imaging • Medications • EDS (other • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Vertebral artery torsion • EDS (subtypes • Advanced imaging • Medications unspecified) • Physical therapy • Occupational therapy • Environmental modifications • Surgical intervention Myodural bridges • hEDS/HSD • Advanced imaging • Medications • EDS (other • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Tethered cord syndrome • hEDS/HSD • Advanced imaging • Physical therapy • EDS (other • Surgical intervention subtypes unspecified) continued 215

ANNEX TABLE 5-4 Continued 216 HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments Segmental instability • hEDS/HSD • Advanced imaging • Medications • EDS (other • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Segmental kyphosis • EDS (subtypes • Advanced imaging • Medications unspecified) • Physical therapy • Occupational therapy • Environmental modifications • Surgical intervention Scoliosis • hEDS/HSD • Advanced imaging • Medications • EDS (other • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • MFS • Surgical intervention Tarlov cysts • hEDS/HSD • Advanced imaging • Surgical intervention • EDS (other subtypes unspecified) Dural ectasia • EDS (subtypes • Advanced imaging • Medications unspecified) • Physical therapy • Occupational therapy • Environmental modifications • Surgical intervention

Instability or • EDS (subtypes • Advanced imaging • Medications malformation of the unspecified) • Physical therapy cervical and thoracic • MFS • Occupational therapy spine • LDS • Environmental modifications • Surgical intervention Movement disorders Dystonia • hEDS/HSD • Advanced imaging • Medications • EDS (other • Clinical • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • MFS • LDS Tremor • EDS (subtypes • Advanced imaging • Medications unspecified) • Clinical • Physical therapy • MFS • Occupational therapy • LDS • Environmental modifications Chorea • EDS (subtypes • Advanced imaging • Medications unspecified) • Clinical • Physical therapy • MFS • Occupational therapy • LDS • Environmental modifications Myoclonus • EDS (subtypes • Advanced imaging • Medications unspecified) • Clinical • Physical therapy • MFS • Occupational therapy • LDS • Environmental modifications Tic disorders • EDS (subtypes • Advanced imaging • Medications unspecified) • Clinical • Physical therapy • MFS • Occupational therapy • LDS • Environmental modifications continued 217

ANNEX TABLE 5-4 Continued 218 HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments Neuropathies Compression • hEDS/HSD • Advanced imaging • Medications neuropathy • EDS (other • Clinical • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Overstretch neuropathy • hEDS/HSD • Advanced imaging • Medications • EDS (other • Clinical • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Brachial plexopathy • hEDS/HSD • Advanced imaging • Medications • EDS (other • Clinical • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Common peroneal • hEDS/HSD • Clinical • Surgical intervention neuralgia • EDS (other • Physical therapy subtypes unspecified) Complex regional pain • hEDS/HSD • Clinical • Medications syndrome • EDS (other • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications Axonal polyneuropathy • EDS (subtypes • Clinical • Medications unspecified) • Laboratory testing • Physical therapy • Occupational therapy • Environmental modifications

Small fiber neuropathy • hEDS/HSD • Clinical • Medications • EDS (other • Laboratory testing • Physical therapy subtypes • Skin biopsy • Occupational therapy unspecified) • Environmental modifications Dysautonomia POTS • hEDS/HSD • Clinical • Medications • EDS (other • Laboratory testing • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • MFS • Self-care: diet, compression • LDS garments Hyperadrenergic POTS • hEDS/HSD • Clinical • Medications • EDS (other • Laboratory testing • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • MFS • LDS Neurocardiogenic • hEDS/HSD • Clinical • Medications syncope • EDS (other • Laboratory testing • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • MFS • LDS Multiple system atrophy • hEDS/HSD • Clinical • Medications • EDS (other • Laboratory testing • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • MFS • LDS continued 219

ANNEX TABLE 5-4 Continued 220 HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments Pure autonomic failure • EDS (subtypes • Clinical • Medications unspecified) • Laboratory testing • Physical therapy • MFS • Occupational therapy • LDS • Environmental modifications Autoimmune autonomic • EDS (subtypes • Clinical • Medications ganglionopathy unspecified) • Laboratory testing • Physical therapy • MFS • Occupational therapy • LDS • Environmental modifications Thoracic outlet Neurogenic TOS • hEDS/HSD • Clinical • Medications syndrome (TOS) • EDS (other • Advanced imaging • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Venous TOS • hEDS/HSD • Clinical • Medications • EDS (other • Advanced imaging • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Arterial TOS • hEDS/HSD • Clinical • Medications • EDS (other • Advanced imaging • Physical therapy subtypes • Occupational therapy unspecified) • Environmental modifications • Surgical intervention Anterior cutaneous • hEDS/HSD • Clinical • Surgical intervention nerve entrapment • EDS (other • Diagnostic nerve blocks • Physical therapy syndrome subtypes unspecified)

Mitochondrial • EDS (subtypes • Clinical • Medications dysfunction, unspecified) • Laboratory testing • Physical therapy secondary • Occupational therapy • Environmental modifications NOTE: CSF = cerebrospinal fluid; EDS = Ehlers-Danlos syndrome; HDCT = heritable disorder of connective tissue; hEDS = hypermobile Ehlers-Danlos syndrome; HSD = hypermobility spectrum disorders; LDS = Loeys-Dietz syndrome; MFS = Marfan syndrome. SOURCES: Bozkurt et al., 2018; Bragée et al., 2020; Carvalho et al., 2020; Castori et al., 2015a; Castori and Voermans, 2014; Cazzato et al., 2016; Collins and Orpin, 2021; Corbett et al., 1982; Donkervoort et al., 2015; Ezzeddine et al., 2005; Fu and Levine, 2015, 2018; Galan and Kousseff, 1995; Grabb et al., 1999; Granata et al., 2013; Halko et al., 1995; Henderson et al., 2017; 2019; Jacome, 1999; Klinge, 2015; Levine et al., 2021; Levine and Rigby, 2018; Martin and Neilson, 2014; Milhorat et al., 2007; Papapetropoulos et al., 1981; Pretorius and Butler, 1983; Puledda et al., 2015; Rozen et al., 2006; Rubinstein and Cohen, 1964; Sadler et al., 2020; Savasta et al., 2011; Schievink et al., 1990; 1996; Schoolman and Kepes, 1967; Song et al., 2020; Toprak Celenay and Ozer Kaya, 2017; Vitaliti et al., 2017; Voermans et al., 2010a. 221

ANNEX TABLE 5-5 Selected Cardiovascular and Hematologic Manifestations Associated with Heritable Disorders of Connective Tissue 222 Manifestations HDCTs (Selected) Common Diagnostic Potential Treatments Techniques Ascending aortic aneurysm • MFS • Echocardiogram • Limitations and restrictions • LDS • Advanced imaging • Beta-adrenergic blockade • CCA (e.g., CT, magnetic • Angiotension receptor blockade • SGS (rare) resonance axial • Aortic replacement depending on • Vascular EDS (vEDS) imaging with image diameter and gene mutation • Familial aortopathies reconstruction) Descending aortic • MFS • Advanced imaging • Emergency evaluation in acute situation dissection • LDS • Chest and abdominal imaging at 1 and 3 • vEDS months following dissection, and every 6 months thereafter • Surgery to replace descending aorta when progression of aortic diameter or extent of dissection occurs Ascending aortic dissection • MFS • Advanced imaging • Emergency aortic surgery • LDS • vEDS • Familial aortopathies Aortic regurgitation • MFS • Echocardiogram • Aortic valve replacement based on • LDS severity of regurgitation and left • Familial aortopathies ventricular function  Bicuspid aortic valve • ~1–1.5% in general population, • Echocardiogram • Aortic valve replacement higher in LDS • Surgery to replace a moderately or severely dilated ascending aorta • Surgery to repair aortic coarctation

Mitral valve prolapse  • MFS • Echocardiogram • Mitral valve repair or replacement • LDS • Treatment for atrial fibrillation • CCA • EDS (most types) Arterial tortuosity • MFS • Advanced imaging • Regular imaging; frequency depends of • LDS severity of tortuosity and association with arterial dilatation • Arterial surgery in cases of severity and rapid progression of dilatation • Beta-adrenergic blockade, angiotensin receptor blockade, or both Arterial rupture  • vEDS • Emergency surgery Varicose veins • MFS • Compression sleeve if varicosities are • LDS superficial • EDS (most types) • Vein stripping of superficial varicosities • Anticoagulation if deep veins involved and clots formed Anemia • EDS (many types) • CBC • Iron, B12, and/or folate supplementation • Red cell transfusion continued 223

ANNEX TABLE 5-5 Continued 224 Manifestations HDCTs (Selected) Common Diagnostic Potential Treatments Techniques Excessive bleeding • EDS (many types) • ISTH Bleeding • Iron, B12, and/or folate supplementation associated with minor • MFS (very rare) Assessment Tool • Red cell or platelet transfusion trauma, dental procedures, • CBC • Tranexamic acid surgical interventions, • Platelet function and menstruation, postpartum coagulation tests bleeding, etc. • Factor VIII activity, vWF antigen, and activity assays NOTE: CBC = complete blood count; CCA = congenital contractural arachnodactyly; CT = computed tomography; EDS = Ehlers-Danlos syndromes; HDCT = heritable disor- der of connective tissue; ISTH = International Society on Thrombosis and Haemostasis; LDS = Loeys-Dietz syndrome; MFS = Marfan syndrome; SGS = Shprintzen Goldberg syndrome; vWF = von Willebrand Factor. SOURCES: Beighton, 1969; Castori et al., 2012; D’Hondt et al., 2018; Drera et al., 2011; Gilliam et al., 2020; Jesudas et al., 2019; Kornhuber et al., 2019; Lind and Wallenburg, 2002; Makatsariya et al., 2020; Murray et al., 2014.

ANNEX TABLE 5-6 Selected Respiratory Manifestations Associated with Heritable Disorders of Connective Tissue Manifestations HDCTs (Selected) Common Diagnostic Techniques Potential Treatments Inflammatory Asthma • EDS Objective confirmation of diagnosis • Inhaled medications • Classical EDS • Spirometry with flow-volume loops (corticosteroids, anticholinergic, (cEDS) • Bronchodilator response with beta-agonists) • Hypermobile spirometry using flow-volume (Note: adverse effects of beta- EDS (hEDS)/ loops agonists in MFS are possible; HSD • Challenge testing (methacholine, use caution) • Kyphoscoliotic cold air, exercise) • Environmental restrictions EDS (kEDS) • Exhaled nitric oxide • Treatment of comorbid • MFS Assessment of control disorders: • LDS • Spirometry • Mast cell dysfunction • Patient Reported Outcome (Annex Table 5-7, Measures immunologic table) Asthma phenotype screening • Atopy (see immunologic • Eosinophilia table) • Atopic disease/allergy testing • Eosinophilia (see • Primary immunodeficiency disease immunologic table) (PIDD) Screen • Immunodeficiency (see • Immunodeficiency evaluation immunologic table) Environmental screening • GERD, LPR, (Annex Table • Tobacco product use/exposure 5-8, GI table) • Uncontrolled moisture • Rhinitis • Environmental allergens •­ Sleep disorder Exclusionary testing •­ Obesity • Chest X-ray •­ Tobacco use disorder • Chest CT scan (if severe–persistent • Respiratory rehabilitation for to bronchiectasis) moderate–severe asthma • Rhinolaryngoscopy (if cough or • Breathing arts, such as yoga, tai extrathoracic airflow obstruction chi, Pilates on flow-volume loops) • Evaluation for laryngopharyngeal reflux continued 225

ANNEX TABLE 5-6 Continued 226 Manifestations HDCTs (Selected) Common Diagnostic Techniques Potential Treatments Chronic or • EDS (subtypes • CT of sinuses—evaluation for • Treatment of the underlying recurrent sinusitis unspecified) structural abnormalities, chronic process (e.g., vaccination, • MFS mucosal disease immunoglobulin replacement, • Rhinoscopy allergen immunotherapy, topical • Complete blood count (CBC) and therapies [corticosteroids, differential biologics], sinus surgery) If chronic sinusitis: • Breathing arts, such as yoga, tai • Immune dysfunction evaluation chi, qigong (allergy testing, immunodeficiency • See immunologic table evaluation) • Evaluation for cystic fibrosis and ciliary dykinesias Recurrent • EDS (subtypes • CT sinuses • Treatment of predisposing bronchitis or unspecified) • Rhinoscopy condition (aspiration, pneumonia • CT chest (obstructing lesion— immunodeficiency, obstruction) foreign body, neoplasm), bronchiectasis • Evaluation for GERD/aspiration • Immune dysfunction evaluation • See Annex Table 5-7 (allergy testing, immunodeficiency (immunologic table) evaluation) Bronchiectasis • EDS (subtypes • CT of chest • Mucous mobilization measures unspecified) • Culture for acid-fast and other • Treat predisposing condition • MFS bacteria, and fungi • Cutis laxa • Immunoglobin E test • CBC and differential • Evaluation for cystic fibrosis • Alpha-1-antitrypsin • Immunodeficiency evaluation • Evaluation for GERD/aspiration

Costochondritis • hEDS/HSD • Physical examination • Physical therapy (see Annex • EDS (other • Rib X-rays Table 5-3, musculoskeletal table) subtypes) • Self-administered interventions (see musculoskeletal table) • Medications (oral, topical, injectable) • Orthoses, compression clothing, etc. • Environmental modifications • Occupational therapy (see musculoskeletal table) Functional Obstructive sleep • Arthrochalasia • Polysomnography • Nocturnal continuous positive apnea EDS (aEDS) airway pressure (CPAP) • cEDS • Myofunctional therapy (may be • hEDS/HSD provided by speech therapy) • Vacsular EDS (vEDS) • MFS Central sleep • MFS • Polysomnography • Nocturnal bilevel positive airway apnea pressure (BiPAP) Tracheomalacia • vEDS • Spirometry • CPAP/BiPAP • Chest CT scan with inspiratory and • Surgical repair expiratory maneuvers • Bronchoscopy Reduced • hEDS • Negative inspiratory force • Inspiratory muscle training inspiratory muscle • 6-minute walk distance (6MWD) • Breathing arts: yoga, tai chi, strength qigong Obstructive • MFS • Spirometry, plethysmographic lung • Observation physiology volumes, diffusion capacity • Inhaler therapy • 6MWD Thoracic • MFS • Spirometry • Aggressive conservative and/or Insufficiency • Arterial blood gases surgical intervention Syndrome 227

ANNEX TABLE 5-6 Continued 228 Manifestations HDCTs (Selected) Common Diagnostic Techniques Potential Treatments Structural, lung Spontaneous • vEDS • Chest X-ray • Oxygen pneumothorax • cEDS • Chest CT scan • Tube thoracostomy • Classical-like • Pleurodesis (clEDS) • Pleurectomy • MFS • Avoidance of extremes of • LDS barometric pressure, contact • Cutis Laxa sports, high intensity exercise • BHDS Pulmonary cysts, • vEDS • Chest CT scan • Observation, bullectomy (rarely) blebs, and/or • MFS bullae Hemopneumo- • vEDS • Chest CT scan • Tube thoracostomy thorax, lung • Surgical repair hemorrhage • Bronchial artery embolization Early onset • MFS • Spirometry and plethysmographic • Inhaled medications emphysema • Cutis laxa lung volumes (corticosteroids, anticholinergic, • Diffusion capacity beta agonists) • 6MWD • Intravenous replacement • Chest CT scan therapy (e.g., alpha-proteinase • Alpha-1-antitrypsin level inhibitor) • Environmental restrictions • Treatment of comorbid disorders (e.g., GERD, LPR, rhinitis, sleep disorder, obesity) • Pulmonary rehabilitation Fibrous nodules • vEDS • Chest CT scan • Monitoring to assure stability

Structural, Diaphragm • EDS (subtypes • Chest CT scan • Surgical correction musculoskeletal rupture unspecified) Cervical spine • vEDS • Physical Exam • See Annex Tables 5-3 and instability • EDS (other • Spirometry 5-4 (musculoskeletal and subtypes) • Negative inspiratory force neurological tables) Kyphosis or • kEDS • Spine films • Observation scoliosis • MFS • Chest CT scan • Physical therapy • Spirometry and plethysmographic • Surgical correction lung volumes to assess degree of restriction • If advanced, arterial blood gas Pectus excavatum • cEDS • Spirometry, plethysmographic lung • Observation or carinatum • hEDS volumes to assess for restrictive • Surgical correction • vEDS physiology • Noninvasive ventilation • EDS (other • Comparison of seated and supine • Mechanical ventilation subtypes) forced vital capacity • MFS • Negative inspiratory force (to evaluate diaphragmatic weakness) • 6MWD • Pulse oximetry • Arterial blood gas Rib subluxation • HSD • Physical exam (imaging • Physical therapy (see Annex • EDS (subtypes often cannot pick up subtle Table 5-3, musculoskeletal table) unspecified) malalignments) • Self-administered interventions (see musculoskeletal table) continued 229

ANNEX TABLE 5-6 Continued 230 Manifestations HDCTs (Selected) Common Diagnostic Techniques Potential Treatments Procedural or Increased rates of • MFS • Continuous pulse oximetry • Noninvasive ventilation (e.g., postprocedural respiratory failure BiPAP) complications post–vascular • Mechanical ventilation surgery Hemorrhage • EDS (subtypes • Radiographic imaging • Emergency control of bleeding unspecified) (surgical and nonsurgical management) NOTE: BHDS = Birt-Hogg-Dubé syndrome; CT = computed tomography; EDS = Ehlers-Danlos syndrome; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HSD = hypermobility spectrum disorder; HDCT = heritable disorder of connective tissue; LDS = Loeys-Dietz syndrome; LPR = laryngopharyngeal reflux; MFS = Marfan syndrome. SOURCES: Abishek et al., 2019; American Thoracic Society and European Respiratory Society, 2002; Bascom et al., 2021; Bezerra et al., 2014; Birchall et al., 2021; Boone et al., 2019; Camacho et al., 2015; Chohan et al., 2021; Cloutier et al., 2020; Culver et al., 2017; Global Initiative for Asthma, 2021; Graham et al., 2019; Hakim et al., 2021; Halvorsen et al., 2017; Henderson et al., 2017; Henneberger et al., 2011; Holguin et al., 2020; Holland et al., 2014, 2021; Jayarajan et al., 2020; Khatri et al., 2021; Mott et al., 2021; Oliveira et al., 2018b; Qiu et al., 2021; Reychler et al., 2019; Rosen et al., 2018; Rueda et al., 2020; Schoser et al., 2017; Shusterman et al., 2017; Stachler et al., 2018; Tun et al., 2021.

ANNEX TABLE 5-7 Selected Immunologic Manifestations Associated with Heritable Disorders of Connective Tissue HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments Mast cell activation Skin • Hypermobile • Allergen specific IgE • Avoidance measures for disease (MCAD)— • Atopic dermatitis EDS (hEDS)/ testing suspected foods, medications, single organ • Urticaria HSD • Complete blood count airborne allergens) • Angioedema • EDS (CBC) with differential • Oral medications: antihistamines, (unspecified • Serum IgE total leukotriene antagonists, mast cell subtypes) • Target organ biopsy stabilizers Airway • End organ challenge • For asthmatics: bronchodilators • Rhinitis • Tryptase • Topical medications • Asthma • Urine methylhistamine, • Biologics therapy prostaglandin metabolites • Immunotherapy • Anaphylaxis: epinephrine Gastrointestinal disorders • Allergen-specific IgE • Hypersensitivity/ testing gastroenteritis • Esophagogastroduodenos- • Eosinophilic copy (EGD)/colonoscopy esophagitis/ • Tryptase levels gastroenteritis • Urine methylhistamine, prostaglandin metabolites • Empirical trial of 6- or 8-food elimination diet • Fecal leukocyte stain • Calprotectin Neuropsychiatric • Allergen specific IgE • Allergen avoidance (foods, • Neurocognitive testing medications) disorders • CBC with differential • Oral medications: antihistamines, • Some headache • Serum IgE total leukotriene antagonists), mast disorders • Tryptase cell stabilizers • Mood disorders • Urine methylhistamine, • Biologics therapies in the context of prostaglandin metabolites • Acute episodes: epinephrine general medical • Imaging (head, spinal condition cord) 231 continued

ANNEX TABLE 5-7 Continued 232 HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments Mast cell activation Genitourinary • Tryptase • Oral medications (antihistamines) disease (MCAD)— • Interstitial cystitis • Urine methylhistamine, • Intravesical therapies single organ prostaglandin metabolites • Digital and manometric pelvic floor muscle examination • Cystoscopy MCAD—multiorgan • Systemic • hEDS/HSD • Tryptase • Oral medications: antihistamines, disease mastocytosis • EDS • Allergen specific IgE leukotriene antagonists, mast cell Mast cell activation • Monoclonal mast cell (unspecified testing stabilizers syndrome (MCAS) activation syndrome subtypes) • Urine methylhistamine • Biologics (omalizumab, • Hereditary alpha prostaglandin metabolites dupilumab) tryptasemia • Positive KIT D816V • anti-IgE therapy • Anaphylaxis mutation • Allergen avoidance (medications • Atypical mast cells in such as opioids and, certain bone marrow or another antibiotics and analgesic agents) extracutaneous biopsy • Immunotherapy • Cervical spine instability • Anaphylaxis: epinephrine • Advanced clonal mast cell activation disease: tyrosine kinase inhibitors • Bone disease: osteopenia, bone fractures—bisphosphonates, Interferon alfa-2a

Delayed-type • Skin (atopic or • hEDS/HSD • CBC with differential • Oral medications: hypersensitivity contact dermatitis) • EDS • Elevated blood eosinophil immunosuppressants (DTH) • Eosinophilic lung (unspecified count • Biologics therapy Eosinophilic/T2 disease subtypes) • Eosinophilic cationic • Allergen avoidance inflammation • Eosinophilic protein • Immunotherapy gastrointestinal • Organ specific assessment • Anaphylaxis: epinephrine disease (eosinophilic (e.g., biopsy, urine esophagitis, eosinophils, sputum gastroenteritis) eosinophils) Primary • Severe combined • hEDS/HSD • CBC with differential • Prophylactic antibiotics immunodeficiency immunodeficiency • EDS • Serum, IgG, IgA, IgM • Immunizations (PID)/dysfunction (SCID) (unspecified • IgG subclasses • Supplemental immunoglobulin • Antibody subtypes) • Lymphocyte subset • Monitor for concurrent deficiencies • Peridontal analysis autoimmune/malignant disorders • Complement EDS • Pathogen protection • Curative treatment (HSCT and deficiencies, (pneumococcal gene therapy) mannose binding haemophilus influenza, lectin measles, mumps, rubella, • Neutropenia varicella) • Lymphocytopenia • Complement levels • IPEX syndrome • Genetic testing • Chronic granulomatous disease • Omenn syndrome • Connective tissue (filaggrin deficiency) continued 233

ANNEX TABLE 5-7 Continued 234 HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments Autoinflammatory • 3 cryopyrin- • hEDS/HSD • CBC • Oral immunosuppressants disorders associated periodic • EDS (other • Blood biochemistries • Biologics therapies syndromes types, • Sedimentation rate • Schnitzler syndrome unspecified) • Hepatitis studies • Familial cold • Urinalysis autoinflammatory • Complement studies syndrome • Autoantibody testing • Periodic fever (antinuclear antibody syndromes [ANA], anti–double- • Vascultides stranded DNA, anti-Ro, • X-linked anti-L, anti-Smith, lymphoproliferative ribonuclear protein disease antibody, antineutrophil • 27 and IL-2-inducible cytoplasmic antibody T cell kinase [ANCA], rheumatoid deficiency factor) • Nijmegen breakage • Chest X-ray syndrome • Pulmonary function studies • Defects in nucleic • Screening for cardiac acid disposal involvement • Immuno- osteodysplasias • SAMHD1 deficiency • Aicardi-Goutières syndrome

DTH: Hypersensitivity • hEDS /HSD • Esophagogastroduodenos- • Dietary elimination of suspected Gastrointestinal gastroenteritis (see • EDS copy (EGD) culprit foods disorders above) (unspecified • Colonoscopy • Oral medications (corticosteroids, subtypes) • IgE—Foods, aeroallergens proton pump inhibitors Eosinophilic esophagitis/ (immunoCAP, percutane- • Biologics (anti-IgE) gastroenteritis ous allergen testing) • 6- or 8-food elimination diet • Fecal leukocyte stain • Calprotectin Inflammatory bowel • Biopsy on colonoscopy • Dietary elimination disease (ulcerative • Fecal calprotectin • Oral medications colitis, Crohn’s • Biologics therapies disease) Celiac disease • Blood test • Complete elimination of gluten • Endoscopy from the diet continued 235

ANNEX TABLE 5-7 Continued 236 HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments DTH: Addison’s disease • hEDS/HSD • ACTH, morning cortisol • Mineral corticoid replacement Endocrinopathies • EDS • Advanced imaging and emergency protocol of (unspecified intravenous fluid replacement subtypes) and rescue of 100 mg hydrocortisone Thyroiditis (Hashimoto’s • Serum TSH, T3, T4 • If euthyroid, monitor disease) • Antithyroid • Hypothyroidism: thyroid replacement therapy • Autoimmune • Percutaneous testing to • Desensitization using progesterone progesterone progesterone anaphylaxis • Liver function tests • Oral agents • Asthma • Thyroid function tests • Anaphylaxis treatment: • Urticaria • Urinalysis epinephrine autoinjectors • Dermatitis • RAST for foods and latex • ANA, rheumatoid factor, ESR • Complement studies tryptase • 24-hour urine for histamine DTH: Cutaneous Contact dermatitis • hEDS /HSD • Patch testing • Contact allergen avoidance disorders • EDS • IgE- allergen testing • Oral medications (unspecified • Primary immunodeficiency • Topical agents subtypes) disorders (PIDD) screen • Biologics therapy • Immunodeficiency evaluation

Hereditary angioedema • hEDS /HSD • Complement studies C1- Acute attacks: (swelling): skin, • EDS INH, C4, CH50 • Intravenous C1-esterase inhibitor oropharynx (unspecified replacement subtypes) • Fresh frozen plasma Prophylaxis—long term: • Intravenous, subcutaneous C1- INH concentrate • Androgens • Tranexamic acid continued 237

ANNEX TABLE 5-7 Continued 238 HDCTs Common Diagnostic Manifestations (Selected) Techniques Potential Treatments DTH: Neurological Autoimmune • hEDS/HSD • Sinus questionnaire disorders neuropathies/ • EDS • Asthma screening encephalopathies (unspecified questionnaire subtypes) • Food allergy/intolerance questionnaire • Cervical-spine instability evaluation • Occult tethered cord evaluation • CSF leak • Urodynamics study Chronic immune • Autoantibody serologies demyelinating anti-ribosomal anti- neuropathy endothelial cell, anti- ganglioside, anti-dsDNA, anti-2A/2B subunits of N-methyl-D-aspartate receptors (NMDAR), and anti-phospholipid antibodies Multiple sclerosis • Clinical • Laboratory testing • Lumbar puncture: CSF analysis • Advanced imaging • Electrodiagnostic testing

Postural orthostatic • Clinical • Medications tachycardia • Laboratory testing • Physical therapy syndrome/ • Lean test/tilt table (assess • Occupational therapy neuronal mediated cervical spine) • Environmental modifications hypotension Small fiber neuropathy • Clinical • Medications • Laboratory testing • Physical therapy • Small fiber neuropathy • Occupational therapy symptom inventory • Environmental modifications questionnaire (SFN-SIQ) • Sural sensory nerve action potential (SNAP) amplitude and conduction velocity • Skin biopsy DTH: Arthritides • hEDS/HSD • X-rays of affected joints • Oral medications Musculoskeletal and • Rheumatoid arthritis • EDS • Blood testing: CBC • Diet restriction rheumatological • Sjogren’s syndrome (unspecified with differential, • Biologics disorders • Mixed connective subtypes) complete metabolic tissue disease panel, autoantibodies, • Dermatomyositis/ complement studies ESR, polymyositis CRP • Scleroderma • Atopic and PIDD evaluations • Infection (Epstein-Barr virus, ASO+Dnase, viral hepatitis) continued 239

ANNEX TABLE 5-7 Continued 240 NOTE: ACTH = adrenocorticotropic hormone; CRP = C-reactive protein; CSF = cerebrospinal fluid; EDS = Ehlers-Danlos syndromes; ESR = erythrocyte sedimentation rate; HDCT = heritable disorder of connective tissue; HSCT = hematopoietic stem cell transplantation; HSD = hypermobility spectrum disorder; IPEX = immune dysregulation, polyendocrinopathy, enteropathy, X-linked; RAST = radioallergosorbent test. SOURCES: Abonia et al., 2013; Arkwright and Gennery, 2011; Cazzato et al., 2016; Cheung and Vadas, 2015; Dang et al., 2019; Hamilton, 2018; Hamilton et al., 2021; Khan, 2013; Leganger et al., 2022; Louisias et al., 2013; Luskin et al., 2021; Lyons et al., 2016; Morgan et al., 2007; Shin et al., 2010; Theoharides et al., 2015; Whitmore and Theoha- rides, 2011.

ANNEX TABLE 5-8 Selected Gastrointestinal Manifestations Associated with Heritable Disorders of Connective Tissue Common Diagnostic Manifestations HDCTs (Selected) Techniques Potential Treatments GastrointestinaI (GI) • EDS (unspecified • Upper- and lower-GI • Medication management bleeding subtypes) endoscopy • Surgical intervention • Vascular EDS (vEDS) • Advanced imaging • LDS • Stool test Visceroptosis • EDS (unspecified • Advanced imaging • Surgical intervention subtypes) Intussusception/ • EDS (unspecified • Ultrasound (children) • Surgical intervention volvulus subtypes) • Computed tomography (CT) scan (adults) Diverticulitis • EDS (multiple subtypes) • Advanced imaging • Medical management • vEDS • Colonoscopy • MFS Organ rupture (e.g., • vEDS • Advanced imaging • Surgical intervention bowel, liver, spleen) Median arcuate • EDS (unspecified • Duplex • Surgical intervention ligament syndrome subtypes) ultrasonography • Advanced imaging • Endoscopy continued 241

ANNEX TABLE 5-8 Continued 242 Common Diagnostic Manifestations HDCTs (Selected) Techniques Potential Treatments Superior mesenteric • EDS (unspecified • Duplex • Surgical intervention artery syndrome subtypes) ultrasonography • LDS • Advanced imaging Eventration of the • EDS (unspecified • Diagnostic imaging • Physical therapy diaphragm subtypes) • Pulmonary function • Respiratory rehabilitation testing • Surgical intervention Immune-mediated Irritable bowel • HDS • Clinical • Nutritional consultation GI disorders syndrome • EDS (unspecified • Testing based on • Medication management subtypes) presentation • Physical therapy • MFS • Surgical intervention Gastroparesis • EDS (unspecified • Barium swallow X-ray • Nutritional consultation subtypes) • Barium egg swallow • Medication management • LDS • Radioisotope gastric • Physical therapy emptying scan • Gastric manometry • Wireless motility capsule • Autonomic nervous system testing • Autoimmune testing

Inflammatory bowel • EDS (unspecified • Biopsy by endoscopy • Nutritional consultation diseases: subtypes) • Fecal calprotectin • Medication management • Crohn’s disease • LDS • Stool samples • Physical therapy • Ulcerative colitis • CBC • Surgical intervention • Microscopic colitis • Food allergy testing • Other mucosal inflammatory disorders Celiac disease • EDS (unspecified • Blood test • Nutritional consultation subtypes) • Endoscopy • Medication management • Stool samples • Food allergy testing Eosinophilic • EDS (unspecified • Biopsy • Nutritional consultation gastrointestinal disease subtypes) • Stool samples • Medication management • LDS • CBC • Endoscopic procedures • Food allergy testing NOTE: CBC = complete blood count; EDS = Ehlers-Danlos syndrome; HDCT = heritable disorder of connective tissue; LDS = Loeys-Dietz syndrome; MFS = Marfan syndrome. SOURCES: Brooks et al., 2021; Castori et al., 2015b; de Leeuw et al., 2012; Dordoni et al., 2013; Fikree et al., 2017; Frank et al., 2019; Guerrerio et al., 2016; Hassan et al., 2002; Huynh et al., 2019; Inayet et al., 2018; Iwama et al., 1989; Kahn et al., 1988; Kucera and Sullivan, 2017; Laszkowska et al., 2016; Leganger et al., 2016; Lybil and Genie, 2019; MacCarrick et al., 2014; Malyuk et al., 2022; Nelson et al., 2015a; Reinstein et al., 2012; Suster et al., 1984; Yasuda et al., 2013. 243

ANNEX TABLE 5-9 Selected Cutaneous Manifestations Associated with Heritable Disorders of Connective Tissue 244 Common Diagnostic Manifestations HDCTs (Selected) Techniques Potential Treatments Structural • Poor wound • Classical EDS • Full skin examination—assess • Perform skin closure in healing; failure (cEDS) for hyperextensibility of the two layers (cutaneous and of surgical • Hypermobile EDS skin, wound healing defects, subcutaneous) without excessive wound closure (hEDS) atrophic or abnormal tension • Kyphoscoliotic EDS scarring • Use generous sutures, deep (kEDS) • Beighton scoring scale— stitches, and Steri-Strips as • BCS assess for hypermobility of a reinforcement devices • Musculocontractural joint, in which a score of 5 or • Leave sutures twice as long as (mcEDS) more indicates generalized normally recommended • LDS joint hypermobility • Molecular genetic testing • Skin biopsy • Capillary • vEDS • Clinical • Vitamin C fragility; • cEDS • Protective devices ecchymoses • hEDS • Environmental modification • kEDS • BCS • mcEDS • LDS

Inflammatory Inflammatory • cEDS • Environmental and food • Environmental modification dermatoses • hEDS allergen-specific IgE testing • Topical or systemic Atopic dermatitis • BCS • Eosinophilic cationic protein immunosuppressants • LDS • Skin biopsy • Barrier emollients • Biologics—Dupilumab Urticaria/ • hEDS/HSD • Allergen-specific IgE testing • Conservative management angioedema • cEDS • Serum tryptase, urine • Environmental modification • LDS histamine • Medications (oral and topical) • CBC with differential • Biologics • Serum immunoglobulins • ANA, ESR • CH50, C3+C4, C1-inhibitor • Chronic urticaria panel anti- IgE or anti-FcRe1 IgG continued 245

ANNEX TABLE 5-9 Continued 246 Common Diagnostic Manifestations HDCTs (Selected) Techniques Potential Treatments Neuropathic Complex regional • hEDS/HSD • Clinical • Medications pain syndrome • cEDS • Physical therapy Reflex sympathetic • Occupational therapy dystrophy • Environmental modifications syndrome Erythromelalgia • hEDS/HSD • Photographs of the affected • Topical lidocaine, capsaicin, • Gerhardt • cEDS areas during symptoms diclofenac gel 1%, brimonidine, disease are helpful (e.g., photos and compounded gabapentin • Mitchell disease of red feet or hands ointment 6% • Weir-Mitchell during symptoms—the • Oral therapies include aspirin, disease redness is almost unique gabapentin, amitriptyline, to erythromelalgia when cyproheptadine, pregabalin, associated with the history) diltiazem, and venlafaxine • Exercise or immersion of • Misoprostol an affected region in hot • Systemic glucocorticoids, water for a certain period intravenous gamma globulin (e.g., approximately 10–30 minutes) to provoke a flare so a diagnosis may be made Diaphoresis or • hEDS/HSD • Clinical • Management of underlying hyperhidrosis • cEDS • Sweat test condition • Diagnosis of underlying • Medications (oral, topical, condition injectable) • Environmental modifications • Surgical intervention

NOTE: ANA = antinuclear antibody; BCS = brittle cornea syndrome; EDS = Ehlers-Danlos syndrome; ESR = erythrocyte sedimentation rate; HDCT = heritable disorder of connective tissue; HSD = hypermobility spectrum disorder; LDS = Loeys-Dietz syndrome; MFS=Marfan syndrome. SOURCES: American Academy of Dermatology Association, 2022; Bechara et al., 2007; Castori, 2012; Catala-Pétavy et al., 2009; Kalava et al., 2013; Malfait et al., 2017; Oaklander and Klein, 2013; Tang et al., 2015. 247

ANNEX TABLE 5-10 Selected Genitourinary Manifestations Associated with Heritable Disorders of Connective Tissue 248 Manifestations HDCTs (Selected) Common Diagnostic Techniques Potential Treatments Pelvic floor Stress urinary • MFS • Medical history and physical • Dependent on type of urinary disorders incontinence • Hypermobile exam that may include pelvic and incontinence EDS (hEDS)/ rectal exam • Behavioral training Urge urinary HSD • Urine analysis • Pelvic floor physical therapy (PFPT) incontinence • EDS (other • Urinary stress tests • Medications (i.e., anticholinergics, Urinary retention subtypes) • Urodynamic tests, including mirabegron, alpha blockers, topical and voiding video urodynamics estrogen) dysfunction • Cystoscopy • Electrical stimulation • Medical devices (i.e., pessary) • Interventional therapies (i.e., Botox) • Surgical intervention Urinary problems • Same as above but may also • As above but also includes secondary to include X-rays and advanced catheterization, surgeries that vascular and imaging (e.g., MRI, CT) include urinary diversion, bladder neurologic resection, and sphincter resection complications Pelvic organ • MFS • Medical history and physical • PFPT prolapse (bowel, • LDS examination • Surgical intervention uterus, bladder) • hEDS/HSD • Dynamic MRI • EDS (other • Perineal ultrasound subtypes)

Vulvodynia and • hEDS/HSD • Medical history and physical • PFPT dyspareunia • Classical EDS exam that includes the cotton • Psychological interventions (cEDS) swab test • Medications (antinociceptive • Vascular EDS agents, anti-inflammatory agents, (vEDS) neuromodulating medications, hormonal agents, and muscle relaxants) • Vestibulectomy Chronic pelvic pain • hEDS/HSD • Pelvic exam • Topical medications • vEDS • Ultrasonography • PFPT • cEDS • Advanced imaging • Psychological interventions • Laparoscopy • Oral medications Uterine Menorrhagia • vEDS • Detailed history and physical • Medical management (including disorders • cEDS examination hormonal management as tolerated) • hEDS/HSD • Laboratory investigations • Surgical management • Ultrasonography with instillation of saline solution • Hysteroscopy and biopsy • Advanced imaging Dysmenorrhea • Detailed medical, psychosocial, • Medications (nonsteroidal anti- and gynecologic history inflammatories, hormonal treatments • Physical examination (age as tolerated based on diagnosis) dependent) • Ultrasonography continued 249

ANNEX TABLE 5-10 Continued 250 Manifestations HDCTs (Selected) Common Diagnostic Techniques Potential Treatments Renal Cysts • MFS • Ultrasonography • Management is based on abnormalities • vEDS • Advanced imaging symptomology • Renal cyst aspiration (usually with sclerotherapy) • Laparoscopic decortication Focal • MFS • Laboratory evaluation • Medical management glomerulosclerosis • Renal biopsy Interstitial cystitis • hEDS/HSD • Urine analysis • Diet restrictions • Cystoscopy • Oral agents (histamine blockade, • Immune dysfunction (immune tricyclic agents, prophylactic deficiency—complement, antibiotics) mannose binding lectin) • Intravesical treatments (dimethyl sulfoxide, Botox, bicarbonate- lidocaine-heparin-hydrocortisone) Pregnancy- Preterm delivery/ • hEDS • Pelvic exam • Progesterone prophylaxis (consider) related premature rupture • EDS (other • Transvaginal ultrasound for • Short-term treatment for fetal lung diagnoses of membranes subtypes) cervical length maturity and neurologic protection • Uterine monitoring (steroids, magnesium sulfate, • Fetal fibronectin antibiotics) Cervical • EDS • Pelvic exam • Cerclage insufficiency (unspecified • Transvaginal ultrasonography • Progesterone prophylaxis (consider) subtypes) Aortic root • MFS • Medical and physical examination • Surgical management dissection • LDS • Echocardiogram • vEDS • Arthrochalasia EDS

Uterine rupture • vEDS • Physical examination • Surgical management • EDS (other • Imaging if appropriate subtypes) • LDS Obstetrical • MFS • Physical and laboratory • Medical and surgical management hemorrhage • LDS examinations • vEDS • cEDS • Classical-like EDS NOTE: CT = computed tomography; EDS = Ehlers-Danlos syndrome; HDCT = heritable disorder of connective tissue; HSD = hypermobility spectrum disorder; LDS = Loeys- Dietz syndrome; MFS = Marfan syndrome. SOURCES: Bas et al., 2015; Berglund and Björck, 2012; Blagowidow, 2021; Carley and Schaffer, 2000; Carr et al., 1994; Castori et al., 2012; Cauldwell et al., 2019a,b; Chan et al., 2019; Chow et al., 2007; De Martino et al., 2019; De Toma et al., 2000; Demirdas et al., 2017; Donnez, 2011; Drera et al., 2011; Gilliam et al., 2020; Glayzer et al., 2021; Gupta et al., 2010; Henderson et al., 2017; Hentzen et al., 2018; Hernandez and Dietrich, 2020; Hugon-Rodin et al., 2016; Hurst et al., 2014; Jabs and Child, 2016; Jesudas et al., 2019; Kho and Shields, 2020; Kliethermes et al., 2016; Lind and Wallenburg, 2002; Makatsariya et al., 2020; Practice bulletin no. 176: Pelvic organ prolapse, 2017; Ritelli et al., 2013; Rosen et al., 2019; Russo et al., 2018; Sorokin et al., 1994; van de Laar et al., 2011; van de Laar et al., 2012; Wallace et al., 2019. 251

ANNEX TABLE 5-11 Selected Vision, Hearing, and Speech Manifestations Associated with Heritable Disorders of Connective Tissue 252 Common Diagnostic Manifestations HDCTs (Selected) Techniques Potential Treatments Vision Disorders of Thinning and steepening • Classical EDS (cEDS) • Pachymetry • Refractive prosthesis (e.g., cornea • Hypermobile EDS (hEDS) • Cornea topography contact lens, spectacle) • Kyphoscoliotic EDS (kEDS) • BCS • Musculocontractural (mcEDS) • LDS • Microcornea • kEDS • Slit lamp exam • Refractive correction • Sclerocornea • Low-vision rehabilitation • Cornea plana • Hyperosmotic agents • Prone to rupture • Patch graft for impending • Acute hydrops rupture • Microcornea • mcEDS • Slit lamp exam • Refractive correction • Low-vision rehabilitation • Megalocornea • BCS • Slit lamp exam • Lubrication • Keratoconus • Pachymetry • Amniotic graft • Keratoglobus • Corneal topography • Cornea crosslinking • Prone to rupture • Corneal graft (partial or full thickness) • Conjunctival flap

Disorders of • Dry eye • cEDS • Schirmer’s test • Artificial lubrication conjunctiva • hEDS • Tear osmolarity • Punctal occlusion • Slit lamp exam • Tear quality improvement • Tear break-up time medications • Conjunctivochalasis • cEDS • Slit lamp exam • Conjunctivoplasty • hEDS • Schirmer’s test • Artificial lubrication • Classical-like EDS (clEDS) • Tear break-up time • Punctal occlusion • Tear osmolarity • Tear quality improvement medications • Subconjunctival • clEDS • Slit lamp exam • Wait for hemorrhage to clear hemorrhage • Blue sclera • mcEDS • Gross examination • Counseling for psychological • cEDS effects of unusual cosmesis • hEDS • Scleral patch graft (if scleral • vEDS ectasia) • kEDS • BCS continued 253

ANNEX TABLE 5-11 Continued 254 Common Diagnostic Manifestations HDCTs (Selected) Techniques Potential Treatments Disorders of • Cataract • MFS • Slit lamp exam • Refraction/retinoscopy lens/iris • Cataract extraction • Ectopia lentis/ • MFS • Slit lamp exam • Refraction dislocation • Ultrasound • Lensectomy biomicroscopy • Iris coloboma • mcEDS • Slit lamp exam • Glare reduction by • Anterior segment UBM spectacles, specialty contact or OCT lenses, window tint, screen guards • Iris prosthesis • Iridoplasty • Iris transillumination • MFS • Slit lamp exam • Glare reduction by spectacles, specialty contact lenses, window tint, screen guards

Disorders of • Floppy eyelid • cEDS • Manual exam of eyelid • Nocturnal lubrication eyelid/face/ • Plastic surgery orbit • Proptosis (from • vEDS • CTA/MRA and CTV/MRV • Endovascular embolization cavernous-carotid • Hertel’s fistula) exophthalmometry • Hypertelorism • Arthrochalasia EDS • Pupillary distance • Observation (aEDS) measurement • Plastic surgery, when • mcEDS indicated for functional or • LDS aesthetic reasons • MFS continued 255

ANNEX TABLE 5-11 Continued 256 Common Diagnostic Manifestations HDCTs (Selected) Techniques Potential Treatments Disorders of • Amblyopia • MFS • Refraction • Treatment of underlying optic nerve/ • LDS • Slit lamp exam cause brain • EDS (unspecified • Possibly brain imaging • Occlusion of better- subtypes) seeing eye by patching or pharmacological penalization • Glaucoma (including • Dermatosparaxis EDS • Slit lamp exam • Topical medication angle closure) (dEDS) • Tonometry • Oral medication (in acute • mEDS • Pachymetry setting) • BCS • OCT • Glaucoma surgery • Spondylodysplastic EDS • Perimetry (spEDS) • MFS • Strabismus • mcEDS • Orthoptic examination • Refractive correction • MFS • Prism glasses • LDS • Strabismus surgery • Optic atrophy • mcEDS • Slit lamp exam • Treatment for reversible • Hypoplastic optic • Perimetry causes of atrophy nerve • Color vision testing • Observation • Optic nerve coloboma • B-scan ultrasonography • OCT • Convergence • EDS (unspecified • Orthoptic examination • Orthoptic exercises insufficiency subtype)

• Papilledema (from • hEDS • Dilated fundoscopic • ICP-lowering medication Chiari) • LDS exam • Memantine for nystagmus • Downbeat nystagmus • B-scan ultrasonography • Surgical decompression of (from Chiari) • Fluorescein angiography Chiari • Perimetry • Optic nerve OTC • MRI • Visual field loss • dESD • Dilated fundoscopic • IOP-lowering medication (from glaucoma • mcEDS exam • IOP-lowering surgery or dissection from • BCS • OCT • Low-vision rehabilitation carotid, vertebral or • spEDS • Perimetry • Surgical repair of dissection basilar artery) • MFS • Bruit in eye/neck/face • Advanced imaging (e.g., MRI, CT) • MRA/CTA brain/neck • Horner syndrome • vEDS • Carotid sonogram • Surgical reconstruction (carotid dissection) • Angiography continued 257

ANNEX TABLE 5-11 Continued 258 Common Diagnostic Manifestations HDCTs (Selected) Techniques Potential Treatments Disorders of • Retinal detachment • Cardiac-valvular EDS • Refraction • Laser retinopexy for retina retina (cvEDS) • Dilated fundoscopic tear • hEDS exam • Surgical repair by scleral • dEDS • OCT buckle or vitrectomy • kEDS • B-scan ultrasonography • BCS • mcEDS • MFS • Fragile retina vessels • kEDS • Dilated fundoscopic • Precautionary measured • vEDS exam • High myopia • hEDS • Dilated fundoscopic • Refractive correction with • mcEDS exam glasses or contact lenses • MFS • Refraction • Phakic or aphakic intraocular • OTC lenses • Wide field imaging • Fluorescein angiography Hearing Disorders of • Sensorineural hearing • EDS (unspecified • Advanced imaging • Medication hearing impairment subtype) • Clinical • Environmental modification • kEDS (FKBP14, FKBP22 • Diagnostic pure tone • Hearing aids subtypes) audiometry • Personal sound amplification • mEDS • Speech audiometry products • Stickler syndrome • Bone conduction testing • Auditory rehabilitation • MFS • LDS

• Conductive hearing • EDS (unspecified • Advanced imaging • Hearing aids impairment subtype) • Clinical • Medication • MFS • Diagnostic pure tone • Surgical intervention • LDS audiometry • Environmental modification • Speech audiometry • Bone conduction testing • Mixed sensorineural • EDS (unspecified • Advanced imaging • Medication and conductive subtype) • Clinical • Environmental modification hearing impairment • MFS • Diagnostic pure tone • LDS audiometry • Speech audiometry • Bone conduction testing • Tinnitus • EDS (unspecified • Advanced imaging • Treatment of underlying subtype) • Clinical condition • Audiological exam • Enviromental modification • Physical therapy • Behavioral therapy Speech Disorders of • Temporomandibular • EDS (unspecified • Advanced imaging • Speech and language speech joint dysfunction subtype) • Clinical therapy • Laryngeal dysfunction • Physical therapy • Vocal fatigue • Medications • Surgical intervention NOTE: BCS = brittle cornea syndrome; CT= computed tomography; CTA = computed tomography angiography; EDS = Ehlers-Danlos syndrome; HDCT = heritable disorder of connective tissue; HSD = hypermobility spectrum disorder; ICP = intracranial pressure; IOP = intraocular pressure; LDS = Loeys-Dietz syndrome; MFS = Marfan syndrome; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; MRV = magnetic resonance venography; OCT = optical coherence tomography; UBM = ultra- sound biomicroscopy. SOURCES: ASHA, 2005; Braverman et al., 2020; Gao et al., 2021; Hamberis et al., 2020; Hear.com, n.d.; Islam et al., 2020; Jeon et al., 2022; Kanigowska et al., 2006; NASEM, 2016, p. 82; NORD, 2017a; Perez-Roustit et al., 2019; Rezar-Dreindl et al., 2019; Roeser et al., 2000; Romano et al., 2002; Segev et al., 2006; University of California San Fransico Health, n.d. 259

ANNEX TABLE 5-12 Selected Neuropsychiatric Conditions Potentially Connected with Heritable Disorders of Connective Tissue 260 Conditions HDCTs (Selected) Common Diagnostic Techniques Potential Treatments Cognitive dysfunction/mild • EDS (all types) Structured interviews: • Management of associated cognitive impairment • HSD • Structured clinical interview disorders (e.g., neurologic, • MFS for DSM (SCID) immunologic) • Mini international • Lifestyle measures (e.g., exercise, neuropsychiatric interview diet, sleep, avoiding alcohol and (MINI) drugs, enhance leisure activities) Performance-based measures: • Number span forward (attention) and backward (working memory) • Trail Making Test parts A and B (processing speed and executive functioning, respectively) • Phonemic and category fluency (language) • Hopkins Verbal Learning Test– Revised (memory encoding, recall, and recognition) Depression • EDS (all types) Structured interviews: • Medication management • HSD • SCID • Psychotherapy • MFS • MINI • Brain stimulation therapies Self-reported measures: • Hamilton Depression Rating Scale • Beck Depression Inventory • Hospital Anxiety and Depression Scale

Anxiety disorders • hEDS/HSD Structured interviews: • Psychotherapy • MFS • SCID • Medication management • MINI • Support groups Self-reported measures: • Stress management techniques • Beck Anxiety Inventory • Occupational therapy • Hospital Anxiety and • Physical therapy Depression Scale • Panic and Agoraphobia Scale (Bandelow, 1999) continued 261

ANNEX TABLE 5-12 Continued 262 Conditions HDCTs (Selected) Common Diagnostic Techniques Potential Treatments Intellectual disability • SGS Performance-based measures: • Occupational therapy • Differential Abilities Scale-II • Self-care (e.g., grooming, (Elliott, 2007) (children and dressing, feeding, bathing) adolescents) • Employment activities and skills • Kaufman Assessment Battery • Leisure activities (e.g., knitting, for Children, Second Edition playing games) Normative Update (Kaufman • Domestic activities (e.g., and Kaufman, 2018) (children cooking, cleaning, laundry) and adolescents) • Speech therapy • Leiter International • Improves communication skills Performance Scale, Third • Improves receptive and Edition (Roid et al., 2013) expressive languages skills • Wechsler Adult Intelligence • Improves speech articulation Scale, Fourth Edition • Improves vocabulary (Wechsler, 2008) • Physical therapy • Wechsler Abbreviated Scales • Enhances quality of life by of Intelligence, Second Edition maximizing mobility and (Wechsler, 2011) self-locomotion • Wechsler Intelligence Scale • Provides adaptive solutions to for Children, Fifth Edition mobility problems (Wechsler, 2014) • Increases sensory integration • Wechsler Preschool and • Adapted Dialectical Behavior Primary Scale of Intelligence, Therapy Fourth Edition (Wechsler, • Pain Management 2012) • Family support • Reynolds Intellectual Assessment Scales, Second Edition (Reynolds and Kamphaus, 2015) • Kaufman Brief Intelligence Test, Second Edition (Kaufman and Kaufman, 2004)

Personality disorder • hEDS/HSD Self-reported measures: • Psychotherapy • MFS • Borderline Personality • Medication management Disorder Checklist • Support groups • International Personality • Stress management techniques Disorder Examination • Occupational therapy • Personality Assessment Inventory Sleep disorders • hEDS/HSD • Sleep study • Psychotherapy • MFS Structured interviews: • Medication management • SCID • Support groups • MINI • Insomnia management techniques Self-reported measures: • Occupational therapy • Epworth Sleepiness Scale • Physical therapy Eating disorders • hEDS/HSD • Evaluation of gastrointestinal • Nutritional • MFS symptoms and disordered • Psychotherapy eating • Medication management Structured interviews: • Support groups • SCID • Stress management techniques • MINI • Occupational therapy Self-reported measures: • Eating Disorder Examination • Eating Attitudes Test (26) Attention-deficit/ • hEDS/HSD Structured interviews: • Medication management hyperactivity disorder • MFS • SCID • Psychotherapy and psychosocial (ADHD) • MINI interventions Self-reported measures: • Support groups • Adult ADHD Self-Report Scale • Stress management techniques • Barrat Impulsiveness Scale • Occupational therapy • Physical therapy continued 263

ANNEX TABLE 5-12 Continued 264 NOTE: ADL = activities of daily living; EDS = Ehlers-Danlos syndrome; HDCT = heritable disorder of connective tissue; hEDS = hypermobile EDS; HSD = hypermobility spec- trum disorder; MFS = Marfan syndrome; SGS = Shprintzen-Goldberg syndrome. SOURCES: Arnold et al., 2015; Baeza-Velasco et al., 2016, 2017, 2018, 2021, 2022a,b; Becker et al., 2021; Berglund et al., 2015; Bulbena-Cabré et al., 2021; Cederlöf et al., 2016; Cicerone et al., 2019; Doğan et al., 2011; Domany et al., 2018; Eccles et al., 2014; Greally, 2020; Hershenfeld et al., 2016; Hofman et al., 1988; Huang et al., 2020; Kandola and Stubbs, 2020; Kandola et al., 2018; Lambez et al., 2020; Langhinrichsen-Rohling et al., 2021; Lannoo et al., 1996; Moss et al., 2018; Nijs et al., 2018; NORD, 2017b; Oppizzi and Umberger, 2018; Pasquini et al., 2014; Reisberg et al., 1982; Ross et al., 2013; Shiari et al., 2013; Smith et al., 2013; Tsui et al., 2017; Wasim et al., 2019; Wells et al., 2020; Zhang and Yuan, 2019.

ANNEX TABLE 5-13 Global Functioning Associated with Heritable Disorders of Connective Tissue Selected Assistive Potential Reasons for Technologies and Relevant Domain Limitation or Symptom Selected Assessments Accommodations Full-body functioning • Pain (see annex tables Performance-based measures: • These will be determined (physical) 5-3, musculoskeletal; • Bruininks-Oseretsky Test of Motor by the specific activity 5-4, neurological; 5-8, Proficiency, 2nd Edition (BOT-2)* that is limiting full-body gastrointestinal; and 5-10, (Bruininks and Bruininks, 2005) functioning (see annex genitourinary) (pediatric population) tables 5-14 and 5-15 • Weakness • Bruininks Motor Ability Test (BMAT)* for physical and vision, • Fatigue/deconditioning (Bruininks and Bruininks, 2012) (adult hearing, and speech • Joint instability (see Annex version of BOT-2) functioning) Table 5-3, musculoskeletal • Functional capacity evaluation (Chen, table) 2007; Fore et al., 2015; Genovese and • Orthostatic intolerance/ Galper, 2009; Jahn et al., 2004; Kuijer et dysautonomia al., 2012; Soer et al., 2008) • Balance dysfunction • Exercise testing to include aerobic • Cardiovascular and capacity and neuromuscular respiratory impairments performance (Liguori and American (see annex tables 5-5 and College of Sports Medicine, 2021) 5-6, cardiovascular and Self-reported measures: respiratory) • Composite Autonomic Symptom • Neurological compromise Score-31 (COMPASS-31) (Sletten et al., (see Annex Table 5-4, 2012) neurological table) • See Annex Table 5-14 (physical functioning) for additional reasons • Gastrointestinal dysfunction (see Annex Table 5-8, gastrointestinal table) 265 continued

ANNEX TABLE 5-13 Continued 266 Selected Assistive Potential Reasons for Technologies and Relevant Domain Limitation or Symptom Selected Assessments Accommodations Work-related functioning, • Pain Performance-based measures: • Orthoses (e.g., splints, activities of daily living • Fatigue/deconditioning • ADL Profile (head injury and stroke) braces) (ADLs), and instrumental • Weakness (Dutil et al., 1990) • Built-up handles for items activities of daily living • Joint instability • ADL-Focused Occupations- used at home for ADLs (IADLs) • Brain fog Based Neurobehavioral Evaluation (e.g., toothbrush, fork, and • Orthostatic intolerance/ (Gardarsdóttir and Kaplan, 2002) others) dysautonomia • Assessment of Motor and Processing • Reachers to assist with • Neurological compromise Skills (Fisher and James, 2012; Shirley reaching and manipulating Ryan AbilityLab, 2019) objects and avoid bending • Bay Area Functional Performance • Reorganization of home Evaluation (Houston et al., 1989) to facilitate pain-free • Executive Function Performance Test activities (Baum et al., 2008) • Compression clothing • Functional Independence Measure • Assistive devices (e.g., (Ottenbacher et al., 1996) walker, cane, wheelchair) • Katz ADL Scale (elderly and chronically • Devices with large ill) (Katz, 1983; Katz and Akpom, 1976) numbers (e.g., telephone, • Kohlman Evaluation of Living Skills medication box) (IADLs—psychiatric geriatric) (Burnett et al., 2009; Kohlman-Thomson, 1992) Observation and interview-based measures: • Multiple Errands Test (brain injury, stroke—executive functioning) (Morrison et al., 2013) • Performance Assessment of Self-Care Skills (Chisholm et al., 2014)

Self-reported measures: • Work Disability Functional Assessment Battery (WD-FAB) Physical Function (Meterko et al., 2015; Meterko et al., 2019) • Work Ability Index (Ilmarinen, 2007; Tuomi et al., 1998) • Sheehan Disability Scale (Sheehan, 1983) • Social and Occupational Functioning Assessment Scale (Rybarczyk, 2011) • Mental Illness Research, Education, and Clinical Center (MIRECC) version of the Global Assessment of Functioning scale (Niv et al., 2007) • Barthel Index (Quinn et al., 2011) • Frenchay Activities Index (IADLs) (Schuling et al., 1993) • The Lawton IADL Scale (Graf, 2008) • Manual Ability Measure (neurological and musculoskeletal conditions) (Chen and Bode, 2010) Caregiver-reported measures: • Cleveland Scale of Activities of Daily Living (dementia) (Patterson and Mack, 2001) continued 267

ANNEX TABLE 5-13 Continued 268 Selected Assistive Potential Reasons for Technologies and Relevant Domain Limitation or Symptom Selected Assessments Accommodations Pain • Musculoskeletal disorders Self-reported measures: • Orthoses (e.g., braces, (see musculoskeletal table) • Visual Analog Scale (VAS) for Pain splints) • Neurological compromise (Bijur et al., 2001) • Compression clothing (see neurological and • Numeric Pain Rating Scale (Shirley Ryan • Assistive devices (e.g., musculoskeletal tables) AbilityLab, 2013c) crutches, wheelchair, • Gastrointestinal dysfunction • Patient-Reported Outcomes reachers) (see gastrointestinal table) Measurement Information System • Psychological support for • Mast cell activation (PROMIS)—Pain Interference pain management dysfunction/mast cell Instruments (HealthMeasures, 2021) • Mind–body arts, such as activation disease (see • Functional Disability Inventory (Claar yoga, Pilates, tai chi) immunologic table) and Walker, 2006; Walker and Greene, • Reorganization of the • Poor sleep quality 1991) (pediatric population) home to decrease unnecessary movement, reaching, etc., that can exacerbate pain

Fatigue • Poor sleep quality Performance-based measures: • Orthoses (e.g., braces, • Chronic pain • Polysomnography splints) • Deconditioning • Exercise testing to include aerobic • Compression clothing • Orthostatic intolerance/ capacity and neuromuscular • Assistive devices (e.g., dysautonomia performance (Liguori and American crutches, wheelchair, • Nutritional deficiencies College of Sports Medicine, 2021) reachers) • Anxiety and/or depression • Psychological support (see mental disorders table) Self-reported measures: • Mind–body arts, such as • Neuromuscular disorders • Brief Fatigue Inventory [BFI] yoga, Pilates, tai chi) (see musculoskeletal and • Fatigue Severity Scale [FSS] neurological tables) • Fatigue Symptom Inventory • Cardiovascular and • Multidimensional Assessment of respiratory disorders Fatigue (see cardiovascular and • Fatigue Impact Scale (modified) respiratory tables) • Multidimensional Fatigue Symptom Inventory • Multidimensional Fatigue Symptom Inventory Short Form • Profile of Mood States-Brief, Fatigue subscale PedsQL • Multi-Dimensional Fatigue Scale • Profile of Fatigue • Functional Assessment Chronic Illness • Therapy Checklist Individual Strength • Patient-Reported Outcomes Measurement Information System—Fatigue • Pittsburgh Sleep Quality Assessment (Buysse et al., 1989) • VAS to Evaluate Fatigue Severity *Multidimensional assessment: Balance, coordination, dexterity, functional mobility, gait, strength, upper-extremity, function, vestibular. 269

ANNEX TABLE 5-14 Functional Implications for Physical Activities of Conditions Associated with Heritable Disorders of Connective Tissue 270 Potential Reasons for Activity Selected Assistive Technologies and Activity Limitation Selected Functional Assessments Reasonable Accommodations Sitting • Pain (see musculoskeletal, Physical performance measures: • Orthoses (e.g., braces, splints) Note: especially neurological, • Functional Capacity Evaluation • Worksite modification, especially prolonged sitting gastrointestinal, and global (FCE) or specific function testing by ergonomic chairs and adjustable functioning tables) a trained health care provider (e.g., workstations that can raise and • Instability of cervical or physical or occupational therapist) lower lumbar spine, pelvis, knees • Berg Balance Scale (Shirley Ryan • Reorganization of worksite to (see musculoskeletal table) AbilityLab, 2020a) minimize need to sit or allow • Weakness (see • Function in Sitting Test (for people alternating between sitting and musculoskeletal and who are unable to perform standing other positioning neurological tables) balance testing) (Samuel Merritt • Reorganization of job requirements • Balance dysfunction University, n.d.) to minimize need to sit or allow affecting trunk (see Self-reported outcome measures: alternating between sitting and neurological table) • Roland-Morris Disability Questionnaire other positioning • Fatigue/deconditioning (see (RMDQ) (Chansirinukor et al., 2005; • Rest breaks global functioning table) Stevens et al., 2016) • Compression clothing • Neurological compromise • Oswestry Disability Index (ODI) • Telework, work from home (see neurological table) (Shirley Ryan AbilityLab, 2013d) • Orthostatic intolerance/ • Neck Disability Index (NDI) (Shirley dysautonomia (see Ryan AbilityLab, 2015b) neurological and global • Multidimensional Assessment of functioning tables) Fatigue (Shirley Ryan AbilityLab, 2020b) • Fatigue Severity Scale (Shirley Ryan AbilityLab, 2016)

Standing • Pain Physical performance measures: • Ability to sit or stand at will Note: especially • Instability of lower-extremity • Sensory Organization Test (NeuroCom • Rest breaks prolonged standing, (LE) joints or UE joints if SMART EquiTest) (Shirley Ryan • Compression clothing but intermittent assisted devices required AbilityLab, 2013f) • Orthoses standing and • Weakness • Modified Balance Error Scoring • Assistive devices (e.g., crutches, ability to get to • Balance dysfunction System (M-BESS) (Iverson and Koehle, walker, wheelchair) standing may • Fatigue/deconditioning 2013) • Handrails or devices to assist with also be affected; • Neurological compromise • Star Excursion Balance Test balance using assistive • Orthostatic intolerance/ performance (Hegedus et al., 2015) • Reorganization of worksite to devices can be very dysautonomia • Romberg (Shirley Ryan AbilityLab, minimize need to stand and allow stressful to upper- 2013e) for changes in positioning extremity (UE) • Berg Balance Scale • Reorganization of job requirements joints • 30-second sit-to-stand, or 5x or 10x to minimize need to stand and stand tests (Shirley Ryan AbilityLab, allow for changes in positioning 2013a) • Telework, work from home • Foot Posture Index-6 • FCE or specific function testing by a trained health care provider Self-reported outcome measures: • Lower Extremity Functional Scale (LEFS) (Shirley Ryan AbilityLab, 2013b) • Foot and Ankle Ability Measures (FAAM) (Shirley Ryan AbilityLab. 2015a) • RMDQ • ODI • NDI • The Activities-specific Balance Confidence (ABC) Scale (Powell and Myers, 1995) • Composite Autonomic Symptom Score (COMPASS 31) questionnaire • WOMAC, KOOS , KOOS-PS, or other knee outcome measures (Collins et al., 2011) 271 continued

ANNEX TABLE 5-14 Continued 272 Potential Reasons for Activity Selected Assistive Technologies and Activity Limitation Selected Functional Assessments Reasonable Accommodations Walking • Pain Physical performance measures: • Orthoses Note: may be • Instability of spinal or LE • 6-minute walk test • Assistive devices impaired for or UE joints if assistive • 10-meter walk test (Physiopedia, n.d.) • Reorganization of worksite and/or long or short devices required; includes • Functional Gait Assessment adaptations to the worksite or how distances, over subluxations • Sensory Organization Test (NeuroCom the work is performed to minimize uneven ground or • Fatigue/deconditioning SMART EquiTest) mobility needs different surfaces; • Weakness • M-BESS • Handrails or devices to assist with using assistive • Balance dysfunction • FCE or specific function testing by a balance and walking devices can be • Orthostatic intolerance/ trained health care provider • Reorganization of job requirements very stressful to UE dysautonomia • Berg Balance Scale to minimize mobility needs joints • Neurological compromise • 30-second, 5x, or 10x sit-to-stand test • Rest breaks • Cardiac dysfunction • Foot Posture Index-6 • Compression clothing • Respiratory dysfunction Self-reported outcome measures: • Telework, work from home • LEFS • FAAM • RMDQ • ODI • NDI • ABC Scale • WOMAC, KOOS , KOOS-PS, or other knee outcome measures

Strenuous physical • Exercise intolerance Physical performance measures: • Potentially anything listed in this activity • Pain • Exercise testing table for other activities Note: potentially • Instability in any joint • Sensory Organization Test (NeuroCom includes all other • Fatigue/deconditioning SMART EquiTest) activities in this • Weakness Self-reported outcome measures: table, plus running • Balance dysfunction • LEFS and impact • Orthostatic intolerance/ • Disabilities of the Arm, Shoulder activities dysautonomia and Hand (DASH) questionnaire and • Neurological compromise QuickDASH (Aasheim and Finsen, • Cardiac dysfunction (see 2013; Beaton et al., 2001; Bilberg et al., cardiovascular table) 2012; Dixon et al., 2008; Jester et al., • Respiratory dysfunction (see 2005; Kennedy et al., 2013) respiratory table) Lifting from floor to • Pain Physical performance measures: • Mechanical lifting equipment waist or overhead • Instability in any joint • FCE or specific function testing by a • Reachers • Fatigue/deconditioning trained health care provider • Adjustable high–low table • Weakness Self-reported outcome measures: • Adjustable high–low seating • Balance dysfunction • DASH and QuickDASH • Reorganization of worksite to • Orthostatic intolerance/ • Patient-Reported Outcomes minimize lifting needs dysautonomia Measurement Information System • Reorganization of job requirements • Neurological compromise (PROMIS) Upper-Extremity to minimize lifting needs • Cardiac dysfunction (see Questionnaire (Overbeek et al., 2015) • Rest breaks cardiovascular table) • Patient-Rated Elbow Evaluation • Orthoses • Aortic dysfunction (see (PREE) cardiovascular table) • Patient-Rated Wrist Evaluation (PRWE) (MacDermid et al., 1998; Packham and MacDermid, 2013) • Michigan Hand Outcomes Questionnaire (MHQ) (Chung et al., 1998; Shauver and Chung, 2013) • Western Ontario Shoulder Instability Index (WOSI) (Johannessen et al., 2016) continued 273

ANNEX TABLE 5-14 Continued 274 Potential Reasons for Activity Selected Assistive Technologies and Activity Limitation Selected Functional Assessments Reasonable Accommodations Carrying • Pain Physical performance measures: • Orthoses Note: usually • Instability in any joints • FCE or specific function testing by a • Assistive devices requires ability to • Weakness trained health care provider • Reorganization of worksite to stand, lift, and walk • Balance dysfunction • M-BESS minimize need to carry, such as a • Fatigue/deconditioning • Sensory Organization Test (NeuroCom counter of some kind that could • Orthostatic intolerance/ SMART EquiTest) allow pushing an item instead of dysautonomia • Foot Posture Index-6 carrying it • Neurological compromise Self-reported outcome measures: • Reorganization of job requirements • ABC Scale to minimize need to carry • DASH and QuickDASH • Devices to help with lifting and/ • PROMIS Upper-Extremity or carrying (e.g., carts, mechanical Questionnaire lifts) • PREE • Crossbody bags for carrying item • PRWE • Rest breaks • MHQ • Compression clothing • WOSI Pushing or pulling • Pain Physical performance measures: • Orthoses Note: includes UE • Instability in any joints • FCE or specific function testing by a • Reorganization of worksite to and LE; for UE, • Weakness trained health care provider minimize need to push/pull usually requires • Balance dysfunction • Sit-and-reach test (Pescatello et al., • Reorganization of job requirements ability to stand • Fatigue/deconditioning 2014; Wells and Dillon, 1952) to minimize need to push/pull and walk (or move • Orthostatic intolerance/ Self-reported outcome measures: • Manual devices to help with moving wheelchair) with at dysautonomia • DASH and QuickDASH materials (e.g., carts, trolleys) least one hand free • Neurological compromise • PROMIS Upper-Extremity • Powered devices to help with for pushing/pulling Questionnaire moving materials • PREE • Rest breaks • PRWE • Compression clothing • MHQ • WOSI

Reaching • Pain Physical performance measures: • Orthoses Note: may require • Instability in any joints • FCE or specific function testing by a • Reorganization of worksite to standing • Weakness trained health care provider minimize need to push/pull • Balance dysfunction • Sit-and-reach test • Reorganization of job requirements • Fatigue/deconditioning Self-reported outcome measures: to minimize need to push/pull • Orthostatic intolerance/ • DASH and QuickDASH • The use of reachers to assist with dysautonomia • PROMIS Upper-Extremity reaching for objects • Neurological compromise Questionnaire • Manual devices to help with moving • PREE materials (e.g., carts, trolleys) • PRWE • Powered devices to help with • MHQ moving materials • WOSI • Rest breaks • Compression clothing Reaching overhead • Pain Physical performance measures: • Orthoses Note: requires neck • Instability of UE or spine • FCE or specific function testing by a • Reorganization of worksite to extension; may joints trained health care provider minimize need to reach require standing • Weakness Self-reported outcome measures: • Reorganization of job requirements • Balance dysfunction • DASH and QuickDASH to minimize need to reach • Fatigue • PROMIS Upper-Extremity • The use of reachers to assist with • Orthostatic intolerance Questionnaire reaching for objects • Neurological compromise • PREE • Devices to help with reaching (e.g., • PRWE grabbers) • MHQ • Rest breaks • WOSI • Compression clothing Reaching at or • Pain Physical performance measures: • Orthoses below the shoulder • Instability in any joints • FCE or specific function testing by a • Reorganization of worksite to Note: may require • Weakness trained health care provider minimize need to reach standing • Balance dysfunction • Sit-and-reach test • Reorganization of job requirements • Fatigue/deconditioning Self-reported outcome measures: to minimize need to reach • Orthostatic intolerance/ • WOSI • The use of reachers to assist with dysautonomia reaching for objects • Neurological compromise • Rest breaks • Compression clothing 275 continued

ANNEX TABLE 5-14 Continued 276 Potential Reasons for Activity Selected Assistive Technologies and Activity Limitation Selected Functional Assessments Reasonable Accommodations Gross manipulation • Pain Physical performance measures: • Orthoses Note: requires • Instability in spine or UE • FCE or specific function testing by a • Ergonomic tools ability to sit and/or joints trained health care provider • The use of reachers to assist with stand • Weakness • Sequential Occupational Dexterity reaching and manipulating objects • Balance dysfunction Assessment (SODA) (van Lankveld et • Reorganization of worksite • Fatigue/deconditioning al., 1996) to minimize need for gross • Orthostatic intolerance/ Self-reported outcome measures: manipulation dysautonomia • DASH and QuickDASH • Reorganization of job requirements • Neurological compromise • PROMIS Upper-Extremity to minimize need for gross • Coordination deficit Questionnaire manipulation • PRWE • Rest breaks • MHQ • Compression clothing • WOSI Fine manipulation • Pain Physical performance measures: • Orthoses • Instability in cervical or UE • FCE or specific function testing by a • Wrist weights joints trained health care provider • Ergonomic tools • Weakness • Nine-hole peg board test • Add built up handles to items used • Balance dysfunction • SODA at work, such as pencils/pens, • Fatigue/deconditioning Self-reported outcome measures: tools, and other items used in the • Orthostatic intolerance/ • Functional Dexterity Test (Shirley Ryan workplace and at home to minimize dysautonomia AbilityLab, 2017) the need for fine manipulation • Neurological compromise • PRWE • Reorganization of worksite to • Coordination deficit • MHQ minimize need for fine manipulation • Reorganization of job requirements to minimize need for fine manipulation • Rest breaks • Compression clothing

Foot/leg controls • Pain Physical performance measures: • Orthoses • Instability in lumbar or LE • FCE or specific function testing by a • Ergonomic tools joints trained health care provider • Reorganization of worksite to • Weakness Self-reported outcome measures: minimize need for foot/leg controls • Balance dysfunction • LEFS • Reorganization of job requirements • Fatigue/deconditioning • FAAM to minimize need for foot/leg • Orthostatic intolerance/ controls dysautonomia • Rest breaks • Neurological compromise • Compression clothing Climbing • Pain Physical performance measures: • Orthoses Note: may include • Instability any joints • FCE or specific function testing by a • Assistive devices stairs, ramps, • Weakness trained health care provider • Reorganization of worksite to ladders, scaffolding, • Balance dysfunction • Sensory Organization Test (NeuroCom minimize need to climb ropes, etc. Normal • Fatigue/deconditioning SMART EquiTest) • Handrails, grab bars, or other ambulation devices • Orthostatic intolerance/ • M-BESS devices to assist with balance might not be usable dysautonomia Self-reported outcome measures: • Reorganization of job requirements for climbing. • Neurological compromise • ABC Scale to minimize need to climb • LEFS • Rest breaks • WOMAC, KOOS, KOOS-PS, or other • Compression clothing knee outcome measures continued 277

ANNEX TABLE 5-14 Continued 278 Potential Reasons for Activity Selected Assistive Technologies and Activity Limitation Selected Functional Assessments Reasonable Accommodations Low work, including • Pain Physical performance measures: • Orthoses stooping, crouching, • Instability any joints • FCE or specific function testing by a • Kneepads kneeling, crawling • Weakness trained health care provider • Assistive devices (e.g., reachers, or lying on the • Balance dysfunction, Self-reported outcome measures: scooters, rolling sit-carts, high–low ground including vestibular issues • LEFS chairs/stools) Note: includes need • Fatigue/deconditioning • WOMAC, KOOS, KOOS-PS, or other • Reorganization of job requirements to get up and down • Orthostatic intolerance/ knee outcome measures or work environment to minimize from the ground dysautonomia need for low work • Neurological compromise • Reorganization of worksite to minimize need for low work • Raise the level where work is done • Handrails or devices to assist with getting up and down • Rest breaks • Compression clothing NOTE: KOOS = Knee Injury and Osteoarthritis Outcome Score; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

ANNEX TABLE 5-15 Functional Implications for Vision, Hearing, and Speaking Activities of Conditions Associated with Heritable Disorders of Connective Tissue Potential Reasons for Activity Selected Assistive Technologies and Activity Limitation Selected Functional Assessments Reasonable Accommodations Near visual acuity • Uncorrected refractive error • Snellen Chart • Over-the-counter reading glasses, • Accommodative insufficiency • Bailey-Lovie Chart prescription glasses or contact • Glare • Brightness acuity testing lenses, occasionally prism glasses • Cataract • Low-vision devices • Dislocated lens • Auditory replacements for vision • Cornea scarring tasks • Keratoconus • Glare-reducing equipment • Dry Eye • Retina scarring • Amblyopia Distance (far) • Uncorrected refractive error • Snellen Chart • Prescription glasses or contact visual acuity • Cataract • Bailey-Lovie Chart lenses • Dislocated lens • Brightness acuity testing • Low-vision devices • Cornea scarring • Orientation and mobility training • Keratoconus • Dry eye • Retina scarring • Amblyopia Binocular function • Reduced stereopsis • Orthoptic examination • Computerized orthoptic therapy • Strabismus • Titmus stereo test • Prism glasses • Deficient pursuits • Howard-Dolman test • Strabismus surgery • Vergence infacility • Infrared oculography • Sectoral occlusion • Deficient saccades continued 279

ANNEX TABLE 5-14 Continued 280 Potential Reasons for Activity Selected Assistive Technologies and Activity Limitation Selected Functional Assessments Reasonable Accommodations Peripheral vision • Glaucoma • Perimetry • Low-vision devices • Retina scarring/detachment • Auditory accessories • Stroke (including ischemic and • Orientation and mobility training hemorrhagic) Hearing • Sensorineural hearing impairment Performance-based measures: • Hearing aids • Conductive hearing impairment • Pure tone audiometry • Personal sound-amplification • Mixed sensorineural and conductive • Speech recognition in noise products hearing impairment testing • Remote-microphone hearing • Internet- and telephone-based assistive technology screening • Captioning Self-reported outcome measures: • Telecommunications relay service • Hearing Handicap Inventory for • Other assistive technologies Adults (Newman et al., 1990) • Environmental modification • Speech, Spatial, and Qualities of Hearing Questionnaire (Gatehouse and Noble, 2004)

Speaking • Temporomandibular joint • Speech/Phoneme Intelligibility • Assistive technologies dysfunction Test (Madonna Rehabilitation • Environmental modification • Laryngeal dysfunction Hospitals, n.d.) • Occupational therapy • Vocal fatigue • Assessment of Intelligibility in Dysarthric Speech (Yorkston and Beukelman, 1984) • Frenchay Dysarthria Assessment, Second Edition (Enderby and Palmer, 2008) • Apraxia Battery for Adults, Second Edition (Dabul, 2000) • Apraxia of Speech Rating Scale (Strand et al., 2014) • Communication Participation Item Bank (Baylor et al., 2013) • Levels of Speech Usage (Baylor et al., 2008) • Fatigue Severity Scale (Krupp et al., 1989) • Quality of Communication Life Scale (Paul et al., 2004) • ASHA Functional Assessment of Communication Skills for Adults (Frattali et al., 2017) NOTE: ASHA = American Speech-Language-Hearing Association; EDS = Ehlers-Danlos syndrome. SOURCES: Giguère et al., 2008; Laroche et al., 2003; McBride et al., 1994; Smits et al., 2004; Watson et al., 2012; Yueh et al., 2003. 281

ANNEX TABLE 5-16 Functional Implications for Mental Activities of Conditions Associated with Heritable Disorders of Connective Tissue 282 Potential Reasons for Selected Assistive Technologies and Activity Activity Limitation Selected Functional Assessments Reasonable Accommodations Understand, remember, • Pain Intellectual abilities and • Short, step-by-step instructions, and apply information • Fatigue general cognition recorded for play-back on cell • Mild cognitive impairment • Leiter International Performance phone (sometimes described as Scale, Third Edition (Roid et al., • Short, step-by-step, written “brain fog”) 2013) instructions in plain language, on • Mood (low, high) • Repeatable Battery for Assessment cell phone, pocket cards, or wall • Depression of Neuropsychological Status signs • Anxiety Update (Randolph, 2012) • Tasks broken down into sequential • Cognitive impairment • Montreal Cognitive Assessment steps, outlined in simple language, (screen) (Nasreddine et al., 2005) and posted within view at the • Brief Assessment of Cognition worksite (Keefe et al., 2004; Keefe et al., • Tasks broken down into sequential 2008) steps and outlined in simple • Short Orientation-Memory- language via recordings in short, Concentration Test of Cognitive simple, sentences, that provide Impairment (Katzman et al., 1983) specific instructions for work tasks • Cognitive Capacity Screening • Work performed in a quiet area Examination (Jacobs et al., 1977) without distractions • Stanford-Binet Intelligence Scales, • Work performed sitting instead of Fifth Edition (Roid, 2003) standing, with breaks as needed • Wechsler Adult Intelligence Scale, • Provision of a job coach Fourth Edition (Wechsler, 2008) • Wechsler Abbreviated Scales of Intelligence, Second Edition (Wechsler, 2011) • Reynolds Intellectual Assessment Scales, Second Edition (Reynolds and Kamphaus, 2015) • Kaufman Brief Intelligence Test, Second Edition (Kaufman and Kaufman, 2004)

Executive functioning • Delis-Kaplan Executive Function System (Delis et al., 2001) • Symbol Digit Modalities Test (Smith, 1973) • Tower of London-DX, Second Edition (Culbertson and Zillmer, 2005) • Wisconsin Card Sorting Test (Grant and Berg, 1981) Attention and working memory • Conners Continuous Performance Test Third Edition (Conners, 2014) • The Test of Variables of Attention, Version 9 (Greenberg et al., 2017) • Wide Range Assessment of Memory and Learning, Second Edition (Sheslow and Adams, 2003) Self-reported measures: • Work Disability Functional Assessment Battery (WD-FAB) (Marfeo et al., 2019) • Beck Anxiety Inventory (BAI) • Beck Depression Inventory (BDI) • Hospital Anxiety and Depression Scale • Autism Spectrum Quotient continued 283

ANNEX TABLE 5-16 Continued 284 Potential Reasons for Selected Assistive Technologies and Activity Activity Limitation Selected Functional Assessments Reasonable Accommodations Problem solve • Mild cognitive impairment Intellectual abilities and • Short, step-by-step instructions, • Pain general cognition recorded for play-back on cell • Fatigue • See above phone • Mood (low, high) Executive functioning • Short, step-by-step, written • Depression • See above instructions in plain language, on • Anxiety Self-reported measures: cell phone, pocket cards, or wall • Hyperactivity • BAI signs • Attention deficit • BDI • Tasks broken down into sequential • Hospital Anxiety and Depression steps, outlined in simple language, Scale and posted within view at the worksite • Tasks broken down into sequential steps and outlined in simple language via recordings in short, simple, sentences, that provide specific instructions for work tasks • Work performed in a quiet area without distractions • Provision of a job coach

Concentrate, persist, or • Pain Attention and working memory • Work performed in a quiet area maintain pace • Fatigue • See above without distractions • Cognitive impairment Processing speed • Use of a noise-canceling headset • Mood (low, high) • Symbol Digit Modalities Test (Smith, • Short, step-by-step instructions, • Depression 1973) recorded for play-back on cell • Anxiety Self-reported measures: phone • Impulsivity • Adult ADHD Self-Report Scale • Short, step-by-step, written • Hyperactivity • Barrat Impulsiveness Scale instructions in plain language, on • Attention deficit • BAI cell phone, pocket cards, or wall • BDI signs • Hospital Anxiety and Depression • Tasks broken down into sequential Scale steps, outlined in simple language, and posted within view at the worksite • Tasks broken down into sequential steps and outlined in simple language via recordings in short, simple, sentences, that provide specific instructions for work tasks • Provision of a job coach continued 285

ANNEX TABLE 5-16 Continued 286 Potential Reasons for Selected Assistive Technologies and Activity Activity Limitation Selected Functional Assessments Reasonable Accommodations Interact with others • Fatigue Adaptability/personal interactions • Structured, work-related, and/or • Cognitive impairment Self-reported measures: social activities • Mood (low, high) • WD-FAB (Marfeo et al., 2013) • Option to work independently, away • Depression • Personal and Social Performance from others • Anxiety Scale (Morosini et al., 2000) • Option to work with others in a • Impulsivity • Sheehan Disability Scale (Sheehan, structured work environment, with • Hyperactivity 1983) or without breaks • Attention deficit • Social and Occupational Functioning • Provision of a job coach Assessment Scale (Rybarczyk, 2011) • Mental Illness Research, Education, and Clinical Center (MIRECC) version of the Global Assessment of Functioning scale (Niv et al., 2007) • Adult ADHD Self-Report Scale • Borderline Personality Disorder Checklist • International Personality Disorder Examination • Personality Assessment Inventory (Morey, 1991) • Panic and Agoraphobia Scale • Autism Spectrum Quotient Language • Verbal Tasks from IQ Batteries (Kaufman and Kaufman, 2004; Reynolds and Kamphaus, 2015; Roid, 2003; Wechsler, 2008, 2011, 2012, 2014) • Expressive Vocabulary Test, Third Edition (Williams, 2018) • Peabody Picture Vocabulary Test, Fifth Edition (Dunn, 2018)

Adapt or manage • Depression Adaptive functioning • Work performed in a quiet area oneself • Anxiety • Adaptive Behavior Assessment without distractions • Fatigue System, Third Edition (Harrison and • Structured, work-related, and/or • Mood (low, high) Oakland, 2015) social activities • Cognitive impairment • Vineland Adaptive Behavior Scales, • Option to work independently, away Third Edition (Sparrow et al., 2016) from others Adaptability/personal interactions • Option to work with others in a • See above structured work environment, with Attention and working memory or without breaks • See above • Self-pacing of work performed with Processing speed short, step-by-step instructions, • See above recorded for play-back on cell Executive functioning phone • See above • Short, step-by-step, written Self-reported measures: instructions in plain language, on • Sheehan Disability Scale cell phone, pocket cards, or wall • Adult ADHD Self-Report Scale signs • Personality Assessment Inventory • Tasks broken down into sequential • Panic and Agoraphobia Scale steps, outlined in simple language, • Autism Spectrum Quotient and posted within view at the worksite • Tasks broken down into sequential steps and outlined in simple language via recordings in short, simple, sentences, that provide specific instructions for work tasks, and when breaks can occur • Provision of a job coach NOTE: ADHD = attention deficit hyperactivity disorder. 287

288 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE ANNEX TABLE 5-17 Examples of Social Security Administration Listings That May Apply to Individuals with Heritable Disorders of Connective Tissue Listings* Notes 1.15 Disorders of the skeletal Standard imaging may not clearly demonstrate spine resulting in compromise abnormalities. Flexion and extension imaging, or of a nerve root(s) magnetic resonance imaging (upright, if tolerated) may be needed. 1.16 Lumbar spinal stenosis Standard imaging might not detect abnormalities. resulting in compromise of the Specialized imaging such as flexion or extension cauda equine imaging may be needed. Some individuals may be unable to use mobility devices due to upper-extremity impairments. 1.17 Reconstructive surgery or Individuals with HDCTs are more likely to have a poor surgical arthrodesis of a major outcome with major surgery, especially if the HCDT weight-bearing joint was not previously recognized or taken into account in performing surgery and after-care. Wound healing is slow in many HDCTs and wound dehiscence may occur despite excellent surgical and postoperative care. Some individuals may be unable to use mobility devices due to upper-extremity impairments. Patients are sometimes unable to fully engage in postoperative therapy because of associated problems such as fatigue, orthostatic intolerance, mast cell activation disease, depression, brain fog, gastrointestinal disorders, or other musculoskeletal issues. Surgical outcomes may therefore be compromised. 1.18 Abnormality of a major Frequent episodes of subluxation or dislocation joint(s) in any extremity strongly impacting function often influence how consistent people can be in performing work activities. For example, if a person’s hip dislocates, they will be unable to stand or walk. Individuals prone to dislocations may be afraid to perform certain activities or even to leave their homes for fear of causing a dislocation. Physical examination and standard imaging might not identify subluxations that only occur with movement or weight bearing. Specific imaging such as dynamic imaging, imaging at end-range, or visualization of soft- tissue damage may be needed. Patients with significant upper-extremity involvement may not be candidates for assistive technology to aid mobility. Consequently, the patient might not have been given a mobility device because he/she would not have been able to effectively use it.

EFFECTS ON FUNCTION 289 ANNEX TABLE 5-17 Continued Listings* Notes 1.21 Soft-tissue injury or Soft-tissue injuries/pain are very common. Sometimes abnormality under continuing a single body part is severely involved, but it is also surgical management common that there may be many body parts that combine to create severe functional limitations. For example, involvement of bilateral upper-extremity involvement in addition to bilateral lower-extremity involvement may limit capacity to use mobility devices. For example, using a wheelchair may aggravate hand instability and pain, thus incapacitating the hands as well. Surgery is often less successful and more often avoided in patients with than in those without hypermobility. Therefore, the requirement of past surgery is less likely to be met even though a patient may have equally severe functional limitations due to soft-tissue problems. Patients are sometimes unable to fully engage in therapy because of associated problems such as fatigue, depression, brain fog, gastrointestinal disorders, or other musculoskeletal issues. 2.02 Loss of central visual acuity (meeting the specified criteria) 2.03 Contraction of the visual field in the better eye (meeting the specified criteria) 2.04 Loss of visual efficiency, or visual impairment, in the better eye (meeting the specified criteria) 2.07 Disturbance of Might meet vestibular criteria but hearing criteria may labyrinthine-vestibular function not be applicable. (including Ménière’s disease), characterized by a history of frequent attacks of balance disturbance, tinnitus, and progressive loss of hearing 3.03 Asthma 3.07 Bronchiectasis 3.14 Respiratory failure 4.10 Aneurysm of aorta or major branches 5.08 Weight loss due to any digestive disorder (meeting the specified criteria) continued

290 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE ANNEX TABLE 5-17 Continued Listings* Notes 11.08 Spinal cord disorders 12.04 Depressive, bipolar, and related disorders 12.06 Anxiety and obsessive- compulsive disorders 14.09 Inflammatory arthritis *SSA, n.d.-b, provides the criteria for each of the listings included here.

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Heritable disorders of connective tissue (HDCTs) are a diverse group of inherited genetic disorders and subtypes. Because connective tissue is found throughout the body, the impairments associated with HDCTs manifest in multiple body systems and may change or vary in severity throughout an affected individual's lifetime. In some cases, these impairments may be severe enough to qualify an eligible child or adult for monetary benefits through the U.S. Social Security Administration's (SSA's) Social Security Disability Insurance or Supplemental Security Income program. SSA asked the National Academies of Sciences, Engineering, and Medicine to convene an expert committee that would provide current information regarding the diagnosis, treatment, and prognosis of selected HDCTs, including Marfan syndrome and the Ehlers-Danlos syndromes, and the effect of the disorders and their treatment on functioning. The resulting report, Selected Heritable Disorders of Connective Tissue and Disability, presents the committee's findings and conclusions.

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