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Suggested Citation:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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:"6 Overall Conclusions." 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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6 Overall Conclusions1 This chapter presents eight overall conclusions derived by the com- mittee from evidence provided throughout the report. The first section includes narrative summaries of evidence supporting these overall conclu- sions. Chapters 2 through 5 of the report each end with a set of chapter- specific findings and conclusions based on the evidence presented in that chapter. The second section of the present chapter includes a selection of those chapter-specific findings and conclusions that support each of the overall conclusions. OVERALL CONCLUSIONS Nature of Heritable Disorders of Connective Tissue Heritable disorders of connective tissue (HDCTs) are a heterogeneous group of inherited disorders that affect connective tissues throughout the body. Connective tissue is an integral component of all organ systems and plays a crucial role in their function. Hence, the physical and mental sec- ondary impairments (i.e., medical diagnoses, syndromes, or comorbid and other health conditions) associated with HDCTs manifest throughout the body and can affect functioning in every body system. Marfan syndrome (MFS) often manifests in cardiovascular, nervous, respiratory, musculoskeletal, and ocular system impairments. Loeys-Dietz 1 This chapter does not include references. Citations to support the text and conclusions herein are provided in previous chapters of the report. 291

292 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE syndrome (LDS) and congenital contractural arachnodactyly are related he- reditary aortopathies that manifest particularly in cardiovascular, cerebro- vascular, respiratory, musculoskeletal, craniofacial, ocular, and neurological impairments. Shprintzen-Goldberg syndrome manifests in developmental delays and intellectual disability, as well as impairments associated with the other hereditary aortopathies. The Ehlers-Danlos syndromes (EDS) are a group of HDCTs that share common elements of joint hypermobility and skin and soft-tissue involve- ment. Hypermobility spectrum disorders (HSD) are clinically similar to hypermobile EDS (hEDS) with respect to their manifestations and manage- ment. EDS/HSD manifest in secondary impairments in any organ system and often in multiple organ systems in a given individual, although the likelihood of specific manifestations depends on the type of EDS. Vascular impairments, which can be life-threatening, are characteristic of vascular EDS (vEDS), for example. As with many other chronic conditions, mental disorders (e.g., depression and anxiety) are also commonly experienced by individuals with EDS. Additional features of pain; fatigue; mild cognitive impairment; dysautonomia; and gastrointestinal, respiratory, neurological, and immune dysfunction are also common among EDS patients but often underappreciated, particularly given their waxing and waning nature in affected individuals. Physical and mental secondary impairments associated with HDCTs may develop and vary in severity over time. Many manifestations of MFS and the related hereditary aortopathies worsen over time, with some mani- festations not appearing until adulthood. The type and severity of EDS manifestations frequently vary both among individuals and throughout an affected individual’s lifetime. Secondary impairments associated with EDS often emerge or worsen during puberty. Notably, mortality resulting from unanticipated vascular events was found to have increased 3-fold in males with vEDS under age 20. The severity of HDCTs is linked to the severity of affected individuals’ physical and mental secondary impairments, includ- ing the combined effects of multiple impairments, as well as the frequency, severity, and predictability of their fluctuations. Secondary impairments in any of the body systems can be severe and affect an individual’s physical and mental functioning. MFS and related hereditary aortopathies have multiple clinical manifes- tations that, individually or in combination, can cause functional limitations of varying severity, often involving multiple body systems. Increases in the life spans of affected individuals resulting from improvements in manage- ment of previously fatal complications (e.g., aortic rupture, spontaneous pneumothorax) are accompanied by concurrent increases in the occur- rence and severity of age-related secondary impairments. General physical activity guidelines exist for people with MFS and related disorders, such

OVERALL CONCLUSIONS 293 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. Individuals with EDS/HSD also exhibit multiple clinical manifesta- tions that, individually or in combination, can affect their functioning with varying degrees of severity. Limitations associated with pain, fatigue, and anxiety may be particularly pronounced. Chronic pain, chronic fatigue, and cognitive dysfunction are some of the most common and potentially disabling manifestations of EDS, especially hEDS/HSD, and MFS. The func- tional limitations experienced by individuals with HDCTs are also affected by environmental factors (e.g., extreme heat and cold, noise, vibration, wet- ness, humidity, atmospheric conditions) and physical and mental demands. In addition, physical and mental demands related to school or work may precipitate or exacerbate these limitations. For these reasons, the committee drew the following overall conclusion: 1. Heritable disorders of connective tissue (HDCTs) comprise a large and varied group of disorders in children and adults that share the com- mon feature of pronounced involvement of connective tissues, usually in multiple organ systems. HDCTs can lead to a variety of physical and mental secondary impairments (i.e., manifestations, medical diagnoses, syndromes, comorbidities, or other health conditions) and associated functional limitations. Impairments can range from minor to severe and even life-threatening and may fluctuate in severity over time in an individual. Functional limitations may be sufficiently severe to interfere with participation in work and school, as well as social and recreational activities, and may include precautions and restrictions on activities to avoid aggravating the condition. Heritable Disorders of Connective Tissue and Disability A challenge in assessment of functioning in individuals with HDCTs is capturing the full effect of their impairment(s) on their daily activities, including participation in work and school. This is particularly true when a person has multiple impairments. Numerous validated performance-based and self-reported measures are available for assessing physical and mental functioning in persons with HDCTs, including several that can be used to perform an integrated assessment of an individual’s overall physical and mental functioning. 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 unpredictable and may limit the ability to sustain gainful employment.

294 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE Upon reviewing SSA’s Listing of Impairments–Adult Listings, the com- mittee found that some of the listings include severity criteria for some of the secondary impairments that may be experienced by individuals with MFS, EDS, and other HDCTs. The committee also concluded that other listings, with some modification, could apply to certain secondary impair- ments experienced by individuals with HDCTs. In addition, the combined effects of the secondary impairments experienced by an individual may limit function with a degree of severity sufficient to preclude the person’s ability to participate in work on a “regular and continuing basis” (i.e., 8 hours per day, 5 days per week, or an equivalent work schedule) or, for children, to result in “marked and severe functional limitations.” 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. For these reasons, the committee drew the following overall conclusion: 2. Some of SSA’s Adult Listings apply directly to secondary impairments experienced by individuals with HDCTs and could be used to evaluate disability in those individuals. Other listings, with some modification, could apply to certain secondary impairments experienced by individu- als with HDCTs. Diagnosis Early diagnosis of HDCTs is important to reduce physical injury, re- duce psychological harm to the affected individual and family members, and prevent the risks associated with inappropriate or fragmented medical care. HDCTs are diagnosed through a combination of clinical findings and established clinical criteria, followed by confirmatory molecular genetic testing when specific genes have been identified for the suspected disorder. Some HDCTs, such as hEDS, do not yet have a known genetic marker or test, and the absence of molecular genetic testing should not necessarily rule out the diagnosis if the clinical suspicion remains based on clinical findings. An HDCT diagnosis should be considered for individuals who present with previously undiagnosed complex multisystem disorders; however, diagnosis of some HDCTs, in particular EDS, is often delayed, in some cases for a decade or more. One reason for delayed diagnosis is that because HDCTs can cause a wide variety of physical and mental secondary impairments involving multiple organ systems, patients often are referred to a succes- sion of different specialists. Other factors that may contribute to delays in

OVERALL CONCLUSIONS 295 diagnosis of HDCTs include minimal training in and knowledge about the disorders among health care providers and a corresponding shortage of providers with expertise in diagnosing and managing them. Delayed diagnosis may exacerbate manifestations of HDCTs or have life-threatening consequences. For example, lack of monitoring for aortic root enlargement in MFS or LDS could lead to aortic dissection and death. Likewise, failure to recognize a characteristic phenotype (e.g., of MFS) in a patient presenting with chest pain could result in delayed diagnosis of aor- tic dissection, with potentially catastrophic results. When diagnosed early, and with appropriate management, most people with classic MFS have a relatively normal life expectancy. Conversely, in addition to complications from secondary impairments, individuals with undiagnosed EDS may face unanticipated EDS-specific risks and harms, such as tissue fragility and physiologic reactivity resulting from autonomic and immune dysregulation, that attend routine procedures and therapies. Similarly, people with versus those without EDS often have a worse trajectory following trauma or sur- gery, in terms of both length of recovery and frequency of complications. Affected individuals also report inappropriate assessments and incorrect diagnoses, and many develop a mistrust of medical professionals and nega- tive expectations about future health care encounters, which may lead them to avoid further medical consultations. For these reasons, the committee drew the following overall conclusion: 3. Early diagnosis of HDCTs is important to reduce physical injury, reduce psychological harm to the individual and family members, and prevent the risks associated with inappropriate or fragmented medical care. • Diagnosis of HDCTs is often delayed because of – the multisystem, complex, and phenotypically variable nature of the disorders; – lack of knowledge about HDCTs among health care providers, patients and family members, and other stakeholders; – lack of experience with using the syndromic approach to diag- nosis, in which diagnosis is based on characteristic groups of symptoms and signs; – lack of access to comprehensive, multidisciplinary care teams with expertise in HDCTs (due to a shortage of clinicians, espe- cially in some geographic areas); – historical bias and denial among health care providers, pa- tients, and family members about the reality of the lived experi- ence of manifestations of the disorders; and – inaccurate expectations that there will be a diagnostic genetic test for every HDCT.

296 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE • Delayed or misdiagnosis of individuals with HDCTs can result in – inappropriate medical interventions; – inability to accurately assess the risks and benefits associated with medical procedures; – inability to access necessary reasonable accommodations at work or school; – family stress and dysfunction; – stress associated with unexplained and repeated evidence of trauma, leading to inappropriate suspicion of child abuse; – inappropriate assessments and incorrect diagnoses; and – mistrust of health care providers and negative expectations for future health care encounters. • Timely diagnosis and recognition of the many physical and mental secondary impairments with which HDCTs can present and action to address them, even if in the absence of a specific molecular di- agnosis, can dramatically improve individuals’ quality of life and functional status, including the ability to participate in work and school. Management HDCTs are lifelong disorders for which there presently exist no cura- tive treatments, but appropriate management can reduce the frequency and severity of the disorders’ manifestations and resulting functional limita- tions. Management of HDCTs involves supportive care, early diagnosis and treatment of associated physical and mental secondary impairments, and preventive strategies to lessen or prevent problems that may occur over time. Because of the complex, multisystem nature of HDCTs, high-quality care for individuals with these disorders relies on effective coordination among a team of health care providers across a broad range of disciplines with expertise in the disorders. For these reasons, the committee drew the following overall conclusion: 4. Although curative treatments for HDCTs do not exist at this time, ap- propriate understanding and management of the disorders can reduce the frequency and severity of their manifestations and resulting func- tional consequences. High-quality care for individuals with HDCTs relies on effective coordination among a team of clinicians across a broad range of physical and mental health care disciplines who are knowledgeable about these disorders.

OVERALL CONCLUSIONS 297 Barriers to Access to Care Individuals with HDCTs often experience difficulty obtaining appro- priate and integrated multidisciplinary care to address the wide range of associated impairments. Barriers to appropriate care include insufficient training in and knowledge about the disorders among health care provid- ers, which contributes to a shortage of clinicians with expertise in their diagnosis and management. In addition, access to multidisciplinary teams and relevant specialists is limited or nonexistent in rural areas; even many university centers lack multidisciplinary teams with expertise in HDCTs. For these reasons, the committee drew the following overall conclusion: 5. Access to comprehensive, multidisciplinary care for the diagnosis and management of HDCTs can be limited by geography and other factors, including the availability of care teams with expertise in the disorders. Education Education about HDCTs, including their multisystem manifestations, diagnosis, and management, is important for all health care providers to help increase recognition and earlier diagnosis of the disorders. With appro- priate education, a variety of health care providers, including, for example, physicians, nurses, psychologists, neuropsychologists, rehabilitation special- ists (e.g., physiatrists; physical, occupational, and speech therapists), nutri- tionists, and others, should be able to recognize HDCTs and direct affected individuals to the appropriate care providers for management. Clinicians performing procedures or providing anesthesia and periprocedures manage- ment need to be aware of the altered procedural and postprocedural risks associated with HDCTs and to have a screening strategy for these disorders. It is also important for individuals with HDCTs and their family members to learn about strategies for preventing or mitigating symptoms, as well as the risks associated with certain activities that may result in physical trauma, such as physically demanding activities or pregnancy and child- birth. Relevant support groups provide valuable education regarding the manifestations and lived experience of the disorders. Increased recognition of the breadth and scope of HDCTs is needed among health care profes- sional education programs, professional organizations, and publishers of quality biomedical research. For these reasons, the committee drew the following overall conclusions:

298 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 6. Education about HDCTs, including their multisystem manifestations, diagnosis, and management, is important for all clinicians to help in- crease recognition and earlier diagnosis of the disorders and enable the provision of appropriate care. • A variety of health care providers should be able to recognize HDCTs and direct affected individuals to the appropriate clinicians for management. • Individuals with HDCTs and relevant support groups can provide valuable insight regarding the manifestations and lived experience of the disorders. • Increased recognition of the breadth and scope of HDCTs by health care professional education programs, professional organizations, and publishers of quality biomedical research is needed. 7. Education of individuals with the disorders and their families, as well as employers and school staff, is important to improve the quality of life for affected individuals and their families, to facilitate appropriate accommodations at work and school, and to help inform the disability assessment and determination process. Research Gaps HDCTs can be difficult to diagnose, and the true prevalence of many of these disorders is unknown. As noted above, HDCTs are diagnosed through a combination of clinical findings and established clinical criteria, followed by confirmatory molecular genetic testing when specific genes have been identified for the suspected disorder. However, diagnosis of hEDS and HSD is based solely on clinical criteria, since currently no associated causative genes have been identified for either disorder. Understanding of and diag- nostic criteria for these disorders continue to evolve. There currently are no curative treatments for MFS and related hereditary aortopathies, EDS, or HSD, making this an important area for research. In addition, more research is needed to improve understanding of the pathophysiological mechanisms of EDS/HSD and the recognition, management, and outcomes of the many secondary impairments associated with these disorders. The clinical course of HDCTs and their effects on functioning vary greatly among affected individuals. Longitudinal studies of individuals with different HDCTs would increase understanding of the clinical course of the disorders; associated functional limitations; and potentially the impact of

OVERALL CONCLUSIONS 299 interventions, including reasonable accommodations, on participation in work and school. While the severity of HDCTs is linked to the severity of the affected individual’s physical and mental secondary impairments, including the combined effects of multiple impairments, improved understanding and measurement of the effects of impairments and multiple impairments on functioning could advance management of the disorders and improve func- tional status and quality of life for patients. For these reasons, the committee drew the following overall conclusion: 8. Ongoing research on HDCTs is important to advance understanding of the disorders and their effects. In particular, research on care services and interventions for HDCTs and secondary impairments is needed, including • more specific diagnostic criteria and biomarkers; • functional and biomeasures of severity; • effective treatment for HDCTs and management of their physical and mental manifestations, including comparative treatment trials; • the clinical course of the disorders throughout the lifetime of af- fected individuals; • the impact of relevant reasonable accommodations on affected individuals’ ability to participate in work and school; and • benefits versus risks of participation in common childhood activi- ties (e.g., contact sports, gymnastics, dance). SELECTED FINDINGS AND CONCLUSIONS IN SUPPORT OF THE COMMITTEE’S OVERALL CONCLUSIONS Box 6-1 shows the links between the overall conclusions presented above and some of the most relevant chapter-specific findings and conclu- sions that support them.2 2 Not all of the committee’s chapter-specific findings and conclusions are included in Box 6-1. Those that are included are numbered according to the chapter in which they appear.

300 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE BOX 6-1 Overall Conclusions and Selected Chapter- Specific Findings and Conclusions 1. Heritable disorders of connective tissue (HDCTs) comprise a large and varied group of disorders in children and adults that share the com- mon feature of pronounced involvement of connective tissues, usually in multiple organ systems. HDCTs can lead to a variety of physical and mental secondary impairments (i.e., manifestations, medical di- agnoses, syndromes, comorbidities, or other health conditions) and associated functional limitations. Impairments can range from minor to severe and even life-threatening and may fluctuate in severity over time in an individual. Functional limitations may be sufficiently severe to interfere with participation in work and school, as well as social and recreational activities, and may include precautions and restrictions on activities to avoid aggravating the condition. Findings 2-1. Heritable disorders of connective tissue (HDCTs) are a heterogeneous group of inherited disorders that affect connective tissues in organ systems throughout the body. 2-2. Connective tissues are an integral component of every organ system and play a crucial role in the function of those systems. Hence, the physical and mental secondary impairments associated with HDCTs, which may develop and potentially progress or wax and wane over time, manifest throughout the body and affect functioning in every body system. 3-1. Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), congenital con- tractural arachnodactyly (CCA; also known as Beals-Hecht syndrome), and Sphrintzen-Goldberg syndrome (SGS) affect multiple body systems, often with cardiovascular, skeletal, and ocular manifestations. 3-3. Many manifestations of hereditary aortopathies worsen over time, with some not appearing until adulthood. 3-6. As the life spans of patients with these syndromes increase with improve- ments in management of previously fatal complications (e.g., aortic rupture, spontaneous pneumothorax), concurrent increases are seen in the occur- rence and severity of age-related secondary impairments. 3-7. Hereditary aortopathies can affect individuals’ everyday physical and men- tal functioning, often impacting multiple body systems. MFS frequently manifests in cardiovascular, nervous, respiratory, musculoskeletal, and ocular system impairments. LDS and CCA manifest particularly in cardio- vascular, cerebrovascular, respiratory, musculoskeletal, craniofacial, ocular, and neurological impairments. SGS manifests in developmental delays and intellectual disability as well as impairments associated with the other hereditary aortopathies. 4-1. The Ehlers-Danlos syndromes (EDS) are a group of multisystem, heritable disorders of connective tissue (HDCTs) that share common elements of joint hypermobility and skin and soft tissue involvement. Hypermobility spectrum disorders (HSD) are also multisystem connective tissue disorders

OVERALL CONCLUSIONS 301 that are clinically similar to hypermobile EDS (hEDS) with respect to their manifestations and management. 4-3. EDS/HSD can manifest in physical and mental secondary impairments in any organ system and often in multiple organ systems in a given individual. 4-4. The type and severity of physical and mental manifestations associated with EDS/HSD often vary both among individuals and throughout an af- fected individual’s lifetime. Epidemiologic evidence supports multi–organ system manifestations, high treatment burden, and high disease burden. Conclusions 3-1. MFS and related hereditary aortopathies have multiple physical and mental manifestations that, individually or in combination, can cause functional limitations of varying severity. Some manifestations may become appar- ent only with age, and the severity of manifestations may, and often does, progress with age. Treatment can be successful in reducing impairments in selected cases. 4-1. EDS and HSD have multiple clinical manifestations that, individually or in combination, can cause functional limitations of varying severity. Some manifestations may become apparent only with age, and the types and severity of manifestations may vary throughout an affected individual’s lifetime. 2. Some of SSA’s Adult Listings apply directly to secondary impairments experienced by individuals with HDCTs and could be used to evaluate disability in those individuals. Other listings, with some modification, could apply to certain secondary impairments experienced by individu- als with HDCTs. Findings 2-9. The clinical course of HDCTs is highly variable and can be impacted not only by the disease-specific manifestations of each unique syndrome, but also by individuals’ physical and mental secondary impairments, as well as environmental factors and physical and psychological demands. 2-10. The severity of HDCTs is linked to the severity of affected individuals’ physi- cal and mental secondary impairments, including the combined effects of multiple impairments, as well as the frequency, severity, and predictability of their fluctuations. 3-1. Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), congenital con- tractural arachnodactyly (CCA; also known as Beals-Hecht syndrome), and Sphrintzen-Goldberg syndrome (SGS) affect multiple body systems, often with cardiovascular, skeletal, and ocular manifestations. 3-3. Many manifestations of hereditary aortopathies worsen over time, with some not appearing until adulthood. 3-6. As the life spans of patients with these syndromes increase with improve- ments in management of previously fatal complications (e.g., aortic rupture, spontaneous pneumothorax), concurrent increases are seen in the occur- rence and severity of age-related secondary impairments. continued

302 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE BOX 6-1 Continued 3-7. Hereditary aortopathies can affect individuals’ everyday physical and men- tal functioning, often impacting multiple body systems. MFS frequently manifests in cardiovascular, nervous, respiratory, musculoskeletal, and ocular system impairments. LDS and CCA manifest particularly in cardio- vascular, cerebrovascular, respiratory, musculoskeletal, craniofacial, ocular, and neurological impairments. SGS manifests in developmental delays and intellectual disability, as well as impairments associated with the other hereditary aortopathies. 3-8. Pregnancy can be a high-risk condition in some individuals with hereditary aortopathies. 4-1. The Ehlers-Danlos syndromes (EDS) are a group of multisystem, heritable disorders of connective tissue (HDCTs) that share common elements of joint hypermobility and skin and soft tissue involvement. Hypermobility spectrum disorders (HSD) are multisystem connective tissue disorders that are clinically similar to hypermobile EDS (hEDS) with respect to their manifestations and management. 4-3. EDS/HSD can manifest in physical and mental secondary impairments in any organ system and often in multiple organ systems in a given individual. 4-4. The type and severity of physical and mental manifestations associated with EDS/HSD often vary both among individuals and throughout an af- fected individual’s lifetime. Epidemiologic evidence supports multi–organ system manifestations, high treatment burden, and high disease burden. 4-13. EDS/HSD can affect individuals’ everyday physical and mental function- ing, particularly as a result of limitations associated with pain, fatigue, and anxiety. 4-14. Secondary impairments in any of the body systems can be severe and affect the functioning of individuals with EDS/HSD. 4-15. Physical and mental secondary impairments associated with EDS/HSD often manifest or worsen during puberty, especially in females. Males with vascular EDS (vEDS) are at higher risk for complications during puberty. 4-16. Pregnancy can be a high-risk condition in some individuals with EDS; women with vEDS have an increased risk of uterine rupture or peripartum hemorrhage. 5-1. The number, type, and severity of the physical and mental secondary impairments experienced by an individual with a heritable disorder of con- nective tissue (HDCT) drive the person’s functioning and potential disability. 5-3. Both physical and mental conditions can precipitate or exacerbate decre- ments 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), hypermo- bility spectrum disorders (HSD), and Marfan syndrome (MFS). 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.

OVERALL CONCLUSIONS 303 5-7. Fatigue associated with EDS 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. 5-13. 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 pres- sure (e.g., scuba diving), and exercise to the point of exhaustion. 5-17. Individuals with HDCTs may experience significant variability in their physi- cal and/or mental secondary impairments from day to day or even within a single day. This variability is often unpredictable and may limit the ability to sustain gainful employment. Conclusions 3-1. MFS and related hereditary aortopathies have multiple physical and mental manifestations that, which individually or in combination, can cause func- tional limitations of varying severity. Some manifestations may become apparent only with age, and the severity of manifestations may, and often does, progress with age. Treatment can be successful in reducing impair- ments in selected cases. 4-1. EDS and HSD have multiple clinical manifestations that, individually or in combination, can cause functional limitations of varying severity. Some manifestations may become apparent only with age, and the types and severity of manifestations may vary throughout an affected individual’s lifetime. 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, including at work and in school. 3. Early diagnosis of HDCTs is important to reduce physical injury, reduce psychological harm to the individual and family members, and prevent the risks associated with inappropriate or fragmented medical care. Findings 2-9. The clinical course of HDCTs is highly variable and can be impacted not only by the disease-specific manifestations of each unique syndrome, but also by individuals’ physical and mental secondary impairments, as well as environmental factors and physical and psychological demands. 2-10. The severity of HDCTs is linked to the severity of affected individuals’ physi- cal and mental secondary impairments, including the combined effects of multiple impairments, as well as the frequency, severity, and predictability of their fluctuations. continued

304 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE BOX 6-1 Continued 5-1. The number, type, and severity of the physical and mental secondary im- pairments experienced by an individual with an HDCT drive the person’s functioning and potential disability. 5-9. A challenge in assessment of functioning is capturing the full effect 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, including several that can be used to perform an integrated assessment of an individual’s overall physical and mental functioning. 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 experi- enced by individuals with HDCTs such as MFS, EDS, and related disorders. 5-17. Individuals with HDCTs may experience significant variability in their physi- cal and/or mental secondary impairments from day to day or even within a single day. This variability is often unpredictable and may limit the ability to sustain gainful employment. Conclusions 5-2. Accurately assessing the full effect of an individual’s impairment(s) is es- pecially important for SSA disability determinations. This is particularly 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. 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. 5-5. 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 individuals. Other listings, with some modification, could apply to individuals with certain secondary impairments associated with their HDCTs. 5-6. The combined effects of an individual’s physical and/or mental second- ary impairments may limit function with a degree of severity sufficient to preclude the ability to participate in work on a “regular and continuing basis” (8 hours per day, 5 days per week, or an equivalent work sched- ule) or, for children, to cause “marked and severe functional limitations.” 4. Although curative treatments for HDCTs do not exist at this time, appro- priate understanding and management of the disorders can reduce the frequency and severity of their manifestations and resulting functional consequences. High-quality care for individuals with HDCTs relies on effective coordination among a team of clinicians across a broad range of physical and mental health care disciplines who are knowledgeable about these disorders.

OVERALL CONCLUSIONS 305 Findings 2-9. The clinical course of HDCTs is highly variable and can be impacted not only by the disease-specific manifestations of each unique syndrome, but also by individuals’ physical and mental secondary impairments, as well as environmental factors and physical and psychological demands. 3-4. No curative treatments currently exist for MFS, LDS, CCA, SGS, or other hereditary aortopathies. Management of these disorders involves early diagnosis and aggressive monitoring and treatment of manifestations in multiple organ systems, including treatment of associated physical and mental secondary impairments present at the time of identification and measures to reduce or prevent problems that may occur with age. 4-8. There are currently no curative treatments for EDS or HSD. Management of the disorders involves early diagnosis and recognition; monitoring; and treatment of the manifestations in multiple organ systems, including treat- ment of associated physical and mental secondary impairments present at the time of identification and preventive measures to lessen or prevent problems that may develop over time. 4-12. Delayed diagnosis may result in a lack of or inappropriate management that may exacerbate physical and mental manifestations of EDS/HSD. Un- anticipated risks and harms may attend routine procedures and therapies that carry EDS/HSD-specific risks, such as tissue fragility and physiologic reactivity resulting from autonomic and immune dysregulation. 4-13. EDS/HSD can affect individuals’ everyday physical and mental function- ing, particularly as a result of limitations associated with pain, fatigue, and anxiety. 4-14. Secondary impairments in any of the body systems can be severe and affect the functioning of individuals with EDS/HSD. 4-15. Physical and mental secondary impairments associated with EDS/HSD often manifest or worsen during puberty, especially in females. Males with vEDS are at higher risk for complications during puberty. 4-17. Following trauma or surgery, individuals with versus those without EDS/ HSD often have a worse trajectory in terms of both length of recovery and frequency of complications. Conclusions 2-2. Early diagnosis of HDCTs is important to reduce physical injury, reduce psychological harm to affected individuals and their family members, and prevent the risks associated with inappropriate medical care. 2-3. Appropriate multisystem assessments are important at the time of HDCT diagnosis and at intervals across a person’s life. 2-4. Appropriate multidisciplinary understanding and management of HDCTs can reduce the frequency and severity of their manifestations and resulting functional limitations. continued

306 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE BOX 6-1 Continued 3-2. Management of MFS and related hereditary aortopathies requires a mul- tidisciplinary approach and involves early diagnosis of the multisystem findings associated with these syndromes, treatment of associated physical and mental secondary impairments, and measures to reduce or prevent problems that may present with aging. 4-2. Development of a screening tool to identify EDS/HSD could provide timely diagnosis of the disorder and help mitigate the negative effects of delayed diagnosis and EDS/HSD-specific risks that may attend routine procedures and therapies. 4-3. Management EDS/HDS requires a multidisciplinary approach and involves early diagnosis of the multisystem findings, treatment of associated physi- cal and mental secondary impairments, and measures to reduce or prevent problems that may present over time. 4-6. Health care providers need to be aware of the EDS/HSD-specific risks that may attend routine procedures and therapies. 5. Access to comprehensive, multidisciplinary care for the diagnosis and management of HDCTs can be limited by geography and other factors, including the availability of care teams with expertise in the disorders. Findings 2-6. HDCTs are lifelong disorders for which no curative treatments currently ex- ist. Management involves supportive care, treatment of associated second- ary impairments, and preventive measures to mitigate or prevent problems that may occur or worsen over time. 2-9. The clinical course of HDCTs is highly variable and can be impacted not only by the disease-specific manifestations of each unique syndrome, but also by individuals’ physical and mental secondary impairments, as well as environmental factors and physical and psychological demands. 3-4. No curative treatments currently exist for MFS, LDS, CCA, SGS, or other hereditary aortopathies. Management of these disorders involves early diagnosis and aggressive monitoring and treatment of manifestations in multiple organ systems, including treatment of associated physical and mental secondary impairments present at the time of identification and measures to reduce or prevent problems that may occur with age. 3-5. Management of MFS and related hereditary aortopathies is lifelong and involves specialists across multiple physical and mental health disciplines. 4-8. There are currently no curative treatments for EDS or HSD. Management of the disorders involves early diagnosis and recognition; monitoring; and treatment of the manifestations in multiple organ systems, including treat- ment of associated physical and mental secondary impairments present at the time of identification and preventive measures to lessen or prevent problems that may develop over time. 4-10. Individuals with vEDS have a decreased life expectancy, with a median survival age of 46 for males and 54 for females.

OVERALL CONCLUSIONS 307 4-12. Delayed diagnosis may result in a lack of or inappropriate management that may exacerbate physical and mental manifestations of EDS/HSD. Un- anticipated risks and harms may attend routine procedures and therapies that carry EDS/HSD-specific risks, such as tissue fragility and physiologic reactivity resulting from autonomic and immune dysregulation. 4-13. EDS/HSD can affect individuals’ everyday physical and mental function- ing, particularly as a result of limitations associated with pain, fatigue, and anxiety. 4-14. Secondary impairments in any of the body systems can be severe and affect the functioning of individuals with EDS/HSD. 4-17. Following trauma or surgery, individuals with versus those without EDS/ HSD often have a worse trajectory in terms of both length of recovery and frequency of complications. Conclusions 2-1. Consideration of a diagnosis of an HDCT is warranted for individuals who present with previously undiagnosed complex multisystem disorders. 2-2. Early diagnosis of HDCTs is important to reduce physical injury, reduce psychological harm to affected individuals and their family members, and prevent the risks associated with inappropriate medical care. 2-3. Appropriate multisystem assessments are important at the time of HDCT diagnosis and at intervals across a person’s life. 2-4. Appropriate multidisciplinary understanding and management of HDCTs can reduce the frequency and severity of their manifestations and resulting functional limitations. 3-1. MFS and related hereditary aortopathies have multiple physical and mental manifestations that, individually or in combination, can cause functional limitations of varying severity. Some manifestations may become appar- ent only with age, and the severity of manifestations may, and often does, progress with age. Treatment can be successful in reducing impairments in selected cases. 3-2. Management of MFS and related hereditary aortopathies requires a mul- tidisciplinary approach and involves early diagnosis of the multisystem findings associated with these syndromes, treatment of associated physical and mental secondary impairments, and measures to reduce or prevent problems that may present with aging. 4-2. Development of a screening tool to identify EDS/HSD could provide timely diagnosis of the disorder and help mitigate the negative effects of delayed diagnosis and EDS/HSD-specific risks that may attend routine procedures and therapies. 4-3. Management of EDS/HSD requires a multidisciplinary approach and in- volves early diagnosis of the multisystem findings, treatment of associated physical and mental secondary impairments, and measures to reduce or prevent problems that may present over time. 4-6. Health care providers need to be aware of the EDS/HSD-specific risks that may attend routine procedures and therapies. continued

308 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE BOX 6-1 Continued 6. Education about HDCTs, including their multisystem manifestations, diagnosis, and management, is important for all clinicians to help in- crease recognition and earlier diagnosis of the disorders and enable the provision of appropriate care. Findings 2-1. Heritable disorders of connective tissue (HDCTs) are a heterogeneous group of inherited disorders that affect connective tissues in organ systems throughout the body. 2-2. Connective tissues are an integral component of every organ system and play a crucial role in the function of those systems. Hence, the physical and mental secondary impairments associated with HDCTs, which may develop and potentially progress or wax and wane over time, manifest throughout the body and affect functioning in every body system. 2-4. Because HDCTs can cause a wide variety of physical and mental second- ary impairments involving multiple organ systems, affected individuals often are referred to a succession of different specialists, resulting in delayed diagnosis of the underlying HDCT. 2-6. HDCTs are lifelong disorders for which no curative treatments currently ex- ist. Management involves supportive care, treatment of associated second- ary impairments, and preventive measures to mitigate or prevent problems that may occur or worsen over time. 3-5. Management of MFS and related hereditary aortopathies is lifelong and involves specialists across multiple physical and mental health disciplines. 4-1. The Ehlers-Danlos syndromes (EDS) are a group of multisystem, heritable disorders of connective tissue (HDCTs) that share common elements of joint hypermobility and skin, and soft tissue involvement. Hypermobility spectrum disorders (HSD) are HDCTs that are clinically similar to hyper- mobile EDS (hEDS) with respect to their manifestations and management. 4-11. Diagnosis and management of EDS and HSD involve specialists across multiple physical and mental health disciplines. Conclusions 2-3. Appropriate multisystem assessments are important at the time of HDCT diagnosis and at intervals across a person’s life. 2-4. Appropriate multidisciplinary understanding and management of HDCTs can reduce the frequency and severity of their manifestations and resulting functional limitations. 3-2. Management of MFS and related hereditary aortopathies requires a mul- tidisciplinary approach and involves early diagnosis of the multisystem findings associated with these syndromes, treatment of associated physical and mental secondary impairments, and measures to reduce or prevent problems that may present with aging.

OVERALL CONCLUSIONS 309 4-3. Management EDS/HDS requires a multidisciplinary approach and involves early diagnosis of the multisystem findings, treatment of associated physi- cal and mental secondary impairments, and measures to reduce or prevent problems that may present over time. 7. Education of individuals with the disorders and their families, as well as employers and school staff, is important to improve the quality of life for affected individuals and their families, to facilitate appropriate accommodations at work and school, and to help inform the disability assessment and determination process. Findings 2-3. HDCTs can be difficult to diagnose, and the true prevalence of many of these disorders is unknown. 2-4. Because HDCTs can cause a wide variety of physical and mental second- ary impairments involving multiple organ systems, affected individuals often are referred to a succession of different specialists, resulting in delayed diagnosis of the underlying HDCT. 2-5. HDCTs are diagnosed through a combination of clinical findings and estab- lished clinical criteria, followed by confirmatory molecular genetic testing when specific genes have been identified for the suspected disorder. 2.7 Individuals with HDCTs often experience difficulty with obtaining appro- priate and integrated multidisciplinary care to address the wide range of physical and mental impairments associated with these disorders. 2-8. Access to comprehensive, multidisciplinary care for the diagnosis and management of HDCTs can be limited by geography and other factors, including the availability of care teams with expertise in the disorders. 3-5. Management of MFS and related hereditary aortopathies is lifelong and involves specialists across multiple physical and mental health disciplines. 4-7. Diagnosis of hEDS and HSD is based solely on clinical criteria, since nei- ther has a known genetic test. Understanding of and diagnostic criteria for hEDS and HSD continue to evolve. 4-11. Diagnosis and management of EDS and HSD involve specialists across multiple physical and mental health disciplines. Conclusion 2-4. Appropriate multidisciplinary understanding and management of HDCTs can reduce the frequency and severity of their manifestations and resulting functional limitations. 8. Ongoing research on HDCTs is important to advance understanding of the disorders and their effects. In particular, research on care services and interventions for HDCTs and secondary impairments is needed, including continued

310 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE BOX 6-1 Continued • more specific diagnostic criteria and biomarkers; • functional and biomeasures of severity; • effective treatment for HDCTs and management of their physical and mental manifestations, including comparative treatment trials; • the clinical course of the disorders throughout the lifetime of affected individuals; • the impact of relevant reasonable accommodations on affected individuals’ ability to participate in work and school; and • benefits versus risks of participation in common childhood activities (e.g., contact sports, gymnastics, dance). Findings 2-3. HDCTs can be difficult to diagnose, and the true prevalence of many of these disorders is unknown. 2-5. HDCTs are diagnosed through a combination of clinical findings and estab- lished clinical criteria, followed by confirmatory molecular genetic testing when specific genes have been identified for the suspected disorder. 2-6. HDCTs are lifelong disorders for which no curative treatments currently ex- ist. Management involves supportive care, treatment of associated second- ary impairments, and preventive measures to mitigate or prevent problems that may occur or worsen over time. 3-4. No curative treatments currently exist for MFS, LDS, CCA, SGS, or other hereditary aortopathies. Management of these disorders involves early diagnosis and aggressive monitoring and treatment of manifestations in multiple organ systems, including treatment of associated physical and mental secondary impairments present at the time of identification and measures to reduce or prevent problems that may occur with age. 4-5. The pathophysiologic relationship between EDS/HSD and many of their manifestations and comorbid conditions are unclear, and the evidence linking them is primarily associative. 4-6. Diagnosis of EDS/HSD is based on established clinical criteria, and most, though not all, types can be confirmed through genetic testing.

OVERALL CONCLUSIONS 311 4-7. Diagnosis of hEDS and HSD is based solely on clinical criteria, since nei- ther has a known genetic test. Understanding of and diagnostic criteria for hEDS and HSD continue to evolve. 4-8. There are currently no curative treatments for EDS or HSD. Management of the disorders involves early diagnosis and recognition; monitoring; and treatment of the manifestations in multiple organ systems, including treat- ment of associated physical and mental secondary impairments present at the time of identification and preventive measures to lessen or prevent problems that may develop over time. 4-9. The prognosis and clinical course of EDS/HSD depend on individual patient factors, which vary greatly among affected individuals and are often related to the severity of disease-associated physical and mental secondary im- pairments, as well as the EDS/HSD type. 5-5. A complex relationship exists among pain, fatigue, postural orthostatic tachycardia syndrome, and mast cell activation disease. Conclusions 4-2. Development of a screening tool to identify EDS/HSD could provide timely diagnosis of the disorder and help mitigate the negative effects of delayed diagnosis and EDS/HSD-specific risks that may attend routine procedures and therapies. 4-4. More research is needed on the pathophysiological mechanisms of EDS/ HSD and their comorbid conditions and the implications for appropriate management and outcomes of the many secondary impairments associ- ated with EDS/HSD. 4-5. Longitudinal studies of individuals with different types of EDS/HSD would increase understanding of the clinical course of the disorders; their effects on physical and mental functioning; and potentially the impact of interven- tions, including reasonable accommodations, on participation in work and school. 4-6. Health care providers need to be aware of the EDS/HSD-specific risks that may attend routine procedures and therapies.

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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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