6

Overall Conclusions¹

This chapter presents eight overall conclusions derived by the committee from evidence provided throughout the report. The first section includes narrative summaries of evidence supporting these overall conclusions. 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 secondary 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

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¹ This chapter does not include references. Citations to support the text and conclusions herein are provided in previous chapters of the report.

syndrome (LDS) and congenital contractural arachnodactyly are related hereditary aortopathies that manifest particularly in cardiovascular, cerebrovascular, 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 involvement. Hypermobility spectrum disorders (HSD) are clinically similar to hypermobile EDS (hEDS) with respect to their manifestations and management. 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 manifestations 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, including 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 manifestations 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 management of previously fatal complications (e.g., aortic rupture, spontaneous pneumothorax) are accompanied by concurrent increases in the occurrence and severity of age-related secondary impairments. 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.

Individuals with EDS/HSD also exhibit multiple clinical manifestations 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 functional limitations experienced by individuals with HDCTs are also affected by environmental factors (e.g., extreme heat and cold, noise, vibration, wetness, 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 common 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.

Upon reviewing SSA’s Listing of Impairments–Adult Listings, the committee 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 impairments 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 individuals with HDCTs.

Diagnosis

Early diagnosis of HDCTs is important to reduce physical injury, reduce 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 succession of different specialists. Other factors that may contribute to delays in

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 aortic 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 surgery, 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 negative 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 diagnosis, 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, especially in some geographic areas);
     • historical bias and denial among health care providers, patients, and family members about the reality of the lived experience of manifestations of the disorders; and
     • inaccurate expectations that there will be a diagnostic genetic test for every HDCT.

• 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 diagnosis, 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 curative treatments, but appropriate management can reduce the frequency and severity of the disorders’ manifestations and resulting functional limitations. 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, appropriate 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.

Barriers to Access to Care

Individuals with HDCTs often experience difficulty obtaining appropriate 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 providers, 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 appropriate education, a variety of health care providers, including, for example, physicians, nurses, psychologists, neuropsychologists, rehabilitation specialists (e.g., physiatrists; physical, occupational, and speech therapists), nutritionists, 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 management 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 childbirth. 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 professional education programs, professional organizations, and publishers of quality biomedical research.

For these reasons, the committee drew the following overall conclusions:

6. Education about HDCTs, including their multisystem manifestations, diagnosis, and management, is important for all clinicians to help increase 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 diagnostic 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

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 functional 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 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).

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 conclusions that support them.²

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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.

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