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Selected Heritable Disorders of Connective Tissue and Disability Paul A. Volberding, Carol Mason Spicer, Tom Cartaxo, and Roberta A. Wedge, Editors Committee on Selected Heritable Disorders of Connective Tissue and Disability Board on Health Care Services Health and Medicine Division A Consensus Study Report of
THE NATIONAL ACADEMIES PRESSâ 500 Fifth Street, NWâ Washington, DC 20001 This activity was supported by Contract/Task Order No. 28321318D00060015/00003 between the National Academy of Sciences and the U.S. Social Security Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-27553-8 International Standard Book Number-10: 0-309-27553-9 Digital Object Identifier: https://doi.org/10.17226/26431 Library of Congress Control Number: 2022943401 Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2022 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2022. Selected heritable disorders of connective tissue and disability. Washington, DC: The National Academies Press. https://doi.org/10.17226/26431.
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Consensus Study Reports publishedÂ by the National Academies of Sciences, Engineering, and MedicineÂ document the evidence-based consensusÂ on the studyâs statement of task by an authoring committee of experts.Â Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committeeâs deliberations. Each report has been subjected to a rigorous and independent peer-review process and it representsÂ theÂ positionÂ ofÂ the National Academies on the statement of task. ProceedingsÂ publishedÂ by the National Academies of Sciences, Engineering, and MedicineÂ chronicle the presentations and discussions at a workshop, symposium, or otherÂ eventÂ convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visitÂ www.nationalacademies.org/about/whatwedo.
COMMITTEE ON SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE AND DISABILITY PAUL A. VOLBERDING (Chair), Professor Emeritus, Department of Epidemiology and Biostatistics, University of California, San Francisco REBECCA BASCOM, Professor, Department of Medicine and Department of Public Health Sciences, Penn State College of Medicine ADAM D. BITTERMAN, Assistant Professor of Orthopaedic Surgery, Zucker School of Medicine at Hofstra/Northwell ANTONIO BULBENA-VILARRASA, Distinguished Professor of Psychiatry and Chair, Department of Psychiatry and Forensic Medicine, Universitat AutÃ²noma de Barcelona PRADEEP CHOPRA, Assistant Professor (Clinical), Department of Medicine, Warren Alpert Medical School of Brown University; Director, Center for Complex Conditions, Rhode Island HARRY C. DIETZ, III (through July 2021), Victor A. McKusick Professor of Medicine and Genetics; Investigator, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine CLAIR A. FRANCOMANO, Professor of Medical and Molecular Genetics, Indiana University School of Medicine; Director, Ehlers- Danlos Society Center for the Ehlers-Danlos Syndromes, Indiana University Health Center WALTER R. FRONTERA, Professor, Department of Physical Medicine, Rehabilitation, and Sports Medicine, and Department of Physiology, University of Puerto Rico School of Medicine PETRA M. KLINGE, Director, Pediatric Neurosurgery Division; Director, Center for CSF Disorders of the Brain and Spine; Professor, Department of Neurosurgery, Warren Alpert Medical School of Brown University BARBARA L. KORNBLAU, Executive Director, Coalition for Disability Health Equity; Professor and Director, Occupational Therapy Program, Idaho State University DEBORAH KRAKOW, Professor and Chair, Department of Obstetrics and Gynecology; Professor of Human Genetics, Pediatrics, and Orthopedic Surgery, David Geffen School of Medicine at the University of California, Los Angeles CHERYL L. MAIER, Medical Director, Emory Special Coagulation Laboratory; Assistant Professor, Department of Pathology and Laboratory Medicine, Emory University School of Medicine v
ANNE L. MAITLAND, Assistant Professor, Department of Medicine, Icahn School of Medicine at Mount Sinai; Attending Physician, Mount Sinai South Nassau Chiari EDS Center Program; Medical Director, Comprehensive Allergy & Asthma Care and 3 Pillars Therapeutics REED E. PYERITZ, William Smilow Professor of Medicine Emeritus, and Professor of Genetics Emeritus, University of Pennsylvania Perelman School of Medicine LESLIE N. RUSSEK, Professor Emeritus, Department of Physical Therapy, Clarkson University ERIC L. SINGMAN, Professor, Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine Study Staff CAROL MASON SPICER, Study Director TOM CARTAXO, Associate Program Officer (through December 2021) ROBERTA A. WEDGE, Senior Program Officer (from December 2021) AUSTEN APPLEGATE, Research Associate (from May 2022) VICTORIA BROWN, Senior Program Assistant SHARYL NASS, Senior Director, Board on Health Care Services vi
Reviewers This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manu- script remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: JAMES H. BLACK, III, Johns Hopkins Hospital ANN BURKHARDT, Independent Consultant JEFFERSON J. DOYLE, Johns Hopkins Hospital HOWARD H. GOLDMAN, University of Maryland School of Medicine DAVID LEVINE, University of Tennessee at Chattanooga MARC A. NORMAN, University of California, San Diego LAURA A. PACE, Metrodora Institute JONATHAN RODIS, Marfan Foundation, Massachusetts Chapter JOHNATHAN G. SEIDMAN, Harvard Medical School MAXWELL SLEPIAN, University Health Network Canada JOYCE SO, University of California, San Francisco School of Medicine PAUL DAVID SPONSELLER, Kennedy Krieger Institute WENDY WAGNER, Wendy 4 Therapy JESSICA J. WANG, University of California, Los Angeles vii
viii REVIEWERS Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of this report was overseen by ALAN JETTE, MGH Institute of Health Professions, and ROBERT S. LAWRENCE, Johns Hopkins Bloomberg School of Public Health. They were responsible for making certain that an independent examination of this report was car- ried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.
Preface The U.S. Social Security Administration (SSA) provides support for individualsâadults and childrenâwho are unable to function in employ- ment or school due to chronic disabling medical conditions. While some conditions are straightforward, for example, a disease affecting a single organ, others are more complex, such as disorders that involve multiple organs and body systems. In these, impairments may reflect a summation of dysfunction from an array of sources. Also, while many disabling conditions can be diagnosed easily, others cannot be confirmed with a single biologic test. For these complex disorders affecting multiple organs and body sys- tems determining disability can be challenging. An example of such complex and difficult-to-diagnose disorders leading to impaired occupational and school function are those termed hereditary disorders of connective tissue (HDCTs). HDCTs, including Marfan syn- drome and the Ehlers-Danlos syndromes, can disrupt the structure and function of many organs. Most are inherited with known genetic causes, while some demonstrate involvement of genetic factors with unknown genetic causes. Although often considered uncommon, HDCTs frequently go undiagnosed or are only detected after prolonged delays. Disability in HDCTs varies by the organs affected and the severity of resulting dysfunc- tion. Additionally, many people with these conditions experience pain, fatigue, impaired cognition, and other neurological and immunological disorders. The constellation of clinical manifestations and severity in each person often varies over time. Functional disability in HDCTs can be linked to a single or multiple comorbidities potentially affecting multiple organ ix
x PREFACE systems. HDCTs are not curable, and treatment is directed at preventing or mitigating specific consequences, often termed secondary impairments. SSA, appreciating the difficulty in disability determinations for HDCTs, asked the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine to convene a committee of experts to review these disorders. SSA sought clarification on the epidemiology and diagnosis of HDCTs, on the ways in which these conditions affect the in- dividual and insights into the disability determination process. To this end, the HMD convened a committee who carefully considered evidence in the literature and from invited discussants with both professional and personal experience in this area. The committee collected their findings and conclu- sions to assist SSA in its consideration of this group of medical conditions. On behalf of the committee and the HMD project staff, I extend my sincere thanks to the many individuals who shared their time and expertise to support the committeeâs work and inform its deliberations. The study was sponsored by the SSA, and we thank Andrea Bento, Megan Butson, Gina Clemons, Alayna Ness, Vincent Nibali, and Steven Rollins for their guidance and support. The committee also acknowledges SSA for verifying relevant technical content pertaining to the disability determination pro- cess for accuracy. The committee benefited greatly from discussions with individuals who presented at the committeeâs open sessions: Andrea Bento, Maggie Buckley, Antonio Bulbena-Vilarrasa, Laura Pace, Jon Rodis, Peter Rowe, and Alissa Zingman. The committee is grateful to these presenters for volunteering to share their expertise, knowledge, data, and opinions with the committee and SSA. We also thank Peter Rowe for preparing a commissioned paper based on his presentation. Our appreciation goes to the reviewers for their invaluable feedback on an earlier draft of the report and to the monitor and coordinator who oversaw the report review. The committee acknowledges the many staff within HMD who pro- vided support in various ways to this project, including Carol Mason Spicer (study director), Tom Cartaxo (associate program officer), Victoria Brown (senior program assistant), Roberta Wedge (senior program officer), Austen Applegate (research associate), Karen Helsing (senior program of- ficer), Micah Winograd (senior finance business partner), and Ron Brown (deputy director program finance). The committee extends great thanks and appreciation to Sharyl Nass, senior board director of the Board on Health Care Services, who oversaw the project. Rebecca Morgan (senior librarian) provided research assistance, and the report review, production, and com- munications staff all provided valuable guidance to ensure the success of the final product. Rona BriÃ¨re and her staff are to be credited for the superb editorial assistance they provided in preparing the final report.
PREFACE xi Finally, I would like to deeply thank the committee of experts who volunteered their invaluable service in this review. The field of HDCTs is extremely broad, involving experts on a wide variety of affected body systems and the diagnosis and management of persons with HDCTs. The committee worked selflessly to ensure that the final report could be most effective in assisting SSA address their crucial efforts to guide the disability determination process in an accurate and efficient manner. Paul A. Volberding, Chair Committee on Selected Heritable Disorders of Connective Tissue and Disability
Contents ACRONYMS AND ABBREVIATIONS xxi SUMMARY 1 Study Approach and Scope, 2 Overall Conclusions, 6 1 INTRODUCTION 13 Context for This Study, 13 Study Charge and Scope, 15 Study Approach, 15 Report Organization, 22 References, 22 2 OVERVIEW OF HERITABLE DISORDERS OF CONNECTIVE TISSUE 25 History of the Hereditary Disorders of Connective Tissue, 25 Epidemiology, 26 Genetics, 27 Connective Tissue, 28 Diagnosis, 32 Clinical Course, 35 Disease State Management, 37 Findings and Conclusions, 38 References, 39 xiii
xiv CONTENTS 3 MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 47 History of Marfan Syndrome and Related Hereditary Aortopathies, 47 Diagnosis of Marfan Syndrome and Related Hereditary Aortopathies, 48 Characteristics of Marfan Syndrome and Related Hereditary Aortopathies, 49 Treatment and Management, 58 Emerging Treatments, 61 Findings and Conclusions, 61 References, 63 Annex Table, 70 4 EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY SPECTRUM DISORDERS 73 History of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders, 73 Diagnosis of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders, 77 Characteristics of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders, 81 Treatment and Management, 88 Prognosis, 95 Emerging Treatments, 96 Findings and Conclusions, 97 References, 99 Annex Table, 114 5 HERITABLE DISORDERS OF CONNECTIVE TISSUE AND EFFECTS ON FUNCTION 125 Secondary Impairments, 126 Environmental Factors and Functioning, 128 Global Functioning, 129 Physical Functioning, 145 Vision, Hearing, and Speech Functioning, 149 Mental Functioning, 152 Heritable Disorders of Connective Tissue and the U.S. Social Security Administrationâs Listing of Impairments, 155 Findings and Conclusions, 158 References, 161 Annex Tables, 195
CONTENTS xv 6 OVERALL CONCLUSIONS 291 Overall Conclusions, 291 Selected Findings and Conclusions in Support of the Committeeâs Overall Conclusions, 299 APPENDIXES A Public Session Agendas 313 B Commissioned Paper 317 C Selected Resources 357 D Biographical Sketches of Committee Members 363
Boxes, Figures, and Tables BOXES 1-1 Statement of Task, 16 3-1 Revised Ghent Criteria for Diagnosis of Marfan Syndrome and Related Conditions, 50 3-2 Ghent II Criteria for Scoring of Systemic Measures, 52 6-1 Overall Conclusions and Selected Chapter-Specific Findings and Conclusions, 300 B-1 Methods and Reporting Form for the Passive Standing Test, 326 FIGURES 1-1 ICF model of functioning and disability, 18 2-1 Connective tissue, 29 B-1 Pathophysiologic factors in orthostatic intolerance, 320 B-2 Changes in cerebral blood flow during 30 minutes of head-up tilt compared to supine values in 44 healthy controls and 429 adults with ME/CFS, 331 B-3 Reductions in cerebral blood flow (CBF) from supine values after 30 minutes of head-up tilt in 100 hypermobile and 100 nonhypermobile xvii
xviii BOXES, FIGURES, AND TABLES adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), 334 TABLES 4-1 Clinical Classification of the Ehlers-Danlos Syndromes, Inheritance Pattern, and Genetic Basis, 75 4-2 Selected Hypermobility Assessment Scales, 78 4-3 Surgical and Anesthetic Recommendations for Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type (JHS/ EDS-HT), 94 B-1 Symptoms of Orthostatic Intolerance, 319 B-2 Medications for Orthostatic Intolerance, 338 B-3 Response to Ivabradine in a Young Adult with Joint Hypermobility and Inappropriate Sinus Tachycardia, 341 ANNEX TABLES Annex Table 3-1 Overview of Marfan Syndrome and Related Hereditary Aortopathies, 70 Annex Table 4-1 Overview of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders, 114 Annex Table 5-1 Levels of Work Based on Physical Exertion Requirements, 195 Annex Table 5-2 Physical; Vision, Hearing, and Speech; and Mental Activities, 197 Annex Table 5-3 Selected Musculoskeletal Manifestations Associated with Heritable Disorders of Connective Tissue, 201 Annex Table 5-4 Selected Neurologic Manifestations Associated with Heritable Disorders of Connective Tissue, 213 Annex Table 5-5 Selected Cardiovascular and Hematologic Manifestations Associated with Heritable Disorders of Connective Tissue, 222 Annex Table 5-6 Selected Respiratory Manifestations Associated with Heritable Disorders of Connective Tissue, 225 Annex Table 5-7 Selected Immunologic Manifestations Associated with Heritable Disorders of Connective Tissue, 231 Annex Table 5-8 Selected Gastrointestinal Manifestations Associated with Heritable Disorders of Connective Tissue, 241
BOXES, FIGURES, AND TABLES xix Annex Table 5-9 Selected Cutaneous Manifestations Associated with Heritable Disorders of Connective Tissue, 244 Annex Table 5-10 Selected Genitourinary Manifestations Associated with Heritable Disorders of Connective Tissue, 248 Annex Table 5-11 Selected Vision, Hearing, and Speech Manifestations Associated with Heritable Disorders of Connective Tissue, 252 Annex Table 5-12 Selected Neuropsychiatric Conditions Potentially Connected with Heritable Disorders of Connective Tissue, 260 Annex Table 5-13 Global Functioning Associated with Heritable Disorders of Connective Tissue, 265 Annex Table 5-14 Functional Implications for Physical Activities of Conditions Associated with Heritable Disorders of Connective Tissue, 270 Annex Table 5-15 Functional Implications for Vision, Hearing, and Speaking Activities of Conditions Associated with Heritable Disorders of Connective Tissue, 279 Annex Table 5-16 Functional Implications for Mental Activities of Conditions Associated with Heritable Disorders of Connective Tissue, 282 Annex Table 5-17 Examples of Social Security Administration Listings that May Apply to Individuals with Heritable Disorders of Connective Tissue, 288
Acronyms and Abbreviations 6MWD six minute walk distance ABC Scale Activities-specific Balance Confidence Scale ACTH adrenocorticotropic hormone ADA Americans with Disabilities Act ADHD attention-deficit/hyperactivity disorder ADL activity of daily living aEDS arthrochalasia-type Ehlers-Danlos syndrome ANA antinuclear antibody ANCA antineutrophil cytoplasmic antibody ASHA American Speech-Language-Hearing Association BAI Beck Anxiety Inventory BCS brittle cornea syndrome BDI Beck Depression Inventory BFI Brief Fatigue Inventory BHS Birt-Hogg-DubÃ© syndrome BiPAP bilevel positive airway pressure BLS U.S. Bureau of Labor Statistics BMAT Bruininks Motor Ability Test BOT-2 Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition CBC complete blood count CBT cognitive behavioral therapy xxi
xxii ACRONYMS AND ABBREVIATIONS CCA congenital contractural arachnodactyly CDC Centers for Disease Control and Prevention cEDS classical Ehlers-Danlos syndrome CFS chronic fatigue syndrome, also myalgic encephalomyelitis clEDS classical-like Ehlers-Danlos syndrome CNS central nervous system COMPASS 31 Composite Autonomic Symptom Score CPAP continuous positive airway pressure CRP C-reactive protein CSF cerebrospinal fluid CT computed tomography CTA computed tomography angiography cvEDS cardiac-valvular Ehlers-Danlos syndrome DASH Disabilities of the Arm, Shoulder and Hand questionnaire dEDS dermatosparaxis Ehlers-Danlos syndrome DTH delayed-type hypersensitivity ECM extracellular matrix EDS Ehlers-Danlos syndromes EGD esophagogastroduodenoscopy EMG electromyogram ESR erythrocyte sedimentation rate FAMM Foot and Ankle Ability Measure FCE Functional Capacity Evaluation FSS Fatigue Severity Scale GAF Global Assessment of Functioning scale GERD gastroesophageal reflux disease G-HSD generalized (joint) hypermobility spectrum disorder GI gastrointestinal HAT hereditary alpha tryptasemia HDCT heritable disorder of connective tissue hEDS hypermobile Ehlers-Danlos syndrome HRQoL health-related quality of life HSCT haematopoietic stem cell transplantation HSD hypermobility spectrum disorder JAN Job Accommodations Network JH joint hypermobility
ACRONYMS AND ABBREVIATIONS xxiii IADL instrumental activity of daily living ICF International Classification of Functioning, Disability and Health ICP intracranial pressure IOM Institute of Medicine IOP intraocular pressure IPEX immune dysregulation, polyendocrinopathy, enteropathy, X-linked ISTH International Society on Thrombosis and Haemostasis kEDS kyphoscoliotic Ehlers-Danlos syndrome KOOS Knee Injury and Osteoarthritis Outcome Score LDS Loeys-Dietz syndrome LE lower extremity LEFS Lower Extremity Functional Scale LPR laryngopharyngeal reflux M-BESS Modified Balance Error Scoring System MCAD mast cell activation disease mcEDS musculocontractural Ehlers-Danlos syndrome ME myalgic encephalomyelitis, also chronic fatigue syndrome MET metabolic equivalent of task MFI Mutidimensional Fatigue Inventory MFS Marfan syndrome MHQ Michigan Hand Outcomes Questionnaire MINI mini international neuropsychiatric interview MIRECC Mental Illness Research, Education, and Clinical Center MRA magnetic resonance angiography MRI magnetic resonance imaging MRV magnetic resonance venography NASEM National Academies of Sciences, Engineering, and Medicine NDI Neck Disability Index NLM U.S. National Library of Medicine NMDAR N-methyl-D-aspartate receptors NMH neurally mediated hypotension NORD National Organization for Rare Disorders NRS Numeric Rating Scale OCT optical coherence tomography ODI Oswestry Disability Index
xxiv ACRONYMS AND ABBREVIATIONS OI osteogenesis imperfecta ORS Occupational Requirements Survey PCORI Patient-Centered Outcomes Research Institute PedsQL Functional Disability Inventory of Pediatric Quality of Life PEM postexertional malaise PID primary immunodeficiency PIDD primary immunodeficiency disease POTS postural orthostatic tachycardia syndrome PREE Patient-Rated Elbow Evaluation PROMIS Patient-Reported Outcomes Measurement Information System PRWE Patient-Rated Wrist Evaluation RAST radioallergosorbent test RFC residual functional capacity RMDQ Roland-Morris Disability Questionnaire SCID severe combined immunodeficiency SCID structured clinical interview for DSM SDS Sheehan Disability Scale SFN-SIQ small fiber neuropathy Symptom Inventory Questionnaire SGA substantial gainful activity SGS Shprintzen-Goldberg syndrome SLE systemic lupus erythematosus SNAP sensory nerve action potential SODA Sequential Occupational Dexterity Assessment SOFAS Social and Occupational Functioning Assessment Scale spEDS spondylodysplastic Ehlers-Danlos syndrome SSA U.S. Social Security Administration SSDI Social Security Disability Insurance SSI Supplemental Security Income TENS transcutaneous electric nerve stimulation UBM ultrasound biomicroscopy UE upper extremity VAS Visual Analog Scale vEDS vascular Ehlers-Danlos syndrome VUS variants of uncertain significance vWF von Willebrand Factor
ACRONYMS AND ABBREVIATIONS xxv WAI Work Ability Index WD-FAB Work Disability Functional Assessment Battery WHO World Health Organization WOMAC Western Ontario and McMaster Universities Osteoarthritis Index WOSI Western Ontario Shoulder Instability Index