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 PRESS
Washington, DC
www.nap.edu
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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
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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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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 Autònoma 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
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
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 manuscript remain confidential to protect the integrity of the deliberative process.
We thank the following individuals for their review of this report:
Although the reviewers listed above provided many constructive comments 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 carried 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 individuals—adults and children—who are unable to function in employment 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 systems 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 syndrome 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 dysfunction. 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
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 individual 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 conclusions 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 committee’s 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 process for accuracy. The committee benefited greatly from discussions with individuals who presented at the committee’s 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 provided 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 officer), 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 communications staff all provided valuable guidance to ensure the success of the final product. Rona Brière and her staff are to be credited for the superb editorial assistance they provided in preparing the final report.
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
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3 MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES
History of Marfan Syndrome and Related Hereditary Aortopathies
Diagnosis of Marfan Syndrome and Related Hereditary Aortopathies
Characteristics of Marfan Syndrome and Related Hereditary Aortopathies
4 EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY SPECTRUM DISORDERS
History of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders
Diagnosis of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders
Characteristics of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders
5 HERITABLE DISORDERS OF CONNECTIVE TISSUE AND EFFECTS ON FUNCTION
Environmental Factors and Functioning
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Boxes, Figures, and Tables
BOXES
3-1 Revised Ghent Criteria for Diagnosis of Marfan Syndrome and Related Conditions
3-2 Ghent II Criteria for Scoring of Systemic Measures
6-1 Overall Conclusions and Selected Chapter-Specific Findings and Conclusions
B-1 Methods and Reporting Form for the Passive Standing Test
FIGURES
1-1 ICF model of functioning and disability
adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
TABLES
4-1 Clinical Classification of the Ehlers-Danlos Syndromes, Inheritance Pattern, and Genetic Basis
4-2 Selected Hypermobility Assessment Scales
B-1 Symptoms of Orthostatic Intolerance
B-2 Medications for Orthostatic Intolerance
ANNEX TABLES
Annex Table 3-1 Overview of Marfan Syndrome and Related Hereditary Aortopathies
Annex Table 4-1 Overview of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders
Annex Table 5-1 Levels of Work Based on Physical Exertion Requirements
Annex Table 5-2 Physical; Vision, Hearing, and Speech; and Mental Activities
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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-Dubé 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 |
| 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 |
| 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 |
| 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 |
| 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 |
