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Disease Profile

Classical Ehlers-Danlos syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 100 000

3,310 - 29,790

US Estimated

1-9 / 100 000

5,135 - 46,215

Europe Estimated

Age of onset

Infancy

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ICD-10

Q79.6

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Classic Ehlers-Danlos syndrome; Ehlers-Danlos syndrome type 1 (formerly); Ehlers-Danlos syndrome type 2 (formerly);

Categories

Connective tissue diseases

Summary

Classical Ehlers-Danlos syndrome (EDS) is a genetic connective tissue disorder that is caused by defects in a protein called collagen. Common symptoms include skin hyperextensibility, abnormal wound healing, and joint hypermobility.[1][2] More than 90% of people with classical EDS have mutations in COL5A1 or COL5A2, two genes which encode type V collagen. In rare cases, mutations in the gene encoding type I collagen, COL1A1 gene, may be found.[3] The condition is inherited in an autosomal dominant manner.[2] Treatment and management is focused on preventing serious complications and relieving associated symptoms.[2][4]

Symptoms

The signs and symptoms of classical EDS vary but may include:[2][1]

  • Smooth, velvety skin that is highly elastic (stretchy) and bruises easily
  • Abnormal wound healing that may result in wide, atrophic scars (flat and/or depressed scars)
  • Joint hypermobility that leads to frequent dislocations and subluxations (partial dislocations)
  • Molluscoid pseudotumors (calcified hematomas over pressure points such as the elbow)
  • Subcutaneous spheroids (fat-containing cysts that are often found on the forearms and/or shins)
  • Hypotonia
  • Delayed motor development
  • Tissue fragility that may lead to hernias, rectal prolapse, and other complications
  • Cardiovascular abnormalities such as mitral valve prolapse or aortic root dilatation (enlargement of the blood vessel that distributes blood from the heart to the rest of the body)
  • Pregnancy may be complicated by premature rupture of membranes

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Cigarette-paper scars
'cigarette paper scarring'
Cigarette paper scarring

[ more ]

0001073
Fragile skin
Skin fragility
0001030
Generalized joint laxity
Hypermobility of all joints
0002761
Hyperextensible skin
Hyperelastic skin
Skin hyperelasticity
Stretchable skin

[ more ]

0000974
Soft, doughy skin
0001027
Striae distensae
Stretch marks
0001065
30%-79% of people have these symptoms
Chronic constipation
Infrequent bowel movements
0012450
Fatigue
Tired
Tiredness

[ more ]

0012378
Gastroesophageal reflux
Acid reflux
Acid reflux disease
Heartburn

[ more ]

0002020
Muscle spasm
0003394
Muscle weakness
Muscular weakness
0001324
Muscular hypotonia
Low or weak muscle tone
0001252
Nausea
0002018
Osteopenia
0000938
Poor wound healing
0001058
Pulp stones
0003771
Vomiting
Throwing up
0002013
5%-29% of people have these symptoms
Abnormal cornea morphology
0000481
Abnormality of the temporomandibular joint
Abnormality of the jaw joint
Deformity of the jaw joint
Malformation of jaw joint

[ more ]

0010754
Acrocyanosis
Persistent blue color of hands, feet, or parts of face
0001063
Aortic root aneurysm
Bulge in wall of root of large artery that carries blood away from heart
0002616
Arterial dissection
0005294
Arterial rupture
0025019
Arteriovenous fistula
0004947
Arthralgia
Joint pain
0002829
Bladder diverticulum
0000015
Blepharochalasis
0010749
Bruising susceptibility
Bruise easily
Easy bruisability
Easy bruising

[ more ]

0000978
Cervical insufficiency
0030009
Dermatochalasis
Baggy eyes
Droopy eyelid skin
Extra eyelid skin
Redundant eyelid skin

[ more ]

0010750
Dilatation of the cerebral artery
0004944
Dislocated radial head
0003083
Ecchymosis
0031364
Epicanthus
Eye folds
Prominent eye folds

[ more ]

0000286
Hiatus hernia
Stomach hernia
0002036
Hip dislocation
Dislocated hips
Dislocation of hip

[ more ]

0002827
Incisional hernia
0004872
Inguinal hernia
0000023
Joint swelling
0001386
Limb pain
0009763
Molluscoid pseudotumors
0000993
Motor delay
0001270
Osteoarthritis
Degenerative joint disease
0002758
Patellar dislocation
Dislocated kneecap
0002999
Pes planus
Flat feet
Flat foot

[ more ]

0001763
Phalangeal dislocation
0006243
Piezogenic pedal papules
0025509
Premature birth
Premature delivery of affected infants
Preterm delivery

[ more ]

0001622
Premature rupture of membranes
0001788
Prematurely aged appearance
Precociously senile appearance
0007495
Prolonged bleeding time
0003010
Rectal prolapse
Rectum protrudes through anus
0002035
Scoliosis
0002650
Shoulder dislocation
0003834
Subcutaneous spheroids
0025014
Talipes equinovarus
Club feet
Club foot
Clubfeet
Clubfoot

[ more ]

0001762
Umbilical hernia
0001537
Uterine prolapse
Sagging uterus
0000139
1%-4% of people have these symptoms
Headache
Headaches
0002315
Mitral regurgitation
0001653
Mitral valve prolapse
0001634
Orthostatic hypotension
Decrease in blood pressure upon standing up
0001278
Tricuspid valve prolapse

Cause

More than 90% of people affected by classical EDS have an identifiable mutation in the COL5A1 gene or the COL5A2 gene that is known to cause the condition.[2] These genes provide instructions for making different components of type V collagen. Collagen is a protein that provides structure and strength to connective tissues throughout the body. Mutations in COL5A1 or COL5A2 lead to defects in the structure and function of type V collagen molecules. This causes the many signs and symptoms associated with classical EDS.[5][6]

In rare cases, mutations in the genes encoding type I collagen (COL1A1 gene) can be found in people with classical EDS.[3]

Diagnosis

A diagnosis of classical EDS is typically based on the presence of characteristic signs and symptoms. More than 90% of classical EDS patients have mutations in one of the genes encoding type V collagen (the COL5A1 gene or the COL5A2 gene). Rare cases are caused by a mutation in the COL1A1 gene. Genetic testing for a mutation in these genes can then be ordered to confirm the diagnosis in some cases.[1][2] 

Collagen typing performed on a skin biopsy may be recommended if genetic testing is not available or inconclusive. Transmission electron microscopy (TEM) (a very powerful microscopy) findings of collagen flowers on skin biopsy can support the clinical diagnosis, but cannot confirm it. Collagen is a tough, fiber-like protein that makes up about a third of body protein. It is part of the structure of tendons, bones, and connective tissues. Although this test is generally not helpful in confirming a diagnosis of classical EDS, it can be used to rule out some of the other forms of EDS.[2]

Absence of these findings does not rule-out the diagnosis of classical EDS; however, alternative diagnoses should be considered in the absence of a type V collagen gene mutation or electron microscopy findings.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    The treatment of classical EDS varies based on the signs and symptoms present in each person. For example, children with hypotonia and/or delayed motor milestones may benefit from physical therapy and occupational therapy. These treatments can also help improve joint stability. Assistive devices such as braces may also be necessary depending on the severity of joint instability. Anti-inflammatory medications may be prescribed for joint pain. Because classical EDS is associated with fragile skin with abnormal wound healing, people with the syndrome, especially children, may need to wear protective bandages or pads over exposed areas, such as the knees, shins, and forehead. Children and adolescents may be monitored for the development of aortic root dilatation (enlargement of the blood vessel that distributes blood from the heart to the rest of the body).[2][4]

    Please speak to your healthcare provider if you have any questions about your personal medical management plan.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Social Networking Websites

      • The Ehlers-Danlos, Marfan and Related CTDs New England/MA Facebook Support Group offers educational and peer support through this forum.
      • RareConnect has an online community for patients and families with this condition so they can connect with others and share their experiences living with a rare disease. The project is a joint collaboration between EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders).

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
        • Genetics Home Reference (GHR) contains information on Classical Ehlers-Danlos syndrome. This website is maintained by the National Library of Medicine.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
            Ehlers-Danlos Syndrome
            Genetics of Ehlers-Danlos Syndrome
          • MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Classical Ehlers-Danlos syndrome. Click on the link to view a sample search on this topic.

            References

            1. Pauker SP & Stoler J. Clinical manifestations and diagnosis of Ehlers-Danlos syndromes. UpToDate. February 22, 2016; https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-ehlers-danlos-syndromes.
            2. Fransiska Malfait, MD, PhD, Richard Wenstrup, MD, and Anne De Paepe, MD, PhD. Ehlers-Danlos Syndrome, Classic Type. GeneReviews. August 2011; https://www.ncbi.nlm.nih.gov/books/NBK1244/.
            3. Malfait F, Francomano C, Byers P et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. March, 2017; 175(1):8-26. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.c.31552/full.
            4. Pauker SP & Stoler J. Overview of the management of Ehlers-Danlos syndromes. UpToDate. 2016; https://www.uptodate.com/contents/overview-of-the-management-of-ehlers-danlos-syndromes.
            5. COL5A1. Genetics Home Reference. May 2006; https://ghr.nlm.nih.gov/gene/COL5A1.
            6. COL5A2. Genetics Home Reference. May 2006; https://ghr.nlm.nih.gov/gene/COL5A2.

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