The prevalence of Classical Ehlers-Danlos syndrome is estimated to be roughly 1 in 20,000 to 1 in 40,000 individuals worldwide. All types of EDS combined have a prevalence of 1 in 5,000 to 1 in 20,000.

The primary genetic cause of Classical Ehlers-Danlos are mutations affecting the COL5A1 and COL5A2 genes that provide instructions for producing the α1- and α2-chains of type V collagen, a protein crucial for the structural integrity of connective tissues. It is estimated that mutations in the COL5A1 gene are present in approximately 75% of individuals with clinically confirmed cEDS, while mutations in the COL5A2 gene are found in about 14% of cases. In a smaller percentage of individuals, around 1%, a cEDS phenotype can result from specific mutations in the COL1A1 gene, which encodes type I collagen. The majority of mutations identified in the COL5A1 and COL5A2 genes cause a premature termination of protein synthesis or structural alterations that result in a deficiency in normal type V collagen in the body. These mutations are inherited in an autosomal dominant pattern (see RareShare Guide on Genetic Inheritance), meaning that inheritance of a mutated gene from one parent is sufficient to produce the disease.

Key clinical features of cEDS include:

Skin Manifestations:

• Hyperextensible skin (stretches easily and returns slowly), soft, and velvety texture

• Atrophic scars (wide, paper-this scars), especially over pressure areas

• Easy bruising

• Delayed wound healing

Joint Manifestations:

• Generalized joint hypermobility

• Frequent joint dislocations and subluxations (partial dislocation)

• Chronic joint pain

• Muscle hypotonia (low muscle tone) and delayed motor milestones in infancy

• Early-onset osteoarthritis

Other features:

• Hernias (umbilical, inguinal)

• Rectal prolapse (positional displacement)

• Molluscoid pseudotumors (fleshy lesions over scars or pressure areas)

• Subcutaneous spheroids (hard, movable lumps under skin)

• Mitral valve prolapse (less common, mitral valve in heart fails to close properly)

Individuals with EDS may have fragile skin, which can lead to being prone to cuts, bruises, scarring on the knees, elbows, shins, forehead, and chin (common sites of scrapes during childhood). This can also make healing after surgery difficult as cuts tend to remain widened. In early childhood, skin fragility and muscular hypotonia may occur, which can delay motor development milestones. Fragile tissues of the organs may increase risk of complications such as hernias, or a prolapsed pregnancy or cervical insufficiency for people who are pregnant. 

Joint hypermobility can increase a person’s chance of dislocations or subluxations, and may also be associated with chronic joint pain.

According to the 2017 International Classification of EDS, a diagnosis of cEDS requires the presence of either both major criteria, or major criterion 1 along with three or more of the minor criteria.

Major criteria:

1. Skin hyperextensibility with atrophic scarring

2. Generalized joint hypermobility

Minor criteria (supportive but not required for diagnosis):

• Easy bruising

• Soft, doughy skin

• Molluscoid pseudotumors

• Subcutaneous spheroids

• Hernias

• Epicanthal folds in eyelids

• Complications of joint hypermobility

• Family history of a first-degree relative meeting clinical criteria

Other testing:

• Molecular testing for pathogenic variants in COL5A1, COL5A2 or COL1A1 genes is recommended to confirm a diagnosis

• Skin biopsy (electron microscopy may show disorganized collagen fibrils, but is rarely performed today)

An official diagnosis of Ehlers-Danlos syndrome may require a genetic screen to determine if a mutation of a collagen gene is present, but there are other measures for evaluating an individual for potential EDS diagnoses. 

1. Skin hyperextensibility is measured against a scale of normal skin elasticity, and is considered hyperextensible when it can be stretched over 1.5cm in the forearms and hands, over 3cm in the neck, elbow, and knees, and over 1cm on the palm of the hand. 

2. Joint hypermobility is measured against a scale known as the Beighton score, where a score of over 5 is considered positive for generalized joint hypermobility (GJH); this is also evaluated on the basis of age as joints decrease in mobility with age

3. Skin biopsy is an examination of a small piece of affected tissue under a microscope to confirm the presence of collagen flowers, an abnormal structure of collagen fibres that indicates EDS.

There is no cure for cEDS. Disease management is symptomatic and preventive, involving a multidisciplinary approach.

• Dermatologic care:

  • Gentle wound care

  • Avoiding unnecessary surgery

  • Scar management

• Joint care:

  • Physical therapy for stabilization and proprioception

  • Bracing/splints as needed

  • Avoiding high-impact sports

• Pain management:

  • NSAIDs, physical therapy

  • Multimodal pain management approaches

• Monitoring:

  • Periodic cardiovascular assessment (echocardiogram)

  • Genetic counseling for families

Most treatments for Ehlers-Danlos syndrome are given based on the symptoms an individual may experience. One of the most crucial treatments occurs after injury, when the skin is less likely to heal with normal elasticity. Individuals with EDS should receive quick and precise treatment to open wounds to prevent reopening or scarring. This can involve receiving care to close the wound as soon as possible, and in some cases seeking a plastic surgeon to close wounds. Stitches may need to remain in place for longer than normal skin conditions, and other types of bandages to support this tissue type can be applied (steri-strips and tubular bandages).

The general prognosis for cEDS is good, with a normal life expectancy for most affected individuals. The quality of life may be impacted by joint pain, dislocations and skin fragility. Risks include chronic pain and progressive deterioration of joint function with age. With supportive care and precautions, many individuals can lead functional and productive lives.

Many individuals with EDS have few complications associated with this rare disease, and other than skin abnormalities and joint hypermobility, may live relatively unaffected lives. However, it is common for individuals with EDS to be misdiagnosed with Munchausen’s syndrome, in which the individual effectively makes up their symptoms. EDS is a real rare disease with its own associated symptoms and complications and should be treated as such.

People with the COL1A1 mutation may be at an increased risk of vascular complications and should receive regular monitoring of their heart health. 

1. https://www.healthing.ca/wellness/what-is-ehler-danlos-the-disease-jameela-jamil-claims-to-have

2. https://www.ehlers-danlos.org/information/classical-ehlers-danlos-syndrome/

3. https://www.nhs.uk/conditions/ehlers-danlos-syndromes/

4. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=287 

5. https://franklincardiovascular.com/classical-ehlers-danlos-syndrome/

6. https://medlineplus.gov/genetics/condition/ehlers-danlos-syndrome/

7. Malfait, F., Francomano, C., Byers, P., et al. (2017). “The 2017 International Classification of the Ehlers–Danlos Syndromes.” American Journal of Medical Genetics Part C, 175C(1), 8–26. https://doi.org/10.1002/ajmg.c.31552.

8. Bowen, J. M., Sobey, G. J., Burrows, N. P., et al. (2017). “Ehlers–Danlos syndrome, classical type.” Orphanet Journal of Rare Diseases, 12, 1–20. https://doi.org/10.1186/s13023-017-0680-3.

9. The Ehlers-Danlos Society: What is EDS?

10. Orphanet: Classical Ehlers-Danlos syndrome.