History

Ehlers-Danlos syndrome is a group of inherited connective tissue disorders that primarily affects the skin, joints, and blood vessel walls1 but can affect every organ system and result in significant morbidity and mortality.2 Typical clinical manifestations are skin hyperelasticity, hypermobility of joints, the fragility of blood vessels, 2 and atrophic scarring.

In 1936 the syndrome was given the eponymous title of Ehlers-Danlos, named after dermatologists Edvard Ehlers (1863–1937) and Henri-Alexandre Danlos (1844–1912) for their roles in providing recognition for the disorder.3 There are currently thirteen distinctive subtypes of the disorder, each with different diagnostic criteria, symptoms, and health risks.4

Epidemiology

The combined prevalence of all types of Ehlers-Danlos is best estimated to be between 1 in 25002 and 1 in 5,000individuals worldwide. Hypermobility Ehlers-Danlos syndrome (formerly known as Ehlers-Danlos syndrome type 3) and classical Ehlers-Danlos syndrome are the two most common subtypes, with incident rates of 1 in 5,000 to 20,000 people and 1 in 20,000 to 40,000 people, respectively.5

Most other subtypes of Ehlers-Danlos syndrome are rare. It should be noted that there is a likely underestimation of the overall incidence of EDS. People with more mild presentations and only minimal joint or skin involvement may not seek medical care as they do not have significant patterns of disease.2

Ehlers-Danlos Syndrome Diagnosis & Presentation

The most common clinical presentations are skin hyperextensibility and hyperflexible joints, although presentations will vary widely based on the respective underlying subtype. Most presentations occur in the young; however, it is possible to have symptoms present later in life due to disease progression. Some common manifestations of Ehlers-Danlos syndromes are as follows:2

  • Skin-specific Manifestations: hyperextensibility, fragility, delayed wound healing, thin atrophic scars after wound healing, and smooth and velvet-like texture.
  • Musculoskeletal Manifestations: hypermobility that potentially leads to repeated subluxation and dislocation. This can be a cause of early osteoarthritis and chronic pain.
  • Tissue Fragility: hollow and solid internal organ fragility due to the underlying collagen dysfunction. Patients can be subject to spontaneous and traumatic rupture or perforation of affected organs. Hernias and rectal prolapse are also common features.
  • Neurological Manifestations: hypotonia, generalized pain, insomnia, and chronic fatigue. Hypotonia may delay motor milestones in the developing child, such as walking.
  • Cardiovascular Manifestations: mitral valve prolapse, tricuspid valve prolapse, and aortic root dilation. Other vessels may be aneurysmal, which predisposes them to rupture, especially in vascular EDS. Easy bruising and bleeding without underlying bleeding diathesis is a potential manifestation of capillary fragility.
  • Facies: blue sclera, down slanting palpebral fissures, micrognathia, epicanthal folds, and the appearance of premature aging.

The diagnosis of EDS is largely based on patient history and clinical findings. Any collection of symptoms listed above should alert the medical practitioner to the possibility of Ehlers-Danlos. Once a diagnosis of Ehlers-Danlos syndrome has been presumed or determined, genetic testing can help differentiate between subtypes.7

Ehlers-Danlos Syndrome Types

The International Classification for the Ehlers-Danlos Syndromes, published in 2017, recognizes thirteen different descriptive subtypes of Ehlers-Danlos syndromes.These clinical subtypes are as follows:7

  • Hypermobile Ehlers-Danlos syndrome (hEDS)
  • Classic Ehlers-Danlos syndrome (cEDS)
  • Classical-like Ehlers-Danlos syndrome (clEDS)
  • Vascular Ehlers-Danlos syndrome (vEDS)
  • Cardiac-valvular Ehlers-Danlos syndrome (cvEDS)
  • Arthrochalasia Ehlers-Danlos syndrome (aEDS)
  • Dermatosparaxis Ehlers-Danlos syndrome (dEDS)
  • Kyphoscoliotic Ehlers-Danlos syndrome (kEDS)
  • Brittle cornea syndrome (BCS)
  • Spondylodysplastic Ehlers-Danlos syndrome (spEDS)
  • Musculocontractural Ehlers-Danlos syndrome (mcEDS)
  • Myopathic Ehlers-Danlos syndrome (mEDS)
  • Periodontal Ehlers-Danlos syndrome (pEDS)

Diagnostic Workup

If Ehlers-Danlos syndrome is suspected, a thorough medical and family history of the patient should be obtained. Skin and joints should be assessed for hyperextensibility. Joint hyperextensibility should be evaluated using the Beighton scale, a clinical rating scale used to assess joint laxity and hypermobility. Motor development should undergo assessment in infants and children, and a baseline echocardiogram for children under age ten is recommended.2

Common cardiovascular concerns, such as mitral valve prolapse and aortic dilatation, can be assessed using computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and echocardiography.7 Specialized X-ray studies may be required to characterize or confirm other abnormalities, such as subcutaneous spheroids, osteopenia, scoliosis, and kyphosis.7

To differentiate between specific subtypes of Ehlers-Danlos, referral to a geneticist who can perform diagnostic genetic testing is recommended.2 A genetic Ehlers-Danlos syndrome test can distinguish twelve of the thirteen subtypes. No genetic testing is available for the most common subtype, hypermobility Ehlers-Danlos syndrome.8

This subtype must be diagnosed through clinical findings, meeting three specific criteria as outlined in the 2017 International Classification for the Ehlers-Danlos Syndromes.A summary of the three criteria are as follows, and all three must be met for a confirmed diagnosis of hypermobility Ehlers-Danlos:

  • Generalized joint hypermobility (GJH) – Breighton score 5 to 9, though cutoff may vary slightly with age
  • Two or more features among three groupings of systemic manifestations, family history and/or musculoskeletal complications
  • Absence of unusual skin frailty and exclusion of other connective tissue disorders and alternative diagnoses

Differential Diagnosis

There are many differential diagnoses for Ehlers-Danlos syndrome. This list includes:

  • Marfan syndrome (MFS)
  • Loeys-Deitz syndrome (LDS)
  • Cutis laxa
  • Osteogenesis imperfecta type I
  • Occipital horn syndrome (OHS)
  • Hypermobility spectrum disorders (HSD)
  • Familial aortic aneurysm (FAA)
  • Familial hypermobility syndrome (FHS)
  • Brittle cornea syndrome 2 (BCS2)

Ehlers-Danlos syndrome patients, especially those with hypermobility Ehlers-Danlos syndrome, are often misdiagnosed with conditions such as chronic fatigue syndrome, depression, or fibromyalgia. Misdiagnosis puts the patient at risk for complications associated with Ehlers-Danlos syndrome, so the clinician should give careful attention and apply a high index of suspicion to any potential cases of Ehlers-Danlos syndrome.2

Ehlers-Danlos Syndrome Management

There is no cure for Ehlers-Danlos syndrome. Treatment is generally focused on implementing preventative measures against disease progression and life-threatening complications.Specialists typically manage specific care within the field of concerning pathology for the particular subtypes of Ehlers-Danlos. For example, a cardiologist would usually monitor cardiovascular concerns for vascular Ehlers-Danlos syndrome patients.2

Collagen abnormalities can lead to poor wound healing of the skin, so wound care should be meticulous, often involving a generous application of deep stitches that are left in for extended periods. Having hypermobile joints increases the risk of joint subluxation and dislocation. Each dislocation increases the risk for subsequent dislocations, and repeated incidents can cause early osteoarthritis and chronic pain.

Prevention revolves around patient counseling regarding the limitation of high-risk activities such as contact sports and weightlifting.2 Structural abnormalities of the heart may require surgical intervention. Pain management and management of gastrointestinal and psychological complications are tailored to the individual.

Patients with hypermobility Ehlers-Danlos may especially benefit from low-resistance exercise, physical therapy, and assistive devices like braces, scooters, and wheelchairs.7 Beta-blockers may be required to help prevent any cardiovascular complications.2

Monitoring

Careful monitoring of Ehlers-Danlos patients is recommended. Regular hypertension and arterial disease screening should be conducted, as these increase the complications associated with blood vessel fragility.7 Pregnant patients with Ehlers-Danlos syndrome should be followed and managed by obstetricians trained in high-risk pregnancy.7 

Psychosocial support is crucial for patients with Ehlers-Danlos, as they face many psychosocial challenges. These challenges stem from the fact that there is no cure, preventative treatments do not often improve current symptoms, the disease may impact the ability to have children, and activity restrictions can be overbearing.2

Due to Ehlers-Danlos being a multi-system disease process, patients benefit most from an inter-professional approach to their care. A knowledgeable primary care physician is needed and should coordinate the patient’s care for both surveillance and treatment needs.2

References

1. Mayo Clinic. Ehlers-Danlos syndrome – Symptoms and causes. Published 2017. Accessed July 20, 2022.

2. Miklovic T, Sieg VC. Ehlers Danlos Syndrome. In: StatPearls. NCBI Bookshelf version. StatPearls Publishing: 2022. Accessed July 20, 2022.

3. Parapia LA, Jackson C. Ehlers-Danlos syndrome – a historical reviewBritish Journal of Haematology. 2008;141(1):32-35. doi:10.1111/j.1365-2141.2008.06994.x

4. The Ehlers-Danlos Society. What are the Ehlers-Danlos Syndromes? Published 2017. Accessed July 20, 2022.

5. U.S. National Library of Medicine. Ehlers-Danlos syndrome. Updated July 2022. Accessed July 20, 2022.

6. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromesAmerican Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):8-26. doi:10.1002/ajmg.c.31552

7. National Organization for Rare Disorders. Ehlers Danlos Syndromes. Published 2015. Accessed July 20, 2022.

8. Mayo Clinic. Ehlers-Danlos syndrome – Diagnosis and treatment. Published 2017. Accessed July 20, 2022.

Author Bio

Jonathan Poole is a freelance writer and copy-editor with a BSc in Exercise Science living in West Lafayette, IN. When not writing, he owns and operates a fitness training company, Unstoppable Athletes. More information regarding his training business can be found here: https://www.unstoppableathletes.com