Ehlers-Danlos syndromes

Introduction

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders primarily affecting the skin, joints, and blood vessel walls. They result from genetic defects in the structure, production, or processing of collagen or collagen-associated proteins.

EDS is characterized by joint hypermobility, skin hyperextensibility, and tissue fragility, although the specific presentation varies by subtype. The condition is lifelong, with varying severity, and certain types carry life-threatening risks such as arterial rupture.

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Epidemiology

• Prevalence: Combined prevalence estimated at 1 in 5,000, though hypermobile type may be more common.

• Gender: Some forms, particularly hypermobile EDS (hEDS), are diagnosed more frequently in females.

• Onset: Present from birth or early childhood; diagnosis often delayed in milder forms.

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Etiology and Genetics

EDS is caused by pathogenic variants in genes encoding collagen chains or proteins involved in collagen biosynthesis and processing.

Examples of genetic defects by type:

• Classical EDS (cEDS): COL5A1, COL5A2 (type V collagen defects)

• Vascular EDS (vEDS): COL3A1 (type III collagen defects)

• Kyphoscoliotic EDS (kEDS): PLOD1, FKBP14 (lysyl hydroxylase deficiency)

• Arthrochalasia EDS (aEDS): COL1A1, COL1A2 (type I collagen defects)

• Dermatosparaxis EDS (dEDS): ADAMTS2 (procollagen processing defect)

• Hypermobile EDS (hEDS): No confirmed genetic marker in most cases; diagnosis remains clinical.

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Pathophysiology

Collagen is the main structural protein in connective tissues. Defects lead to:

• Weak extracellular matrix → reduced tensile strength of tissues.

• Abnormal cross-linking → fragility and stretchability of skin and ligaments.

• Defective vascular and organ support → increased risk of rupture or herniation.

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Classification (2017 International Classification)

Thirteen recognized subtypes:

1. Classical EDS (cEDS)

2. Classical-like EDS (clEDS)

3. Cardiac-valvular EDS (cvEDS)

4. Vascular EDS (vEDS)

5. Hypermobile EDS (hEDS)

6. Arthrochalasia EDS (aEDS)

7. Dermatosparaxis EDS (dEDS)

8. Kyphoscoliotic EDS (kEDS)

9. Brittle cornea syndrome (BCS)

10. Spondylodysplastic EDS (spEDS)

11. Musculocontractural EDS (mcEDS)

12. Myopathic EDS (mEDS)

13. Periodontal EDS (pEDS)

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Clinical Features

General Features (Shared Across Types)

• Joint hypermobility – assessed by Beighton score

• Skin hyperextensibility – stretches easily and returns to normal

• Tissue fragility – easy bruising, atrophic scars

Type-Specific Features

1. Classical EDS (cEDS)

• Marked skin hyperextensibility

• Atrophic, wide scars (papyraceous scars)

• Easy bruising

• Generalized joint hypermobility

2. Hypermobile EDS (hEDS)

• Generalized joint hypermobility

• Chronic joint pain, instability, recurrent dislocations

• Soft, velvety skin without significant scarring

• Fatigue, dysautonomia, gastrointestinal symptoms

3. Vascular EDS (vEDS)

• Thin, translucent skin (visible veins)

• Characteristic facial appearance (thin nose, small lips, prominent eyes)

• Arterial, intestinal, or uterine rupture risk

• Bruising without obvious trauma

4. Kyphoscoliotic EDS (kEDS)

• Congenital muscle hypotonia

• Progressive scoliosis

• Fragile sclerae

• Easy bruising

5. Arthrochalasia EDS (aEDS)

• Severe congenital hip dislocation

• Marked joint hypermobility

• Skin hyperextensibility and fragility

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Complications

• Musculoskeletal: chronic pain, early osteoarthritis, frequent dislocations

• Skin: poor wound healing, keloid formation

• Vascular: aneurysms, dissections, ruptures (especially in vEDS)

• Pregnancy-related: uterine rupture, postpartum hemorrhage

• Ocular: corneal thinning, retinal detachment in certain types

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Diagnosis

Clinical Assessment

• History of hypermobility, skin fragility, and family history

• Beighton score ≥5 in adults (out of 9 points) suggests generalized hypermobility

Diagnostic Criteria

• 2017 criteria for hEDS require:

  1. Generalized joint hypermobility

  2. Two or more of: systemic connective tissue features, family history, musculoskeletal complications

  3. Exclusion of other heritable and acquired connective tissue disorders

Genetic Testing

• Available for all subtypes except hEDS.

• Confirms diagnosis in suspected monogenic types.

Imaging

• Echocardiography for aortic root dilation in certain subtypes

• MRI or ultrasound for joint instability assessment

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Management

No curative treatment; management focuses on symptom control, complication prevention, and quality-of-life improvement.

1. Patient Education and Lifestyle

• Avoid contact sports or activities with high injury risk

• Joint protection strategies

• Regular low-impact exercise (swimming, cycling)

• Skin care to reduce injury risk

2. Pain Management

• NSAIDs (e.g., ibuprofen, naproxen) for mild pain

• Paracetamol for general analgesia

• Avoid long-term opioids when possible

• Neuropathic pain agents (e.g., duloxetine, gabapentin) if indicated

3. Physiotherapy

• Strengthening muscles to stabilize joints

• Postural training

• Balance and proprioception exercises

4. Orthopedic Interventions

• Braces or supports for unstable joints

• Surgical repair in severe instability (with caution due to poor tissue integrity)

5. Cardiovascular Monitoring

• Annual echocardiogram in vEDS and cEDS

• Blood pressure control to reduce vascular stress

• Beta-blockers (e.g., celiprolol in vEDS) to reduce arterial events risk

6. Wound Care

• Use of atraumatic suturing techniques

• Prolonged wound support due to delayed healing

7. Pregnancy Management

• High-risk obstetric care for vEDS and certain other subtypes

• Planned delivery in facilities with vascular surgical support

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Prognosis

• Varies by subtype:

  • hEDS and cEDS: chronic but generally compatible with normal lifespan.

  • vEDS: high risk of life-threatening complications, reduced life expectancy (~50 years median).

• Early diagnosis, lifestyle modification, and multidisciplinary care improve outcomes