What is Ehlers-Danlos Syndrome (EDS)?

What is Ehlers-Danlos Syndrome?

Ehlers-Danlos Syndrome (EDS) is a group of 13 heritable connective tissue disorders caused by mutations in genes involved in collagen synthesis and extracellular matrix structure, characterized by the clinical triad of joint hypermobility with recurrent dislocations, skin hyperextensibility, and tissue fragility. 1

Genetic Basis and Classification

EDS comprises 13 recognized subtypes, with 12 being rare monogenic conditions caused by pathogenic variants in 19-21 different genes, predominantly related to collagen synthesis and stability 1, 2. Almost every family has its own specific mutation, making genetic testing challenging, and no genotype-phenotype correlations exist—meaning the specific mutation does not predict disease type, course, or severity 1.

The hypermobile type (hEDS) is the most common subtype, accounting for 80-90% of all EDS cases, but paradoxically has no identified genetic cause and remains a clinical diagnosis. 1, 3 This subtype is unlikely to represent a single gene disorder in most affected individuals 2.

Core Clinical Features

The defining triad includes 1:

• Joint hypermobility with recurrent dislocations or subluxations
• Skin hyperextensibility (soft, velvety texture with normal or slightly increased extensibility)
• Tissue fragility affecting skin and internal organs

Joint Hypermobility Assessment

Joint hypermobility is confirmed using the Beighton scale with age-specific thresholds 1, 4:

• ≥6/9 points for prepubertal children
• ≥5/9 points for adults under 50 years
• ≥4/9 points for adults over 50 years

The Beighton scale evaluates 3:

• Passive dorsiflexion of fifth fingers >90° (1 point per side)
• Passive thumb apposition to flexor forearm surface (1 point per side)
• Elbow hyperextension >10° (1 point per side)
• Knee hyperextension >10° (1 point per side)
• Forward bend with palms flat on floor, knees extended (1 point)

Skin Characteristics

Skin findings vary by subtype but typically include 1, 4:

• Soft or velvety texture
• Hyperextensibility (can be gently pulled beyond normal limits)
• Easy bruising
• Abnormal scarring (atrophic, "cigarette paper" scars)
• Thin, translucent skin with visible veins (particularly in vascular EDS)

Major EDS Subtypes and Their Risks

Hypermobile EDS (hEDS)

The most common form requires meeting all three major criteria: Beighton score ≥5/9, soft/velvety skin without fragility, and exclusion of alternative diagnoses through genetic testing 4. Up to 98% of hEDS patients experience gastrointestinal manifestations including reflux, abdominal pain, constipation, and bloating. 3, 4

Vascular EDS (Type IV)

This subtype poses the greatest mortality risk due to spontaneous arterial and organ ruptures, even without aneurysm formation. 1 It is caused by mutations in the COL3A1 gene encoding type III collagen, with median survival of 48 years 3. Defective collagen in arterial walls leads to spontaneous dissection and rupture 1.

Classical EDS (Types I and II)

Caused by mutations in COL5A1 or COL5A2 genes, following autosomal dominant inheritance 1, 3.

Cardiovascular Complications

Aortic root dilation occurs in 25-33% of hypermobile and classic EDS cases, requiring regular cardiovascular surveillance. 1, 4 Echocardiogram should be performed every 2-3 years until adult height is reached, and every 6 months if aortic root diameter exceeds 4.5 cm in adults or growth rate exceeds 0.5 cm/year 4.

Associated Comorbidities

Autonomic Dysfunction

Postural orthostatic tachycardia syndrome (POTS) is common in hEDS, affecting up to 37.5% of patients, manifesting as orthostatic intolerance with heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents) within 10 minutes of standing 3, 4.

Musculoskeletal Findings

Patients may experience 4:

• Chronic joint or limb pain
• Recurrent dislocations or subluxations
• Osteoporosis
• Scoliosis
• Congenital hip dislocation
• Short stature (present in 44% of cases)

Pregnancy Risks

Pregnancy in women with EDS is associated with increased bruising, hernias, varicosities, and risk of vascular rupture 1. Postpartum hemorrhage may be severe due to defective vascular collagen, and incisions heal slowly, requiring extended suture retention to avoid wound dehiscence 1.

Pathophysiology

The molecular mechanisms vary by subtype 1:

• Vascular EDS: Structurally abnormal type III collagen production by fibroblasts
• Hypermobile EDS: Altered collagen fibril structure triggering fibroblast dysfunction with abnormal adhesion and cytoskeletal response
• Classical EDS: Defects in type V collagen affecting fibril assembly

Critical Diagnostic Pitfalls

Do not diagnose hEDS without genetic testing to exclude alternative diagnoses, as 26.4% of clinically diagnosed cases had alternative genetic conditions requiring different management. 4

Avoid invasive vascular procedures in vascular EDS due to fatal complication risk—use exclusively non-invasive imaging methods such as Doppler ultrasound, CT, or MRI. 3, 4

Failure to recognize vascular EDS carries significant mortality risk from arterial or organ rupture, making urgent COL3A1 gene mutation testing essential when this life-threatening subtype is suspected 3.

Management Principles

While there is no curative treatment for any EDS type, early diagnosis is critical to optimize symptomatic management and prevent avoidable complications 5. Management includes 4:

• Low-resistance exercise and physical therapy for musculoskeletal symptoms
• Cardiovascular surveillance with regular echocardiography
• Proton pump inhibitors or H2-blockers for gastritis and reflux
• Celiprolol to reduce vascular morbidity in vascular EDS (lacks FDA approval in US)
• Avoid opioid dependence for chronic pain management

Patients must be treated and monitored by multidisciplinary teams in specialized reference centers 5.