What are the different subtypes of Ehlers-Danlos Syndrome (EDS)?

Ehlers-Danlos Syndrome Subtypes

The 2017 International EDS Classification recognizes 13 distinct subtypes of Ehlers-Danlos syndrome, replacing the older Villefranche nosology that identified only 6 subtypes. 1

Overview of Classification

The current classification system divides EDS into 13 subtypes, of which 12 are rare monogenic disorders with identified genetic causes involving 19 different genes, while hypermobile EDS (the most common form) currently has no identified genetic cause. 2, 3 Each subtype has distinct clinical features, genetic causes, and pathogenic mechanisms requiring individualized management approaches. 3

Major EDS Subtypes

1. Hypermobile EDS (hEDS)

• Most common subtype, accounting for 80-90% of all EDS cases 2
• Diagnosis is purely clinical as no causative genes have been identified 2, 4
• Key features include:
  • Joint hypermobility (Beighton score ≥5/9 for adults under 50) 5, 2
  • Soft or velvety skin with normal or slightly increased extensibility 5
  • Chronic joint or limb pain 5
  • Recurrent joint dislocations or subluxations 5
  • Easy bruising 5
  • Functional bowel disorders (present in up to 98% of patients) 4
  • Aortic root dilation occurs in 25-33% of cases 5, 2

2. Classical EDS (cEDS)

• Caused by mutations in COL5A1 or COL5A2 genes 4
• Characterized by:
  • Skin hyperextensibility as a prominent feature 5
  • Tissue fragility 5
  • Joint hypermobility 6
  • Aortic root dilation in 25-33% of cases 2
• Follows autosomal dominant inheritance 2

3. Vascular EDS (vEDS/Type IV)

• Most dangerous subtype due to risk of spontaneous arterial and organ ruptures 2
• Caused by mutations in the COL3A1 gene encoding type III collagen 2, 4
• Critical features include:
  • Spontaneous arterial dissections and aneurysms at young ages 7
  • Organ perforation risk 4
  • Vascular fragility with bleeding complications 7
  • Vessels may rupture without significant dilation 7
• Requires urgent genetic testing when suspected 4
• Almost every family has its own specific mutation 2
• Follows autosomal dominant inheritance 2

4. Musculocontractural EDS Type 1 (mcEDS-CHST14)

• Caused by biallelic mutations in the CHST14 gene on chromosome 15q14 8
• Features include musculocontractural phenotype 8

5. Musculocontractural EDS Type 2 (mcEDS-DSE)

• Caused by mutations in the DSE gene on chromosome 6q22 8
• Presents with musculocontractural phenotype 8

Additional Recognized Subtypes

The remaining 8 subtypes are rare monogenic disorders with identified genetic causes, each involving specific genes related to collagen synthesis, structure, or modification. 2, 1 These include various forms affecting different aspects of connective tissue metabolism and structure. 1

Clinical Triad Common to All Types

The defining triad present across EDS subtypes includes:

• Joint hypermobility with recurrent dislocations or subluxations 2
• Skin hyperextensibility 2, 6
• Tissue fragility 2, 6

Diagnostic Approach by Subtype

For all subtypes except hypermobile EDS, definitive diagnosis requires molecular confirmation with identification of causative genetic variants. 1 The vast genetic heterogeneity and phenotypic variability necessitate genetic testing to distinguish between subtypes and from other heritable connective tissue disorders. 1

Key Diagnostic Tests:

• Vascular EDS: COL3A1 gene mutation testing (urgent when suspected) 4, 7
• Classical EDS: COL5A1 or COL5A2 gene mutation testing 4
• Hypermobile EDS: Clinical diagnosis using 2017 criteria (no genetic test available) 2, 4
• Multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1 when subtype is unclear 4

Critical Clinical Distinction

Determining the specific EDS subtype is crucial because different types have vastly different prognoses, management strategies, and surveillance requirements. 2, 3 Simply labeling a patient as having "EDS" without subtype classification is inadequate and potentially dangerous, particularly given the life-threatening nature of vascular EDS. 3