What is the pathophysiology of Ehler Danlos Syndrome (EDS)?

Pathophysiology of Ehlers-Danlos Syndrome

Fundamental Molecular Defects

Ehlers-Danlos syndrome results from genetic mutations affecting collagen synthesis, structure, or post-translational modification, leading to defective connective tissue throughout the body. 1

The pathophysiology varies by subtype but centers on disrupted collagen biology:

Vascular EDS (Type IV) - Most Severe Pathophysiology

• COL3A1 gene mutations cause production of structurally abnormal type III collagen by fibroblasts, with mutations widely distributed throughout this large, fragmented gene 1
• The defective type III collagen leads to arterial and organ fragility, creating risk for spontaneous rupture without preceding dilatation 2, 1
• Almost every family has its own unique mutation, and no genotype-phenotype correlations exist—the specific mutation does not predict disease severity or course 1

Classical EDS (Types I and II)

• COL5A1 or COL5A2 gene mutations disrupt type V collagen, which regulates fibril diameter and organization 3
• This results in the characteristic skin hyperextensibility and tissue fragility 1

Hypermobile EDS (hEDS) - Most Common Type

• No causative genes have been identified despite accounting for 80-90% of all EDS cases 1, 3
• Skin biopsies reveal altered collagen fibril structure that triggers fibroblast dysfunction within connective tissue, causing abnormal adhesion and cytoskeletal response 1
• The pathophysiology likely involves multiple genetic and environmental factors rather than a single gene defect 4

Spondylodysplastic and Musculocontractural EDS

• B4GALT7 or B3GALT6 mutations (spondylodysplastic type) impair enzymes that initiate glycosaminoglycan synthesis 5
• CHST14 or DSE mutations (musculocontractural type) disrupt dermatan sulfate biosynthesis 5
• These represent proteoglycan abnormalities rather than direct collagen defects 5

Pathogenetic Cascade and Clinical Manifestations

Cardiovascular Pathophysiology

• Defective collagen in arterial walls leads to aortic root dilation in 25-33% of hypermobile and classical EDS cases 6, 1
• In vascular EDS, arterial walls are prone to spontaneous dissection and rupture even without aneurysm formation 2
• The median survival for vascular EDS is only 48 years due to arterial complications 3

Musculoskeletal Pathophysiology

• Abnormal collagen in joint capsules, ligaments, and tendons causes joint hypermobility with recurrent dislocations and subluxations 6, 1
• Defective periosteal collagen contributes to osteoporosis in 44% of cases 6
• Altered connective tissue mechanics lead to chronic joint and limb pain 6

Dermatologic Pathophysiology

• Disrupted dermal collagen architecture produces soft, velvety, or hyperextensible skin depending on subtype 6, 1
• Impaired wound healing results from defective collagen deposition, causing tissue fragility and abnormal scarring 2, 7

Gastrointestinal Pathophysiology

• Up to 98% of hEDS patients experience GI manifestations including reflux, abdominal pain, constipation, and bloating 6
• The mechanism involves visceral hypersensitivity rather than true dysmotility in most cases 6
• Defective connective tissue in the GI tract contributes to functional bowel disorders 6

Autonomic Pathophysiology

• Altered connective tissue in blood vessels and autonomic nerves contributes to postural orthostatic tachycardia syndrome (POTS) 6
• This manifests as orthostatic intolerance with heart rate increases ≥30 beats/min upon standing 6, 3

Inheritance Patterns and Genetic Heterogeneity

• Classical and vascular EDS follow autosomal dominant inheritance, though some patients show recessively inherited presentations 1
• Genetic heterogeneity exists—each family typically has its own specific mutation, making systematic screening impractical 1, 3
• A total of 19 different causative genes have been identified across the 12 monogenic EDS subtypes 1, 8

Critical Pathophysiologic Distinctions

Tissue Fragility Mechanisms

• In vascular EDS, tissue fragility occurs without skin hyperextensibility, distinguishing it from other subtypes 6
• The absence of skin fragility is essential to distinguish hEDS from other types 6

Pregnancy-Related Pathophysiology

• During pregnancy, women with EDS show increased bruising, hernias, varicosities, and risk of vascular rupture 2
• Postpartum hemorrhage may be severe due to defective vascular collagen 2
• Incisions heal slowly, requiring extended suture retention (at least 14 days) to avoid wound dehiscence 2