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 structure and biosynthesis, 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, of which 12 are rare monogenic disorders with identified genetic causes involving 19 different genes, mostly related to collagen synthesis. 1 The pathogenesis stems from disturbances in collagen formation and/or stability, particularly affecting types I, III, and V collagen. 1, 2
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 cannot be diagnosed through genetic testing. 1, 3 This distinguishes it from the other 12 subtypes which have confirmed molecular diagnoses. 4
Core Clinical Features
The defining triad includes: 1
- Joint hypermobility with recurrent dislocations or subluxations, confirmed by Beighton scale scores (≥6/9 for prepubertal children, ≥5/9 for adults under 50, ≥4/9 for adults over 50) 1, 5
- Skin hyperextensibility with soft or velvety texture, though the degree varies by subtype 1, 5
- Tissue fragility affecting skin, blood vessels, and internal organs depending on the specific type 1, 6
Additional common manifestations include chronic joint or limb pain, easy bruising, atrophic scarring, and wound healing difficulties. 1, 2
Critical Subtype Distinctions
Vascular EDS (type IV) poses the greatest mortality risk due to spontaneous arterial and organ ruptures, even without aneurysm formation. 1 This subtype is caused by COL3A1 gene mutations affecting type III collagen, with defective collagen in arterial walls leading to dissection and rupture. 1 The median survival is 48 years. 3
Classical EDS (types I and II) follows autosomal dominant inheritance and is caused by COL5A1 or COL5A2 mutations. 3 Almost every family has its own specific mutation, and no genotype-phenotype correlations exist—the specific mutation does not predict disease severity or course. 1
Associated Complications and Comorbidities
Cardiovascular
- Aortic root dilation occurs in 25-33% of hypermobile and classic EDS cases 1, 5
- Vascular rupture risk, particularly during pregnancy and postpartum 1
Gastrointestinal
- Up to 98% of hEDS patients experience GI manifestations including reflux, abdominal pain, constipation, bloating, and early satiety 3, 5
- High prevalence of pelvic floor dysfunction 3
Autonomic
- Postural orthostatic tachycardia syndrome (POTS) affects a significant proportion of hEDS patients 3, 5
- Neurally mediated hypotension 5
Musculoskeletal
Other Systems
- Mast cell activation syndrome (MCAS) with episodic multisystem symptoms 3
- Elevated celiac disease risk in hEDS patients 3
Pregnancy Considerations
Women with EDS face increased risks during pregnancy including increased bruising, hernias, varicosities, vascular rupture, and severe postpartum hemorrhage due to defective vascular collagen. 1 Incisions heal slowly and require extended suture retention to prevent wound dehiscence. 1
Diagnostic Importance
Accurate diagnosis of the specific EDS subtype is crucial because different types have distinct clinical manifestations, genetic causes, pathogenetic mechanisms, and require individualized surveillance and management strategies. 1 For example, vascular EDS requires urgent genetic testing and vascular surveillance, while hEDS diagnosis is purely clinical and focuses on managing joint instability and comorbid conditions. 3, 5
The diagnosis should be made by medical geneticists who have expertise in evaluating inherited connective tissue disorders and can coordinate appropriate genetic testing and subspecialty referrals. 3