What is Ehlers-Danlos syndrome?

What is Ehlers-Danlos Syndrome?

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders characterized by three cardinal features: articular hypermobility, skin hyperextensibility, and tissue fragility. 1

Classification and Prevalence

• EDS encompasses 14 different subtypes affecting approximately 1 in 5000 births, with 13 subtypes having identified molecular causes involving 20 different genes. 1, 2
• The majority of genetic defects involve fibrillar collagen types I, III, and V, along with their modifying or processing enzymes and enzymes affecting glycosaminoglycan chains of proteoglycans. 2
• The hypermobile type of EDS (hEDS) is the most frequent form but remains without a known molecular basis, making diagnosis purely clinical. 2, 3

Genetic Basis

• Classical EDS and related subtypes result from mutations in collagen and extracellular matrix genes, with over 100 different mutations identified in the fibrillin-1 gene alone. 1
• Vascular EDS (type IV) is transmitted as autosomal dominant and carries the highest risk of life-threatening complications. 1
• Between 7-16% of patients with Marfan-like presentations have normal fibrillin metabolism, indicating genetic heterogeneity. 1

Clinical Manifestations by System

Musculoskeletal Features

• Joint hypermobility is assessed using the Beighton scale with age-specific thresholds: ≥6/9 points in prepubertal children, ≥5/9 points for adults up to age 50, and ≥4/9 points for adults over 50. 4
• Chronic joint dislocations and subluxations lead to long-term disability and pain. 5

Dermatologic Features

• Skin demonstrates hyperextensibility, fragility, and abnormal wound healing with easy bruising. 1, 2
• Incisions heal slowly, requiring retention sutures that should remain in place longer than normal with extended antibiotic coverage until removal. 1

Cardiovascular Complications

• Aortic dissection can occur without preceding dilatation, particularly in vascular EDS (type IV). 1
• Vascular rupture represents a life-threatening complication requiring recognition that surgical interventions carry significant risks due to tissue fragility and vascular vulnerability. 6
• Annuloaortic ectasia is diagnosed in 5-10% of patients undergoing aortic valve replacement for aortic regurgitation. 1

Gastrointestinal Manifestations

• Over 60% of hEDS patients experience at least one gastrointestinal symptom. 7, 4
• Hollow organ rupture can occur, particularly during pregnancy or with mechanical stress. 1

Associated Conditions

Mast Cell Activation Syndrome (MCAS)

• In hEDS patients, altered connective tissue creates an abnormal microenvironment where mast cells migrate, proliferate, and undergo early or excessive degranulation triggered by food, heat, emotion, and mechanical stimuli. 7
• A prospective study of 139 MCAS patients with refractory GI symptoms found 23.7% had EDS, demonstrating significant association. 7
• Testing for MCAS should be targeted to patients with multisystem symptoms triggered by specific stimuli, measuring serum tryptase during symptomatic episodes (looking for baseline increase to plus 20% + 2 ng/mL). 7

Physical Examination Findings in Vascular EDS

• Affected individuals are typically of short, slim build with prematurely aged hands, triangular faces, large eyes and small chins, thin pinched noses, and small lobeless ears. 1
• During pregnancy, increased bruising, hernias, and varicosities may develop. 1

Critical Management Principles

Surgical Considerations

• All surgical interventions require meticulous technique to minimize tissue trauma due to inherent tissue fragility and delayed wound healing. 6
• Postpartum hemorrhage can be severe and should be anticipated. 1

Pain Management

• Occupational therapy and bracing demonstrate the highest efficacy with 70% of patients reporting improvement. 8
• Neuropathic modulators are least well tolerated with 47% of patients reporting adverse effects. 8
• A combination of several different treatment modalities is usually necessary for optimal symptom control rather than relying on a single intervention. 8

MCAS Treatment When Present

• Histamine receptor antagonists (H1 and H2 blockers) are first-line therapy for MCAS-related symptoms in hEDS patients. 7
• Treatment should focus on documented abnormalities rather than empiric therapy. 7

Common Pitfalls to Avoid

• Do not assume all hEDS patients have MCAS—the association exists but is not universal. 7
• Avoid invasive procedures in vascular EDS patients due to risk of fatal complications. 6
• Do not perform routine mast cell staining on endoscopic biopsies for isolated GI symptoms without evidence of generalized mast cell disorder. 7
• Recognize that EDS diagnosis remains challenging due to overlapping symptoms, and cases can remain without well-defined classification even for trained professionals. 5