What is Hypermobile Ehlers-Danlos Syndrome (hEDS)?

What is Hypermobile Ehlers-Danlos Syndrome (hEDS)?

Hypermobile Ehlers-Danlos Syndrome (hEDS) is the most common hereditary connective tissue disorder (representing 80-90% of all EDS cases), characterized by generalized joint hypermobility, chronic musculoskeletal pain, soft velvety skin, and tissue fragility—diagnosed entirely through clinical criteria since no genetic cause has been identified. 1, 2

Core Clinical Features

hEDS presents with three cardinal manifestations that distinguish it from other connective tissue disorders:

Joint Hypermobility

• Beighton score of 5 or more out of 9 points is required for diagnosis 3, 4
• The scoring system includes:
  • Passive dorsiflexion of each fifth finger >90 degrees (1 point per side) 3
  • Passive apposition of each thumb to the flexor surface of the forearm (1 point per side) 3
  • Hyperextension of each elbow >10 degrees (1 point per side) 3
  • Hyperextension of each knee >10 degrees (1 point per side) 3
  • Placing palms flat on the floor when bending forward with knees fully extended (1 point) 3

Skin Manifestations

• Soft or velvety skin texture with normal or slightly increased extensibility 3, 5
• Critically, there must be absence of skin or soft tissue fragility, which would suggest other EDS subtypes 3
• Skin is rarely hyperextensible in hEDS, unlike classic EDS 3

Musculoskeletal and Systemic Complications

• Recurrent joint dislocations or subluxations 3, 5
• Chronic joint or limb pain that may progress to daily pain 5
• Easy bruising 3

Associated Comorbidities

hEDS involves multiple organ systems beyond joints and skin:

Cardiovascular

• Aortic root dilation occurs in 25-33% of patients with hypermobile EDS 3, 1
• Unlike vascular EDS, there is no thought to be a risk of dissection without significant aortic root dilatation 3
• Neurally mediated hypotension or postural orthostatic tachycardia syndrome (POTS) 3, 1

Gastrointestinal

• Functional bowel disorders affect up to 98% of hEDS patients, including functional gastritis and irritable bowel syndrome 3, 1, 6

Other Manifestations

• Osteoporosis 3
• High, narrow palate and dental crowding 3
• Mast cell activation syndrome (MCAS) occurs in approximately 23.7% of patients, causing multisystem symptoms through histamine release 6

Diagnostic Approach

hEDS diagnosis is entirely clinical—no genetic test exists, making it fundamentally different from all other EDS subtypes. 1, 2, 4

Three Required Diagnostic Criteria

All three must be met according to the 2017 International Classification 4:

1. Generalized joint hypermobility (Beighton score ≥5) 3, 1
2. Combination of musculoskeletal and systemic manifestations consistent with connective tissue disorder 4
3. Exclusion of alternative diagnoses—this is critical and underutilized 7, 4

Essential Diagnostic Workup

• Echocardiogram to evaluate for aortic root dilation is mandatory 3, 1
• Detailed family history for autosomal dominant inheritance pattern 3, 1
• Physical examination documenting joint hypermobility using Beighton scale 3, 1
• Genetic testing should be performed to exclude other conditions, as recent data shows 26.4% of patients meeting clinical hEDS criteria actually have alternative genetic diagnoses requiring different management 7

Critical Diagnostic Pitfalls

The Exclusion Problem

A major pitfall is failing to adequately exclude alternative diagnoses through genetic testing. In a 2025 study of 178 patients meeting hEDS criteria, genetic testing identified alternative diagnoses in 47 patients (26.4%) that required distinct management strategies 7. This underscores that hypermobility can be a shared phenotype across inflammatory diseases, monogenic syndromes, and chromosomal abnormalities 7.

Distinguishing from Other Conditions

• Marfan syndrome: Look for ectopia lentis, aortic root dilation >2 standard deviations, and specific systemic features using the scoring system 3
• Vascular EDS (Type IV): Characterized by thin skin with visible veins, characteristic facial features, and risk of arterial/organ rupture—requires COL3A1 genetic testing 3, 1
• Classic EDS: Has significant skin hyperextensibility and fragility, unlike hEDS 3

Management Implications

Cardiovascular Monitoring

• If aortic root is normal with systemic involvement and negative family history: repeat echocardiogram every 2-3 years until adult height is reached 3
• The aortic root should not exceed 40-42 mm even in tall individuals 3
• Long-term prognosis regarding aortic complications is not fully known 3

Mast Cell Activation Syndrome

• Testing for MCAS should be targeted to patients with multisystem symptoms triggered by specific stimuli (food, heat, emotion, mechanical stimuli), not performed universally 6
• Measure serum tryptase during symptomatic episodes, looking for increase from baseline to plus 20% + 2 ng/mL 6
• Histamine receptor antagonists (H1 and H2 blockers) are first-line therapy for documented MCAS 6

Specialist Referrals

• Medical geneticists are the primary specialists for diagnosis and classification 1
• Gastroenterologists should screen using Beighton score and apply 2017 criteria or refer appropriately 1
• Rheumatologists evaluate joint hypermobility 1
• Cardiologists assess aortic involvement 1

Pathophysiology

The molecular etiology of hEDS remains unknown, making it unique among EDS subtypes. 7, 2 A small subset has insertions or deletions in the TNXB gene, but most cases have no identified genetic cause 3. Emerging evidence suggests fascial pathophysiology with abnormalities in fascial thickness, interfascial gliding, myofibroblast activation, and tissue stiffness 8. The altered collagen fibril structure triggers fibroblast dysfunction, creating an abnormal microenvironment where mast cells proliferate and degranulate 6.