What are the diagnostic criteria for Ehlers‑Danlos syndrome?

Diagnostic Criteria for Ehlers-Danlos Syndrome

For hypermobile EDS (hEDS), all three major criteria must be met: (1) generalized joint hypermobility confirmed by Beighton scale, (2) musculoskeletal and systemic manifestations consistent with connective tissue disorder, and (3) exclusion of alternative diagnoses through genetic testing and clinical evaluation. 1

Criterion 1: Generalized Joint Hypermobility (Beighton Scale)

The Beighton scale is scored out of 9 points, with the following thresholds required 1, 2:

• ≥6/9 points for prepubertal children
• ≥5/9 points for adults under 50 years
• ≥4/9 points for adults over 50 years

The 9-point Beighton scale includes 1, 3:

• Passive dorsiflexion of each fifth finger >90° (1 point per side)
• Passive apposition of each thumb to flexor surface of forearm (1 point per side)
• Hyperextension of each elbow >10° (1 point per side)
• Hyperextension of each knee >10° (1 point per side)
• Ability to place palms flat on floor when bending forward with knees fully extended (1 point)

Criterion 2: Clinical Features of Connective Tissue Disorder

Physical examination must document 1:

• Skin characteristics: Soft, velvety texture with normal or mildly increased extensibility (not marked hyperextensibility as in classical EDS)
• Tissue fragility: Atrophic scarring, easy bruising without significant trauma
• Joint manifestations: Recurrent dislocations or subluxations affecting multiple joints
• Chronic pain: Persistent joint and limb pain that can be severely disabling

Additional supportive features 1, 2:

• Functional bowel disorders (present in up to 98% of hEDS patients)
• Autonomic dysfunction (POTS with heart rate increase ≥30 bpm within 10 minutes of standing)
• Gastroesophageal reflux, delayed gastric emptying
• Orthostatic intolerance symptoms

Criterion 3: Exclusion of Alternative Diagnoses

This is the most critical and underutilized criterion—genetic testing identified alternative diagnoses in 26.4% of patients who initially met clinical criteria for hEDS. 4

Essential Diagnostic Workup

Cardiovascular assessment 1, 3:

• Echocardiogram is required for all suspected EDS cases to evaluate for aortic root dilation (occurs in 25-33% of classical and hypermobile EDS)
• Annual echocardiogram if aortic root is normal; every 6 months if diameter >4.5 cm or growth >0.5 cm/year

Ophthalmologic evaluation 1:

• Dilated eye examination to exclude Marfan syndrome, which shares overlapping features

Genetic testing strategy 1, 3, 4:

• Multi-gene panel testing covering COL5A1, COL5A2, COL3A1, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes is the most efficient approach when EDS is suspected but subtype is unclear
• Avoid routine genetic testing specifically for hEDS, as no causative genes have been identified
• Genetic testing is essential to exclude other EDS subtypes and overlapping conditions

Subtype-Specific Diagnostic Approaches

Vascular EDS (Type IV) - Life-Threatening Subtype

Urgent COL3A1 gene mutation testing is required when the following features are present 1, 2, 3:

• Thin, translucent skin with visible veins
• Characteristic facial features
• History of arterial, intestinal, or uterine rupture
• Family history of sudden death or arterial complications

Critical pitfall: Avoid invasive vascular imaging in suspected vascular EDS, as fatal complications have been reported. 3

Classical EDS (Types I and II)

Diagnostic features 1, 5:

• Marked skin hyperextensibility (not just soft/velvety as in hEDS)
• Atrophic scarring ("cigarette paper" scars)
• Easy bruising
• Joint hypermobility

Molecular confirmation: COL5A1 or COL5A2 gene mutation testing 3, 5

Common Diagnostic Pitfalls

Failure to recognize vascular EDS carries significant mortality risk from arterial or organ rupture (median survival 48 years). 3 Any patient with thin, translucent skin requires urgent COL3A1 testing. 2

Overdiagnosis of hEDS occurs when criterion 3 (exclusion of alternatives) is not rigorously applied. Genetic testing revealed alternative diagnoses in over one-quarter of patients meeting initial clinical criteria. 4

Inadequate screening for comorbidities 2, 3:

• POTS affects up to 37.5% of hEDS patients—measure postural vital signs
• Celiac disease risk is elevated—perform serological testing earlier in hEDS patients with GI symptoms
• Mast Cell Activation Syndrome—test baseline serum tryptase only if episodic multisystem symptoms involving ≥2 physiological systems are present

When to Refer to Medical Genetics

Medical geneticists are the primary specialists who diagnose and classify EDS 3. Refer when:

• Clinical features suggest EDS
• Family history shows autosomal dominant inheritance pattern
• Arteriopathy is suspected
• Genetic counseling is needed before mutation screening due to financial, insurance, familial, and social implications

The 2017 International EDS Classification recognizes 13 subtypes, with definite diagnosis of all subtypes except hypermobile EDS relying on molecular confirmation. 6