How is Ehlers-Danlos syndrome (EDS) diagnosed?

Diagnosis of Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome diagnosis is primarily clinical, based on specific major and minor criteria combined with targeted diagnostic testing to exclude alternative diagnoses and assess cardiovascular complications. 1

Diagnostic Approach by EDS Subtype

Hypermobile EDS (hEDS) - Most Common Subtype

All three major criteria must be met for diagnosis: 1

1. Joint hypermobility confirmed by Beighton scale ≥5/9 points:

   • Passive dorsiflexion of fifth finger >90° (1 point each side) 1
   • Passive thumb apposition to flexor forearm surface (1 point each side) 1
   • Elbow hyperextension >10° (1 point each side) 1
   • Knee hyperextension >10° (1 point each side) 1
   • Forward bend with palms flat on floor, knees extended (1 point) 1

2. Soft or velvety skin with normal or slightly increased extensibility 1

3. Absence of skin or soft tissue fragility (which would suggest other EDS subtypes) 1

Minor criteria are supportive but insufficient alone: 1

• Autosomal dominant family history without skin abnormalities 1
• Recurrent joint dislocations/subluxations 1
• Chronic joint or limb pain 1
• Easy bruising 1
• Functional bowel disorders (gastritis, IBS) 1
• Neurally mediated hypotension or POTS 1
• High narrow palate and dental crowding 1

Vascular EDS (Type IV) - Life-Threatening Subtype

COL3A1 gene mutation testing is the definitive diagnostic test and should be performed urgently when this subtype is suspected. 2 This is critical because vascular EDS carries significant mortality risk from arterial or organ rupture. 2

Classical EDS (Types I and II)

COL5A1 or COL5A2 gene mutation testing provides molecular confirmation. 2

Essential Diagnostic Evaluation

Required Testing for All Suspected EDS Cases

1. Physical examination focusing on joint hypermobility (Beighton scale), skin characteristics, and tissue fragility 1

2. Detailed family history assessing for autosomal dominant inheritance pattern 1

3. Echocardiogram to evaluate for aortic root dilatation, which occurs in 25-33% of classic and hypermobile EDS types 1, 3

4. Dilated eye examination to exclude Marfan syndrome and assess for ectopia lentis 1

When Genetic Testing is Indicated

Genetic testing is NOT routinely performed for hEDS because no causative genes have been identified. 2, 4 However, genetic testing becomes essential when:

• Vascular EDS is suspected - COL3A1 testing is mandatory 2
• Clinical features overlap with other connective tissue disorders - multi-gene panel testing (covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1) is most efficient 2
• Patient meets hEDS criteria but alternative diagnosis needs exclusion - genetic testing identified alternative diagnoses in 26.4% of patients who initially met hEDS criteria 4

A critical finding: Among children who did not fully meet clinical EDS criteria but had overlapping features, 22% were later confirmed to have EDS molecularly. 5 This underscores the importance of genetic testing when clinical presentation is atypical.

Additional Screening Tests

For suspected POTS (common in hEDS):

• Postural vital signs with heart rate increase ≥30 beats/min within 10 minutes of standing during active stand test 2
• Tilt table testing for autonomic function assessment 2

For suspected Mast Cell Activation Syndrome:

• Baseline serum tryptase level if symptoms suggest generalized mast cell disorder (flushing, urticaria, wheezing, multisystem symptoms) 2

For suspected vascular EDS:

• MR angiography of head, neck, thorax, abdomen, and pelvis to assess arterial tortuosity and aneurysms 2

Critical Diagnostic Pitfalls to Avoid

Do not perform routine genetic testing for hEDS - no causative genes exist, making this testing futile and costly. 2

Do not miss vascular EDS - failure to recognize this subtype leads to preventable mortality from arterial rupture. 2 Inappropriate invasive diagnostic procedures in vascular EDS patients can cause fatal complications. 2

Do not rely solely on Beighton score - while a score ≥5 is required for hEDS diagnosis, joint hypermobility alone is insufficient and can occur in multiple other conditions including Marfan syndrome. 1, 6

Do not overlook alternative diagnoses - genetic testing revealed alternative or additional diagnoses requiring distinct management in 26.4% of patients who met hEDS criteria. 4

Correlation of Clinical Features with Positive Molecular Diagnosis

The following features correlate with positive molecular genetic testing: 5

• Generalized joint hypermobility 5
• Poor wound healing 5
• Easy bruising 5
• Atrophic scars 5
• Skin hyperextensibility 5
• Developmental dysplasia of the hip 5

When to Refer to Medical Genetics

Refer to medical genetics specialists when: 2

• Clinical features suggest EDS but subtype is unclear 2
• Family history shows autosomal dominant inheritance 2
• Arteriopathy is suspected 2
• Genetic counseling is needed before mutation screening due to complex financial, insurance, familial, and social implications 2

Medical geneticists are the primary specialists who diagnose and classify EDS because they have expertise in evaluating inherited connective tissue disorders and can coordinate appropriate genetic testing. 2

Ongoing Cardiovascular Surveillance

For patients with normal aortic root size:

• Repeat echocardiogram every 2-3 years until adult height reached 1
• If no dilatation present, repeat only if cardiovascular symptoms develop or when major increase in physical activity is planned 1

For patients with aortic root dilation:

• Echocardiogram every 6 months if diameter >4.5 cm in adults or rate of increase >0.5 cm/year 1
• Annual echocardiogram for root diameter <4.5 cm in adults and rate of increase <0.5 cm/year 1

The aortic root diameter should not exceed 40-42 mm even in tall individuals. 7