What investigations are used to diagnose Ehlers-Danlos syndrome (EDS)?

Diagnostic Investigations for Ehlers-Danlos Syndrome

The diagnosis of EDS is primarily clinical, based on physical examination using the Beighton scale (≥5/9 points), family history, and skin assessment, with genetic testing reserved for specific subtypes—particularly COL3A1 testing for suspected vascular EDS, which is life-threatening. 1, 2

Initial Clinical Assessment

Physical Examination Components

Joint hypermobility assessment using the Beighton scale is the cornerstone of diagnosis, requiring ≥5 points on the 9-point scale: 1

• Passive dorsiflexion of each fifth finger >90 degrees (1 point each side) 1
• Passive apposition of each thumb to the flexor surface of the forearm (1 point each side) 1
• Hyperextension of each elbow >10 degrees (1 point each side) 1
• Hyperextension of each knee >10 degrees (1 point each side) 1
• Placing palms flat on the floor when bending over with knees fully extended (1 point) 1

Skin examination should specifically assess for: 1

• Soft or velvety texture with normal or slightly increased extensibility 1
• Absence of skin fragility (which would suggest other EDS subtypes) 1
• Venous visibility, acrogeria, and skin fragility (suggestive of vascular EDS) 3
• Subcutaneous spheroids and molluscoid pseudotumors (suggestive of classical EDS) 3

Family history assessment for autosomal dominant inheritance pattern without skin abnormalities is essential. 1, 2

Cardiovascular Investigations

Echocardiogram to evaluate for aortic root dilatation is mandatory in all suspected EDS cases, as aortic root dilation occurs in 25-33% of classic and hypermobile EDS types. 1, 2

MR angiography of head, neck, thorax, abdomen, and pelvis should be performed when vascular EDS or arteriopathy is suspected to assess arterial tortuosity and aneurysms. 2

Ophthalmologic Assessment

Dilated eye examination is required to exclude Marfan syndrome, which can present with overlapping features. 1

Genetic Testing Strategy

When to Order Genetic Testing

COL3A1 gene mutation testing should be performed urgently when vascular EDS (Type IV) is suspected, as this is the definitive diagnostic test for this life-threatening subtype. 1, 2

Multi-gene panel testing (covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes) is the most efficient approach when EDS is suspected but the subtype is unclear. 2

COL5A1 or COL5A2 gene mutation testing should be ordered for molecular confirmation of Classical EDS (Types I and II). 2

When NOT to Order Genetic Testing

Routine genetic testing for hypermobile EDS (hEDS) should NOT be performed, as no causative genes have been identified and it accounts for 80-90% of all EDS cases. 2, 4, 5

Whole-genome or exome sequencing should be avoided in hEDS. 2

Laboratory Investigations

Essential Screening Labs Before Genetic Testing

When vascular EDS or systemic arteriopathy is suspected, obtain: 2

• Baseline serum tryptase level (elevated in myeloproliferative variants) 2
• Vitamin B12 level (characteristically elevated in myeloproliferative variants with arteriopathy) 2
• Complete blood count with differential (to evaluate for cytopenias or eosinophilia) 2
• Comprehensive metabolic panel including liver and renal function 2
• Lactate dehydrogenase (LDH) as a marker for tissue breakdown 2
• Antinuclear antibody (ANA) and antineutrophil cytoplasmic antibodies (ANCA) if systemic arteriopathy suspected 2
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory assessment 2
• Quantitative immunoglobulin levels including IgE if allergic or mast cell symptoms present 2

Gastrointestinal Screening

Celiac disease serological testing should be performed earlier in hEDS patients with any GI symptoms, as up to 98% meet criteria for disorders of gut-brain interaction. 2, 6

Autonomic Function Testing

Postural vital signs measurement with heart rate increase ≥30 beats/min within 10 minutes of standing should be performed to screen for POTS, which commonly affects hEDS patients. 2, 6

Tilt table testing for autonomic function assessment should be considered in POTS patients. 2

Bone Density Assessment

DXA scan should be ordered for height loss greater than one inch, as osteoporosis is common in EDS. 1, 7

Skin Biopsy Considerations

Skin biopsy has limited diagnostic utility, as only 30.3% show features suggestive of EDS using light microscopy and 71.4% using transmission electron microscopy. 3

Fibroblast culture demonstrating structurally abnormal collagen type III provides supportive evidence for Vascular EDS diagnosis when genetic testing is inconclusive. 2

Critical Pitfalls to Avoid

Failure to recognize vascular EDS carries significant mortality risk from arterial or organ rupture—maintain high clinical suspicion and test urgently. 2, 4

Inappropriate invasive diagnostic procedures in vascular EDS patients can lead to fatal complications. 2

Do NOT perform routine MCAS testing in all hEDS patients with isolated GI symptoms. 2

Mutation identification may fail even when protein analysis confirms a collagen defect, as only coding sequences and closely surrounding regions are investigated. 2

When to Refer for Genetics Consultation

Refer to medical genetics specialists when clinical features suggest EDS, family history shows autosomal dominant inheritance, or when arteriopathy is suspected. 2

Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications. 2