What are the recommended diagnostic tests, including serology, for a patient suspected of having Ehlers-Danlos syndrome?

Diagnosis of Ehlers-Danlos Syndrome: Serology and Testing

Ehlers-Danlos syndrome (EDS) is NOT diagnosed by serology—it is diagnosed clinically using the Beighton scale and confirmed by genetic testing for specific subtypes, with the critical exception that hypermobile EDS (the most common type) has no genetic test available and remains a purely clinical diagnosis. 1

Primary Diagnostic Approach by EDS Subtype

For Suspected Vascular EDS (Life-Threatening Priority)

Urgent COL3A1 gene mutation testing is the definitive diagnostic test when vascular EDS is suspected, as this subtype carries significant mortality risk from arterial or organ rupture with median survival of 48 years. 1, 2 This is NOT a serological test—it is molecular genetic testing of the COL3A1 gene encoding type III collagen. 3

For Suspected Classical EDS

COL5A1 or COL5A2 gene mutation testing provides molecular confirmation, though approximately 50% of clinically diagnosed classical EDS patients harbor mutations in these genes. 1, 4 Again, this is genetic testing, not serology.

For Suspected Hypermobile EDS (Most Common: 80-90% of Cases)

No genetic testing or serology exists—diagnosis is purely clinical using the 2017 diagnostic criteria available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf. 1, 3 The Beighton score must be ≥5/9 for adults under 50, ≥4/9 for adults over 50, and ≥6/9 for prepubertal children. 1, 2

Essential Clinical Assessment (Not Serology)

Joint Hypermobility Evaluation (Beighton Scale)

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

Skin and Tissue Assessment

• Evaluate for soft, velvety, or hyperextensible skin 1, 3
• Document thin, translucent skin with visible veins (suggests vascular EDS) 1
• Assess for easy bruising patterns and abnormal scarring 1

Laboratory Tests That ARE Recommended (But These Are Not "Serology" for EDS Diagnosis)

Screening for Common Comorbidities

• Celiac disease serological testing should be performed earlier in hEDS patients with any GI symptoms, as risk is elevated 1
• Baseline serum tryptase level ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) to screen for Mast Cell Activation Syndrome—NOT routine 1
• Postural vital signs with heart rate increase ≥30 beats/min (≥40 in adolescents 12-19 years) within 10 minutes of standing to screen for POTS 1, 2

For Suspected Vascular EDS Specifically

• Baseline serum tryptase level to help distinguish vascular complications, as elevated levels are commonly observed in myeloproliferative variants 1
• Vitamin B12 level is characteristically elevated in myeloproliferative variants of EDS with arteriopathy 1

Essential Imaging Studies (Not Serology)

• Echocardiogram is required for ALL suspected EDS cases to evaluate aortic root diameter, as dilation occurs in 25-33% of hypermobile and classic EDS 1, 2
• MR angiography of head, neck, thorax, abdomen, and pelvis for suspected vascular EDS or Loeys-Dietz syndrome to assess arterial tortuosity and aneurysms 1
• Dilated eye examination to exclude Marfan syndrome 1

Multi-Gene Panel Testing Strategy

When EDS is suspected but subtype is unclear, multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes is the most efficient diagnostic approach. 1 Avoid routine whole-genome or exome sequencing in hEDS, as no causative genes have been identified. 1

Critical Pitfalls to Avoid

• Do NOT perform routine genetic testing for hEDS—no causative genes exist 1
• Do NOT perform routine MCAS testing in all hEDS patients with isolated GI symptoms—only test those with multisystem episodic symptoms 1
• Do NOT delay COL3A1 testing if vascular EDS is suspected—this is a medical emergency 1
• Do NOT perform invasive vascular imaging in suspected vascular EDS, as fatal complications have been reported 1

When to Refer to Medical Genetics

Refer when clinical features suggest EDS, family history shows autosomal dominant inheritance (three-generation pedigree with sudden deaths, arterial ruptures, organ perforations), or when arteriopathy is suspected. 1 Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications. 1