What are the steps to diagnose Ehlers‑Danlos syndrome?

Diagnosing Ehlers-Danlos Syndrome

Refer all suspected EDS cases to a medical geneticist for definitive diagnosis and classification, as they have the expertise to coordinate appropriate genetic testing and distinguish between the 13 recognized EDS subtypes. 1

Initial Clinical Assessment

Begin by calculating the Beighton score to quantify joint hypermobility 1, 2:

• Passive dorsiflexion of each 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
• Forward bend with palms flat on floor, knees extended (1 point) 1

Diagnostic thresholds: ≥6/9 for prepubertal children, ≥5/9 for adults under 50, ≥4/9 for adults over 50 1, 3

Examine the skin for 1, 2:

• Soft, velvety, or hyperextensible texture 1
• Thin, translucent appearance with visible veins (suggests vascular EDS) 1
• Atrophic scarring or tissue fragility 1
• Easy bruising patterns 1

Document a three-generation family history focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 1

Essential Cardiovascular Screening

Order an echocardiogram for all suspected EDS cases to evaluate aortic root diameter, as dilation occurs in 25-33% of hypermobile and classic EDS cases 1, 2, 3

If aortic root is normal, repeat annually; if diameter >4.5 cm or growth >0.5 cm/year, repeat every 6 months 1

For suspected vascular EDS or Loeys-Dietz syndrome, obtain MR angiography from head to pelvis to assess the entire vascular tree for arterial tortuosity and aneurysms 1

Genetic Testing Strategy

For Suspected Vascular EDS (Life-Threatening Priority)

Order urgent COL3A1 gene mutation testing if you suspect vascular EDS based on thin translucent skin, arterial/organ rupture history, or family history of sudden death 1, 2. This subtype has a median survival of 48 years and carries significant mortality risk 1.

Critical pitfall: Avoid invasive vascular procedures in suspected vascular EDS patients, as fatal complications have been reported 1, 2

For Other EDS Subtypes

Order a comprehensive multi-gene panel covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes when EDS is suspected but subtype is unclear 1

For classical EDS, test COL5A1 or COL5A2 genes 1

For Hypermobile EDS (hEDS)

Do not order genetic testing for hEDS, as no causative genes have been identified 1, 2. hEDS remains a clinical diagnosis of exclusion 2.

However, genetic testing is still essential to exclude alternative diagnoses - a recent study found that 26.4% of patients meeting clinical criteria for hEDS actually had alternative genetic conditions requiring different management 2, 4

Apply the 2017 diagnostic criteria for hEDS (available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf) only after excluding other conditions through genetic testing 1, 2

Screening for Common Comorbidities

Autonomic Dysfunction (POTS)

Measure postural vital signs with active stand test: heart rate increase ≥30 bpm in adults (≥40 bpm in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension 1

If positive, refer for tilt table testing 1

Gastrointestinal Manifestations

Screen for nausea, abdominal pain, constipation, bloating, early satiety, and reflux, as 98% of hEDS patients experience GI symptoms 1, 2

Order celiac disease serological testing earlier in hEDS patients with any GI symptoms, as risk is elevated 1

Consider anorectal manometry, balloon expulsion test, or defecography for incomplete evacuation symptoms given high prevalence of pelvic floor dysfunction 1

Mast Cell Activation Syndrome (MCAS)

Only obtain baseline serum tryptase if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 1

Do not routinely test for MCAS in all hEDS patients with isolated GI symptoms 1

Diagnostic threshold: 20% increase above baseline plus 2 ng/mL during symptom flares 1

Additional Screening Tests

Perform dilated eye examination to exclude Marfan syndrome 1

Order DXA scan if height loss >1 inch to screen for osteoporosis 1

Consider Wood's lamp examination to exclude other connective tissue disorders 1

When to Suspect Vascular EDS Specifically

Look for these red flags requiring urgent COL3A1 testing 1, 3:

• Thin, translucent skin with visible veins 1
• Family history of sudden death, arterial rupture, or organ perforation 1
• Spontaneous arterial dissection or aneurysm 3
• Organ rupture without significant trauma 3

Avoid invasive diagnostic procedures in these patients due to fatal complication risk 1, 2

Genetic Counseling

Provide genetic counseling before mutation screening due to complex financial, insurance, familial, and social implications 1