What is the workup for Ehlers-Danlos (EDS) syndrome?

Workup for Ehlers-Danlos Syndrome

The workup for EDS begins with clinical assessment using the Beighton scale (≥5/9 points for adults under 50), followed by echocardiography to evaluate aortic root size, and urgent COL3A1 genetic testing if vascular EDS is suspected due to its life-threatening nature. 1, 2, 3

Initial Clinical Assessment

Physical Examination Components

Joint Hypermobility Assessment (Beighton Scale):

• Passive dorsiflexion of fifth fingers >90 degrees (1 point each side) 1
• Passive thumb apposition to flexor forearm surface (1 point each side) 1
• Elbow hyperextension >10 degrees (1 point each side) 1
• Knee hyperextension >10 degrees (1 point each side) 1
• Forward bend with palms flat on floor with knees extended (1 point) 1
• Score ≥5/9 required for adults under 50 years, ≥4/9 for those over 50, and ≥6/9 for prepubertal children 2, 4

Skin and Tissue Evaluation:

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

Vascular EDS Warning Signs (Require Urgent Workup):

• Characteristic facial features: thin nose, thin upper lip, small earlobes, prominent eyes 3
• History of spontaneous arterial rupture or dissection 1
• Gastrointestinal perforation without trauma 1
• Family history of sudden death or arterial events 1

Family History Documentation

• Obtain three-generation pedigree focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 2

Essential Cardiovascular Imaging

Echocardiography (Required for All Suspected EDS):

• Evaluate aortic root diameter, as dilation occurs in 25-33% of hypermobile and classic EDS 1, 2
• Assess for valvular abnormalities (prolapse occurs in up to 43% of cases) 5
• If aortic root is normal: Repeat every 2-3 years until adult height reached, then only if symptomatic or planning major physical activity increase 1
• If aortic root dilated but <4.5 cm in adults with growth <0.5 cm/year: Annual echocardiogram 1
• If diameter >4.5 cm or growth >0.5 cm/year: Echocardiogram every 6 months 1

MR Angiography (For Suspected Vascular EDS or Loeys-Dietz):

• Image entire vascular tree from cerebrovascular circulation to pelvis 1, 2, 3
• Assess for arterial tortuosity and aneurysms throughout 1, 3
• Critical: Use noninvasive imaging only, as invasive procedures have caused fatal complications in vascular EDS 1
• Annual surveillance required once vascular EDS confirmed 3

Genetic Testing Strategy

Urgent Testing (Suspected Vascular EDS):

• COL3A1 gene mutation testing is the definitive diagnostic test and should be ordered immediately 1, 2, 3
• This is life-threatening subtype with median survival 48 years and arterial rupture risk 1

Multi-Gene Panel (Unclear Subtype):

• Order panel covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes 2, 3
• Most efficient approach when clinical picture unclear 2

Hypermobile EDS (Most Common Subtype):

• No genetic testing available or recommended - diagnosis is purely clinical 2
• Apply 2017 diagnostic criteria available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf 2

Genetic Counseling:

• Refer before mutation screening due to financial, insurance, familial, and social implications 2, 3

Laboratory Workup

Pre-Genetic Testing Labs:

• Complete blood count with differential (evaluate cytopenias, eosinophilia) 2, 3
• Comprehensive metabolic panel including liver and renal function 2, 3
• Baseline serum tryptase level (distinguish myeloproliferative variants; only if multisystem symptoms present) 2, 3
• Vitamin B12 level (elevated in myeloproliferative variants) 2, 3

Additional Labs Based on Clinical Presentation:

• Lactate dehydrogenase (marker for tissue breakdown) 2
• ANA and ANCA if systemic arteriopathy suspected 2
• ESR and CRP for inflammatory assessment 2
• Quantitative immunoglobulins including IgE if allergic/mast cell symptoms present 2

Screening for Common Comorbidities

Autonomic Dysfunction (POTS):

• Measure postural vital signs with active stand test 1, 2, 4
• Positive if heart rate increases ≥30 beats/min in adults (≥40 in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension 2, 4
• Consider tilt table testing if active stand test equivocal 2

Gastrointestinal Assessment (98% of hEDS patients affected):

• Screen for nausea, abdominal pain, constipation, bloating, early satiety, reflux 2, 4
• Consider anorectal manometry, balloon expulsion test, or defecography if incomplete evacuation symptoms present 2
• Perform celiac disease serological testing earlier than usual in hEDS patients with any GI symptoms 2

Bone Density:

• Order DXA scan for height loss >1 inch 1
• All patients in one study demonstrated osteoporosis 5

Ophthalmologic:

• Dilated eye examination to exclude Marfan syndrome 1, 2

Subspecialty Referrals

Medical Genetics (Primary Diagnostic Specialty):

• Refer all suspected EDS cases for definitive diagnosis and classification 2
• Geneticists coordinate appropriate testing and long-term surveillance 2

Cardiology:

• Manage aortic surveillance and beta-blocker therapy 1
• Evaluate POTS if lifestyle modifications fail 2

Vascular Surgery:

• Refer suspected vascular EDS for surveillance imaging protocols 2

Gastroenterology:

• Refer refractory GI symptoms despite appropriate management 2

Allergy/Mast Cell Specialist:

• Refer if MCAS diagnosis supported (tryptase increases 20% above baseline plus 2 ng/mL during symptom flares) 2

Critical Pitfalls to Avoid

• Never perform invasive vascular imaging in suspected vascular EDS - fatal complications reported 1
• Do not delay COL3A1 testing if vascular EDS suspected - this is a medical emergency 3
• Avoid routine genetic testing for hypermobile EDS - no causative genes identified 2
• Do not perform MCAS testing in all hEDS patients with isolated GI symptoms - only if multisystem symptoms present 2
• Recognize that mutation identification may fail even with confirmed collagen defect - each family typically has unique mutation 2
• Do not overlook pregnancy risks in women with EDS - uterine and arterial rupture risk, especially in vascular type 1, 3