How should I evaluate and manage a patient with suspected Ehlers‑Danlos syndrome?

Evaluation and Management of Suspected Ehlers-Danlos Syndrome

Begin with clinical assessment using the Beighton scale and skin examination, followed by targeted genetic testing to exclude alternative diagnoses—this approach is critical because 26.4% of patients meeting clinical criteria for hypermobile EDS actually have alternative genetic conditions requiring different management. 1

Initial Clinical Assessment

Joint Hypermobility Evaluation (Beighton Scale)

Systematically assess the following five maneuvers, scoring one point per side where applicable (maximum 9 points) 2:

• Passive dorsiflexion of each fifth finger >90 degrees (1 point per side) 2
• Passive apposition of each thumb to flexor surface of forearm (1 point per side) 2
• Hyperextension of each elbow >10 degrees (1 point per side) 2
• Hyperextension of each knee >10 degrees (1 point per side) 2
• Ability to place palms flat on floor when bending forward with knees fully extended (1 point) 2

Diagnostic thresholds vary by age: ≥6/9 for prepubertal children, ≥5/9 for adults under 50 years, and ≥4/9 for adults over 50 years 2, 3

Skin and Tissue Examination

Document the following specific features 2, 4:

• Skin texture: Assess for soft, velvety quality or hyperextensibility (gently pull skin on volar forearm) 2
• Vascular visibility: Look for thin, translucent skin with visible veins (suggests vascular EDS) 2
• Scarring patterns: Document atrophic or abnormal scarring 2
• Bruising: Assess for easy bruising without adequate trauma 2
• Tissue fragility: Note any history of poor wound healing or tissue tears 2

Family History

Obtain a three-generation pedigree focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 2, 4

Essential Screening Tests for All Suspected EDS Cases

Cardiovascular Evaluation

Echocardiography is mandatory for all suspected EDS cases, as aortic root dilation occurs in 25-33% of hypermobile and classic EDS patients 2, 3, 4

• If aortic root is normal: Annual echocardiogram 2
• If diameter >4.5 cm or growth >0.5 cm/year: Echocardiogram every 6 months 2, 4

Autonomic Function Screening

Measure postural vital signs with active stand test to screen for POTS, which affects up to 37.5% of hEDS patients 2:

• Document heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension 5, 2
• If positive, refer for tilt table testing and expanded autonomic function assessment 2

Ophthalmologic Evaluation

Dilated eye examination should be performed to exclude Marfan syndrome, which shares overlapping features 2, 4

Genetic Testing Strategy

Critical Decision Point: Vascular EDS Must Be Ruled Out First

If you suspect vascular EDS (thin translucent skin, visible veins, family history of arterial rupture or sudden death), order urgent COL3A1 gene mutation testing immediately—this is a life-threatening subtype with median survival 48 years and high arterial rupture risk 2

CRITICAL PITFALL: Never perform invasive vascular imaging in suspected vascular EDS, as fatal complications have been reported 2, 4

For Unclear EDS Subtype

Order multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes as the most efficient diagnostic approach 2

For Suspected Hypermobile EDS

Genetic testing is essential to exclude alternative diagnoses before confirming hEDS, as 26.4% of clinically diagnosed hEDS cases had alternative genetic conditions requiring different management 4, 1

Do not diagnose hEDS without genetic testing to exclude alternatives 4

Avoid routine whole-genome or exome sequencing in hEDS, as no causative genes have been identified 2

Screening for Common Comorbidities

Gastrointestinal Manifestations (Present in 98% of hEDS Patients)

Screen systematically for the following 5, 2:

• Celiac disease serological testing should be performed earlier in hEDS patients with any GI symptoms (not just diarrhea), as risk is elevated 5, 2
• Anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation, given high prevalence of pelvic floor dysfunction 5, 2
• Gastric emptying studies for chronic upper GI symptoms after excluding anatomical/structural disease 5, 2

Mast Cell Activation Syndrome (MCAS) Screening

Only test for MCAS if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 5, 2:

• Obtain baseline serum tryptase level 5, 2
• Repeat tryptase 1-4 hours following symptom flares 5
• Diagnostic threshold: Increase of 20% above baseline plus 2 ng/mL 5, 2
• If positive, refer to allergy specialist or mast cell disease research center for additional testing (urinary N-methylhistamine, leukotriene E4, 11b-prostaglandin F2) 5, 2

CRITICAL PITFALL: Do not perform routine MCAS testing in all hEDS patients with isolated GI symptoms 2, 4

Management Approach

Musculoskeletal Management

Low-resistance exercise to improve joint stability by increasing muscle tone is the cornerstone of management 2, 4

• Physical therapy for myofascial release to facilitate participation in low-resistance exercise 4
• Delay orthopedic surgery if possible in favor of physical therapy and bracing, as hEDS patients experience decreased stabilization and shorter duration of improvement compared to those without EDS 4

Pain Management

Refer to pain management specialist for chronic pain 2, 4

CRITICAL PITFALL: Avoid opioid dependence, particularly problematic in patients with gastrointestinal manifestations 2, 4

Gastrointestinal Management

Focus treatment on the most prominent GI symptoms and abnormal function test results 5:

• Proton pump inhibitors, H2-blockers, or sucralfate for gastritis and reflux 4
• Promotility agents for delayed gastric emptying 4
• Gastroparesis diet (small particle diet) and various elimination diets (low fermentable carbohydrates, gluten- or dairy-free, low-histamine diets) can be considered, but must be delivered with appropriate nutritional counseling to avoid restrictive eating 5

CRITICAL PITFALL: Do not escalate to invasive nutrition support in hEDS with pain-predominant presentation, as most hEDS patients have visceral hypersensitivity rather than true dysmotility 4

POTS Management

Treatment includes increasing fluid and salt intake, exercise training, and compression garments 5

• For patients not responding to conservative measures, consider pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from cardiology and neurology 5

MCAS Management

When MCAS is confirmed, treat with histamine receptor antagonists and/or mast cell stabilizers 5

• Avoid triggers: certain foods, alcohol, strong smells, temperature changes, mechanical stimuli (friction), emotional distress, allergens (pollen, mold), or specific medications (opioids, NSAIDs, iodinated contrast) 5

Vascular EDS-Specific Management

For confirmed vascular EDS 4:

• Celiprolol is recommended to reduce vascular morbidity (lacks FDA approval in US) 4
• Annual surveillance imaging for any dilated or dissected segments using non-invasive methods (Doppler ultrasound, CT, or MRI) 4
• Avoid invasive vascular procedures due to fatal complication risk 4

When to Refer

• Medical genetics: All suspected EDS cases for definitive diagnosis and classification 2
• Gastroenterology: Refractory GI symptoms despite appropriate management 2
• Cardiology/Neurology: POTS not responding to lifestyle modifications 2
• Allergy/Mast cell disease research center: MCAS diagnosis supported through clinical and/or laboratory features 5, 2
• Vascular surgery: Suspected vascular EDS for surveillance imaging protocols 2