Diagnosis and Management of Ehlers-Danlos Syndrome
Immediate Diagnostic Priority: Identify the Subtype
The first critical step is determining whether the patient has vascular EDS (type IV), which requires urgent COL3A1 genetic testing due to life-threatening arterial rupture risk, versus hypermobile EDS (the most common form, 80-90% of cases), which is diagnosed clinically without available genetic testing. 1, 2, 3
Red Flags for Vascular EDS (Requires Urgent Genetic Testing)
- Thin, translucent skin with visible veins 2
- Easy bruising without significant trauma 2
- Family history of sudden death, arterial rupture, or organ perforation 2
- Spontaneous arterial dissection or rupture (can occur without preceding aneurysm) 4
If vascular EDS is suspected, order COL3A1 gene mutation testing immediately—this is a medical emergency with median survival of 48 years. 2 Avoid all invasive vascular procedures, as fatal complications have been reported. 2, 3
Clinical Diagnosis of Hypermobile EDS
For hypermobile EDS, diagnosis requires meeting ALL three major criteria: 2, 3
Criterion 1: Joint Hypermobility (Beighton Scale ≥5/9 in adults <50 years)
Award one point for each of the following: 1, 2
- Passive dorsiflexion of each fifth finger >90° (1 point per side)
- Passive thumb apposition to flexor forearm surface (1 point per side)
- Elbow hyperextension >10° (1 point per side)
- Knee hyperextension >10° (1 point per side)
- Forward bend with palms flat on floor, knees extended (1 point)
Scoring thresholds: ≥6/9 for prepubertal children, ≥5/9 for adults <50 years, ≥4/9 for adults ≥50 years 2, 4
Criterion 2: Skin and Tissue Features
- Soft or velvety skin texture with normal or slightly increased extensibility 2, 3
- Absence of skin fragility or atrophic scarring (distinguishes hEDS from other subtypes) 3
- Easy bruising without significant trauma 2
Criterion 3: Exclusion of Alternative Diagnoses
This is where genetic testing becomes critical. A 2025 study found that 26.4% of patients meeting clinical criteria for hEDS had alternative genetic diagnoses requiring different management. 3, 5
Do not diagnose hEDS without genetic testing to exclude other conditions. 3
Essential Baseline Testing for All Suspected EDS Patients
Cardiovascular Assessment (Non-Negotiable)
- Echocardiogram to measure aortic root diameter (dilation occurs in 25-33% of hEDS cases) 2, 3, 4
- Dilated eye examination to exclude Marfan syndrome 2, 4
Genetic Testing Strategy
For unclear presentations, order multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes. 2 This is more efficient than sequential single-gene testing when the subtype is uncertain.
For hypermobile EDS specifically: No causative genes have been identified, so genetic testing serves only to exclude alternative diagnoses. 1, 3 Do not order whole-genome or exome sequencing for hEDS. 2
Screening for Common Comorbidities
Postural Orthostatic Tachycardia Syndrome (POTS): 1, 2
- Perform active stand test: measure heart rate increase
- Diagnostic threshold: ≥30 beats/min increase in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing, without orthostatic hypotension
- POTS affects up to 37.5% of hEDS patients 2
Mast Cell Activation Syndrome (MCAS): 1, 2
- Only test if patient has episodic multisystem symptoms involving ≥2 organ systems (flushing, urticaria, wheezing)
- Obtain baseline serum tryptase
- Repeat 1-4 hours after symptom flare
- Diagnostic threshold: 20% increase above baseline plus 2 ng/mL
Do not routinely test for MCAS in all hEDS patients with isolated GI symptoms. 2
Gastrointestinal Screening (98% of hEDS patients have GI symptoms): 1, 3
- Celiac disease serological testing should be performed earlier in hEDS patients with any GI symptoms (not just diarrhea) 1, 2
- Anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation (high prevalence of pelvic floor dysfunction) 1, 2
- Gastric emptying studies for chronic upper GI symptoms after excluding structural disease 1, 2
Cardiovascular Surveillance Schedule
For normal aortic root: 2
- Echocardiogram every 2-3 years during growth
- Annually once adult height reached
For aortic root dilation: 2
- Every 6 months if diameter >4.5 cm or growth rate >0.5 cm/year
- Annually if diameter <4.5 cm and growth <0.5 cm/year
- Baseline MR angiography of entire aorta and branch vessels (head to pelvis)
- Annual surveillance imaging for any dilated or dissected segments
- Use only non-invasive imaging (Doppler ultrasound, CT, MRI)—avoid invasive procedures
Management Principles
Musculoskeletal Management
Low-resistance exercise to improve joint stability by increasing muscle tone 3, 4
- Physical therapy for myofascial release to facilitate exercise participation 4
- Delay orthopedic surgery in favor of physical therapy and bracing (hEDS patients experience decreased stabilization and shorter duration of improvement compared to non-EDS patients) 4
Gastrointestinal Management
Treat the most prominent GI symptoms and abnormal function test results: 1
- Proton pump inhibitors, H2-blockers, or sucralfate for gastritis/reflux 3
- Promotility agents for delayed gastric emptying 3
- Gastroparesis diet (small particle diet) for upper GI symptoms 1
- Elimination diets (low FODMAP, gluten-free, dairy-free, low-histamine) with nutritional counseling to avoid restrictive eating 1
Do not escalate to invasive nutrition support in hEDS with pain-predominant presentation—most hEDS patients have visceral hypersensitivity rather than true dysmotility. 3
POTS Management
Conservative measures first: 1
- Increase fluid and salt intake
- Exercise training
- Compression garments
Pharmacological treatment for volume expansion, heart rate control, and vasoconstriction if conservative measures fail (requires cardiology/neurology consultation) 1
MCAS Management (When Confirmed)
Histamine receptor antagonists and/or mast cell stabilizers 1
Avoid triggers: 1
- Certain foods, alcohol, strong smells
- Temperature changes
- Mechanical stimuli (friction)
- Emotional distress
- Specific medications (opioids, NSAIDs, iodinated contrast)
Vascular EDS-Specific Management
Celiprolol to reduce vascular morbidity (lacks FDA approval in US but recommended by European guidelines) 3
Pain Management
Involve pain management specialist early 4
Avoid opioid dependence—particularly problematic in patients with GI manifestations 2, 3
Critical Pitfalls to Avoid
Failing to recognize vascular EDS: This subtype carries significant mortality risk from arterial or organ rupture. 2 Thin, translucent skin with visible veins is the key clinical clue. 2
Diagnosing hEDS without genetic testing: 26.4% of clinically diagnosed cases had alternative genetic conditions requiring different management. 3, 5
Performing invasive procedures in vascular EDS: Fatal complications have been reported. 2, 3 Use only non-invasive imaging.
Overlooking comorbid POTS and MCAS: These conditions significantly impact quality of life and require specific treatment. 1, 2
Prescribing stimulant medications (e.g., methylphenidate) in patients with POTS: These can exacerbate autonomic instability. 2
Ignoring psychosocial burden: Anxiety, depression, and maladaptive coping are common in chronic dysmotility and hEDS—multidisciplinary care including clinical psychology is essential. 2