What are the diagnostic criteria and testing for Ehlers-Danlos syndrome (EDS)?

Diagnostic Criteria and Testing for Ehlers-Danlos Syndrome

Medical geneticists are the primary specialists who diagnose and classify EDS, though gastroenterologists and other specialists can screen using the Beighton score and 2017 diagnostic criteria for hypermobile EDS (hEDS), with referral to genetics when appropriate. 1

Initial Clinical Assessment

Joint Hypermobility Evaluation (Beighton Scale)

• Score ≥6/9 points required for prepubertal children 1, 2
• Score ≥5/9 points required for adults under 50 years 1, 2
• Score ≥4/9 points required for adults over 50 years 1, 2

Skin and Tissue Assessment

• Evaluate for soft, velvety, or hyperextensible skin 1
• Document easy bruising patterns without significant trauma 1, 2
• Assess for abnormal scarring, atrophic scars, or tissue fragility 1, 3
• For suspected vascular EDS: look for thin, translucent skin with visible veins 1

Family History Documentation

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

Essential Cardiovascular Screening

• Echocardiogram is required for all suspected EDS cases to evaluate aortic root diameter, as dilation occurs in 25-33% of hypermobile and classic EDS cases 1, 2
• Annual echocardiogram if aortic root is normal; every 6 months if diameter >4.5 cm or growth >0.5 cm/year 1
• MR angiography of head, neck, thorax, abdomen, and pelvis for suspected vascular EDS or Loeys-Dietz syndrome to assess arterial tortuosity and aneurysms 1

Genetic Testing Strategy by Subtype

For Suspected Vascular EDS (Life-Threatening - Urgent Testing)

• COL3A1 gene mutation testing is the definitive diagnostic test and should be performed urgently 4, 1
• Baseline serum tryptase level to help distinguish vascular complications (elevated in myeloproliferative variants) 1
• Vitamin B12 level (characteristically elevated in myeloproliferative variants) 1

For Classical EDS

• COL5A1 or COL5A2 gene mutation testing for molecular confirmation 1

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

• No genetic testing is indicated, as no causative genes have been identified 1, 5
• 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
• Avoid routine whole-genome or exome sequencing in hEDS 1

When EDS 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
• Recent data shows genetic testing identified an alternative or additional diagnosis in 26.4% of patients meeting hEDS criteria, with clinical implications requiring distinct management 6

Screening for Common Comorbidities

Autonomic Dysfunction (POTS)

• Measure postural vital signs with active stand test: heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension 4, 1, 2
• Tilt table testing for formal autonomic function assessment if indicated 1

Mast Cell Activation Syndrome (MCAS)

• Baseline serum tryptase level ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 4, 1
• If MCAS suspected: obtain serum tryptase levels at baseline and 1-4 hours following symptom flares 4
• Diagnostic threshold: increase of 20% above baseline plus 2 ng/mL during symptom flares 4, 1
• Do NOT perform MCAS testing in all hEDS patients with isolated GI symptoms 1

Gastrointestinal Evaluation

• Celiac disease serological testing should be performed earlier in hEDS patients with any GI symptoms (not just diarrhea), as risk is elevated compared to general population 4, 1
• Anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation, given high prevalence of pelvic floor dysfunction 4, 1
• Gastric emptying studies for chronic upper GI symptoms after excluding anatomical/structural disease 4

Ophthalmologic Assessment

• Dilated eye examination to exclude Marfan syndrome 1

Additional Screening Labs (When Systemic Involvement Suspected)

• Complete blood count with differential to evaluate for cytopenias or eosinophilia 1
• Comprehensive metabolic panel including liver and renal function 1
• Lactate dehydrogenase (LDH) as marker for tissue breakdown 1
• Antinuclear antibody (ANA) and antineutrophil cytoplasmic antibodies (ANCA) if systemic arteriopathy suspected 1
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory assessment 1
• Quantitative immunoglobulin levels including IgE if allergic or mast cell symptoms present 1

Critical Pitfalls to Avoid

• Never perform invasive vascular imaging in suspected vascular EDS, as fatal complications have been reported 1
• Do not delay COL3A1 testing if vascular EDS is suspected - this is a medical emergency with median survival 48 years and high arterial rupture risk 1
• Failure to recognize vascular EDS carries significant mortality risk from arterial or organ rupture 1
• Do not perform routine genetic testing for hEDS 1
• Avoid opioids in patients with chronic pain 4

When to Refer

To Medical Genetics

• When clinical features suggest EDS, family history shows autosomal dominant inheritance, or when arteriopathy is suspected 1
• Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications 1

To Allergy/Mast Cell Specialist

• If MCAS diagnosis is supported through clinical and/or laboratory features (serum tryptase increases of 20% above baseline plus 2 ng/mL during symptom flares) 4, 1

To Vascular Surgery

• Patients with suspected or confirmed vascular EDS for surveillance imaging protocols 1

To Gastroenterology

• Patients with refractory gastrointestinal symptoms despite appropriate management 1

Limitations of Genetic Testing

• Mutation identification may fail even when protein analysis confirms a collagen defect, as only coding sequences and closely surrounding regions are investigated 1
• Each family typically has its own specific mutation, making systematic screening impractical and costly 1
• No genotype-phenotype correlations exist - the specific mutation does not predict disease type, course, or severity 5