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

Primary Care Workup for Ehlers-Danlos Syndrome

Begin with clinical assessment using the Beighton scale for joint hypermobility (≥5/9 points for adults under 50, ≥4/9 for adults over 50), evaluate skin hyperextensibility and tissue fragility, obtain echocardiogram to assess for aortic root dilation, and urgently refer to medical genetics for definitive diagnosis and subtype classification. 1

Initial Clinical Assessment

Joint Hypermobility Evaluation

• Apply the Beighton scale systematically with age-specific thresholds: ≥6/9 points in children before puberty, ≥5/9 points for adults up to age 50, and ≥4/9 points for adults over 50 2
• All patients with EDS will have a Beighton score >5 points 3
• Joint hypermobility is present in 99% of EDS patients 4

Skin and Tissue Assessment

• Evaluate for skin hyperextensibility (doughy/velvety, soft, thin texture) 5
• Assess for easy bruising and abnormal wound healing 6
• Check for tissue fragility and atrophic scarring 1
• All patients will demonstrate skin hyperextensibility and tissue fragility 3

Family History

• Document autosomal dominant inheritance pattern, as 50% of patients have positive family history 3
• Each family typically has its own specific mutation 1

Essential Baseline Testing in Primary Care

Cardiovascular Screening

• Order echocardiogram immediately to evaluate for aortic root dilation, which occurs in 25-33% of classic and hypermobile EDS types 1
• Aortic root dilation/valve prolapse is present in 43% of patients 3
• This is critical because vascular EDS (type IV) carries the greatest mortality risk from spontaneous arterial and organ ruptures 7

Autonomic Function Screening

• Measure postural vital signs with heart rate increase ≥30 beats/min within 10 minutes of standing to screen for POTS, which affects many hEDS patients 1
• POTS is a common comorbidity requiring early identification 1

Laboratory Workup Before Genetics Referral

• Obtain baseline serum tryptase level if symptoms suggest mast cell activation (flushing, urticaria, wheezing, multisystem symptoms) 1
• Check celiac disease serological testing earlier in patients with any GI symptoms, as up to 98% of hEDS patients have GI manifestations 1
• Measure complete blood count with differential to evaluate for cytopenias or eosinophilia 1
• Order comprehensive metabolic panel including liver and renal function 1

Additional Screening When Vascular EDS Suspected

• Obtain vitamin B12 level, which is characteristically elevated in myeloproliferative variants with arteriopathy 1
• Check lactate dehydrogenase (LDH) as a marker for tissue breakdown 1
• Measure inflammatory markers (ESR, CRP) for inflammatory assessment 1
• Test ANA and ANCA if systemic arteriopathy is suspected 1

Critical Imaging Studies

Vascular Imaging

• Order MR angiography of head, neck, thorax, abdomen, and pelvis when vascular EDS or arteriopathy is suspected to assess arterial tortuosity and aneurysms 1
• This is essential before invasive procedures, as inappropriate invasive diagnostic procedures in vascular EDS can lead to fatal complications 1

Ophthalmologic Evaluation

• Refer for dilated eye examination to exclude related conditions like Marfan syndrome 1

Bone Density Assessment

• Consider bone mineral density testing, as all patients in one study demonstrated osteoporosis 3

Genetic Testing Strategy

When to Order Genetic Testing

• Do NOT order routine genetic testing for hypermobile EDS (hEDS), as no causative genes have been identified 1
• Order COL3A1 gene mutation testing urgently when vascular EDS is suspected, as this is the definitive diagnostic test for this life-threatening subtype 1
• Consider multi-gene panel testing (covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes) when EDS is suspected but subtype is unclear 1
• Avoid routine whole-genome or exome sequencing in hEDS 1

Genetic Testing Limitations

• Mutation identification may fail even when protein analysis confirms a collagen defect, as only coding sequences and closely surrounding regions are investigated 1
• Genetic heterogeneity exists, making systematic screening impractical and costly 1

Urgent Referral to Medical Genetics

Refer immediately to medical genetics when:

• Clinical features suggest EDS based on Beighton scale and skin findings 1
• Family history shows autosomal dominant inheritance 1
• Arteriopathy is suspected 1
• Vascular EDS is a consideration, given the risk of fatal arterial or organ rupture 1

Medical geneticists are the primary specialists who diagnose and classify EDS, as they have expertise in evaluating inherited connective tissue disorders and can coordinate appropriate genetic testing 1

Common Pitfalls to Avoid

Diagnostic Errors

• Failure to recognize vascular EDS, which carries significant mortality risk from arterial or organ rupture 1
• Performing inappropriate invasive diagnostic procedures in vascular EDS patients, which can lead to fatal complications 1
• Ordering routine genetic testing for hEDS when no causative genes exist 1
• Performing MCAS testing in all hEDS patients with isolated GI symptoms 1

Clinical Management Errors

• Failing to obtain echocardiogram for aortic surveillance 1
• Not screening for POTS with postural vital signs 1
• Delaying celiac testing in patients with GI symptoms 1

Subtype-Specific Considerations

Hypermobile EDS (80-90% of cases)

• Diagnosis is primarily clinical as no specific genetic markers exist 1, 7
• Joint pain occurs in 99% of patients 4
• Chronic fatigue affects 82%, anxiety 73%, depression 69%, and fibromyalgia 42% 4
• 46% report constant pain described as aching and tiring/exhausting 4

Vascular EDS (Type IV)

• Poses the greatest risk due to spontaneous arterial and organ ruptures 7
• Requires urgent COL3A1 genetic testing 1
• Baseline and surveillance imaging of entire aorta and branch vessels is essential 1
• Avoid invasive procedures when possible 1