What is the recommended workup for a patient suspected of having Ehlers-Danlos Syndrome (EDS)?

Workup for Ehlers-Danlos Syndrome

The workup for suspected EDS begins with clinical assessment using the Beighton scale (≥5/9 for adults under 50, ≥4/9 for those over 50, ≥6/9 for prepubertal children), followed by targeted genetic testing based on clinical phenotype, with COL3A1 mutation testing being urgent for suspected vascular EDS, while hypermobile EDS remains a clinical diagnosis without available genetic testing. 1

Initial Clinical Assessment

Joint Hypermobility Evaluation (Beighton Scale)

The following maneuvers should be systematically assessed, with one point awarded for each positive finding 1, 2:

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

Skin and Tissue Assessment

Examine for the following features that distinguish EDS subtypes 3, 1:

• Soft, velvety, or hyperextensible skin (pull skin on volar forearm to assess) 3, 1
• Thin, translucent skin with visible veins (suggests vascular EDS) 4
• Easy bruising patterns without significant trauma 3, 4
• Abnormal scarring (atrophic, cigarette paper-like scars) or tissue fragility 3, 2

Family History Documentation

Obtain a three-generation pedigree focusing on 4:

• Sudden deaths or deaths at young age
• Arterial ruptures or aneurysms
• Organ perforations (bowel, uterus)
• Autosomal dominant inheritance pattern (50% transmission risk)
• Similar features in relatives without skin abnormalities 3

Essential Cardiovascular Imaging

Echocardiography (Required for All Suspected Cases)

Transthoracic echocardiogram must be performed to evaluate aortic root diameter, as dilation occurs in 25-33% of hypermobile and classic EDS cases 3, 1, 5. Follow-up intervals depend on findings 3:

• Normal aortic root: Repeat every 2-3 years until adult height reached, then only if symptomatic or planning major physical activity increase
• Aortic root <4.5 cm with growth <0.5 cm/year: Annual echocardiogram
• Aortic root >4.5 cm or growth >0.5 cm/year: Echocardiogram every 6 months

Advanced Vascular Imaging (For Suspected Vascular EDS)

MR angiography from head to pelvis should be performed when vascular EDS or arteriopathy is suspected to assess for arterial tortuosity, aneurysms, and dissections throughout the entire vascular tree 1, 4. Avoid invasive vascular imaging in suspected vascular EDS, as fatal complications have been reported 1.

Genetic Testing Strategy

Urgent Testing for Vascular EDS

COL3A1 gene mutation testing must be ordered immediately when vascular EDS is suspected based on characteristic facial features (thin nose, thin upper lip, small earlobes, prominent eyes), thin translucent skin, or family history of arterial/organ rupture 1, 4. This is a medical emergency, as vascular EDS has a median survival of 48 years with high risk of arterial rupture 1.

Multi-Gene Panel Approach

When EDS is suspected but subtype is unclear, order a comprehensive multi-gene panel covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes 1, 4. This is more efficient than sequential single-gene testing 1.

Hypermobile EDS (hEDS) - Clinical Diagnosis Only

Do not order genetic testing for suspected hEDS, as no causative genes have been identified and testing is unrewarding 1, 6, 7. Diagnosis relies entirely on clinical criteria available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf 1.

Essential Laboratory Studies

Pre-Genetic Testing Laboratory Work

Order the following labs before or concurrent with genetic testing 1, 4:

• Complete blood count with differential (evaluate for cytopenias or eosinophilia) 1
• Comprehensive metabolic panel (liver and renal function) 1
• Baseline serum tryptase level (only if episodic multisystem symptoms involving ≥2 systems present, to distinguish myeloproliferative variants) 1, 4
• Vitamin B12 level (characteristically elevated in myeloproliferative variants with arteriopathy) 1, 4
• ESR and CRP (inflammatory markers) 1

Screening for Common Comorbidities

The following tests should be performed based on clinical presentation 1:

• Postural vital signs with active stand test: Heart rate increase ≥30 bpm in adults (≥40 bpm in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension diagnoses POTS, which affects up to 37.5% of hEDS patients 1
• Celiac disease serological testing: Perform earlier in hEDS patients with any GI symptoms, as risk is elevated 1
• Anorectal manometry, balloon expulsion test, or defecography: Consider for lower GI symptoms like incomplete evacuation, given high prevalence of pelvic floor dysfunction 1
• Gastric emptying studies: For chronic upper GI symptoms after excluding structural disease 1

Additional Diagnostic Studies

Ophthalmologic Evaluation

Dilated eye examination should be performed to exclude Marfan syndrome and evaluate for lens dislocation or other ocular manifestations 3, 1.

Bone Density Assessment

DXA scan should be ordered for height loss >1 inch, as osteoporosis is common in EDS 3, 5. All patients in one study had osteoporosis on bone mineral density testing 5.

Full-Body Imaging (When Available)

Full-body (vertex-to-toes) FDG-PET-CT including distal extremities can aid in diagnosis and define extent of disease, though this is more commonly used in research settings 3.

Critical Pitfalls to Avoid

Do Not Perform Routine Testing

• Do not order genetic testing for all suspected hEDS cases - it is unrewarding and hEDS remains a clinical diagnosis 1, 6
• Do not perform MCAS testing in all hEDS patients with isolated GI symptoms - only test if episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) are present 1
• Do not use whole-genome or exome sequencing for hEDS - no causative genes identified 1

Recognize Life-Threatening Vascular EDS

Failure to recognize vascular EDS carries significant mortality risk from arterial or organ rupture 1, 8. Thin translucent skin, characteristic facial features, or family history of sudden death/arterial events mandate urgent COL3A1 testing 4.

Avoid Invasive Procedures in Vascular EDS

Invasive diagnostic procedures can lead to fatal complications in vascular EDS patients due to tissue fragility 1. Use non-invasive imaging (MRA) instead of angiography 1, 4.

Referral Strategy

Mandatory Genetic Counseling

Refer for formal genetic counseling before mutation screening due to complex financial, insurance, familial, and social implications 1, 4. This is particularly important for vascular EDS given pregnancy risks (uterine and arterial rupture) and need for lifelong surveillance 1, 4.

Subspecialty Referrals Based on Findings

• Medical genetics: All suspected EDS cases for definitive diagnosis and classification 1
• Cardiology: Aortic root dilation or vascular complications 3, 1
• Gastroenterology: Refractory GI symptoms despite appropriate management (affects up to 98% of hEDS patients) 1
• Allergy/Mast Cell Disease Center: If MCAS diagnosis supported through clinical and laboratory features (tryptase increases of 20% above baseline plus 2 ng/mL during symptom flares) 1
• Autonomic specialist: POTS confirmed on postural vital signs for tilt table testing 1