What is the diagnostic approach for a patient suspected of having Ehlers-Danlos syndrome (EDS)?

Diagnostic Approach for Ehlers-Danlos Syndrome

The diagnosis of EDS begins with clinical assessment using the Beighton scale (≥5/9 points required for adults under 50), followed by subtype-specific genetic testing—with urgent COL3A1 mutation testing for suspected vascular EDS due to its life-threatening nature. 1

Initial Clinical Assessment

Joint Hypermobility Evaluation (Beighton Scale)

• Score each of the following maneuvers (maximum 9 points): 2
  • Passive dorsiflexion of fifth finger >90° (1 point each side)
  • Passive thumb apposition to flexor forearm surface (1 point each side)
  • Elbow hyperextension >10° (1 point each side)
  • Knee hyperextension >10° (1 point each side)
  • Forward bend with palms flat on floor, knees extended (1 point)
• Diagnostic thresholds: ≥5/9 for adults <50 years, ≥4/9 for adults >50 years, ≥6/9 for prepubertal children 1

Skin and Tissue Assessment

• Evaluate for soft, velvety, or hyperextensible skin with normal or slightly increased extensibility 2
• Document thin, translucent skin with visible subcutaneous veins (suggests vascular EDS) 1, 3
• Assess for easy bruising patterns without significant trauma 1, 3
• Check for abnormal scarring or tissue fragility 1

Critical Red Flags for Vascular EDS (Type IV)

• Characteristic facial features: thin nose, thin upper lip, small earlobes, prominent eyes 3
• Arterial dissection or rupture in patients <45 years 4, 5
• Spontaneous colonic perforation 4, 5
• Translucent skin with highly visible vessels on trunk and lower back 5

Essential Diagnostic Testing by Suspected Subtype

For Suspected Vascular EDS (URGENT)

• Order COL3A1 gene mutation testing immediately—this is the gold standard and must not be delayed 1, 3
• Obtain baseline serum tryptase level to distinguish myeloproliferative variants 3
• Check vitamin B12 level (characteristically elevated in myeloproliferative variants) 3
• Perform MR angiography from head to pelvis to assess arterial tortuosity, aneurysms, and dissections 1, 3
• Avoid invasive arteriography—it is contraindicated due to risk of fatal complications 4, 5

For Suspected Hypermobile EDS (Most Common Subtype)

• Diagnosis is purely clinical—no genetic test is available or recommended 2, 1
• All three major criteria must be met: 2
  1. Beighton score ≥5/9
  2. Soft/velvety skin with normal or slightly increased extensibility
  3. Absence of skin/soft tissue fragility (which would suggest other subtypes)
• Supportive minor criteria include: recurrent joint dislocations, chronic joint/limb pain, easy bruising, functional bowel disorders, neurally mediated hypotension/POTS, high narrow palate, dental crowding 2

For Suspected Classical EDS

• Order COL5A1 or COL5A2 gene mutation testing for molecular confirmation 1

When Subtype is Unclear

• Order multi-gene panel covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes 1, 3
• Do not order whole-genome or exome sequencing for hypermobile EDS—no causative genes have been identified 1

Mandatory Screening Tests for All EDS Patients

Cardiovascular Evaluation

• Echocardiogram to assess aortic root diameter (dilation occurs in 25-33% of hypermobile and classical EDS) 2, 1
• Repeat every 2-3 years until adult height reached if normal 2
• Repeat every 6 months if diameter >4.5 cm or growth >0.5 cm/year 2, 1

Autonomic Function Assessment

• 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 indicates POTS 1

Ophthalmologic Evaluation

• Dilated eye examination to exclude Marfan syndrome 2, 1

Gastrointestinal Screening (for Hypermobile EDS)

• Perform celiac disease serological testing earlier than general population if any GI symptoms present 1
• Consider anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms given high prevalence of pelvic floor dysfunction 1

Mast Cell Activation Syndrome (MCAS) Testing

• Only test if patient has episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 1
• Obtain baseline serum tryptase level 1
• Diagnostic threshold: 20% increase above baseline plus 2 ng/mL during symptom flares 1
• Do not perform routine MCAS testing in all hEDS patients with isolated GI symptoms 1

Bone Density Assessment

• Order DXA scan for height loss >1 inch 2, 1

Pre-Genetic Testing Laboratory Panel

• Complete blood count with differential (evaluate for cytopenias or eosinophilia) 1, 3
• Comprehensive metabolic panel including liver and renal function 1, 3
• 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

Referral Strategy

Immediate Referral to Medical Genetics

• All suspected EDS cases require genetics consultation for definitive diagnosis and classification 1
• Genetic counseling is mandatory before mutation screening due to financial, insurance, familial, and social implications 1, 3

Subspecialty Referrals Based on Findings

• Vascular surgery: for surveillance imaging protocols in confirmed or suspected vascular EDS 1
• Cardiology: for aortic root dilation management 2, 1
• Gastroenterology: for refractory GI symptoms despite appropriate management 1
• Rheumatology: for joint hypermobility assessment and management 1

Critical Pitfalls to Avoid

• Never delay COL3A1 testing if vascular EDS is suspected—median survival is 48 years with high arterial rupture risk 1
• Avoid invasive vascular procedures in suspected vascular EDS—fatal complications have been reported 1, 4, 5
• Do not perform routine genetic testing for hypermobile EDS—it is a clinical diagnosis only 1
• Recognize that mutation identification may fail even when protein analysis confirms collagen defect, as only coding sequences are investigated 1
• Pregnancy in vascular EDS carries high maternal mortality risk from uterine and arterial rupture—requires specialized high-risk obstetric care 1, 4, 5