What is the recommended workup and management for a patient presenting with symptoms suggestive of Ehlers-Danlos syndrome (EDS)?

Workup for Ehlers-Danlos Syndrome

Begin with urgent COL3A1 gene mutation testing if vascular EDS is suspected based on thin translucent skin with visible veins, easy bruising, or family history of arterial rupture, as this life-threatening subtype requires immediate diagnosis and has a median survival of 48 years. 1

Initial Clinical Assessment

Assess joint hypermobility using the Beighton scale, requiring ≥5/9 points in adults under 50 years, ≥4/9 for those over 50, and ≥6/9 for prepubertal children 1:

• Passive dorsiflexion of fifth finger >90° (1 point per side) 1
• Passive thumb apposition to flexor forearm surface (1 point per side) 1
• Elbow hyperextension >10° (1 point per side) 1
• Knee hyperextension >10° (1 point per side) 1
• Forward bend with palms flat on floor, knees extended (1 point) 1

Examine skin for specific features including soft velvety texture, hyperextensibility (gently pull volar forearm skin), thin translucent appearance with visible veins (suggests vascular EDS), abnormal scarring patterns, and easy bruising 1

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

Essential Cardiovascular Evaluation

Obtain echocardiogram immediately to evaluate aortic root diameter, as dilation occurs in 25-33% of hypermobile and classic EDS cases 1:

• If normal: repeat annually until adult height reached 2
• If diameter >4.5 cm or growth >0.5 cm/year: repeat every 6 months 1

Perform MR angiography of head, neck, thorax, abdomen, and pelvis if vascular EDS or Loeys-Dietz syndrome suspected, to assess arterial tortuosity and aneurysms 1

Genetic Testing Strategy

For suspected vascular EDS (Type IV): Order urgent COL3A1 gene mutation testing as the definitive diagnostic test 1

For suspected classic EDS (Types I/II): Order COL5A1 or COL5A2 gene mutation testing 1

When EDS subtype is unclear: Order multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes as the most efficient approach 1

For hypermobile EDS (hEDS): Do NOT order routine genetic testing, as no causative genes have been identified; diagnosis is 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

Refer to medical genetics specialist before mutation screening due to complex financial, insurance, familial, and social implications 1

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 1

• If positive, refer for tilt table testing and expanded autonomic function assessment 1

Gastrointestinal Manifestations (98% of hEDS patients)

Screen for celiac disease early with serological testing in any hEDS patient with GI symptoms, as risk is elevated compared to general population 1

Consider anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation, given high prevalence of pelvic floor dysfunction 1

Order gastric emptying studies for chronic upper GI symptoms after excluding anatomical/structural disease, especially with comorbid POTS 1

Mast Cell Activation Syndrome (MCAS)

Obtain baseline serum tryptase level ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 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

Ophthalmologic Evaluation

Perform dilated eye examination to exclude Marfan syndrome 1

Bone Health

Order DXA scan if height loss >1 inch to screen for osteoporosis 1

Additional Laboratory Testing

Complete blood count with differential to evaluate for cytopenias or eosinophilia suggesting systemic involvement 1

Comprehensive metabolic panel including liver and renal function 1

Baseline serum tryptase and vitamin B12 levels to help distinguish vascular complications in myeloproliferative variants 1

If systemic arteriopathy suspected: ANA, ANCA, ESR, CRP, LDH, and quantitative immunoglobulin levels including IgE 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 1

Avoid routine whole-genome or exome sequencing in hEDS, as no causative genes have been identified 1

Recognize that 26.4% of clinically diagnosed EDS cases have alternative genetic conditions requiring different management, making genetic testing essential 3

Perform Wood's lamp examination to exclude other connective tissue disorders 1

Subspecialty Referrals

Medical genetics: Primary specialists for diagnosis and classification of all EDS types 1

Vascular surgery: For suspected vascular EDS requiring surveillance imaging protocols 1

Cardiology: For aortic root monitoring and POTS evaluation 1

Gastroenterology: For refractory GI symptoms despite appropriate management 1

Allergy/mast cell disease research center: If MCAS diagnosis is supported through clinical and/or laboratory features 1