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

How to Diagnose Ehlers-Danlos Syndrome

Refer all suspected EDS cases to a medical geneticist for definitive diagnosis and classification, as they are the primary specialists with expertise in evaluating inherited connective tissue disorders and coordinating appropriate genetic testing. 1

Initial Clinical Assessment

Joint Hypermobility Evaluation (Beighton Scale)

Calculate the Beighton score by assessing the following (1 point per side where applicable): 1, 2

• Passive dorsiflexion of fifth fingers >90° (2 points total) 1
• Passive thumb apposition to flexor forearm surface (2 points total) 1
• Elbow hyperextension >10° (2 points total) 1
• Knee hyperextension >10° (2 points total) 1
• Forward bend with palms flat on floor, knees extended (1 point) 1

Diagnostic thresholds: ≥6/9 for prepubertal children, ≥5/9 for adults under 50 years, ≥4/9 for adults over 50 years 1, 2

Skin and Tissue Assessment

Document the following features: 1, 2

• Soft or velvety skin texture with normal or slightly increased extensibility 2
• Skin hyperextensibility by gently pulling skin on volar forearm 1
• Thin, translucent skin with visible veins (suggests vascular EDS) 1
• Abnormal scarring patterns (atrophic, cigarette-paper scars) 1, 3
• Easy bruising without significant trauma 1, 3
• Tissue fragility (absence distinguishes hEDS from other subtypes) 2

Family History Documentation

Obtain a three-generation pedigree focusing on: 1, 2

• Sudden deaths or arterial ruptures (vascular EDS concern) 1
• Organ perforations 1
• Joint hypermobility patterns 2
• Autosomal dominant inheritance pattern 1, 2

Essential Screening Tests

Cardiovascular Imaging (Required for All Suspected Cases)

• Echocardiogram to evaluate aortic root diameter, as dilation occurs in 25-33% of hypermobile and classic EDS cases 1, 2, 4
• Surveillance schedule: Annual echocardiogram if aortic root is normal; every 6 months if diameter >4.5 cm or growth >0.5 cm/year 1, 2

Ophthalmologic Evaluation

• Dilated eye examination to exclude Marfan syndrome 1, 4

Autonomic Function Screening

• Postural vital signs with active stand test: Measure heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension to diagnose POTS 1
• Consider tilt table testing if postural vital signs confirm POTS 1

Genetic Testing Strategy

For Suspected Vascular EDS (URGENT)

Perform COL3A1 gene mutation testing immediately when vascular EDS is suspected, as this is a life-threatening subtype with median survival 48 years and high arterial rupture risk 1, 2

For Suspected Classic EDS

COL5A1 or COL5A2 gene mutation testing for molecular confirmation 1

For Unclear EDS Subtype

Multi-gene panel testing (covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes) is the most efficient diagnostic approach 1

For Suspected Hypermobile EDS (hEDS)

• Do NOT perform routine genetic testing for hEDS, as no causative genes have been identified 1, 5
• However, genetic testing is MANDATORY to exclude alternative diagnoses before confirming hEDS, as 26.4% of clinically diagnosed hEDS cases had alternative genetic conditions requiring different management 2, 6
• Apply the 2017 diagnostic criteria for hEDS (available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf) 1

Genetic Counseling

Obtain genetic counseling before mutation screening due to complex financial, insurance, familial, and social implications 1

Screening for Common Comorbidities

Gastrointestinal Manifestations (98% of hEDS patients)

• Screen for nausea, abdominal pain, constipation, bloating, early satiety, and reflux 1
• Perform celiac disease serological testing earlier in hEDS patients with any GI symptoms 1
• Consider anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation 1
• Consider gastric emptying studies for chronic upper GI symptoms after excluding anatomical/structural disease 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: Tryptase increase of 20% 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 Health

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

Imaging for Vascular EDS or Loeys-Dietz Syndrome

MR angiography of head, neck, thorax, abdomen, and pelvis to assess arterial tortuosity and aneurysms 1

Critical Pitfalls to Avoid

• Never perform invasive vascular imaging or procedures in suspected vascular EDS, as fatal complications have been reported 1, 2
• Do not delay COL3A1 testing if vascular EDS is suspected—this is a medical emergency 1
• Do not diagnose hEDS without genetic testing to exclude alternative diagnoses, as over one-quarter of clinically diagnosed cases have alternative genetic conditions 2, 6
• Avoid escalating to invasive nutrition support in hEDS with pain-predominant presentation, as most hEDS patients have visceral hypersensitivity rather than true dysmotility 2
• Do not overlook pregnancy risks in women with EDS, including uterine and arterial rupture risk, especially in vascular type 1

When to Refer to Subspecialists

• Medical genetics: All suspected EDS cases for definitive diagnosis 1, 2
• Cardiology/vascular surgery: Vascular EDS for surveillance imaging protocols 1
• Gastroenterology: 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