How do you test for Ehlers‑Danlos syndrome?

How to Test for Ehlers-Danlos Syndrome

The diagnosis of Ehlers-Danlos syndrome begins with clinical assessment using the Beighton scale for joint hypermobility (requiring ≥5/9 points in adults under 50), followed by phenotype-guided genetic testing for all subtypes except hypermobile EDS, which remains a purely clinical diagnosis. 1, 2

Initial Clinical Screening

Beighton Scale Assessment (Required First Step)

The Beighton scale quantifies joint hypermobility and is essential for diagnosis 1, 3:

• Passive dorsiflexion of each fifth finger >90 degrees (1 point per side) 1
• Passive apposition of each thumb to flexor 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
• Palms flat on floor when bending forward with knees extended (1 point) 1

Scoring thresholds: ≥5/9 for adults under 50 years, ≥4/9 for adults over 50 years, ≥6/9 for prepubertal children 3, 4

Skin and Tissue Examination

Assess for the following clinical features 1, 5:

• Soft, velvety, or hyperextensible skin (pull skin on volar forearm to assess) 1
• Atrophic scarring (particularly over pressure points like knees and elbows) 1
• Easy bruising without significant trauma 1
• Thin, translucent skin with visible veins (suggests vascular EDS—urgent workup needed) 3
• Subcutaneous spheroids or molluscoid pseudotumors (suggests classical EDS) 5

Mandatory Baseline Testing for All Suspected EDS Cases

Cardiovascular Screening

• Echocardiogram to evaluate aortic root diameter (dilation occurs in 25-33% of hypermobile and classical EDS) 1, 3
• 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 screen for POTS 3, 4

Family History Documentation

• Three-generation pedigree focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 3

Genetic Testing Strategy (Subtype-Specific)

For Suspected Vascular EDS (URGENT—Life-Threatening)

COL3A1 gene mutation testing is the definitive diagnostic test and must be performed urgently when vascular EDS is suspected based on thin translucent skin, arterial/organ rupture, or extensive bruising 1, 3. This subtype has a median survival of 48 years with significant arterial rupture risk 3.

Critical pitfall: Avoid invasive vascular imaging in suspected vascular EDS, as fatal complications have been reported 3.

For Suspected Classical EDS

• COL5A1 or COL5A2 gene mutation testing for molecular confirmation 3
• Biochemical testing shows abnormal collagen patterns in only 2/48 patients (4%), making it a poor screening method 6
• Genetic testing identifies mutations in approximately 52% of classical EDS cases 6

For Suspected Hypermobile EDS (Most Common—80-90% of Cases)

No genetic testing is available or recommended 1, 3. Diagnosis is purely clinical using the 2017 diagnostic criteria:

1. Generalized joint hypermobility (Beighton score as above) 1
2. Soft or velvety skin with normal or slightly increased extensibility 1
3. Absence of skin or soft tissue fragility (which would suggest other EDS subtypes) 1
4. Exclusion of alternative diagnoses through genetic testing 7

Important caveat: In one study, 26.4% of patients meeting clinical criteria for hypermobile EDS were found to have alternative genetic diagnoses with distinct management implications, underscoring the importance of exclusionary genetic testing 7.

Multi-Gene Panel Testing Approach

When EDS is suspected but subtype is unclear, multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes is the most efficient diagnostic approach 3. This identified molecular diagnoses in 25% of patients who met clinical criteria and 22% who had overlapping features but didn't fully meet criteria 8.

Additional Testing for Common Comorbidities

Gastrointestinal Screening

• Celiac disease serological testing should be performed earlier in hEDS patients with any GI symptoms (98% have GI manifestations) 3, 4
• Anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms like incomplete evacuation 3

Mast Cell Activation Syndrome Screening (Only If Indicated)

• Baseline serum tryptase level ONLY if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 3
• Diagnostic threshold: 20% increase above baseline plus 2 ng/mL during symptom flares 3

Critical pitfall: Do NOT perform routine MCAS testing in all hEDS patients with isolated GI symptoms 3.

When to Refer to Medical Genetics

Refer to medical genetics for all suspected EDS cases for definitive diagnosis and classification, particularly when 3, 4:

• Vascular EDS is suspected (urgent referral)
• Clinical features suggest EDS but subtype is unclear
• Family history shows autosomal dominant inheritance of connective tissue features
• Arteriopathy is suspected on imaging

Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications 3.

Surveillance After Diagnosis

Cardiovascular Monitoring

• Repeat echocardiogram every 2-3 years if aortic root is normal until adult height is reached 1, 4
• Annual echocardiogram if aortic root diameter <4.5 cm in adults with rate of increase <0.5 cm/year 1
• Echocardiogram every 6 months if diameter >4.5 cm or rate of increase >0.5 cm/year 1, 4
• MR angiography of entire aorta starting in young adulthood for vascular EDS or if aortic root replacement/dissection history 1, 3