What is the diagnostic approach for Ehlers-Danlos syndrome (EDS)?

Diagnosis of Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome diagnosis requires a three-step approach: clinical assessment using the Beighton scale (≥5/9 for adults under 50), evaluation of skin characteristics, and mandatory genetic testing to exclude alternative diagnoses—even when clinical criteria are met, as 26.4% of clinically diagnosed cases have alternative genetic conditions requiring different management. 1, 2

Primary Diagnostic Pathway

Step 1: Clinical Assessment with Beighton Scale

• Calculate the Beighton score by assessing five specific maneuvers: passive dorsiflexion of fifth fingers >90° (1 point each hand), passive thumb apposition to flexor forearm surface (1 point each hand), elbow hyperextension >10° (1 point each arm), knee hyperextension >10° (1 point each leg), and forward bend with palms flat on floor with knees extended (1 point) 1
• Age-adjusted thresholds apply: ≥6/9 points for prepubertal children, ≥5/9 for adults under 50, and ≥4/9 for adults over 50 3
• Document skin characteristics: soft or velvety texture with normal or slightly increased extensibility, absence of skin/soft tissue fragility (critical to distinguish from other EDS subtypes) 1

Step 2: Identify Red Flags for Vascular EDS (Life-Threatening Subtype)

• Immediately suspect vascular EDS if patient has family history of sudden death, arterial ruptures, or organ perforations with autosomal dominant pattern 4
• Order urgent COL3A1 gene mutation testing when vascular EDS is suspected—this is the definitive diagnostic test and takes priority over all other evaluations 4
• Obtain baseline serum tryptase and vitamin B12 levels to help distinguish vascular complications, as elevated levels suggest myeloproliferative variants 4

Step 3: Mandatory Genetic Testing (Even When Clinical Criteria Are Met)

• Never diagnose hypermobile EDS without genetic testing to exclude alternatives—this is a critical pitfall, as 26.4% of clinically diagnosed cases had alternative genetic conditions 1, 2
• Order multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes when EDS is suspected but subtype is unclear 4
• For suspected vascular EDS: COL3A1 gene testing is definitive 4
• For suspected classical EDS: COL5A1 or COL5A2 gene mutation testing provides molecular confirmation 4
• Avoid routine whole-genome or exome sequencing in hypermobile EDS, as no causative genes have been identified 4

Essential Screening Tests for All Suspected EDS Patients

Cardiovascular Evaluation

• Perform echocardiogram to evaluate for aortic root dilation, which occurs in 25-33% of classic and hypermobile EDS types 4, 1, 3
• Obtain MR angiography of head, neck, thorax, abdomen, and pelvis for suspected vascular EDS or when arteriopathy is suspected to assess arterial tortuosity and aneurysms 4

Autonomic and Mast Cell Screening

• Measure postural vital signs with active stand test: heart rate increase ≥30 beats/min (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension suggests POTS 4
• Obtain baseline serum tryptase level only if patient presents with episodic multisystem symptoms (flushing, urticaria, wheezing, abdominal cramping, pruritus) involving ≥2 physiological systems 5, 4
• Do not routinely test for MCAS in all hEDS patients with isolated GI symptoms—this is inappropriate and not supported by evidence 4

Gastrointestinal Screening

• Test for celiac disease earlier in hEDS patients with any GI symptoms (not just diarrhea), as GI manifestations affect up to 98% of hEDS patients 4
• Consider anorectal manometry, balloon expulsion test, or defecography in patients with lower GI symptoms like incomplete evacuation, given high prevalence of pelvic floor dysfunction 5

Additional Screening Labs

• Perform dilated eye examination to exclude Marfan syndrome 4
• Document three-generation family history focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 4

When to Refer to Specialists

Medical Genetics (Primary Diagnostic Specialty)

• Refer all suspected EDS cases to medical geneticists for definitive diagnosis and classification, as they have expertise in evaluating inherited connective tissue disorders and coordinating genetic testing 4
• Genetic counseling is mandatory before mutation screening due to complex financial, insurance, familial, and social implications 4

Subspecialty Referrals Based on Findings

• Cardiology/vascular surgery: For vascular EDS patients requiring surveillance imaging protocols, or when aortic root dilation is detected 4
• Gastroenterology: For patients with refractory GI symptoms despite appropriate management 4
• Allergy/mast cell disease research center: If MCAS diagnosis is supported through clinical and/or laboratory features (serum tryptase increases of 20% above baseline plus 2 ng/mL during symptom flares) 5

Critical Diagnostic Pitfalls to Avoid

• Never diagnose hEDS without genetic testing—26.4% of clinically diagnosed cases have alternative genetic conditions requiring different management 1, 2
• Never perform invasive diagnostic procedures in vascular EDS patients—use non-invasive imaging exclusively due to fatal complication risk 4, 1
• Never overlook vascular EDS screening—this subtype carries significant mortality risk from arterial or organ rupture 4
• Never routinely test for MCAS in all hEDS patients with isolated GI symptoms—only test when multisystem symptoms involving ≥2 physiological systems are present 5, 4
• Never assume genetic testing failure means no EDS—mutation identification may fail even when protein analysis confirms a collagen defect, as only coding sequences are investigated 4

Diagnostic Criteria for Hypermobile EDS (Most Common Subtype)

All three criteria must be met 1:

1. Beighton score ≥5/9 for joint hypermobility (age-adjusted thresholds apply) 1
2. Soft/velvety skin without fragility, plus supportive features: recurrent joint dislocations/subluxations, chronic joint/limb pain, easy bruising, functional bowel disorders, or POTS 1
3. Exclusion of alternative diagnoses through genetic testing—this criterion is frequently overlooked but essential 1, 2