What are the diagnostic tests and management strategies for Ehlers-Danlos Syndrome (EDS)?

Ehlers-Danlos Syndrome Laboratory Testing

For hypermobile EDS (hEDS), which represents 80-90% of cases, diagnosis is entirely clinical with no available genetic testing, while other EDS subtypes require genetic confirmation through specific collagen gene testing. 1, 2

Primary Diagnostic Approach by EDS Subtype

Hypermobile EDS (Most Common)

• No laboratory tests exist for hEDS diagnosis—it remains a purely clinical diagnosis based on the 2017 diagnostic criteria 1, 2, 3
• Apply the Beighton score (≥5 required) for joint hypermobility assessment 1
• Use the 2017 hEDS diagnostic checklist available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf 4
• Genetic testing is indicated to exclude alternative diagnoses, as 26.4% of patients meeting hEDS criteria actually have a different genetic condition requiring distinct management 5

Vascular EDS (Type IV)

• COL3A1 gene mutation testing is essential for definitive diagnosis 4, 1
• Fibroblast culture demonstrating structurally abnormal collagen type III provides supportive evidence 4
• Linkage analysis with intragenic polymorphic markers can be performed but is technically difficult 4

Classical EDS (Types I and II)

• COL5A1 or COL5A2 gene mutation testing is required for molecular confirmation 4
• These mutations show autosomal dominant inheritance but lack phenotype-genotype correlations 4

Essential Screening Tests for All EDS Patients

Cardiovascular Assessment

• Echocardiogram to evaluate aortic root dilatation is mandatory at diagnosis 6, 1
• For normal aortic root: repeat echocardiogram every 2-3 years until adult height is reached 6
• For aortic root dilation: increase monitoring frequency based on diameter and rate of progression 6

Gastrointestinal Evaluation

• Celiac disease serological testing should be performed earlier in hEDS patients with any GI symptoms (not just diarrhea), as risk is elevated in this population 4, 6
• Gastric emptying studies when upper GI symptoms are present, particularly with comorbid POTS, as abnormal gastric emptying is more common than in the general population 4
• Anorectal manometry, balloon expulsion test, or defecography for lower GI symptoms with incomplete evacuation, given high prevalence of pelvic floor dysfunction and rectal hyposensitivity 4

Testing for Common Comorbidities

Postural Orthostatic Tachycardia Syndrome (POTS)

• Postural vital signs: measure heart rate increase of ≥30 beats/min with 10 minutes of standing during active stand test 4
• Tilt table testing for autonomic function assessment 4
• Sudomotor testing if POTS is confirmed 4
• Autoantibody panel if POTS is confirmed 4

Mast Cell Activation Syndrome (MCAS)

• Baseline serum tryptase level should be obtained if symptoms suggest generalized mast cell disorder (flushing, urticaria, wheezing, multisystem symptoms) 4
• Repeat tryptase 1-4 hours following symptom flares: increases of 20% above baseline PLUS 2 ng/mL are necessary to demonstrate mast cell activation 4
• CD-117 immunohistochemical staining on duodenal or ileal biopsies is more sensitive than mast cell counting, though thresholds remain controversial 4
• Referral to allergy specialist or mast cell disease research center for additional testing (urinary N-methylhistamine, leukotriene E4, 11β-prostaglandin F2) if MCAS is supported 4

Critical Pitfalls to Avoid

• Do not perform routine genetic testing for hEDS—no causative genes have been identified 1, 3
• Do not skip genetic testing to exclude alternative diagnoses in suspected hEDS, as over one-quarter have a different condition 5
• Do not routinely test for disaccharidase deficiencies in hEDS—insufficient evidence supports this practice 4
• Do not perform MCAS testing in all hEDS patients with isolated GI symptoms—reserve for those with multisystem symptoms suggesting generalized mast cell disorder 4
• Do not perform invasive procedures in suspected vascular EDS without extreme caution, as these can lead to fatal complications 1

When Genetic Testing Fails

• Mutation identification may fail even when protein analysis confirms a collagen defect, as only coding sequences and closely surrounding regions are investigated 4
• Genetic heterogeneity exists—some patients with recessively inherited presentations have apparently normal collagen III metabolism 4
• Each family typically has its own specific mutation, making systematic screening impractical and costly 4