What lab tests are used to diagnose Ehlers-Danlos syndrome?

Laboratory Testing for Ehlers-Danlos Syndrome

Most EDS subtypes require genetic testing for definitive diagnosis, but hypermobile EDS (hEDS)—the most common form—is diagnosed purely clinically without any available genetic test. 1, 2, 3

Primary Diagnostic Approach by EDS Subtype

Vascular EDS (Type IV) - Most Critical to Identify

COL3A1 gene mutation testing is the definitive diagnostic test for vascular EDS and should be performed urgently when this life-threatening subtype is suspected. 4, 1, 5

• Baseline serum tryptase level should be obtained, as elevated levels are commonly observed in myeloproliferative variants and can help distinguish vascular complications 4, 1
• Vitamin B12 level is characteristically elevated in myeloproliferative variants of EDS with arteriopathy 4
• Fibroblast culture demonstrating structurally abnormal collagen type III provides supportive evidence but requires invasive skin biopsy 1, 6

Classical EDS (Types I and II)

• COL5A1 or COL5A2 gene mutation testing provides molecular confirmation 1
• Gene panel testing covering multiple EDS-associated genes is more efficient than single-gene sequencing 7

Hypermobile EDS (hEDS) - 80-90% of All EDS Cases

No genetic test exists for hEDS; diagnosis relies entirely on clinical criteria including Beighton score ≥5/9 for joint hypermobility. 4, 1, 2

• Celiac disease serological testing should be performed earlier in hEDS patients presenting with any GI symptoms 1
• Baseline serum tryptase level if symptoms suggest mast cell activation syndrome (flushing, urticaria, wheezing, multisystem symptoms) 4, 1
• Postural vital signs with heart rate increase ≥30 beats/min within 10 minutes of standing screens for POTS, which affects many hEDS patients 4, 1

Comprehensive Gene Panel Testing Strategy

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. 4, 7

• Gene panels identified molecular diagnoses in 75% of patients meeting clinical EDS criteria and 28% of patients with overlapping features 7
• Whole exome sequencing (WES) may be considered when panel testing is negative but clinical suspicion remains high 7
• Avoid routine whole-genome or exome sequencing in hEDS, as no causative genes have been identified 4, 1

Essential Screening Labs Before Genetic Testing

Baseline Metabolic Assessment

• Complete blood count (CBC) with differential to evaluate for cytopenias or eosinophilia that may suggest systemic involvement 4
• Comprehensive metabolic panel including liver and renal function 4
• Lactate dehydrogenase (LDH) as a marker for tissue breakdown or hemolysis 4

Autoimmune and Inflammatory Markers

• Antinuclear antibody (ANA) and antineutrophil cytoplasmic antibodies (ANCA) if systemic arteriopathy is suspected 4
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory assessment 4
• Quantitative immunoglobulin levels including IgE if allergic or mast cell symptoms present 4

Critical Imaging Studies (Not Labs, But Essential)

• Echocardiogram to evaluate for aortic root dilation, present in 25-33% of classic and hypermobile EDS 1
• MR angiography of head, neck, thorax, abdomen, and pelvis for suspected vascular EDS or Loeys-Dietz syndrome to assess arterial tortuosity and aneurysms 4

Common Diagnostic Pitfalls

The most dangerous error is failing to recognize vascular EDS, which carries high mortality risk from arterial or organ rupture. 1, 5

• Never perform invasive diagnostic procedures (including skin biopsy for fibroblast culture) in suspected vascular EDS without extreme caution, as these can precipitate fatal complications 1, 5
• Do not routinely test for MCAS in all hEDS patients with isolated GI symptoms—reserve tryptase testing for those with multisystem symptoms suggesting generalized mast cell disorder 1
• Genetic testing may fail even when protein analysis confirms a collagen defect, as only coding sequences are investigated and each family typically has its own specific mutation 1
• Avoid using symptom codes when specific joint dysfunction codes are more appropriate for documentation purposes 8

When to Refer for Formal Genetics Consultation

Refer to medical genetics specialists when clinical features suggest EDS, family history shows autosomal dominant inheritance, or when arteriopathy is suspected. 4, 1

• Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications 4
• Medical genetics consultation should be performed at referral centers with experience in genetically mediated arteriopathies 4
• Three-generation pedigree assessment helps identify inheritance patterns and guide testing strategy 4