What laboratory tests are recommended for a patient with hypermobile Ehlers-Danlos Syndrome (hEDS)?

Laboratory Testing for Hypermobile Ehlers-Danlos Syndrome

No Routine Laboratory Tests Are Recommended for hEDS Diagnosis

Hypermobile EDS is diagnosed purely by clinical criteria—no genetic test exists for hEDS, and routine laboratory testing is not indicated for diagnosis. 1, 2 The American Gastroenterological Association explicitly advises against routine genetic testing for hEDS, as no causative genes have been identified. 1

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Critical Exception: Rule Out Vascular EDS First

If there is ANY family history of arterial dissection, organ rupture, sudden death, or thin translucent skin with visible veins, immediately order COL3A1 gene mutation testing to exclude life-threatening vascular EDS. 1, 2 This is a medical emergency—vascular EDS has a median survival of 48 years with significant arterial rupture risk. 1 Fatal complications have been reported from delayed diagnosis. 1

When to Consider Multi-Gene Panel Testing:

• If clinical features suggest EDS but the subtype is unclear, order comprehensive gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes. 1
• Recent data shows that 26.4% of patients meeting clinical hEDS criteria had alternative genetic diagnoses identified on testing that required distinct management strategies. 3

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Targeted Laboratory Testing for Common Comorbidities

Screen for Postural Orthostatic Tachycardia Syndrome (POTS):

• Measure postural vital signs with active stand test: heart rate increase ≥30 beats/min in adults (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension. 1, 2, 4
• POTS affects 33-37.5% of hEDS patients and drives many GI and neurologic symptoms. 1, 5
• If positive, refer for tilt table testing and expanded autonomic function assessment. 1

Screen for Mast Cell Activation Syndrome (MCAS):

• Obtain baseline serum tryptase level ONLY if the patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing, multisystem symptoms). 1, 4
• Diagnostic threshold: 20% increase above baseline plus 2 ng/mL during symptomatic flares. 1
• Do NOT perform MCAS testing in all hEDS patients with isolated GI symptoms—this is explicitly discouraged. 1

Screen for Celiac Disease:

• Perform celiac disease serological testing earlier in hEDS patients with ANY gastrointestinal symptoms, as the risk is elevated compared to the general population. 1

Evaluate Gastrointestinal Dysfunction:

• For chronic upper GI symptoms (nausea, early satiety, bloating): order gastric emptying scintigraphy after excluding anatomical/structural disease. 1, 4
• For lower GI symptoms (incomplete evacuation, constipation): consider anorectal manometry, balloon expulsion test, or defecography given high prevalence of pelvic floor dysfunction. 1, 4

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Essential Cardiovascular Imaging (Not Laboratory, But Critical)

• Echocardiogram is required for all suspected EDS cases to evaluate aortic root diameter—25-33% of hEDS patients develop aortic root dilation. 1, 2
• If normal: repeat annually. If diameter >4.5 cm or growth >0.5 cm/year: repeat every 6 months. 1

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Additional Laboratory Tests for Suspected Vascular EDS or Systemic Involvement

If vascular EDS or systemic arteriopathy is suspected based on clinical features:

• Complete blood count (CBC) with differential to evaluate for cytopenias or eosinophilia. 1
• Comprehensive metabolic panel including liver and renal function. 1
• Lactate dehydrogenase (LDH) as a marker for tissue breakdown or hemolysis. 1
• Baseline serum tryptase and vitamin B12 levels to help distinguish vascular complications—elevated levels are commonly observed in myeloproliferative variants. 1
• Antinuclear antibody (ANA) and antineutrophil cytoplasmic antibodies (ANCA) if systemic arteriopathy is suspected. 1
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory assessment. 1
• Quantitative immunoglobulin levels including IgE if allergic or mast cell symptoms are present. 1

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Critical Pitfalls to Avoid

• Never perform routine genetic testing or whole-genome sequencing for hEDS—it has no diagnostic value and wastes resources. 1
• Never delay COL3A1 testing if vascular EDS is suspected—this is a life-threatening condition requiring urgent diagnosis. 1, 2
• Never perform invasive vascular imaging in suspected vascular EDS—fatal complications have been reported. 1
• Never order MCAS testing in all hEDS patients with isolated GI symptoms—only test those with multisystem episodic symptoms. 1

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When to Refer for Medical Genetics Consultation

• Refer to medical genetics when clinical features suggest EDS, family history shows autosomal dominant inheritance of sudden death/arterial events, or when arteriopathy is suspected. 1, 2
• Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications. 1