What is the recommended workup for a patient suspected of having Ehlers-Danlos Syndrome (EDS)?

Ehlers-Danlos Syndrome Workup

Begin with a medical geneticist referral for suspected EDS, as they are the primary specialists who diagnose and classify this condition, followed by genetic testing for all subtypes except hypermobile EDS (hEDS), which remains a clinical diagnosis. 1, 2

Initial Clinical Assessment

History and Physical Examination

• Evaluate joint hypermobility using the Beighton score (≥5/9 required for hEDS diagnosis), assessing bilateral fifth finger hyperextension >90°, thumb-to-forearm apposition, elbow hyperextension >10°, knee hyperextension >10°, and forward trunk flexion with palms flat on floor 3, 2
• Assess skin characteristics including hyperextensibility (stretch >1.5 cm on volar forearm for classic EDS), velvety texture, fragility, and atrophic scarring patterns 3, 2
• Document three-generation family history focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 4, 2
• Screen for vascular complications including easy bruising, spontaneous ecchymoses, arterial rupture history, and characteristic facial features (thin nose, lobeless ears, prominent eyes) that suggest vascular EDS 2, 5

Cardiovascular Evaluation

• Obtain transthoracic echocardiogram to evaluate for aortic root dilatation, which occurs in 25-33% of classic and hypermobile EDS patients 1, 3, 2
• Perform baseline MR angiography from head to pelvis for suspected vascular EDS or when arteriopathy is suspected, assessing arterial tortuosity and aneurysms 4, 3, 2

Autonomic Function Screening

• Measure postural vital signs with active stand test: heart rate increase ≥30 beats/min within 10 minutes of standing indicates postural orthostatic tachycardia syndrome (POTS), which commonly complicates hEDS 3, 2

Genetic Testing Strategy

For Suspected Vascular EDS (Type IV)

• Order COL3A1 gene mutation testing urgently as this is the definitive diagnostic test for this life-threatening subtype 3, 2
• Obtain baseline serum tryptase and vitamin B12 levels to help distinguish myeloproliferative variants with arteriopathy 2

For Suspected Classic EDS (Types I/II)

• Order COL5A1 or COL5A2 gene mutation testing for molecular confirmation 2

For Suspected hEDS

• Do NOT order routine genetic testing for hEDS, as no causative genes have been identified; diagnosis remains clinical based on 2017 criteria 3, 2
• Order multi-gene panel testing (covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes) to exclude alternative diagnoses, as 26.4% of clinically diagnosed hEDS cases have alternative genetic conditions requiring different management 3, 6

When EDS Subtype is Unclear

• Order comprehensive multi-gene panel testing as the most efficient diagnostic approach rather than sequential single-gene testing 2
• Avoid whole-genome or exome sequencing as first-line testing unless multi-gene panels are non-diagnostic 2

Essential Laboratory Workup

Baseline Screening Labs

• Complete blood count with differential to evaluate for cytopenias or eosinophilia suggesting systemic involvement 2
• Comprehensive metabolic panel including liver and renal function 2
• Lactate dehydrogenase (LDH) as a marker for tissue breakdown or hemolysis 2
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory assessment 2

Specialized Testing Based on Clinical Presentation

• Celiac disease serological testing should be performed in hEDS patients with any gastrointestinal symptoms (not just diarrhea), as risk is elevated in this population 1, 3, 2
• Baseline serum tryptase level if symptoms suggest mast cell activation syndrome (flushing, urticaria, wheezing, multisystem symptoms) 3, 2
• Quantitative immunoglobulin levels including IgE if allergic or mast cell symptoms are present 2
• Antinuclear antibody (ANA) and antineutrophil cytoplasmic antibodies (ANCA) if systemic arteriopathy is suspected 2

Subspecialty Referrals Based on Findings

Mandatory Referrals

• Medical genetics for all suspected EDS cases for definitive diagnosis and classification 1, 2
• Cardiology if aortic root dilation detected or vascular EDS suspected 1, 3
• Vascular surgery for vascular EDS patients requiring surveillance imaging protocols 4, 3

Conditional Referrals

• Rheumatology for joint hypermobility assessment and musculoskeletal management 1, 2
• Gastroenterology for patients with chronic GI symptoms (affects up to 98% of hEDS patients) 3, 2
• Neurology if POTS or autonomic dysfunction is present 1, 2
• Ophthalmology for dilated eye examination to exclude related conditions like Marfan syndrome 2

Critical Pitfalls to Avoid

• Never delay COL3A1 testing when vascular EDS is suspected, as this carries significant mortality risk from arterial or organ rupture 2, 5
• Do not perform invasive diagnostic procedures in suspected vascular EDS patients without careful consideration, as these can lead to fatal complications 2, 7
• Avoid ordering genetic testing for hEDS alone without multi-gene panel testing to exclude alternative diagnoses, as 26.4% will have a different condition 3, 6
• Do not assume hEDS diagnosis without formally excluding other EDS subtypes and alternative connective tissue disorders through appropriate genetic testing 3, 6
• Never order routine mast cell activation syndrome testing in all hEDS patients with isolated GI symptoms; reserve for those with multisystem symptoms 2