What is the workup for a patient with Ehlers-Danlos syndrome?

Workup for Ehlers-Danlos Syndrome

Initial Clinical Assessment

Begin with joint hypermobility assessment using the Beighton score: ≥6/9 points for prepubertal children, ≥5/9 for adults under 50 years, and ≥4/9 for adults over 50 years. 1, 2

Essential Physical Examination Components

• Assess skin texture for soft, velvety quality with normal or slightly increased extensibility 2
• Evaluate for tissue fragility including easy bruising without significant trauma 2, 3
• Document recurrent joint dislocations or subluxations, particularly shoulders, patellae, and digits 2, 3
• Perform Wood's lamp examination to exclude other connective tissue disorders 4

Critical Family History Elements

• Document three-generation pedigree focusing on sudden deaths, arterial ruptures, organ perforations, and autosomal dominant inheritance patterns 1
• Inquire specifically about family history of Fragile X syndrome or undiagnosed intellectual disability 4

Mandatory First-Tier Testing

Cardiovascular Screening

Obtain echocardiogram to evaluate for aortic root dilation, which occurs in 25-33% of hypermobile and classic EDS types. 1, 2, 3

Ophthalmologic Evaluation

• Perform dilated eye examination to exclude Marfan syndrome and related conditions 1

Postural Orthostatic Tachycardia Syndrome (POTS) Screening

Measure postural vital signs with active stand test: symptomatic heart rate increase ≥30 beats/min (≥40 beats/min in adolescents 12-19 years) within 10 minutes of standing without orthostatic hypotension. 4, 1, 3

• Only perform this testing if patient reports orthostatic intolerance symptoms (lightheadedness, weakness, blurred vision upon standing) 4, 3
• Consider tilt table testing for formal autonomic function assessment if active stand test is positive 1

Genetic Testing Strategy

For Suspected Vascular EDS (Life-Threatening Priority)

Urgently order COL3A1 gene mutation testing if patient has arterial/organ rupture history, spontaneous pneumothorax, or characteristic facial features (thin nose, lobeless ears, prominent eyes). 1, 2

• This is the definitive diagnostic test for vascular EDS and must be performed immediately given mortality risk 1

For Suspected Classical EDS

• Order COL5A1 or COL5A2 gene mutation testing for molecular confirmation 1

For Hypermobile EDS (Most Common Subtype)

Do NOT order genetic testing for hypermobile EDS, as no causative genes have been identified and diagnosis remains purely clinical. 1, 2

• Apply the 2017 diagnostic criteria available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf 4

When EDS Subtype is Unclear

Order multi-gene panel testing covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes as the most efficient diagnostic approach. 1

Gastrointestinal Workup (For Hypermobile EDS Patients)

When to Pursue GI Testing

Perform celiac disease serological testing earlier in hEDS patients with any GI symptoms (nausea, abdominal pain, constipation, bloating, diarrhea, vomiting). 1

• Up to 98% of hEDS patients experience GI manifestations 4, 3

Mast Cell Activation Syndrome (MCAS) Screening

Only test for MCAS if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (cutaneous, GI, cardiac, respiratory, neuropsychiatric) such as flushing, urticaria, wheezing, angioedema, pruritus. 4, 1

• Obtain baseline serum tryptase level as the initial screening test 1
• Do NOT routinely test for MCAS in all hEDS patients with isolated GI symptoms 4, 1

Additional Laboratory Testing for Vascular EDS Suspicion

• Measure baseline serum tryptase level to distinguish vascular complications 1
• Check vitamin B12 level, which is characteristically elevated in myeloproliferative variants with arteriopathy 1
• Obtain complete blood count with differential to evaluate for cytopenias or eosinophilia 1
• Measure lactate dehydrogenase (LDH) as marker for tissue breakdown 1
• Test antinuclear antibody (ANA) and antineutrophil cytoplasmic antibodies (ANCA) if systemic arteriopathy suspected 1
• Measure erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory assessment 1
• Check quantitative immunoglobulin levels including IgE if allergic or mast cell symptoms present 1

Critical Imaging Studies

Perform MR angiography of head, neck, thorax, abdomen, and pelvis for suspected vascular EDS or when arteriopathy is suspected to assess arterial tortuosity and aneurysms. 1

Specialty Referrals

Medical Genetics Consultation

Refer all suspected EDS cases to medical geneticists for definitive diagnosis and classification, as they are the primary specialists with expertise in inherited connective tissue disorders. 1

• Genetic counseling is paramount before mutation screening due to complex financial, insurance, familial, and social implications 1

Cardiology Referral

• Refer for POTS evaluation if postural vital signs are positive and lifestyle modifications (adequate hydration, physical exercise) have failed 4
• Refer for surveillance of aortic root dilation 1

Vascular Surgery Referral

Refer patients with suspected or confirmed vascular EDS to vascular surgery for surveillance imaging protocols. 1

Gastroenterology Referral

• Refer if patient has refractory GI symptoms despite appropriate management 4

Critical Pitfalls to Avoid

Never perform invasive diagnostic procedures in suspected vascular EDS patients without careful consideration, as these can lead to fatal complications from arterial or organ rupture. 1

• Do not perform universal POTS/MCAS testing in all hEDS patients; target testing only to those with specific clinical manifestations 4
• Do not order whole-genome or exome sequencing for hypermobile EDS, as no causative genes exist 1
• Failure to recognize vascular EDS carries significant mortality risk and represents the most dangerous diagnostic miss 1