What is the initial evaluation approach for a patient presenting with concerns of having Ehlers-Danlos syndrome (EDS)?

Initial Evaluation for Suspected Ehlers-Danlos Syndrome

Begin with joint hypermobility assessment using the Beighton scale, followed by targeted skin examination, cardiovascular screening with echocardiogram, and urgent COL3A1 genetic testing if vascular EDS is suspected based on clinical features. 1

Immediate Clinical Assessment

Joint Hypermobility Evaluation (Beighton Scale)

Systematically assess the following to calculate a score out of 9 points 1:

• Passive dorsiflexion of each fifth finger >90 degrees (1 point per side) 1
• Passive apposition of each thumb to flexor surface of forearm (1 point per side) 1
• Hyperextension of each elbow >10 degrees (1 point per side) 1
• Hyperextension of each knee >10 degrees (1 point per side) 1
• Ability to place palms flat on floor when bending forward with knees extended (1 point) 1

Diagnostic thresholds: ≥5/9 for adults under 50 years, ≥4/9 for those over 50, and ≥6/9 for prepubertal children 1

Skin and Tissue Examination

Assess for specific connective tissue abnormalities 1:

• Skin hyperextensibility by gently pulling skin on volar forearm 1
• Soft, velvety texture or hyperextensible quality 1
• Easy bruising patterns without significant trauma 2
• Abnormal scarring (atrophic, cigarette-paper scars) 3
• Thin, translucent skin with visible veins (critical red flag for vascular EDS) 1, 2

Vascular EDS Red Flags (Life-Threatening Subtype)

If any of these features are present, this is a medical emergency requiring urgent genetic testing 2:

• Thin nose, thin upper lip, small earlobes, and prominent eyes (characteristic facial features) 2
• Thin, translucent skin with visible venous patterns 2
• Easy bruising without significant trauma 2
• Family history of sudden death, arterial rupture, or organ perforation 1

Essential Cardiovascular Screening

Echocardiography (Required for All Suspected EDS Cases)

Order transthoracic echocardiogram to evaluate aortic root diameter, as dilation occurs in 25-33% of hypermobile and classic EDS cases 1. This is non-negotiable baseline screening 4, 1.

Surveillance protocol based on findings 4:

• Normal aortic root: Repeat every 2-3 years until adult height reached 4
• Aortic root <4.5 cm with growth <0.5 cm/year: Annual echocardiogram 4, 1
• Aortic root >4.5 cm or growth >0.5 cm/year: Every 6 months 4, 1

Advanced Vascular Imaging (If Vascular EDS Suspected)

Order MR angiography from head to pelvis to assess for arterial tortuosity, aneurysms, and dissections throughout the entire vascular tree 1, 2. Critical caveat: Avoid invasive vascular imaging in suspected vascular EDS, as fatal complications have been reported 1.

Comprehensive Family History

Document a three-generation pedigree focusing on 1:

• Sudden deaths at young ages
• Arterial ruptures or dissections
• Organ perforations
• Autosomal dominant inheritance patterns (50% transmission risk)
• Joint hypermobility or chronic pain in relatives

Ophthalmologic Evaluation

Order dilated eye examination to exclude Marfan syndrome and other related connective tissue disorders 4, 1.

Screening for Common Comorbidities

Autonomic Dysfunction (POTS)

Measure postural vital signs with active stand test 1:

• Document 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
• POTS affects up to 37.5% of hEDS patients 1
• If positive, refer for tilt table testing and expanded autonomic function assessment 1

Gastrointestinal Manifestations

Screen for GI symptoms, as up to 98% of hypermobile EDS patients experience gastrointestinal manifestations 1:

• Nausea, abdominal pain, constipation, bloating, early satiety, and reflux 1
• Order celiac disease serological testing earlier in hEDS patients with any GI symptoms, as risk is elevated 1
• Consider anorectal manometry, balloon expulsion test, or defecography for incomplete evacuation symptoms given high prevalence of pelvic floor dysfunction 1

Mast Cell Activation Syndrome (MCAS)

Only obtain baseline serum tryptase level if patient presents with episodic multisystem symptoms involving ≥2 physiological systems (flushing, urticaria, wheezing) 1. Do not routinely test all hEDS patients with isolated GI symptoms 1. Diagnostic threshold: 20% increase above baseline plus 2 ng/mL during symptom flares 1.

Genetic Testing Strategy

Urgent Testing for Vascular EDS

If vascular EDS is suspected, order COL3A1 gene mutation testing immediately 1, 2. This is the gold standard for diagnosis and should not be delayed, as median survival is 48 years with significant arterial rupture risk 1.

Multi-Gene Panel for Unclear Subtype

Order comprehensive multi-gene panel covering COL3A1, COL5A1, COL5A2, TGFBR1, TGFBR2, PLOD1, and other arteriopathy genes when EDS is suspected but subtype is unclear 1, 2.

Hypermobile EDS (Most Common Subtype)

Do not order routine genetic testing for hEDS, as no causative genes have been identified 1. Diagnosis is purely clinical using the 2017 diagnostic criteria available at https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf 1.

Critical caveat: Recent data shows that genetic testing identified an alternative or additional diagnosis in 26.4% of patients who met clinical criteria for hEDS, requiring distinct management strategies 5. This underscores the importance of excluding alternative diagnoses through genetic testing even when hEDS criteria are met.

Pre-Testing Laboratory Work (If Vascular EDS or Arteriopathy Suspected)

• Baseline serum tryptase level (to distinguish myeloproliferative variants) 2
• Vitamin B12 level (characteristically elevated in myeloproliferative variants) 2
• Complete blood count with differential (evaluate for cytopenias or eosinophilia) 2
• Comprehensive metabolic panel including liver and renal function 2

Genetic Counseling Requirement

Refer for formal genetic counseling before mutation screening due to complex financial, insurance, familial, and social implications 1, 2. This is paramount for discussing:

• Lifelong surveillance strategies
• Family screening needs
• Pregnancy planning (high maternal mortality risk from uterine and arterial rupture in vascular EDS) 2
• Surgical risk stratification due to tissue fragility 2

Additional Screening Tests

Bone Density

Order DXA scan for height loss >1 inch to screen for osteoporosis 1.

Wood's Lamp Examination

Perform Wood's lamp examination to exclude other connective tissue disorders 1.

Critical Pitfalls to Avoid

• Never delay COL3A1 testing if vascular EDS is suspected - this is a medical emergency 1
• Avoid invasive diagnostic procedures in vascular EDS patients - fatal complications have been reported 1
• Do not use R codes (symptom codes) when M codes for joint dysfunction are more specific for documentation 6
• Do not routinely test for MCAS in all hEDS patients with isolated GI symptoms - only test those with multisystem episodic symptoms 1
• Do not perform whole-genome or exome sequencing for hEDS - no causative genes identified 1

Subspecialty Referral Indications

Refer to medical genetics for all suspected EDS cases for definitive diagnosis and classification 1. Medical geneticists are the primary specialists who diagnose and classify EDS 1.

Refer to vascular surgery if vascular EDS is confirmed for surveillance imaging protocols 1.

Refer to gastroenterology for refractory GI symptoms despite appropriate management 1.

Refer to cardiology for aortic root dilation management 4.