How do you make a definitive diagnosis of Ehlers-Danlos Syndrome (EDS)?

Definitive Diagnosis of Ehlers-Danlos Syndrome (EDS)

The definitive diagnosis of Ehlers-Danlos Syndrome requires a combination of clinical evaluation, family history assessment, and in specific subtypes, genetic testing to confirm the diagnosis and exclude alternative conditions. 1

Diagnostic Approach by EDS Subtype

Hypermobile EDS (hEDS)

Diagnosis is primarily clinical and requires meeting all three criteria:

1. Generalized Joint Hypermobility:

   • Beighton score ≥5/9 points 1
   • Joint hypermobility assessment includes:
     • Passive dorsiflexion of fifth fingers >90° (1 point each side)
     • Passive thumb apposition to forearm flexor surface (1 point each side)
     • Elbow hyperextension >10° (1 point each side)
     • Knee hyperextension >10° (1 point each side)
     • Placing palms flat on floor with knees extended (1 point)

2. Skin and Soft Tissue Features:

   • Soft or velvety skin with normal or slightly increased extensibility
   • Absence of significant skin or soft tissue fragility (which would suggest other EDS subtypes) 1

3. Exclusion of Alternative Diagnoses:

   • Genetic testing is critical for ruling out other conditions that mimic hEDS 2
   • Up to 26.4% of patients clinically diagnosed with hEDS may have alternative genetic diagnoses requiring different management approaches 2

Other EDS Subtypes

For the remaining 12 subtypes (classical, classical-like, cardiac-valvular, vascular, arthrochalasia, dermosparaxis, kyphoscoliotic, brittle cornea, spondylodysplastic, musculocontractural, myopathic, and periodontal):

• Genetic Testing: Specific gene mutations have been identified for most subtypes 3
  • FBN1 gene sequencing (to rule out Marfan syndrome) 4
  • TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 gene sequencing (to rule out Loeys-Dietz syndrome) 4
  • For hypermobile EDS, a small subset may have TNXB gene insertions or deletions 1

Comprehensive Diagnostic Evaluation

1. Clinical Assessment:

   • Evaluate joint hypermobility using the Beighton scale
   • Assess skin hyperextensibility and fragility
   • Document tissue fragility manifestations (easy bruising, abnormal scarring) 5
   • Check for minor diagnostic criteria:
     • Recurrent joint dislocations/subluxations
     • Chronic joint/limb pain
     • Easy bruising
     • Functional bowel disorders
     • Neurally mediated hypotension/POTS
     • High, narrow palate
     • Dental crowding 1

2. Family History:

   • Document autosomal dominant pattern if present 1

3. Cardiovascular Assessment:

   • Echocardiogram to evaluate for aortic root dilatation (occurs in 25-33% of classic and hypermobile EDS) 1
   • Assess for valve prolapse (found in 43% of patients) 6

4. Ophthalmologic Examination:

   • Dilated eye exam to exclude Marfan syndrome 1, 4

5. Bone Density Assessment:

   • DXA scan if height loss >1 inch
   • Studies show osteoporosis is common in EDS patients 6

Common Diagnostic Pitfalls

1. Failure to exclude alternative diagnoses:

   • Genetic testing is underutilized but critical for proper diagnosis 2
   • Differential diagnoses include:
     • Marfan syndrome
     • Loeys-Dietz syndrome
     • Cutis laxa syndromes
     • Osteogenesis imperfecta
     • Hypermobility spectrum disorders
     • Fibromyalgia 3

2. Over-reliance on joint hypermobility alone:

   • Hypermobility may represent a shared phenotype across multiple disorders 2
   • Must consider inflammatory diseases, monogenic syndromes, and chromosomal abnormalities 2

3. Incomplete cardiovascular assessment:

   • Failure to monitor aortic dimensions can miss potentially life-threatening complications 1, 6

4. Limited follow-up planning:

   • Lack of regular echocardiogram monitoring (every 2-3 years until adult height, then as clinically indicated) 1
   • Inadequate bone density monitoring 6

By following this systematic diagnostic approach, clinicians can accurately diagnose EDS, differentiate between subtypes, exclude alternative diagnoses, and develop appropriate management strategies to reduce morbidity and mortality associated with this complex connective tissue disorder.