How do you diagnose monogenic Ehlers-Danlos syndrome (EDS)?

Diagnosis of Monogenic Ehlers-Danlos Syndrome (EDS)

The diagnosis of monogenic Ehlers-Danlos Syndrome requires targeted genetic testing based on specific clinical presentations, with COL3A1 sequencing being highest priority for vascular EDS due to its life-threatening complications. 1

Clinical Assessment for Suspected EDS

Initial Evaluation

• Complete joint hypermobility assessment using the 9-point Beighton scale:

  • Passive dorsiflexion of each fifth finger >90° (1 point each side)
  • Passive apposition of each thumb to the flexor surface of forearm (1 point each side)
  • Hyperextension of each elbow >10° (1 point each side)
  • Hyperextension of each knee >10° (1 point each side)
  • Place palms flat on floor when bending over with knees extended (1 point)
  • Score ≥5 indicates joint hypermobility 2, 1

• Skin examination:

  • Assess for hyperextensibility
  • Evaluate texture (soft/velvety)
  • Check for thin/translucent appearance
  • Document abnormal scarring
  • Note easy bruising 1

• Family history evaluation:

  • Document autosomal dominant pattern if present
  • Note similar features in family members 2, 1

Cardiovascular Assessment

• Echocardiogram to evaluate:
  • Aortic root dimensions
  • Presence of mitral valve prolapse
  • Aortic dilatation 1

Genetic Testing Strategy

Targeted Testing Based on Clinical Subtype

1. Vascular EDS (highest priority):

   • COL3A1 gene sequencing
   • Clinical features: thin skin with visible veins, characteristic facial features, arterial dissections/aneurysms/ruptures, arteriovenous fistulas, hollow organ rupture 1

2. Classical EDS:

   • COL5A1 and COL5A2 gene sequencing
   • Clinical features: skin hyperextensibility, widened atrophic scars, joint hypermobility 3

3. Kyphoscoliotic EDS:

   • PLOD1 and FKBP14 gene sequencing
   • Clinical features: congenital muscle hypotonia, kyphoscoliosis, joint hypermobility 3, 4

4. Other rare subtypes:

   • Targeted testing based on specific clinical features:
     • Cardiac-valvular: COL1A2 gene
     • Arthrochalasia: COL1A1 and COL1A2 gene
     • Dermatosparaxis: ADAMTS2 gene
     • Classical-like: TNXB gene 3, 4

Important Note on Hypermobile EDS

• No specific genetic test currently available for hypermobile EDS
• Diagnosis remains clinical based on major and minor criteria 2, 1

Diagnostic Pitfalls and Caveats

1. Overlapping symptoms: EDS subtypes have significant clinical overlap with each other and with other connective tissue disorders like Marfan syndrome and Loeys-Dietz syndrome 5

2. Genetic heterogeneity: The 2017 International Classification recognizes 13 subtypes of EDS with different genetic causes, making targeted testing essential 3

3. False negatives: Some patients with clinical EDS may have negative genetic testing due to unidentified genetic variants or mutations in non-coding regions

4. Overdiagnosis risk: Joint hypermobility alone is common in the general population; diagnosis requires meeting full clinical criteria 6

5. Vascular EDS urgency: Prioritize testing for vascular EDS due to life-threatening complications including arterial and organ rupture 1, 7

Diagnostic Algorithm for Monogenic EDS

1. Assess for red flags suggesting vascular EDS:

   • Family history of sudden death
   • Personal/family history of arterial rupture
   • Thin, translucent skin with visible veins
   • Characteristic facial features
   • History of hollow organ rupture
   • If present → Immediate COL3A1 testing 1

2. Evaluate clinical presentation:

   • Match clinical features to specific EDS subtypes
   • Order targeted genetic testing based on most likely subtype 1

3. For negative genetic testing:

   • Reassess clinical features
   • Consider broader genetic panels if high clinical suspicion
   • Consider hypermobility EDS (clinical diagnosis) 2, 1

4. Follow-up cardiovascular monitoring:

   • Repeat echocardiogram every 2-3 years until adult height reached for normal aortic root
   • Every 6 months if diameter >4.5 cm or growth rate >0.5 cm/year 2, 1

The diagnostic approach to monogenic EDS requires careful clinical assessment followed by targeted genetic testing, with particular urgency for suspected vascular EDS due to its potentially fatal complications.