What is the diagnostic approach for Marfan syndrome?

Diagnostic Approach for Marfan Syndrome

The diagnosis of Marfan syndrome requires a comprehensive evaluation including echocardiography, ophthalmologic examination, skeletal assessment, and genetic testing for FBN1 mutations, with calculation of a systemic score to confirm the diagnosis. 1

Initial Diagnostic Testing

Essential Diagnostic Tests

• Echocardiogram: To assess aortic root dimensions and valve function

  • Aortic root dilation defined as Z-score ≥2 in adults and ≥3 in children 1
  • Essential for ruling out aortic dissection risk, the primary mortality concern 2

• Ophthalmologic examination:

  • Slit-lamp examination with fully dilated pupils to detect ectopia lentis 2
  • Should be performed by an ophthalmologist experienced with Marfan features 2

• Skeletal assessment:

  • Evaluation for wrist and thumb signs, pectus deformities, hindfoot deformities
  • Assessment of arm span to height ratio and upper to lower segment ratio 1

• Genetic testing:

  • FBN1 gene sequencing (detects mutations in 90-95% of classic cases) 2
  • Consider testing for related disorders (TGFBR1, TGFBR2) if clinical suspicion 1

Diagnostic Criteria

Revised Ghent Nosology Criteria

Diagnosis can be established by any of these combinations:

1. No family history of Marfan syndrome:

   • Aortic root dilation (Z-score ≥2) AND ectopia lentis
   • Aortic root dilation AND pathogenic FBN1 mutation
   • Aortic root dilation AND systemic score ≥7 points
   • Ectopia lentis AND FBN1 mutation associated with aortic disease 2, 1

2. With family history of Marfan syndrome:

   • Ectopia lentis
   • Systemic score ≥7 points
   • Aortic root dilation (Z-score ≥2 if over 20 years, ≥3 if younger) 2

Systemic Score Calculation

• Wrist AND thumb sign = 3 points (wrist OR thumb sign = 1)
• Pectus carinatum = 2 points (pectus excavatum or chest asymmetry = 1)
• Hindfoot deformity = 2 points (plain flat feet = 1)
• Pneumothorax = 2 points
• Dural ectasia = 2 points
• Protrusio acetabuli = 2 points
• A score ≥7 points is considered positive 2, 1

Additional Imaging and Testing

• MRI or CT angiography:

  • For evaluation of the entire aorta, especially in young adults
  • Essential for detecting dural ectasia 1

• X-rays:

  • For evaluation of protrusio acetabuli and scoliosis when clinically indicated 1

Differential Diagnosis

Several conditions share features with Marfan syndrome and require consideration:

• Loeys-Dietz syndrome (mutations in TGFBR1, TGFBR2)
• Ehlers-Danlos syndrome, hypermobile type
• Familial thoracic aortic aneurysm and dissection
• MASS phenotype (Mitral valve, Aorta, Skin, Skeletal features)
• Familial ectopia lentis 2

Clinical Pitfalls to Avoid

1. Age-dependent manifestations:

   • Many features of Marfan syndrome develop with age
   • Diagnosis in children should be approached with caution 3
   • Regular follow-up is essential for those with suspected but unconfirmed diagnosis

2. Over-reliance on genetic testing alone:

   • Despite high sensitivity, 5-10% of classic cases have no detectable FBN1 mutation 2
   • Clinical diagnosis remains paramount even with negative genetic testing

3. Failure to evaluate the entire aorta:

   • Aortic involvement can extend beyond the root
   • Complete aortic imaging is necessary, especially in adults 1

4. Missing related conditions:

   • Particularly Loeys-Dietz syndrome, which can have aortic dissection without significant dilation 2

Follow-up Recommendations

For patients with confirmed or suspected Marfan syndrome:

• Annual echocardiogram if aortic root diameter <4.5 cm and growth rate <0.5 cm/year
• Echocardiogram every 6 months if diameter >4.5 cm or growth rate >0.5 cm/year
• For those with normal aortic dimensions but systemic features, repeat echocardiogram every 2-3 years until adult height is reached 2, 1

By following this diagnostic algorithm, clinicians can accurately identify patients with Marfan syndrome and initiate appropriate monitoring and treatment to reduce morbidity and mortality from this connective tissue disorder.