What is the approach to evaluating for Marfan syndrome?

Evaluation for Marfan Syndrome

The diagnostic approach to Marfan syndrome requires systematic assessment using the revised Ghent nosology criteria, focusing on cardinal features of aortic root dilation and ectopia lentis, along with systemic manifestations and genetic testing. 1

Diagnostic Criteria

Primary Diagnostic Features

• Aortic Root Dilation/Aneurysm: Z-score ≥2 in adults, ≥3 in children
• Ectopia Lentis (lens dislocation)
• FBN1 Gene Mutation associated with aortic disease

Definitive Diagnosis Can Be Made With:

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

Clinical Evaluation

1. Detailed Physical Examination

• Skeletal Features:

  • Height, arm span, and upper/lower segment ratio
  • Thumb and wrist signs (most specific physical findings) 2
  • Pectus deformities (excavatum or carinatum)
  • Scoliosis or thoracolumbar kyphosis
  • Joint hypermobility
  • Hindfoot valgus

• Craniofacial Features:

  • Dolichocephaly (long, narrow skull)
  • Enophthalmos
  • Downslanting palpebral fissures
  • Malar hypoplasia
  • High-arched palate

• Skin Assessment:

  • Striae atrophicae
  • Recurrent or incisional hernias

2. Specialized Testing

• Cardiovascular Assessment:

  • Echocardiogram to measure aortic root dimensions
  • Evaluation for mitral valve prolapse
  • Assessment for aortic regurgitation

• Ophthalmologic Evaluation:

  • Slit-lamp examination for ectopia lentis
  • Assessment for myopia and other ocular manifestations

• Imaging Studies:

  • MRI for dural ectasia assessment
  • X-rays for protrusio acetabuli and scoliosis measurement

3. Family History

• Document family history of Marfan syndrome or unexplained aortic dissection/aneurysm
• Create a three-generation pedigree

4. Genetic Testing

• FBN1 gene sequencing
• Consider testing for related disorders (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3) if clinical features suggest Loeys-Dietz syndrome 1

Differential Diagnosis

Loeys-Dietz Syndrome (LDS)

• Characterized by arterial tortuosity, hypertelorism, bifid uvula/cleft palate
• Associated with mutations in TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3
• Requires MR angiography of head, neck, thorax, abdomen, and pelvis 3

Ehlers-Danlos Syndrome (EDS) Hypermobile Type

• Joint hypermobility (Beighton score ≥5)
• Soft/velvety skin with normal or slightly increased extensibility
• Absence of skin/tissue fragility
• May have mild aortic root dilation but lower risk of dissection 3

Familial Thoracic Aortic Aneurysm and Dissection (FAA)

• Autosomal dominant predisposition to thoracic aortic aneurysms
• May have minimal skeletal features
• Associated with mutations in TGFBR2, MYH11, and other genes 3

Management Recommendations

Cardiovascular Monitoring

• Normal aortic root size:

  • Echocardiogram every 2-3 years until adult height reached
  • Then repeat if symptomatic or before major physical activity changes

• Aortic root dilation:

  • Echocardiogram every 6 months if diameter >4.5 cm or growth rate >0.5 cm/year
  • Annual echocardiogram if diameter <4.5 cm and growth rate <0.5 cm/year
  • Consider surgical repair for measurements >4.5 cm, growth rate >1 cm/year, or progressive aortic regurgitation 3

Imaging Follow-up

• MR angiography or CT of entire aorta starting in young adulthood
• Annual imaging if history of aortic root replacement or dissection
• Less frequent imaging if no complications 3

Clinical Pearls and Pitfalls

• High-Yield Physical Features: Craniofacial characteristics, thumb and wrist signs, pectus excavatum, and severe hindfoot valgus have the highest diagnostic yield 2

• Referral Threshold: Patients with 3-4 physically evident features or 2 highly specific features (thumb/wrist signs, craniofacial features, dural ectasia, or protrusio) should be referred for echocardiogram or genetics consultation 2

• Caution in Children: The penetrance of some features is age-dependent, so the nosology must be used with caution in children 4

• Multidisciplinary Approach: Diagnosis requires collaboration between cardiologists, ophthalmologists, orthopedists, geneticists, and radiologists 1