What are the characteristic features and management of Marfan syndrome?

Marfan Syndrome: Characteristic Features and Management

Diagnostic Features

Marfan syndrome is primarily a clinical diagnosis requiring involvement of multiple organ systems, with aortic root dilation and ectopia lentis being the most specific cardinal features. 1

Genetic Basis

• Caused by mutations in the FBN1 gene encoding fibrillin-1, a large glycoprotein in the extracellular matrix 1
• Approximately one-third of cases represent new sporadic mutations without family history 1
• Molecular testing detects mutations in only 90-95% of unequivocal cases, limiting its diagnostic utility 1
• No case of classic Marfan syndrome is due to mutations in genes other than FBN1 1

Diagnostic Criteria for Patients WITHOUT Family History

Any ONE of the following four combinations establishes the diagnosis: 1

• Aortic root dilation (Z-score ≥ +2) PLUS ectopia lentis
• Aortic root dilation PLUS pathogenic FBN1 mutation
• Aortic root dilation PLUS systemic score ≥7 points (see below)
• Ectopia lentis PLUS FBN1 mutation previously associated with aortic disease

Diagnostic Criteria for Patients WITH Positive Family History

Any ONE of the following three findings confirms diagnosis in relatives: 1

• Ectopia lentis alone
• Systemic score ≥7 points alone
• Aortic root dilation (Z-score >+2 if age >20 years; Z-score >+3 if age <20 years)

Systemic Features Scoring System

The following point system quantifies systemic involvement: 1

• Wrist AND thumb sign = 3 points (wrist OR thumb sign = 1 point) 1
• Pectus carinatum = 2 points (pectus excavatum or chest asymmetry = 1 point) 1
• Hindfoot deformity = 2 points (plain pes planus = 1 point) 1
• Pneumothorax = 2 points 1
• Dural ectasia = 2 points 1
• Protrusio acetabuli = 2 points 1

A score of ≥7 points constitutes "multiple systemic features" for diagnostic purposes. 1

Clinical Features by System

Cardiovascular manifestations: 1

• Progressive aortic root dilation affecting virtually every patient during their lifetime 1
• Mitral valve prolapse and regurgitation 1, 2
• Aortic regurgitation from distortion of valve cusps by enlarged aortic root 1
• Dilation extending beyond the aortic root to the ascending aorta and arch indicates more severe disease 1

Skeletal manifestations: 1

• Excessive height with disproportionate limb length (dolichostenomelia) 1
• Arachnodactyly (long, slender fingers) 1, 2
• Pectus deformities (carinatum or excavatum) 1, 2
• Scoliosis and kyphosis 1, 2
• Joint laxity 1

Ocular manifestations: 1

• Ectopia lentis (lens dislocation) - highly specific for Marfan syndrome 1
• Flat cornea 2
• Myopia 2

Other features: 1, 2

• Cutaneous striae atrophicae, particularly on shoulders 1, 2
• Dural ectasia (lumbosacral) 1
• Recurrent or incisional hernias 1
• Emerging features in aging patients: renal and hepatic cysts 1

Management Strategy

Cardiovascular Surveillance

For patients meeting diagnostic criteria or with aortic root dilation: 1

• Annual echocardiography when aortic root diameter <4.5 cm in adults AND growth rate <0.5 cm/year 1, 3
• Echocardiography every 6 months when diameter >4.5 cm OR growth rate >0.5 cm/year 1
• Complete aortic imaging (MRA or CT) starting in young adulthood 1
  • Repeat annually if history of aortic root replacement or dissection 1
  • Less frequently if no such history 1
• Measure internal diameter at sinuses of Valsalva as baseline (echocardiography measures internal diameter; CT/MR measures external diameter, which is 0.2-0.4 cm larger) 1

For patients with normal aortic root but systemic involvement without family history: 1

• Repeat echocardiography every 2-3 years until adult height reached 1
• Then repeat only if symptomatic or when major increase in physical activity planned 1

Medical Therapy

β-blocker therapy is indicated for all patients with aortic root dilation or meeting diagnostic criteria for Marfan syndrome. 1, 2

• Slows aortic dilation and may reduce TGF-β activation 4
• Management should be coordinated by a skilled cardiologist 1

Surgical Intervention

Prophylactic aortic root repair is indicated when: 1

• Aortic root diameter >4.5 cm 1
• Growth rate >1 cm/year 1
• Progressive aortic regurgitation 1
• Aortic root diameter >5.0 cm with aortic root-to-height ratio >10 (15% of patients dissect at sizes <5.0 cm) 1

Patient Education and Precautions

Patients with moderate or severe aortic root dilation and/or TGFBR1/2 mutations must: 1

• Be taught signs and symptoms of aortic dissection 1
• Consider wearing a medical alert bracelet 1

Important Clinical Caveats

Diagnostic challenges to recognize: 1

• Features are age-dependent; young relatives show fewer manifestations than older ones 1
• Variable expression occurs beyond age dependency for poorly understood reasons 1
• Many features (myopia, tall stature, pectus excavatum, scoliosis, joint hypermobility, MVP) occur sporadically in the general population 1
• Dural ectasia is highly specific but only warrants imaging if diagnosis is uncertain 1

Family evaluation is critical: 1

• Personally examine siblings and parents of suspected cases 1
• Many diagnostic features (scoliosis, striae, disproportionate stature, MVP, aortic root dilation) are clinically silent 1
• Obtain detailed medical and autopsy records for deceased relatives with "aneurysm" or "cystic medial necrosis" 1

Differential diagnosis considerations: 1

• EDS hypermobile type: joint hypermobility with mild skin hyperextensibility (rare in Marfan syndrome) 1
• Loeys-Dietz syndrome: distinguished by absence of ectopia lentis 1
• Familial aortic aneurysm syndromes without full Marfan criteria 1