What are the next steps in managing a patient suspected of having Marfan syndrome?

Immediate Next Steps When Suspecting Marfan Syndrome

When Marfan syndrome is suspected, immediately perform a comprehensive physical examination focusing on skeletal features, obtain a detailed family history of aortic disease or sudden death, order an echocardiogram to evaluate for aortic root dilatation, and arrange a dilated eye examination to assess for ectopia lentis. 1

Essential Diagnostic Evaluation

The diagnostic workup must include four core components:

1. Physical Examination

Focus specifically on:

• Skeletal features: Wrist AND thumb sign (3 points if both present), pectus carinatum (2 points) or excavatum (1 point), hindfoot deformity (2 points), arm span-to-height ratio >1.05, reduced upper-to-lower segment ratio 1
• Cardiovascular signs: Auscultate for mitral valve prolapse, aortic regurgitation 1
• Skin assessment: Check for striae distensae, which scores 1 point in the systemic feature scoring system 1
• Facial features: High narrow palate, dental crowding 1

2. Family History Documentation

• Specifically ask about: First-degree relatives with aortic dissection, aortic root replacement, sudden cardiac death under age 50, confirmed Marfan syndrome diagnosis 1
• A positive family history significantly lowers the diagnostic threshold—requiring only ectopia lentis, multiple systemic features, OR aortic root Z-score >2 (if over 20 years) or >3 (if under 20 years) 1

3. Echocardiogram (Urgent Priority)

• Measure aortic root diameter at the sinuses of Valsalva and calculate Z-score based on age, sex, and body surface area 1
• Assess for mitral valve prolapse and aortic regurgitation 1
• Critical threshold: Aortic root Z-score >2 is diagnostic when combined with ectopia lentis or FBN1 mutation 1
• If initial echocardiogram shows dilation, repeat in 6 months to establish rate of growth 2

4. Dilated Eye Examination

• Must be performed by an ophthalmologist to definitively identify or exclude ectopia lentis 1, 3
• Ectopia lentis combined with aortic root dilation (Z-score ≥2) is sufficient for Marfan syndrome diagnosis without genetic testing 1
• Also assess for myopia and retinal detachment risk 1

Genetic Testing Considerations

Order FBN1 gene sequencing when:

• Aortic root dilation is present but ectopia lentis is absent 1
• Systemic features are present but neither aortic dilation nor ectopia lentis meet diagnostic thresholds 1
• The patient is a child where age-dependent penetrance makes clinical diagnosis uncertain 4

Important caveat: Genetic confirmation is NOT required for diagnosis if clinical criteria are met (aortic root Z-score ≥2 plus ectopia lentis), but helps distinguish Marfan syndrome from related conditions like Loeys-Dietz syndrome 1, 5

Risk Stratification Based on Initial Findings

If Aortic Root is Normal (Z-score <2):

• Repeat echocardiogram every 2-3 years until adult height is reached 1
• After reaching adult height, repeat only if cardiovascular symptoms develop or major increase in physical activity is planned 1, 3
• Continue monitoring for systemic features that may evolve with age 1

If Aortic Root is Dilated but <4.5 cm in Adults:

• Annual echocardiogram if growth rate <0.5 cm/year 1
• Initiate beta-blocker therapy immediately to slow aortic growth 1, 6
• Refer to cardiologist experienced in connective tissue disorders 1

If Aortic Root >4.5 cm or Growing >0.5 cm/year:

• Echocardiogram every 6 months 1
• Beta-blocker therapy at maximum tolerated dose 1
• Urgent cardiothoracic surgery referral for consideration of prophylactic repair 1
• MRI or CT of entire aorta to assess for additional aneurysms 1

Critical Differential Diagnoses to Exclude

Loeys-Dietz Syndrome (TGFBR1/2 mutations):

• Key distinguishing features: Bifid uvula, craniosynostosis, arterial tortuosity, characteristic facial features 1
• Critical difference: Dissection occurs at SMALLER aortic diameters (even <4.0 cm), requiring earlier surgical intervention 1, 2
• If suspected: Order MR angiography of head, neck, thorax, abdomen, and pelvis PLUS TGFBR1/2 gene sequencing 1

Hypermobile Ehlers-Danlos Syndrome:

• Distinguishing features: Beighton score ≥5/9, soft velvety skin, easy bruising, chronic pain, functional GI disorders 1, 3
• Aortic root dilation occurs in only 25-33% and dissection risk is minimal without significant dilation 1
• Does NOT typically present with ectopia lentis 1

Vascular Ehlers-Danlos Syndrome (Type IV):

• Life-threatening condition requiring immediate genetic confirmation with COL3A1 testing 7
• Median survival only 48-51 years with arterial rupture as leading cause of death 7
• Avoid invasive catheterization—can be fatal due to arterial fragility 7

Common Pitfalls to Avoid

• Do not rely on skeletal features alone: Many tall individuals with joint hypermobility do not have Marfan syndrome 1, 3
• Do not skip the dilated eye exam: Ectopia lentis is a major diagnostic criterion and cannot be adequately assessed without pupillary dilation 1, 3
• Do not delay echocardiography: Aortic dissection can occur in previously undiagnosed patients, and early identification allows for preventive therapy 5, 6
• Do not assume normal childhood echocardiogram excludes future risk: Aortic dilation is age-dependent and may develop during adolescence or early adulthood 1, 4
• Do not apply standard Marfan thresholds if Loeys-Dietz is suspected: These patients require surgical intervention at much smaller aortic diameters (4.2-4.6 cm) 2

Immediate Medical Management if Diagnosis Confirmed

• Initiate beta-blocker therapy (atenolol or metoprolol) to reduce hemodynamic stress on the aortic wall 1, 6
• Aggressive blood pressure control with target <120/80 mmHg 1
• Activity restrictions: Avoid high-intensity static exercise, contact sports, and isometric exercise 4
• Endocarditis prophylaxis if significant valvular disease present 1
• Refer to genetics for counseling regarding 50% transmission risk to offspring 5