What is the management approach for patients with FBN1 (Fibrillin-1) mutations associated with Marfan's disease, particularly those with Fn1 (Fibrillin-1) mutations?

Management of Patients with FBN1 Mutations in Marfan's Disease

Beta blockers and angiotensin receptor blockers are the cornerstone of medical therapy for patients with FBN1 mutations in Marfan's disease, with surgical intervention recommended when aortic root diameter reaches 4.5 cm in adults. 1

Diagnosis and Evaluation

• Marfan syndrome is caused by mutations in the FBN1 gene, which encodes fibrillin-1, a large glycoprotein in the extracellular matrix that contributes to microfibril structure 1, 2
• Diagnosis is based on the revised Ghent criteria, which incorporate genetic testing, systemic score, ectopia lentis, and family history 1, 3
• A definitive diagnosis can be made in patients without family history if they have:
  • Dilated aortic root (Z-score >+2) and ectopia lentis 1
  • Dilated aortic root and a clearly pathologic FBN1 mutation 1
  • Dilated aortic root and multiple systemic features 1
  • Ectopia lentis and an FBN1 mutation previously associated with aortic disease 1

Initial Cardiovascular Assessment

• Transthoracic echocardiography (TTE) is recommended at the time of initial diagnosis to determine aortic root and ascending aorta diameters 1
• Follow-up TTE should be performed 6 months after diagnosis to determine the rate of aortic growth 1
• After initial TTE, CT or MRI of the thoracic aorta is reasonable to confirm aortic diameters and assess the remainder of the thoracic aorta 1
• Measurements at the sinuses of Valsalva provide a baseline for future evaluations as this is the aortic segment that typically dilates in Marfan syndrome 1

Medical Management

• Beta blockers remain the gold standard therapy for patients with Marfan syndrome 1, 4
• Angiotensin receptor blockers (ARBs), particularly losartan, are reasonable for patients with Marfan syndrome to reduce the rate of aortic dilatation unless contraindicated 1
• Combined therapy with both beta blockers and ARBs in maximally tolerated doses should be considered to reduce the rate of aortic dilatation 1, 5
• Treatment with statins to achieve LDL cholesterol <70 mg/dL is reasonable for patients with atherosclerotic aortic aneurysm 1

Imaging Surveillance Protocol

• For patients with aortic root diameter <4.5 cm and stable measurements:
  • Annual TTE if rate of increase is <0.5 cm/year 1
  • TTE every 6 months if diameter is >2 standard deviations in an adult or rate of increase is >0.5 cm/year 1
• For patients with aortic root diameter ≥4.5 cm:
  • TTE at least every 6-12 months in the absence of additional risk factors 1
• Complete peripheral vascular and thoracoabdominal aortic imaging by MRI or CT:
  • At first evaluation 1
  • Every 3-5 years if stable in patients without previous aortic surgery 1
• For patients who have undergone aortic root replacement:
  • Surveillance imaging of the thoracic aorta by MRI or CT is recommended annually initially 1
  • If normal in diameter and unchanged after 2 years, imaging can be performed every other year 1
  • Surveillance imaging every 3-5 years for potential abdominal aortic aneurysm is reasonable 1

Indications for Surgical Intervention

• Surgical repair is recommended for:
  • Aortic root/ascending aorta diameter >4.5 cm in adults 1
  • Rate of increase in aortic diameter >1 cm/year 1
  • Progressive aortic regurgitation 1
• Prophylactic aortic root surgery is recommended in women desiring pregnancy with aortic diameters >45 mm 1
• Prophylactic aortic root surgery may be considered in women desiring pregnancy with aortic diameters of 40-45 mm 1

Physical Activity Recommendations

• Physical activity should be individualized based on aortic diameter, family history of aortic dissection, and pre-existing fitness 1
• Regular moderate aerobic exercise with intensity informed by aortic diameter is recommended for most patients 1
• Patients should avoid heavy isometric exercises, especially if they have arterial hypertension, residual obstruction, or other complications 1
• Post-operative cardiac rehabilitation should be considered for patients who have undergone aortic surgery 1

Special Considerations for Pregnancy

• Pre-conception evaluation is recommended to address risks of maternal cardiovascular complications 1
• Pre-conception genetic counseling should be offered 1
• Imaging of the whole aorta by MRI/CT is recommended prior to pregnancy 1
• Beta blockers should be continued during pregnancy 1
• Follow-up during pregnancy should be determined by aortic diameter and growth 1

Pitfalls and Caveats

• FBN1 mutations are extremely variable, making prediction of disease phenotype and aortic risk challenging 6
• Current clinical molecular testing detects mutations in only 90-95% of unequivocal Marfan syndrome patients 1
• Patients with Marfan syndrome may have dissection at a smaller aortic size (<5.0 cm) than the general population 1
• The severity of aortic disease relates to the degree and segment length of aortic dilatation, with dilatation extending to the aortic arch having a worse prognosis than dilatation limited to the sinuses of Valsalva 1
• Patients should be educated about the signs and symptoms of aortic dissection and should consider wearing a medical alert bracelet 1