13th March 2024

Marfan’s syndrome

Pathophysiology

Marfan’s syndrome is a systemic connective tissue disorder which affects around 1 in 3000 to 5000 people. Around 75% of Marfan’s syndrome is inherited from an affected parent in an autosomal dominant pattern, but inheritance can also be autosomal recessive or occur due to a de novo mutation. 

Marfan’s syndrome most commonly results from a genetic mutation in fibrillin-1 (FNB-1), which affects the elastic properties of connective tissues in multiple body systems, including musculoskeletal, ophthalmic, respiratory and cardiovascular. Some cases of Marfan’s syndrome are due to a mutation in TGF-beta receptor 2 (TGFBR2).

Clinical manifestations

Marfan’s syndrome has a range of musculoskeletal features, including arachnodactyly, scoliosis or kyphosis, pectus carinatum or excavatum and dolichostenomelia (long extremities in comparison to the length of an individual’s trunk). The main ophthalmic complication in Marfan’s is lens dislocation, which is usually in an upward and outward (superotemporal) direction. Other clinical features include an increased risk of pneumothorax, high arched palate and joint hypermobility.

Cardiovascular manifestations

Loss of elastic tissue in the aortic wall results in aortic root dilatation in around 60 to 80% of those with Marfan’s. Aortic dilation is associated with complications, including aortic dissection (typically type A) and aortic regurgitation. 

An estimated 40-54% of those with Marfan’s syndrome will have mitral valve prolapse (MVP). This defect is more common in females and older individuals and results in mitral regurgitation. As a result of cardiac valve disease, heart failure may develop in those affected with Marfan’s syndrome. There is also a risk of infective endocarditis after surgical intervention to manage aortic dilation.

Diagnostics

Diagnosis of Marfan’s syndrome can be complicated, and the criteria generally considers family history, aortic dilation or dissection, ocular lens subluxation, genetic testing for FBN-1 and physical examination findings. 

When investigating cardiovascular features of Marfan’s, aortic dilation is initially diagnosed via transthoracic echocardiogram, with at least annual monitoring. CT and MRI are used in conjugation with echocardiogram to confirm aortic dilation. Echocardiogram is also used to diagnose MVP, which will show a mitral valve with elongated leaflets and redundant appearance, affecting one or both leaflets.

Management

The management of aortic dilation in adults is dependent on the aortic diameter. If this is < 4.5cm (or < 4 cm in women of reproductive age), a beta blocker such as metoprolol should be commenced to prevent further dilation and reduce the risk of aortic dissection. Where betablockade is contraindicated, an angiotensin-II receptor antagonist, e.g., losartan, may be used. Calcium channel blockers are not first-line in the treatment of aortic dilation as there is evidence suggesting they may increase the risk of aortic complications.

Monitoring for aortic dilation is typically through the use of echocardiogram and MRI. Should a patient develop symptomatic thoracic aortic dilation or a type A aortic dissection, then urgent surgery is required.

Where the aortic diameter is 4.5cm or more, surgery should be considered, and this is typically valve-sparing aortic root replacement or a composite valve graft. 

Surgery may also be considered in those with aortic diameter <4.5cm if there is a high risk of dissection, such as increase in aortic diameter of at least 3 mm/year; a family history of aortic dissection, if the patient is pregnant or of reproductive age. After surgical intervention, patients will typically require long-term beta blockade. 

Mitral valve repair is indicated for severe mitral regurgitation (grade 4 or more) or with evidence of haemodynamic compromise. Those who have undergone a valve graft with a replacement mechanical valve will need long-term anticoagulation. 

While there is an increased risk of developing infective endocarditis in people with valve replacement, routine antibiotic prophylaxis is not recommended for dental procedures.

References

• UpToDate – Genetics, clinical features and diagnosis of Marfan syndrome and related disorders
• UpToDate – Management of Marfan syndrome and related disorders
• BMJ Best Practice – Marfan syndrome
• NICE clinical guideline 64 – Prophylaxis against infective endocarditis. Available at: https://www.nice.org.uk/guidance/cg64/evidence/full-guideline-pdf-196759981