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What is Marfan Syndrome?

Marfan syndrome is a common autosomal dominant multisystem connective tissue disorder (Charissa, 2016), with a reported incidence of 1 in 3000 to 5000 (Salik, 2024). It is present in individuals globally with no specific race or gender preference and is one of the most common single-gene malformation syndromes (Salik, 2024).

Pathophysiology of Marfan Syndrome

The primary genetic defect noted is in the FBN1 gene on chromosome 15, which transcripts the formation of Fibrillin-1, a connective tissue protein (Salik, 2024). In 25% of patients, the abnormality in the FBN1 gene can develop after de novo mutation. (Charissa, 2016; Dietz, 1991)

Marfan Syndrome Diagnosis

A suspicion of Marfan syndrome arises mostly after observing the skeletal features. Family history of musculoskeletal, ophthalmic, and cardiovascular features and sudden cardiac death promote genetic testing and diagnosis of Marfan syndrome in other family members. In some individuals, the diagnosis is made only after an individual had aortic dissection or aortic aneurysms were detected on cardiovascular examinations. (Milewicz, 2022) Further testing, including an electrocardiogram, echocardiogram, eye examination, and genetic testing, helps with diagnosis.

Common features associated with Marfan's Syndrome (Salik, 2024; Dean, 2007)

• Musculoskeletal:
  Hypermobility, high arched palate with dental crowding, arachnodactyly, pectus excavatum, pectus carinatum, protrusion acetabuli, characteristic facial features, and pes planus.
• Cardiovascular:
  Aortic root abnormality and abnormalities in cardiac function are the primary causes of morbidity and mortality in 60 to 80% of the patients with Marfan syndrome. Other cardiovascular abnormalities noted are mitral valve prolapse, tricuspid valve prolapse, mitral regurgitation, cardiomyopathy with biventricular enlargement and mild systolic dysfunction, proximal ascending aortic dilatation, dilatation of the proximal pulmonary artery, thickening and prolapse of atrioventricular valves and calcification of the mitral annular structure.
• Ophthalmic:
  Lens dislocation, flat cornea, myopia, hypoplasia of iris or ciliary muscle, retinal detachment.
• Pulmonary:
  Spontaneous pneumothorax and apical blebs.
• Skin:
  Striae atrophicae.
• Spine:
  Scoliosis, spondylolisthesis, Dural ectasia.

Treatment of Marfan Syndrome

The treatment is primarily focused on cardiovascular abnormalities and malfunctions. (Charissa, 2016). Restrictions in vigorous physical exercises, non-invasive monitoring, medical treatment and prophylactic repair of the aorta has improved the prognosis and life expectancy (Salik, 2024). Transthoracic echocardiography is the modality of choice for diagnosing Marfan syndrome, with aortic diameter at the sinus of the Valsalva being the key measurement. (Roman, 1993)

Beta-blockers are considered to be the standard medical therapy to prevent and delay the progression of aortic dilatation and aortic dissection. (Boucek, 1981; Boucek, 1983, Hiratzka, 2010) Beta-blockers reduce stress on the aortic valve by reducing the pulse pressure, decreasing the myocardial contractility and improving the elastic properties of the aorta in patients with an aortic root diameter of less than 40 mm (Groenink, 1998)

Other medical treatments found useful in patients with Marfan syndrome are calcium channel blockers, ACE inhibitors, and Angiotensin II type 1 receptor antagonists (losartan) (Ramirez-Marrero -2012).

Treatment of skeletal and ocular involvement

In advanced stages of scoliosis, surgical stabilisation is the proposed treatment. Abnormalities, such as pectus excavatum and incavatum, are usually cosmetic problems and can be observed. The ocular manifestations can be managed with treatments including contact lenses or spectacles and surgical interventions involving manipulations of the iris diaphragm and lens extraction. Surgical interventions are needed for progressive lens subluxation, lens instability, cataract formation and retinal detachment. (Nemet, 2006; Denniston 2001)

Ongoing care in Marfan Syndrome

In a diagnosed case of Marfan syndrome, it is paramount for the patients to have multidisciplinary management and follow-up, including physiotherapists and allied health specialists, orthopaedic surgeons, cardiologists, ophthalmologists, and cardiothoracic surgeons. Annual cardiovascular monitoring by transthoracic echocardiogram is recommended, especially for patients younger than 20. CT or MRI scans are recommended every 5 years in patients with normal aortic root diameter beyond the aortic root and annually in patients with distal involvement. (Baumgartner, 2010). An annual ophthalmic evaluation is recommended. (Charissa, 2016)

Marfan Syndrome and Pregnancy

Due to the increased risk of cardiovascular problems, such as aortic dissection during or especially soon after pregnancy, pregnant women require regular monitoring (Charissa, 2016). Women with an aorta diameter greater than 45 mm must have an elective aortic repair before getting pregnant. (Meijboom, 2005). Other pregnancy-related complications seen in females with Marfan Syndrome include premature rupture of membranes, premature delivery and neonatal death. (Meijboom, 2006).

Marfan Syndrome and Life Expectancy

With improvements in diagnosis and treatment, the lifespan of untreated Marfan syndrome patients has improved from 32 years in 1982 to over 70% (Saalik, 2024). Aortic complications are the main cause of declining life expectancy. (Charissa, 2016).

Marfan Syndrome and Physical Activity

Like any other individual, patients with Marfan syndrome benefit from regular exercise, which improves their physical and emotional well-being. However, performing exercise to exhaustion and completing competitive and contact sports and activities involving Valsalva manoeuvres increase the systemic risks because increased heart rate and blood pressure can lead to increased stress on the aorta. (Charissa, 2016)

Head impact and other contact activity leading to abnormal deceleration/acceleration can worsen lens dislocation and retinal detachment. Extensive stress on bones and joints can cause increased pain and dislocation of the joints. Further, there can be increased bruising and internal haemorrhage in patients on anticoagulants.

Individuals with Marfan syndrome should avoid activities with intense isometric exercises leading to muscle fatigue and straining or those considered competitive or can causecollision or contact (the 3 C's). Activities that risk rapid changes in atmospheric pressure, such as scuba diving and flying in unpressurised aircraft, should also be avoided, as there is a risk of lung collapse in these conditions. The exercises can be performed 4 to 5 times per week for 30 minutes or include three 10-minute sessions. Using protective gear in the form of helmets while bicycling can help reduce the risks of further injuries. Traditional yoga for relaxation and mindfulness to allay emotional stress can help. However, hot exercise studios, strenuous forms of yoga, headstands, and shoulder stands should be avoided.

The impact of ongoing medication should be considered with physical activity advice in Marfan syndrome patients. Beta-blockers do not allow a person with Marfan syndrome to perform strenuous exercises or play contact sports as they lower the pulse rate at rest and during exercise, making it somewhat difficult to achieve a given level of physical fitness for the amount of physical work being performed. ACE inhibitors do not protect the aorta from strenuous exercise. People who have artificial valves and are on anticoagulants should avoid contact sports because of the risks of bruising and internal haemorrhages. (Marfan Foundation)

Summary

Due to the great variation in how affected individuals present, the fact that age influences many clinical manifestations, the lack of gold-standard diagnostic testing, and the broad differential diagnosis, Marfan syndrome is unavoidably difficult to diagnose. Improved risk stratification, imaging techniques and protocols, medical treatment and prophylactic aortic surgery have improved the prognosis considerably. Genetic testing should be considered for early diagnosis, treatment, and follow-up in family members per the guidelines mentioned above.

References