Genetics of Marfan Syndrome Treatment & Management

General guidelines for all adults diagnosed with Marfan syndrome (MFS) are as follows ^{[7, 8]} :

• Restriction of physical activity with avoidance of contact sports, isometric exercise, and activities that can cause joint injury/pain

• Avoidance of agents that stimulate the cardiovascular system, such as decongestants and caffeine

• Annual ophthalmologic examination - LASIK correction of refractive errors is not recommended.

• Subacute endocarditis prophylaxis for dental work in the presence of mitral or aortic valve regurgitation

• Annual echocardiography to evaluate the ascending aorta in cases of small aortic dimensions and/or a slow aortic dilatation rate - Echocardiography is required with greater frequency when aortic root diameter is over 4.5 cm in adults, if aortic dilatation is greater than 0.5 cm per year, and if significant aortic regurgitation is present

• Beta-blocking treatment to reduce hemodynamic stress on the aortic wall

Key issues in cardiovascular management are as follows ^[9] :

• Beta-blocker therapy should be considered at any age if the aorta is dilated, but prophylactic treatment may be more effective in those patients with an aortic diameter of less than 4 cm.

• Risk factors for aortic dissection include an aortic diameter of over 5 cm, aortic dilatation extending beyond the sinus of Valsalva, rapid rate of dilatation (an increase of 45% per year, or 1.5 mm per year in adults), and a family history of aortic dissection.

• Annual cardiovascular evaluation should be offered and should include clinical history, examination, and echocardiography.

• In children, serial echocardiography at 6- to 12-month intervals is recommended, with the frequency dependent on the aortic diameter (in relation to body surface area) and rate of aortic dilatation.

• Prophylactic aortic root surgery should be considered when the aortic diameter at the sinus of Valsalva is over 5 cm.

Counseling for pregnant women diagnosed with MFS is as follows ^[8] :

• MFS is a genetic disorder historically known to be inherited in an autosomal dominant fashion. About 75% of patients with MFS have an affected parent. In this situation, there is a 50% chance to pass the mutation to offspring. About 25% of patients will have MFS due to a de novo event. 

• Multidisciplinary approach to care is recommended.

• Pregnancy is considered high-risk and should be monitored throughout by a high-risk obstetrician and with continued monitoring into the immediate postpartum period.

• Concurrent and ongoing cardiovascular care - Aortic root diameter of over 40 mm, previous cardiovascular surgery, or severe heart disease is a source of concern. Consider prepartum aortic root replacement with a diameter of more than 40 mm. Serial echocardiography is recommended until 3 months postpartum.

The importance of beta blockers in medical management is as follows:

• Beta-adrenergic receptor antagonists have gained acceptance as potential agents for delaying aortic expansion and for delaying progression to aortic rupture or dissection. The optimal age to initiate beta-blocker therapy has not been determined. Some practitioners begin therapy in infancy, but others wait until the aortic diameter exceeds the 95th percentile or a rapid rate of aortic dilatation is observed. Beta-blocker therapy retards aortic growth in children and adolescents with MFS. The optimal dose of beta blockers to minimize dilatation of the aortic root has not been established. The need for cardiovascular surgical intervention has substantially declined since the start of beta-blocker use.

• A study concluded that data are not sufficient to recommend or discourage the use of beta blockers in children with congestive heart failure. ^[43]

• Calcium antagonist therapy also retards aortic growth, but a recommended dose has not been established.

• In asymptomatic patients, the elastic properties of the aortic root appear to have a heterogeneous response after long-term treatment with the beta blocker atenolol.

• The stiffness index and distensibility are most likely to be useful when the baseline end-diastolic aortic root diameter is over 40 mm.

The importance of angiotensin-converting enzyme (ACE) inhibitors in medical management is as follows ^{[44, 45]} :

• ACE inhibitors reduce central arterial pressure and conduit arterial stiffness and may be useful in MFS. This approach received support by a short-term, nonrandomized study comparing enalapril with beta blockade in which stiffness and rate of dilatation improved with ACE inhibitors. ^[46]

• Another study of patients with MFS maintained on beta blockade examined the impact of adding an ACE inhibitor, perindopril, when compared with placebo. Over a 24-week period, those receiving the ACE inhibitor had a reduction in aortic stiffness and less absolute change in aortic root dimensions. ^[47]

The importance of matrix metalloproteinases (MMPs) in medical management is as follows ^{[45, 47]} :

• Syndromes that resemble MFS, especially with regard to the potential for aortic aneurysm and dissection, were found to be due to mutations in genes encoding TGFβ receptors. ^[33]

• The potential importance of MMPs was investigated in studies of non-MFS abdominal aortic aneurysm in humans and thoracic aortic aneurysm in mice engineered to have MFS. In both case situations, the levels of MMP-2 and MMP-9 were raised. ^{[48, 49]}

• Long-term treatment with doxycycline in a mouse model of MFS suppressed MMPs (MMP-2 and -9) and improved aortic wall architecture and stiffness. When compared with atenolol, doxycycline was more efficacious in preventing thoracic aortic aneurysm (TAA) in the MFS model, through preservation of elastic fiber integrity, normalization of vasomotor function, and reduction in TGFβ activation. ^[48]

Other therapeutic interventions are as follows:

• Anticoagulant medications, such as warfarin, are needed after artificial heart valve placement.

• Intravenous antibiotic therapy is required during cardiac and noncardiac procedures to prevent bacterial endocarditis.

• Progesterone and estrogen therapy have been used to induce puberty and reduce the patient's ultimate height if hormonal treatment is begun before puberty. No conclusive data are yet available to show whether this therapy reduces the degree of scoliosis.

• Conservative treatment of protrusio acetabuli mostly involves physiotherapy by forcible stretching (stress fractures of the femoral neck due to stretching can occur), ^[50] weight extension on an abduction frame, local heating, and reeducation concerning daily activities. ^[21]

• Myopia is treatable with refraction correction.

• Patients with flat feet may wear shoes with adequate arch support, although custom orthotics may be required. Guidelines for the diagnosis and treatment of pediatric flatfoot have been established. ^[51]

• Psychological counseling is helpful for families coping with feelings of denial, anger, blame, depression, or guilt.

Future therapeutic strategies are as follows ^[4] :

• An angiotensin-II receptor blocker (ARB) regimen is now recommended as first-line treatment and should be emphasized. Some cardiologists who specialize in MFS also continue their patients on beta blockers to cover both arms of the pathway. However, no studies have been published as yet to officially recommend this approach.
• The current criterion standard for treatment of aortic aneurysm in MFS is the preventive administration of beta blockers. However, beta blockers do not prevent surgery at a later age.

• The discovery that TGFβ antagonism can rescue aortic aneurysm in C1039G/+ mice prompted the idea to test the efficacy of losartan, a widely used angiotensin-II type I receptor (AT1) antagonist, because of its antihypertensive properties and ability to counteract TGFβ in animal models of chronic renal disease and cardiomyopathy.

• Thus, TGFβ antagonism is a general strategy against aneurysm progression in patients with MFS and other disorders of the TGFβ-signaling network.

• Proof of the above principle was obtained by treating Marfan mice with TGFβ- neutralizing antibody by intraperitoneal injection. ^[52]

• In a preliminary observational study, 17 pediatric MFS patients with progressive aortic enlargement despite optimal medical therapy were given an angiotensin receptor blocker agent and were followed for 12-42 months. Patients had a significant decrease in rate of change of aortic root dimension. This study provided the first evidence for a significant benefit of angiotensin receptor blocker use over current therapies in reducing aortic root dilatation in patients with severe pediatric MFS. ^[53]  

• Study results by Pees et al have added insight regarding the beneficial effect of losartan as monotherapy, even in mild to moderate cases, as confirmed by the reported results in severely affected children and adolescents. ^[54]

• A large randomized clinical trial of MFS patients compared the use of atenolol to losartan in a 3-year treatment plan. The study, which included a total of 608 patients, found that the rate of aortic root dilatation did not significantly differ between the two treatment groups, ie, children and young adults with MFS who were randomly divided between losartan and atenolol therapy. ^[55]

Genetic counseling points for patients and their families include the following ^[56] :

• If neither biological parent is affected, recurrence risk for the patient's siblings is small, although gonadal mosaicism has been reported as the cause of multiple affected offspring being born to unaffected parents. Risk is 50%, if one parent is affected.

• Recurrence risk for the patient's offspring is 50% if the spouse is normal. Homozygous MFS was reported in a case of an affected spouse. Compound heterozygosity at the FBN1 locus was confirmed at the molecular level; the child was severely affected and died early in life.

• During counseling, the variability of MFS should be emphasized because an affected child may be more or less affected than the affected parent.

Prophylactic surgery of the aortic root

Indicators for prophylactic surgery of the aortic root in adults (at least one criterion is needed) include the following ^[8] :

• Aortic root diameter of more than 55 mm or aortic root diameter of greater than 50 mm (45-50 mm according to some authors) in patients with high risk for aortic complications

  • Family history of aortic dissection

  • Growth of the aortic root by over 10 mm per year

  • Dilatation of the aortic sinus involving the ascending aorta

  • More than mild aortic regurgitation

  • Severe mitral regurgitation

  • Before major noncardiovascular surgery

  • Women planning pregnancy

• Aortic ratio of over 1.5.

• Diameter ratio of the aortic root to the descending aorta of more than 2.

Indicators for prophylactic surgery of the aortic root in children include the following ^[8] :

• Aortic root diameters with similar thresholds as adult patients.

• Aortic root diameters outside the upper confidence interval that increase in percentile on follow-up echocardiograms.

If possible, however, surgery should be delayed until adolescence.

Cardiovascular surgery

Cardiovascular surgery can substantially prolong survival. Prophylactic and emergency cardiovascular surgery is needed for treatment of aortic and mitral regurgitation, aortic aneurysm, and aortic dissection. Emergency surgical replacement of the aortic root is indicated for survivors of acute proximal aortic dissection.

The ascending aorta is usually replaced when the aorta exceeds 55-60 mm in diameter. Composite valve-graft replacement is performed, in which the dilated aortic segment is replaced by a prosthetic valve sewn into a tube graft with reimplantation of the coronary ostia (modified Bentall procedure). Composite valve-graft replacement of the aortic root has low rates of morbidity and mortality, produces excellent long-term results, and is currently the treatment of choice for proximal dissection or clinically significant annuloaortic ectasia in patients with Marfan syndrome (MFS).

An aortic valve–sparing procedure is evolving for patients with an aortic aneurysm and favorable characteristics of the aortic valve and annulus. The advantages of this procedure include the avoidance of anticoagulation and a lowered risk of thromboembolism and endocarditis. The aortic valve–sparing procedure is still controversial because of concerns that it poses a risk of progressive valvular degeneration and annular dilation. Additional long-term data are required before routine use of this procedure can be recommended.

Scoliosis surgery

Severe scoliosis requires surgery. Bracing has a limited role in treating the most severe form of infantile scoliosis. Surgery should not be performed on a child younger than 4 years, because many patients with large curves before this age spontaneously die of cardiac complications. Results of spinal fusion are better in children older than 5 years.

Indications for surgery in adults include pain, neurologic signs, and thoracic curves greater than 45°, which can cause restrictive lung disease.

Protrusio acetabuli surgery

This is directed at arresting progression, relieving pain, and restoring hip function through hip replacement with bone grafting of the medial acetabular cavity in older patients and closure of the triradiate cartilage in a child or adolescent. ^[21]

Pectus excavatum repair

The shape of the front of the thorax becomes stable and established by midadolescence. Repair of pectus excavatum to improve respiratory mechanics should be delayed until then, to lessen recurrence risk. Pectus carinatum repair is mainly performed for cosmetic reasons

Pneumothorax therapy

A chest tube is an appropriate initial therapy. After one recurrence, a more aggressive approach involving bleb resection and pleurodesis is recommended.

Ocular therapy

Lasers can be used to restore a detached retina. The risk of retinal detachment related to lens extraction is increased; the lens is removed only in the following few instances:

• Dislocation of a lens in the anterior chamber, especially when it touches the corneal endothelium

• Significant lens opacity

• Evidence of lens-induced uveitis and glaucoma

• Inadequate visual acuity that is not correctable by refraction and iris manipulation

• Imminent complete luxation of the lens

Consultations should include the following specialties to foster a multidisciplinary approach to continuity of care and treatment:

• Clinical geneticist/genetic counselor

• Ophthalmologist

• Cardiologist

• Pulmonologist

• Cardiothoracic surgeon

• Orthopedist/orthopedic surgeon

• Podiatrist

• Physical therapist

• Radiologist - For interpretation of scans from various imaging modalities

• Dentist/orthodontist

• Psychologist/psychiatrist

• High-risk obstetrician - For pregnant women with Marfan syndrome (MFS)

No special diet is needed.

Patients with Marfan syndrome (MFS) can remain fully active unless they are limited by their symptoms. Patients should be discouraged from participating in demanding sports, because several highly trained athletes with undiagnosed MFS have died suddenly from ruptured aortic aneurysms.

Competitive and contact sports are potentially dangerous because of underlying aortic weakness and dilatation, valvular insufficiency, ocular abnormalities, and skeletal problems. Patients should avoid blows to the head (eg, in boxing or high diving) and should protect themselves against blows to the globe (in racquet sports) by wearing cushioned spectacles.

To protect against pneumothorax, patients should avoid the rapid decompression associated with quick ascents in elevators, scuba diving, and flying in unpressurized aircraft. Playing an instrument that requires breathing against resistance, such as a brass instrument, is not recommended.

Patients should avoid activities involving isometric work such as weightlifting, climbing steep inclines, gymnastics, and performing pull-ups. These exercises cause excessive elevations of systolic blood pressure and can lead to sudden death.

Nonstrenuous activities and sports (eg, golf, walking, fishing) are recommended. Appropriate exercise is physically and emotionally beneficial.