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Genetics of Marfan Syndrome Treatment & Management

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
 
Updated: Mar 21, 2016
 

Medical Care

General measures for all adults with Marfan syndrome are as follows[32] :

  • Moderate restriction of physical activity
  • Endocarditis prophylaxis
  • Echocardiography at annual intervals
  • Beta-blocking treatment

Key issues in cardiovascular management are as follows[14] :

  • Beta-blocker therapy should be considered at any age if the aorta is dilated, but prophylactic treatment may be more effective in those with an aortic diameter of less than 4 cm.
  • Risk factors for aortic dissection include aortic diameter greater than 5 cm, aortic dilatation extending beyond the sinus of Valsalva, rapid rate of dilatation (45% per year, or 1.5 mm per y in adults), and family history of aortic dissection.
  • At least annual evaluation should be offered and should include clinical history, examination, and echocardiography.
  • In children, serial echocardiography at 6-month to 12-month intervals is recommended, and the frequency depends on the aortic diameter (in relation to body surface area) and the rate of increase.
  • Prophylactic aortic root surgery should be considered when the aortic diameter at the sinus of Valsalva is more than 5 cm.

Counseling for pregnancy is as follows[32] :

  • Fifty percent risk for transmitting a pathogenic mutation to offspring
  • High-risk pregnancy with aortic root diameter of more than 40 mm or previous cardiovascular surgery or severe heart disease
  • Prepartum aortic root replacement with diameters of more than 40 mm
  • Serial echocardiography until 3 months postpartum

Beta-blockers are as follows:

  • Beta-adrenergic receptor antagonists have gained acceptance as potential agents for delaying aortic expansion and for delaying the progression to rupture or dissection.
  • The rate of surgical interventions has substantially declined during the past decade of beta-blockade use.
  • Beta-blocker therapy retards aortic growth in children and adolescents with Marfan syndrome.
  • A recent study concluded that data are not sufficient to recommend or discourage the use of beta-blockers in children with congestive heart failure. [33]
  • Calcium antagonist therapy also retards aortic growth, but a recommended dose has not been established.
  • The optimal age to begin beta-blockade therapy has not been determined. Some investigators begin therapy during infancy, but others wait until the aortic diameter exceeds the 95th percentile or a rapid rate of dilation is observed.
  • In asymptomatic patients, the elastic properties of the aortic root appear to have a heterogeneous response after long-term treatment with atenolol.
  • The stiffness index and distensibility are most likely to be useful when the baseline end-diastolic aortic root diameter is more than 40 mm.
  • More experience is needed to determine the optimal dose of beta-blockers to minimize growth of the aortic root.

ACE inhibitors are as follows[34, 35] :

  • ACE inhibitors reduce central arterial pressure and conduit arterial stiffness and may be useful in Marfan syndrome. This approach received support by a short-term, nonrandomized study comparing enalapril with beta blockade in which stiffness and rate of dilatation improved with the ACE inhibitors. [36]
  • Another study of patients with Marfan syndrome maintained on beta blockade examined the impact of adding an ACE inhibitor, perindopril, 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. [37]

Matrix metalloproteinases (MMPs) are as follows[35, 37] :

  • Syndromes that resemble Marfan syndrome, especially in the potential for aneurysm and dissection, were found to be due to mutations in genes encoding TGFβ receptors. [24]
  • The potential importance of MMPs was stimulated by studies of non-Marfan syndrome abdominal aortic aneurysm in humans and thoracic aortic aneurysm in mice engineered to have Marfan syndrome, in both of which levels of MMP-2 and MMP-9 were raised. [38]
  • Doxycycline administration to a mouse model of Marfan syndrome suppressed MMPs and improved aortic wall architecture and stiffness compared with atenolol. [39]

Other therapy is 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, but no conclusive data are yet available to show whether this therapy reduces scoliosis.
  • Conservative treatment of protrusio acetabuli mostly involves physiotherapy by forcible stretching (stress fractures of the femoral neck due to stretching are documented), [40] weight extension on an abduction frame, local heating, and re-education concerning daily activities. [11]
  • Myopia is treatable with refraction.
  • 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. [41]
  • Psychological counseling is helpful for families coping with feelings of denial, anger, blame, depression, or guilt.

Future therapeutic strategies are as follows[2] :

An ARB regimen is now recommended as first-line treatment and should be emphasized. Some cardiologists who specialize in Marfan syndrome also have their patients on beta blockers to cover both arms of the pathway. However, no studies have been published as yet to officially recommend the approach.

The current criterion standard for treatment of aortic aneurysm in Marfan syndrome 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 Marfan syndrome and other disorders of the TGFβ-signaling network.
  • Proof of the above principle was obtained by treating Marfan mice with TGF β- neutralizing antibody by intraperitoneal injection. [42]
  • In a preliminary observational study, 17 pediatric Marfan syndrome 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 provides the first evidence for a significant benefit of angiotensin receptor blocker use over current therapies in reducing aortic root dilation in severe pediatric Marfan syndrome.
  • A large, randomized clinical trial in Marfan syndrome patients was initiated and included a total of 608 patients in February 2011 that compares atenolol with losartan for a 3-year treatment. [43] Meanwhile, a nearly a dozen additional trials with different designs and inclusion criteria were initiated in Belgium, France, Italy, the Netherlands, Taiwan, and the United Kingdom. [2]
  • The results of the study by Pees et al have added insight regarding the beneficial effect of losartan as monotherapy, even in mild to moderate cases, in addition to the reported results in severely affected children and adolescents. [44]

Genetic counseling is discussed as follows[45] :

  • Recurrence risk for the patient's siblings is small if neither parent is affected. Gonadal mosaicism is 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. Fifty percent Homozygous Marfan syndrome was reported in case of an affected spouse. Compound heterozygosity at the FBN1 locus was confirmed at the molecular level; the affected child had a severe phenotype, leading to early death.
  • During counseling, the variability of the disease should be emphasized because an affected child may be more or less affected than the parent.
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Surgical Care

Indications for prophylactic surgery of the aortic root in adults (at least one criterion)[32]

  • Aortic root diameter of more than 55 mm (50 mm according to some authors) and aortic root diameter of more than 50 mm (45–50 mm according to some authors) in patients with high risk for aortic complications
    • Family history for aortic dissection
    • Growth of the aortic root of more than 10 mm/y
    • 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 more than 1.5
  • Ratio of the diameters of the aortic root and the descending aorta of more than 2

Indications for prophylactic surgery of the aortic root in children[32]

  • If possible, surgery should be delayed until adolescence
  • Aortic root diameters with similar thresholds as in adults
  • Aortic root diameters outside the upper confidence interval deviate upward from the perused centile on follow-up echocardiograms

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.
  • 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 the function of the hip through hip replacement with bone grafting of the medial acetabular cavity in older patients and closure of the tri-iradiate cartilage in a child or adolescent.[11]

Pectus repair

  • The shape of the front of the thorax becomes stable and established by mid adolescence. Therefore, repair of pectus excavatum to improve respiratory mechanics should be delayed until then to lessen the risk of recurrence.
  • 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
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Consultations

Consultations may include the following:

  • Clinical geneticist
  • Cardiologist
  • Ophthalmologist
  • Cardiovascular surgeon
  • Orthopedic surgeon
  • Orthodontics surgeon
  • Psychologist
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Diet

No special diet is needed.

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Activity

In general, patients can remain fully active unless their symptoms limit them. Patients should be discouraged from participating in demanding sports because several highly trained athletes with unrecognized Marfan syndrome have suddenly died 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, high diving) and to protect themselves against blows to the globe (racquet sports) with 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.
  • Patients should avoid activities involving isometric work such as weightlifting, climbing steep inclines, participating in gymnastics, and performing pull-ups. These exercises cause excessive elevations of systolic blood pressure and may lead to sudden death.
  • Nonstrenuous activities and sports (eg, golf, walking, fishing) are recommended. Appropriate exercise is physically and emotionally beneficial.
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Contributor Information and Disclosures
Author

Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

James Bowman, MD Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical and Translational Research, College of American Pathologists

Disclosure: Nothing to disclose.

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Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.
Positive wrist (Walker) sign.
Positive thumb (Steinberg) sign.
Arachnodactyly.
Pectus excavatum of moderate severity.
Hypermobility of finger joints.
Stretch marks (striae atrophicae) in the lower back.
Dural ectasia in the lumbosacral region.
Typical face seen in a girl with Marfan syndrome characterized by dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures.
 
 
 
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