Marfan Syndrome – Causes, Symptoms, Diagnosis, Treatment

Diagnosis? of Marfan Syndrome

To establish the extent of disease and needs in an individual diagnosed with Marfan syndrome, the following evaluations are recommended, if they have not already been completed:

• Evaluation by an ophthalmologist with expertise in Marfan syndrome, including:
  • Slit lamp examination through a maximally dilated pupil for evidence of lens subluxation
  • Refraction and correction of refractive errors, especially in young children at risk for amblyopia
  • Specific assessment for glaucoma and cataract
• Evaluation for skeletal manifestations that may require immediate attention by an orthopedist (e.g., severe scoliosis)
• Echocardiography
  • Aortic root measurements must be interpreted based on consideration of normal values for age and body size.
  • Selected findings may require the immediate attention of a cardiologist or cardiothoracic surgeon (e.g., severe valve dysfunction, severe aortic dilatation, congestive heart failure, history or evidence suggestive of arrhythmia?).
• Consultation with a clinical geneticist and/or genetic counselor
• Molecular genetic tests (or gene tests) study single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder.
• Chromosomal genetic tests analyze whole chromosomes or long lengths of DNA to see if there are large genetic changes, such as an extra copy of a chromosome, that cause a genetic condition. Biochemical genetic tests study the amount or activity level of proteins; abnormalities in either can indicate changes to the DNA that result in a genetic disorder.
• a magnetic resonance imaging (MRI) test, computed tomography (CT) scan, or X-ray?, which can be performed in some people to look for lower back problems
• an echocardiogram, which is used to examine your aorta for enlargement, tears, or aneurysms (bubble-like swelling? due to weakness? in the artery walls)
• an electrocardiogram (EKG), which is used to check your heart rate and rhythm
• an eye exam, which allows your healthcare provider to examine the overall health of your eyes, to test how accurate your sight is, and to screen for cataracts and glaucoma.

Heart tests

If your doctor suspects Marfan syndrome, one of the first tests he or she may recommend is an echocardiogram. This test uses sound waves to capture real-time images of your heart in motion. It checks the condition of your heart valves and the size of your aorta. Other heart-imaging options include computerized tomography (CT) scans and magnetic resonance imaging (MRI).

If you are diagnosed with Marfan syndrome, you’ll need to have regular imaging tests to monitor the size and condition of your aorta.

Eye tests

Eye exams that may be needed include:

• Slit-lamp exam. This test checks for lens dislocation, cataracts or a detached retina. Your eyes will need to be completely dilated with drops for this exam.
• Eye pressure test. To check for glaucoma, your eye doctor may measure the pressure inside your eyeball by touching it with a special tool. Numbing eyedrops are usually used before this test.

Treatment of

Eye

• The ocular manifestations should be managed by an ophthalmologist with expertise in Marfan syndrome.
• Most often, refractive errors can be adequately controlled with spectacle correction alone.
• Lens dislocation can require surgical aphakia (removal of lens) if the lens is freely mobile or the margin of the lens obstructs vision. An intraocular lens can be implanted after puberty (i.e., once growth is complete). While intraocular lens implants are currently considered quite safe when performed in specialized centers, major complications including retinal detachment can occur.
• Prompt and aggressive assessment and correction of refractive error are mandatory in young children at risk for amblyopia.

Skeletal

• Bone overgrowth and ligamentous laxity can lead to severe problems (including progressive scoliosis) and should be managed by an orthopedist; surgical stabilization of the spine may be required.
• Pectus excavatum can be severe; in rare circumstances, surgical intervention is indicated for medical (rather than cosmetic) reasons.
• Protusio acetabulae can be associated with pain? or functional limitations. Surgical intervention is rarely indicated.
• Pes planus is often associated with inward rotation at the ankle, contributing to difficulty with ambulation, leg fatigue?, and muscle cramps. Orthotics are indicated only in severe cases. Some individuals prefer use of arch supports, while others find them irritating; the choice should be left to personal preference. Surgical intervention is rarely indicated or fully successful.
• Dental crowding may require orthodontia or use of a palatal expander.
• Use of hormone supplementation to limit adult height is rarely requested or considered. Complications can include the psychosocial burden of accelerated puberty, an accelerated rate of growth prior to final closure of the growth plate, and perhaps the undesirable consequences of the increased blood pressure associated with puberty on progression of aortic dilatation. This treatment should only be considered when an extreme height is anticipated. Marfan syndrome-specific growth curves now allow accurate prediction of adult height [Erkula et al 2002].

Cardiovascular

• Cardiovascular manifestations should be managed by a cardiologist familiar with Marfan syndrome.
• Surgical repair of the aorta is indicated after infancy and in adults once:
  • The maximal measurement approaches 5.0 cm; OR
  • The rate of increase of the aortic root diameter approaches 1.0 cm per year; OR
  • There is progressive and severe aortic regurgitation.
  More aggressive therapy may be indicated in individuals with a family history of early aortic dissection. Many individuals can receive a valve-sparing procedure that precludes the need for chronic? anticoagulation.
• Guidelines for surgical repair of the aorta during infancy are based on far less clinical experience than for adults and older children, and need to be tailored to the clinical situation at hand.
  • Aortic root surgery should be considered once:
    • The rate of increase of the aortic root diameter approaches 0.5-1.0 cm per year; OR
    • There is progressive and severe aortic regurgitation.
  • While there is no agreed-upon absolute size threshold for aortic root surgery in childhood, many centers use the adult guideline of 5.0 cm given the extreme rarity of aortic dissection in young children. Every effort is made to allow the aortic annulus to reach a size of at least 2.0 cm, allowing placement of an aortic graft of sufficient size to accommodate body growth.
  • Severe and progressive mitral valve regurgitation with attendant ventricular dysfunction is the leading indication for cardiovascular surgery in children with Marfan syndrome. In this circumstance, caution is warranted when considering concomitant aortic root surgery, as the increased length and complexity of the procedure can put extra tendon?. সহজ বাংলা: মাংসপেশি/টেনডনে টান।" data-rx-term="strain" data-rx-definition="A strain is injury to a muscle or tendon. সহজ বাংলা: মাংসপেশি/টেনডনে টান।">strain? on the myocardium and delay or compromise postoperative recovery.
• When congestive heart failure is present, afterload-reducing agents (in combination with a beta-blocker) can improve cardiovascular function, but surgical intervention may be indicated in refractory cases. Most often the mitral valve can be repaired, rather than replaced.

Other

• Dural ectasia is usually asymptomatic. No effective therapies for symptomatic dural ectasia currently exist.
• Hernias tend to recur after surgical intervention. A supporting mesh can be used during surgical repair to minimize this risk.
• Pneumothorax can be a recurrent problem. Optimal management may require chemical or surgical pleurodesis or surgical removal of pulmonary blebs.

Surgery

• Aortic repair. If your aorta’s diameter reaches about 2 inches (45 to 50 millimeters) or if it enlarges rapidly, your doctor may recommend an operation to replace a portion of your aorta with a tube made of synthetic material. This can help prevent a life-threatening rupture. Your aortic valve may need to be replaced as well.
• Scoliosis treatment. When there is significant scoliosis, a consultation with a spine expert is necessary. Bracing and surgery are needed in some cases.
• Breastbone corrections. Surgical options are available to correct the appearance of a sunken or protruding breastbone. Because these operations are often considered to be for cosmetic purposes, your insurance might not cover the costs.
• Eye surgeries. If parts of your retina have torn or come loose from the back of your eye, surgical repair is usually successful. If you have cataracts, your clouded lens can be replaced with an artificial lens.

Prevention of Primary Manifestations

Medications that reduce hemodynamic stress on the aortic wall, such as beta-blockers (β-blockers) or angiotensin receptor blockers (ARBs), are routinely prescribed. This therapy should be managed by a cardiologist or clinical geneticist familiar with its use. Therapy is generally initiated at the time of diagnosis? with Marfan syndrome at any age or upon appreciation of progressive aortic root dilatation even in the absence of a definitive diagnosis. The dose of β-blockers should be titrated to effect and tolerance:

• Verapamil or other calcium channel blockers have been suggested if β-blockers or ARBs cannot be used. Data documenting either the efficacy or safety of this approach in people with Marfan syndrome are very limited.
• Yetman et al [2005] suggested that use of ACE inhibitors may be more beneficial than β-blockers. Of note, the treatments were not randomized and the dose of β-blocker was not titrated to effect. ACE inhibitors have been used for decades in Marfan syndrome to manage volume overload resulting from valve dysfunction, and (unlike β-blockers or ARBs) have not previously been reported to provide notable protection from progressive aortic enlargement.

Prevention of Secondary Complications

Judicious use of subacute bacterial? endocarditis prophylaxis is indicated for dental work or other procedures expected to contaminate the bloodstream with bacteria in the presence of mitral or aortic valve regurgitation.

Surveillance

Eye. An annual ophthalmologic examination should include a specific assessment for glaucoma and cataracts.

Skeletal. Individuals with severe or progressive scoliosis should be followed by an orthopedist.

Cardiovascular. Echocardiography to monitor the status of the ascending aorta is indicated:

• Yearly when the aortic dimension is relatively small and the rate of aortic dilation is relatively slow;
• More often than yearly when the aortic root diameter exceeds ~4.5 cm in adults, the rate of aortic dilation exceeds ~0.5 cm per year, or significant aortic regurgitation is present.

More frequent evaluations by a cardiologist are indicated with severe or progressive valve or ventricular dysfunction or with documented or suspected arrhythmia?.

All individuals with Marfan syndrome should begin intermittent surveillance of the entire aorta with CT or MRA scans in young adulthood. Such imaging should be performed at least annually in anyone with a history of aortic root replacement or dissection.

Agents/Circumstances to Avoid

The following should be avoided:

• Contact sports, competitive sports, and isometric exercise. Note: Individuals can and should remain active with aerobic activities performed in moderation.
• Activities that cause joint injury or pain?
• Agents that stimulate the cardiovascular system including routine use of decongestants. Caffeine can aggravate a tendency for arrhythmia?.
• Agents that cause vasoconstriction, including triptans
• LASIK eye surgery to correct refractive errors
• For individuals at risk for recurrent pneumothorax, breathing against resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving)

Therapies Under Investigation

For information on the findings in animal models that support the use of losartan in Marfan syndrome, click here (pdf).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Marfan syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 75% of individuals diagnosed with Marfan syndrome have an affected parent.
• Approximately 25% of probands with Marfan syndrome have the disorder as the result of a de novo pathogenic variant.
• It is appropriate to evaluate both parents for manifestations of Marfan syndrome by performing a comprehensive clinical examination and echocardiogram. If the FBN1 pathogenic variant has been identified in the proband, molecular genetic testing to clarify the genetic status of the parents is possible.
• If the FBN1 pathogenic variant found in the proband cannot be detected in infection?. সহজ বাংলা: শ্বেত রক্তকণিকা।" data-rx-term="leukocyte" data-rx-definition="Leukocyte means white blood cell, which helps fight infection. সহজ বাংলা: শ্বেত রক্তকণিকা।">leukocyte? DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism has been reported in rare cases.
• Although 75% of individuals diagnosed with Marfan syndrome have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms.
• Note: If the parent is the individual in whom the FBN1 pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If a parent of the proband is affected, the risk to the sibs is 50%. Sibs who inherit a FBN1 pathogenic variant from a parent will have Marfan syndrome, although the severity cannot be predicted.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but above the population risk because of reported (but rare) instances of somatic and germline mosaicism.

Offspring of a proband

• Each child of an individual with Marfan syndrome has a 50% chance of inheriting the pathogenic variant and the disorder.
• The penetrance of FBN1 pathogenic variants is reported to be 100%; thus, offspring who inherit a FBN1 pathogenic variant from a parent will have Marfan syndrome, although the severity cannot be predicted.

Other family members. The risk to other family members depends on the genetic status of the proband’s parents: if a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis? and treatment.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the FBN1 pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

References