Marfan Syndrome

Clinical characteristics.

Marfan syndrome, a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (the most common ocular feature); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in the Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.

Diagnosis/testing.

The diagnosis of Marfan syndrome is established in a proband (by definition, a person without a known family history of Marfan syndrome) who has one of the following sets of findings:

• An FBN1 pathogenic variant known to be associated with Marfan syndrome AND one of the following:
  • Aortic root enlargement (Z-score ≥2.0)
  • Ectopia lentis
• Demonstration of aortic root enlargement (Z-score ≥2.0) and ectopia lentis OR a defined combination of features throughout the body yielding a systemic score ≥7

Management.

Treatment of manifestations: Comprehensive management by a multidisciplinary team including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon is strongly recommended. Treatment typically includes spectacle correction for refractive errors and sometimes, surgical removal of a dislocated lens with artificial lens implantation (preferably after growth is complete). Scoliosis may require surgical stabilization; repair of pectus deformity is largely cosmetic. Orthotics and arch supports can lessen leg fatigue, joint pain, and muscle cramps associated with pes planus. Surgical repair of the aorta is indicated when the maximal measurement of the aortic root approaches 5.0 cm in adults or older children, 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. For younger children, aortic root surgery should be considered once: (1) the rate of increase of the aortic root diameter approaches 0.5-1.0 cm per year, or (2) there is progressive and severe aortic regurgitation. Severe and progressive mitral valve regurgitation with attendant ventricular dysfunction is the leading indication for cardiovascular surgery in children with Marfan syndrome. Afterload-reducing agents can improve cardiovascular function when congestive heart failure is present.

Prevention of primary manifestations: Medications that reduce hemodynamic stress on the aortic wall, such as use of beta blockers (β-blockers) or angiotensin receptor blockers (ARBs) together, are generally initiated at diagnosis or upon documentation of significant and/or progressive aortic dilatation. Other antihypertensive agents can be used if β-blockers and ARBs are not tolerated; however, evidence as to their efficacy and safety in Marfan syndrome is under investigation.

Prevention of secondary complications: Subacute bacterial endocarditis prophylaxis for dental work with the presence of mitral or aortic valve regurgitation.

Surveillance: Annual ophthalmologic examination; annual echocardiography to monitor the status of the ascending aorta when aortic dimensions are small and/or the rate of aortic dilation is slow; more frequent examinations are indicated when the aortic root diameter exceeds approximately 4.5 cm in adults, rates of aortic dilation exceed approximately 0.5 cm per year, and/or significant aortic regurgitation is present; intermittent surveillance of the entire aorta with CT or MRA scans beginning in young adulthood or after aortic root surgery in childhood.

Agents/circumstances to avoid: Contact sports, competitive sports, and isometric exercise; activities that cause joint injury or pain; agents that stimulate the cardiovascular system, including decongestants and excessive caffeine; agents that cause vasoconstriction, including triptans; LASIK correction of refractive errors; breathing against resistance or positive pressure ventilation in those with a documented predisposition for pneumothorax.

Evaluation of relatives at risk: It is recommended that the genetic status of at-risk relatives be clarified so that affected individuals can undergo routine surveillance for early detection of medically significant complications, particularly potentially life-threatening cardiac manifestations. Genetic status of at-risk relatives can be established EITHER:

• By molecular genetic testing if the FBN1 pathogenic variant in the family is known; OR
• In those with a rigorously defined family history of Marfan syndrome, by the presence of ONE OR MORE of the following:
  • Ectopia lentis
  • A systemic score ≥7
  • Aortic root dilatation (Z-score ≥2.0 for individuals age ≥20 years or Z-score ≥3.0 for those age <20 years)

Pregnancy management: Pregnant women with Marfan syndrome should be followed by a high-risk obstetrician both during pregnancy and through the immediate postpartum period.

In women with Marfan syndrome who anticipate pregnancy or become pregnant, β-blockers should be continued, but some other classes of medications such as ACE inhibitors or ARBs should be stopped because of the risk for fetal loss and birth defects. Cardiovascular imaging with echocardiography every two to three months during pregnancy to monitor aortic root size and growth is recommended. Monitoring should continue in the immediate postpartum period due to an increased risk for aortic dissection.

Genetic counseling.

Marfan syndrome is inherited in an autosomal dominant manner. Approximately 75% of individuals with Marfan syndrome have an affected parent; approximately 25% have a de novo FBN1 pathogenic variant. The offspring of an individual with Marfan syndrome are at a 50% risk of inheriting the FBN1 pathogenic variant. Once the FBN1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Suggestive Findings

Marfan syndrome should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Aortic root enlargement (Z-score ≥2.0). Note: Aortic size must be standardized to age and body size for accurate interpretation. A Z-score ≥2.0 indicates a value at or above the 95th percentile, while a Z-score ≥3.0 indicates a value at or above the 99th percentile. References and calculators for this determination are available at the National Marfan Foundation web site.
• Ectopia lentis; most reliably diagnosed by slit-lamp examination after maximal pupillary dilatation
• A systemic score ≥7 (see Table 1)

Family history. Consistent with autosomal dominant inheritance

Establishing the Diagnosis

The diagnosis of Marfan syndrome is established in a proband (by definition a person without a known family history of Marfan syndrome) who has [Loeys et al 2010a] an FBN1 pathogenic variant known to be associated with Marfan syndrome (see Table 2) and EITHER of the following:

• Aortic root enlargement (Z-score ≥2.0)
• Ectopia lentis

Note: Given that many manifestations of Marfan syndrome emerge with age, it is not advisable to establish definitive alternative diagnoses in individuals younger than age 20 years who have compatible but insufficient physical manifestations of Marfan syndrome. In this circumstance the author suggests the use of tentative diagnostic designations:

• Nonspecific connective tissue disorder. If the systemic score is <7 and/or aortic root measurements are borderline (Z-score <3) (without an FBN1 pathogenic variant), use of this term is suggested until follow-up echocardiographic evaluation shows aortic root dilation (Z-score ≥3).
• Potential Marfan syndrome. If an FBN1 pathogenic variant that has not previously been associated with aortic enlargement is identified in a person who is a simplex case (i.e., a single occurrence in a family) and the aortic root Z-score is <3.0, this term should be used until the aorta reaches this threshold.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Although individuals with the distinctive findings of Marfan syndrome described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), those who do not have sufficiently discriminating features to consider the diagnosis of Marfan syndrome are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Marfan syndrome, a systemic disorder of connective tissue, is part of a broad phenotypic continuum associated with heterozygous FBN1 pathogenic variants that ranges from mild (features of Marfan syndrome in one or a few systems) to severe (rapidly progressive multiorgan disease in neonates). Cardinal manifestations of Marfan syndrome involving the ocular, skeletal, and cardiovascular systems have a high degree of clinical variability. Ocular findings include myopia (the most common ocular feature); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity, disproportionately long extremities for the size of the trunk (dolichostenomelia), overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum), and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery.

As a general rule, clinical manifestations run true within families, suggesting that the FBN1 pathogenic variant is the predominant determinant of phenotype.

Eye. Myopia is the most common ocular feature and often progresses rapidly during childhood.

Displacement of the lens from the center of the pupil (ectopia lentis) is a hallmark feature of Marfan syndrome, but is only seen in approximately 60% of affected individuals.

The globe is often elongated and the cornea may be flat.

Individuals with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation.

Skeletal. The skeletal system is characterized by excessive linear growth of the long bones and joint laxity. The extremities are disproportionately long for the size of the trunk (dolichostenomelia), leading to an increase in the arm span-to-height ratio and a decrease in the upper-to-lower segment ratio. Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Scoliosis is also common and can be mild or severe and progressive (see Management). The combination of bone overgrowth and joint laxity leads to the characteristic thumb and wrist signs. Inward rotation of the medial aspect of the ankle can result in flat feet (pes planus). Paradoxically, some individuals can show reduced joint mobility, especially of the elbow and digits, and can have an exaggerated arch to the foot (pes cavus). The acetabulum can be abnormally deep and show accelerated erosion (protrusio acetabuli). All skeletal findings can develop in young children and tend to progress during periods of rapid growth.

The facial features include a long and narrow face with deeply set eyes (enophthalmos), downward slanting of the palpebral fissures, flat cheek bones (malar hypoplasia), and a small and receding chin (micrognathia, retrognathia). The palate can be highly arched and narrow, often associated with tooth crowding.

It is important to note that individuals with Marfan syndrome are not necessarily tall by population standards; they are taller than predicted for their family [Erkula et al 2002].

Cardiovascular. The major sources of morbidity and early mortality relate to the cardiovascular system.

Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse (MVP) with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery.

Aortic dilatation in the Marfan syndrome tends to progress over time. Histologic examination reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media. This picture of "cystic medial necrosis" does not distinguish Marfan syndrome from other causes of aortic aneurysm. In adults, a significant risk for aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 cm. The onset and rate of progression of aortic dilatation is highly variable. Aortic dissection is exceedingly rare in early childhood. As an aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.

Valvular dysfunction can lead to volume overload with secondary left ventricular dilatation and failure. Indeed, MVP with congestive heart failure is the leading cause of cardiovascular morbidity and mortality – and the leading indication for cardiovascular surgery – in young children with severe Marfan syndrome. The majority of individuals with Marfan syndrome and MVP have a tolerable degree of mitral regurgitation that shows slow, if any, progression with age. A recent study of 50 individuals with Marfan syndrome identified enlarged pulmonary artery root in 74% [Nollen & Mulder 2004].

With proper management of the cardiovascular manifestations, the life expectancy of someone with Marfan syndrome approximates that of the general population [Silverman et al 1995].

Other

Dura. Stretching of the dural sac in the lumbosacral region (dural ectasia) can lead to bone erosion and nerve entrapment. Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain. Leaking of CSF from a dural sac can cause postural drop in CSF pressure and headache [Foran et al 2005].

Skin. Manifestations in the skin and integument include hernias and skin stretch marks (striae distensae). Individuals can show a paucity of muscularity and fat stores despite adequate caloric intake.

Lung bullae can develop, especially of the upper lobes, and can predispose to spontaneous pneumothorax. Increased total and residual lung volume and reduced peak oxygen uptake have been demonstrated, with reduced aerobic capacity [Giske et al 2003].

Pregnancy can be dangerous for women with Marfan syndrome, especially if the aortic root exceeds 4.0 cm. Complications include rapid progression of aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, and the postpartum period.

Self-image. The vast majority of affected individuals older than age 13 years report a positive general self-image [De Bie et al 2004].

Learning disability and/or hyperactivity has been suggested as a rare manifestation of Marfan syndrome, but may simply occur in this context at a frequency observed in the general population.

Genotype-Phenotype Correlations

Few genotype-phenotype correlations exist in the Marfan syndrome; none is definitive [Dietz & Pyeritz 2001]. Identification of an FBN1 pathogenic variant in a proband thus has little prognostic value and has not been proven to reliably guide individual management.

Penetrance

Although intrafamilial clinical variability can be extensive, Marfan syndrome shows high clinical penetrance.

Nomenclature

Outdated terms used in the description of Marfan syndrome include the following:

• Neonatal Marfan syndrome. Although many have used the term "neonatal Marfan syndrome" to describe the earliest and most severe presentation of Marfan syndrome, in reality, this term does not adequately represent a discrete subset of individuals with truly distinguishing characteristics and its use should be abandoned. The terms "early onset" and "rapidly progressive" are adequate to describe the clinical course in these children.
• Marfan syndrome type 2. This term is no longer in use. It was used by Mizuguchi et al [2004] in a report of individuals with a phenotype that resembled Marfan syndrome but is now known to be Loeys-Dietz syndrome, an autosomal dominant disorder caused by a heterozygous pathogenic variant in either TGFBR1 or TGFBR2 (see Differential Diagnosis).

Prevalence

The estimated prevalence of Marfan syndrome is 1:5,000-1:10,000.

There is no apparent enrichment in any ethnic or racial group and no gender preference.

Evaluations Following Initial Diagnosis

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. Click here for a calculator.
  • 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

Treatment of Manifestations

Management is most effectively accomplished through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon.

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 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.

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.

Following a small observational study of losartan in children with severe Marfan syndrome showing a reduction in aortic root growth with the combination of β-blockers and losartan [Brooke et al 2008], multiple prospective trials have shown that the combination of β-blockers and losartan affords better protection against aortic root enlargement than β-blockers alone in both children and adults with Marfan syndrome [Chiu et al 2013, Groenink et al 2013, Pees et al 2013].

In a large multicenter clinical trial of losartan versus atenolol in Marfan syndrome children and young adults demonstrated equivalent efficacy of losartan and β-blockers despite use of atypically high doses of atenolol and standard dosing of losartan [Lacro et al 2014]. Both treatment arms showed a very low rate of aortic root growth compared to many prior studies of children with Marfan syndrome who were either untreated or receiving more standard β-blocker dosing, and both treatment groups showed a significant decline in aortic root Z-score over the course of the trial (number of standard deviations from average when referenced to age and body size).

Studies using higher dosing of ARBs and newer generation medications in this class are ongoing. Multiple studies have suggested that the greatest benefit of β-blockers and/or ARBs will be achieved when medication is started early in the course of disease.

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)

Evaluation of Relatives at Risk

It is recommended that the genetic status of relatives at risk for Marfan syndrome be clarified either by molecular genetic testing or by clinical examination so that affected individuals can undergo routine surveillance for early detection of medically significant complications, particularly potentially life-threatening cardiac manifestations.

Approaches include the following:

• If the FBN1 pathogenic variant has been identified in an affected relative, molecular genetic testing can be used.
• In the presence of a rigorously defined family history of Marfan syndrome, clinical examination can establish the clinical diagnosis of Marfan syndrome in a first-degree relative of an affected individual who has any one of the following three findings [Loeys et al 2010a]:
  • Ectopia lentis
  • Systemic score ≥7 (see Suggestive Findings)
  • Aortic root enlargement (Z-score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) (see Suggestive Findings). Note: (1) Echocardiography of relatives is indicated upon appreciation of any suspicious signs of Marfan syndrome, and even in apparently unaffected individuals if findings are subtle in the index case. (2) It is generally appropriate to delay echocardiography for infants and toddlers until they can cooperate with the examination without needing sedation. Exceptions include those with evidence of valve dysfunction and/or congestive heart failure. (3) All first-degree relatives of an individual with apparent isolated aortic enlargement should be evaluated by echocardiography.

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Pregnancy Management

It is recommended that a woman with Marfan syndrome consider pregnancy only after appropriate counseling from a clinical geneticist or cardiologist familiar with this condition, a genetic counselor, and a high-risk obstetrician because of the risk of more rapid dilation of the aorta or aortic dissection during pregnancy, delivery, or in the immediate postpartum period. This is especially relevant to women who begin pregnancy with a maximal aortic dimension that exceeds 4.0 cm. Note: Some women with Marfan syndrome and aortic root dilatation opt for elective aortic repair with a valve-sparing procedure prior to reaching a conventional threshold for surgical intervention (i.e., at a root dimension <5.0 cm) before becoming pregnant. While this is thought to decrease the risk for ascending aortic dissection in association with pregnancy, it will not lessen risk for descending aortic dissection or other potential cardiovascular manifestations.

Pregnant women with Marfan syndrome should be followed by a high-risk obstetrician both during pregnancy and through the immediate postpartum period.

Women with Marfan syndrome who anticipate pregnancy or become pregnant should continue use of β-blockers; however, some other classes of medications such as ACE inhibitors or ARBs should be discontinued because of the increased risk for fetal loss and birth defects.

See MotherToBaby for further information on medication use during pregnancy.

Efforts should be made to minimize cardiovascular stress through pregnancy and delivery.

Cardiovascular imaging with echocardiography should be performed every two to three months during pregnancy to monitor aortic root size and growth. Monitoring should continue in the immediate postpartum period because of the increased risk for aortic dissection.

The choice between a controlled vaginal delivery and cesarean section remains controversial.

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.