Genetics of Marfan Syndrome

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Background

Marfan syndrome (MFS) is an inherited connective tissue disorder noteworthy for its worldwide distribution, relatively high prevalence, and clinical variability. This autosomal dominant syndrome has pleiotropic manifestations involving primarily the ocular, cardiovascular, and skeletal systems.[1, 2] Classic MFS (MFS type 1, MFS1) has been considered a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1; however, studies of Marfan mouse models and Marfan-related conditions have expanded our current understanding to a pathogenic model that involves dysregulation of cytokine-transforming growth factor beta (TGFβ) signaling.[3, 4] . Patients who have clinical findings of MFS, as well as genetic variants in the transforming growth factor-beta receptor-1 gene (TGFβR1) and the transforming growth factor-beta receptor-2 gene (TGFβR2), are designated as having MFS type 2 (MFS2).[5]

Pathophysiology

Marfan syndrome (MFS) results from heterozygous mutations in the fibrillin-1 gene (FBN1; OMIM #134797), located on chromosome 15 at band q21.1 (15q21.1), which encodes for the glycoprotein fibrillin. Fibrillin is a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the ocular lens and serve as substrates for elastin in the aorta and other connective tissues. Abnormalities involving microfibrils weaken the aortic wall. Progressive aortic dilatation and eventual aortic dissection occur due to the tension caused by left ventricular ejection impulses. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.

Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the abnormal fibrillin-1 disrupts microfibril formation (although other fibrillin genes still encode normal fibrillin). Evidence of this mechanism is shown in studies of cultured skin fibroblasts from patients with MFS who produce greatly diminished and abnormal microfibrils.

A study by Benarroch et al suggested that clinical variability in MFS may result from alternative splicing of FBN1.[6]

FBN1 mutations cause several Marfan-like disorders, such as the MASS (myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, nonspecific skin and skeletal findings) phenotype and isolated ectopia lentis.

Studies have suggested that abnormalities in the transforming growth factor-beta (TGFβ)-signaling pathway may represent a common pathway for the development of the Marfan phenotype.[7] This gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix.

The identification of mutations in TGFβR2 in patients with MFS type 2 (MFS2 mapped at 3p24.2-p25) provided direct evidence of abnormal TGFβ signaling in the pathogenesis of MFS.

Abnormalities in TGFβR1 and TGFβR2 were also reported to cause a new dominant syndrome similar to MFS1; it was associated with aortic aneurysm and congenital anomalies, including Loeys-Dietz syndrome (LDS). LDS is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement (LDS; OMIM #609192).[7] These results define a new group of Marfan syndrome–related connective tissue disorders, namely, TGFβ signalopathies, and include LDS1 and LDS2 (TGFβR1 and TGFβR2) and the SMAD3 and TGFβ2 disorders, with the latter two being classified as Loeys-Dietz-like (or as LDS3 and LDS4).

Shprintzen-Goldberg syndrome (SGS) has been found to be caused by a pathogenic variant in the SKI gene, which encodes a negative regulator of TGFβ signaling. There is phenotypic overlap with MFS and LDS. 

A variant of the fibrillin-2 gene, FBN2, causes congenital contractural arachnodactyly, known as Beals syndrome.[8]

Epidemiology

Frequency

United States

MFS is one of the most common single-gene malformation syndromes. MFS1 affects about 1:5000 to 1:10,000 individuals.[9, 10]  Estimates suggest that at least 200,000 people in the United States have MFS or a related connective-tissue disorder.

A study by Behr et al found that in patients presenting with a chief complaint of pectus deformity, the incidence of MFS was 5.3%, with the incidence being 20% in persons with combined type pectus deformity.[11]

International

No geographic predilection is known. 

Mortality/Morbidity

Cardiovascular disease (aortic dilatation and dissection) is the major cause of morbidity and mortality in MFS. Without proper medical management, MFS can be lethal in young adulthood, with death occurring at an average age of 30-40 years.

Infant morbidity, as related to cardiovascular disease, is due to progression of mitral valve prolapse to mitral regurgitation and often occurs in conjunction with tricuspid prolapse and regurgitation. Progression to congestive heart failure is a leading cause of cardiovascular morbidity and mortality, as well as the leading indicator for cardiovascular surgery.

Death later in life is usually due to chronic aortic regurgitation and ascending aortic dissection. Dissection generally occurs at the aortic root and is uncommon in childhood and adolescence.

A Norwegian study, by Vanem et al, found that out of 84 adults with Marfan syndrome (MFS) first investigated in 2003-2004, 16 (19.0%) were deceased by 2014-2015 follow-up, including 11 (68.8%) who had died of cardiovascular causes. Standardized mortality ratios were 8.20 for men and 3.85 for women.[12]

Race

Marfan syndrome is panethnic.

Sex

No sex predilection is known.

Age

MFS may be diagnosed prenatally, at birth, in childhood, during adolescence, or in adulthood. Neonatal presentation is associated with a severe clinical course.

Many clinical features are specific to age. Some features may not present until later in life, a situation that may make early diagnosis in childhood difficult.

History

Classic Marfan syndrome (MFS1) is currently diagnosed using a criteria-based approach that includes an evaluation of family history, molecular data, and six organ systems. Diagnosis cannot be based on molecular analysis alone because molecular diagnosis is not generally available, mutation detection is imperfect, and not all FBN1 mutations are associated with MFS. As cited by the 1988 Berlin criteria, MFS was diagnosed on the basis of involvement of the skeletal system and two other systems, with the requirement of at least one major manifestation (ie, ectopia lentis, aortic dilatation or dissection, or dural ectasia).

In 1996, a group of the world's leading clinicians in MFS proposed a revised diagnostic criteria. The Ghent-1 criteria were intended to serve as an international standard for clinical and molecular studies and for investigations of genetic heterogeneity and genotype-phenotype correlations. The Ghent nosology identified major and minor diagnostic findings, which were based on clinical observation of various organ systems and on family history. A major criterion was defined as one that carried high diagnostic precision, because it was relatively infrequent in other conditions and in the general population.  Clinical diagnosis in adults should be made using the Ghent criteria, which are considered not as reliable in children.

Further revision of the nosology was necessary, however, because, while the Berlin criteria did not provide for molecular studies and may have led to incorrect diagnoses in relatives of the proband, the Ghent-1 criteria may have been too stringent and hence have excluded MFS in affected patients. For example, 19% of patients whose disease was diagnosed based on the Berlin criteria did not meet the Ghent-1 criteria. Of those patients who were screened for dural ectasia, 23% were diagnosed with MFS by the Berlin criteria; however, these patients were not diagnosed with MFS when the Ghent-1 criteria were applied.[13]

In 2010, an international expert panel revised the Ghent-1 criteria to the Ghent-2 criteria.[14] Ghent-2 gave greater weight to cardiovascular manifestations (aortic aneurysm/dissection) and to molecular testing of the FBN1 gene, as well as other relevant genes, such as TGFβR1/2, COL3A1, and ACTA2. This new scoring system was designed to address systemic features. In the absence of family history, the presence of aortic root aneurysm and ectopia lentis is sufficient for the unequivocal diagnosis of MFS1. In the absence of either aortic aneurysm or ectopia lentis, the presence of an FBN1 mutation or a combination of systemic manifestations is required.

Application of the Ghent-2 criteria should help and support clinicians who are less knowledgeable of the Marfan phenotype. Indeed, even if the diagnosis of MFS is not reached, regular aortic follow-up is mandatory in every patient with a diagnosis of ectopia lentis syndrome, MASS, or mitral valve prolapse syndrome. Longitudinal studies of patient follow-up with such alternative diagnoses are required to determine the proportion of patients who will meet the criteria for MFS in later life.[15]

Family history and results of molecular studies are part of the major criteria; hence the need to carefully obtain a complete family history and pedigree. Major criteria include the following:

If the family and genetic histories are noncontributory, major criteria in two different organ systems and involvement of a third organ system are required to make the diagnosis (organ system criteria are described in the Physical section).

Clinical presentations are as follows:

Physical

Skeletal findings

Patients with Marfan syndrome (MFS) are usually taller and thinner than their family members. Their limbs are disproportionately long when compared with the trunk (dolichostenomelia). Arachnodactyly ("spider fingers," abnormally long and slender fingers) is a common feature. See the images below for examples.



View Image

Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.



View Image

Arachnodactyly.

Although most patients are diagnosed before the age of 10 years, few present with the four skeletal criteria, which tend to develop in later life.[16]

Major skeletal criteria include the following:

Minor criteria are as follows:

For the skeletal system to be involved, at least two major criteria or one major criterion plus two minor criteria must be present.

Ocular findings

The major criterion for the ocular system is ectopia lentis (the dislocation or displacement of the eye's natural crystalline lens). About 50% of patients have lens dislocation, with the dislocation position described as superior and temporal. Ectopia lentis may be present at birth or develop in childhood or adolescence.

Minor criteria for the ocular system are as follows:

At least 2 minor criteria must be present.

Cardiovascular findings

Cardiovascular involvement is the most serious problem associated with MFS.

Major criteria include the following:

Minor criteria are listed as follows:

For the cardiovascular system to be involved, one minor criterion must be present.

Pulmonary findings

For the pulmonary system, only minor criteria are noted. If there is pulmonary system involvement, one minor criterion must be present.

Minor criteria include the following:

Integumentary findings

For integument system, only minor criteria are noted. If there is integument system involvement, one minor criterion must be present.

Minor criteria include the following:

Dural findings

For the dura, only one major criterion is defined: Dural ectasia must be present and confirmed using computed tomography (CT) scanning or MRI modalities. The characteristics of dural ectasia are as follows:

Key issues in the assessment of Marfan syndrome

Diagnosis or exclusion of MFS in an individual should be based on the Ghent-2 diagnostic nosology.[22]

Initial assessment should include a personal history, detailed family history, clinical examination and, specifically, an ophthalmologic examination and a transthoracic echocardiogram. For echocardiographic interpretation, the aortic diameter at the sinus of Valsalva should be related to normal values as based on age and body surface area.

The development of scoliosis and protrusio acetabuli is dependent on age, commonly occurring after periods of rapid growth. Radiography is indicated for these features, depending on age. A positive finding aids confirmation of the diagnosis of MFS.

A pelvic MRI scan to detect dural ectasia is indicated. A positive finding would confirm the diagnosis of MFS.

The Ghent-2 nosology cannot exclude MFS in children, because of the age-dependent penetrance of many clinical features. Young patients with a positive family history but with unsuccessful DNA testing and insufficient clinical features to fulfill the diagnostic criteria, and young patients with no family history who miss fulfilling the diagnostic criteria by one system, should have further clinical evaluations up to least age 18 years or until a diagnosis can be made.

Family history of aortic aneurysm may represent a disorder, such as familial thoracic aortic aneurysm, such that the use of the Ghent-2 nosology to assess risk in relatives is inappropriate.

Revised Ghent criteria (Ghent-2) for the diagnosis of MFS and related conditions

Abbreviations are as follows:

According to the 2010 revised Ghent nosology (Ghent-2), the diagnosis of MFS depends on the following seven rules[14, 15] :

In the absence of family history:

In the presence of family history (FH):  

Systemic score list (maximum total = 20 points; score ≥7 indicates systemic involvement)

Causes

Marfan syndrome (MFS) is caused by mutations in the FBN1 gene located on chromosome 15 at band q21.1. Mutations in TGFβR1 or TGFβR2 genes, located on chromosome 9q22.33 and on chromosome 3p24.2-p25, respectively, are typically associated with Loeys-Dietz syndrome, and there is marked phenotypic overlap with MFS. If the patient has ectopia lentis (dislocation of the lens), this is a more specific finding to MFS versus the other syndromes.

More than 500 fibrillin gene mutations have been identified. Almost all of these mutations are unique to an affected individual or family. Different fibrillin mutations are responsible for genetic heterogeneity. Phenotypic variability in the presence of the same fibrillin mutation suggests the importance of other, yet-to-be-identified factors that affect the phenotype.

Despite intensive international efforts, genotype-phenotype correlations have not been made, with the exception of an apparent clustering of mutations in patients diagnosed with neonatal MFS. Neonatal MFS represents the most severe end of the clinical spectrum of the fibrillinopathies and is associated with FBN1 gene mutation on chromosome 15q21.1 in exons 24–32.[23] Affected individuals are generally diagnosed at birth or shortly thereafter. Unique features include joint contractures, "crumpled" external ears, and loose skin. Congestive heart failure associated with mitral and tricuspid regurgitation is the main cause of death. Aortic dissection is uncommon in neonatal MFS, and survival beyond 24 months is rare.[24]  A study by Ágg et al suggests that for patients with MFS, there are extracardiac predictors of aortic dissection: elevated TGFβ, increased matrix metalloproteinase 3 (MMP3) gene expression in peripheral blood mononuclear cells, and a greater frequency of striae atrophicae.[25]

Genotype-phenotype correlations in MFS have been complicated by the large number of unique mutations reported, as well as by the degree of clinical heterogeneity among individuals with the same mutation.

Mutations in the FBN1 gene have also been found in patients with other fibrillinopathies. Identifying a given mutation is currently of limited value in establishing a phenotype or providing a prognosis in MFS.

MFS is known as an autosomal dominant connective tissue disorder. However, a family was reported to have homozygosity for an FBN1 missense mutation and demonstrated molecular evidence for recessive MFS.[26] This case report has significant implications for genetic counseling and for interpretation of molecular diagnoses.

 

Laboratory Studies

Currently, the standard of care in Marfan syndrome (MFS) is to obtain confirmatory molecular diagnostics on these patients and their family members, due to the variable expression of MFS and the diagnosable "look-alike" conditions.

Molecular studies of the fibrillin-1 (FBN1) gene should be performed in patients in whom MFS is suspected. Mutation analysis can identify the exact mutation in the fibrillin gene, and linkage analysis can be used to track an abnormal fibrillin gene within a family.[38]

The gene structure of FBN1 is large, being greater than 600 kb and containing 65 exons. At least 1000 pathogenic variants in FBN1 that cause MFS and related phenotypes have been described.[39, 40]  Most mutations are missense mutations, small in-frame deletions, or insertions that alter a single peptide. All mutations described produce an abnormal fibrillin-1 protein.

Although ordering FBN1 sequencing with del/dup analysis is appropriate if the patient clearly meets the clinical criteria for MFS, the search should not stop there if the results are negative. Many geneticists and cardiologists are utilizing next-generation sequencing panels that include other connective-tissue disorder genes. It is important to include genes described for Loeys-Dietz syndromes, Stickler syndrome, and Ehlers-Danlos syndromes (especially type IV; COL3A1). These additional gene analyses are becoming more cost-effective for patients. 

Faivre et al reported a comprehensive clinical and molecular description of a large series of pediatric cases with an FBN1 mutation.[41] Most clinical manifestations of MFS become more apparent with age. This highlights the limited usefulness of international criteria for diagnosis in early infancy and also emphasizes the value of FBN1 mutation screening, which confirms the diagnosis and facilitates determination of prognosis and timely management.

Imaging Studies

Advances in noninvasive diagnostic imaging modalities have had a significant impact on case management. These studies provide accurate detection and quantification of the severity of cardiovascular disease, aiding in the appropriate timing for surgical intervention.

Radiography

Chest radiography should be focused on apical blebs. Chest radiographs may also detect a thoracic aortic dissection by demonstrating enlargement of the aortic and cardiac silhouette. Pelvic radiography may be required if a positive finding of protrusio acetabula is needed for the diagnosis.

Echocardiography

Standard echocardiography is valuable to assess mitral valve prolapse, left ventricular size and function, left atrial size, and tricuspid valve function.

Cross-sectional echocardiography is a common tool used to diagnose and manage aortic root dilatation. The upper limit of normal aortic root size is 1.9 cm/m2 of body surface area and is independent of the patient's sex.

Transesophageal echocardiography depicts the distal ascending and descending aorta, and can provide assessment of prosthetic valves. Doppler echocardiography is useful to detect and grade the severity of aortic and mitral regurgitation.

CT scanning and MRI

Magnetic resonance imaging (MRI) is the best choice for assessing chronic dissection of any region of the aorta. It should be performed in any patient at any age who has an aortic root dimension of more than 150% of the mean for their body surface area or a ratio of actual to predicted aortic root dimension of more than 1.5.

CT scanning or MRI of the lumbosacral spine may be needed to detect dural ectasia. The following MRI and CT scan criteria for dural ectasia in adults have been proposed, with the presence of dural ectasia requiring one major criterion or both minor criteria:

Other Tests

An ambulatory electrocardiogram (ECG) should be obtained in patients with symptomatic palpitations, syncope, or near syncope. A baseline ECG that indicates a major rhythm or conduction disturbance should prompt immediate attention.

Procedures

Ocular examination

Ocular care and treatment should be managed by an ophthalmologist with expertise in Marfan syndrome (MFS). Examination should include the following:

Skeletal examination

Evaluation may be required by an orthopedist. Assess for bone overgrowth and ligamentous laxity. This can cause progressive, severe scoliosis requiring surgical intervention for spine stabilization.

Chest wall examination should be performed to assess for the degree of pectus excavatum/pectus carinatum. Surgical correction may be indicated.

 

Histologic Findings

Immunohistologic evaluation of the skin for abnormal fibrillin has been reported. However, there is an incidence of false-positive results in patients who do have connective-tissue disorders but not Marfan syndrome (MFS).

Electron microscopy of fibrillin from cultured fibroblasts has shown a substantial increase in fraying of microfibrils in patients with MFS. In neonatal MFS, electron microscopy of fibrillin strands reveals beads that are not strung together in the usual necklacelike pattern, resulting in poor elastic tissue strength.

Medical Care

General guidelines for all adults diagnosed with Marfan syndrome (MFS) are as follows[10, 42] :

Key issues in cardiovascular management are as follows [22] :

Counseling for pregnant women diagnosed with MFS is as follows[42] :

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

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

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

Other therapeutic interventions are as follows:

Future therapeutic strategies are as follows[4] :

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

Surgical Care

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[42] :

Indicators for prophylactic surgery of the aortic root in children include the following[42] :

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.[18]

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:

Consultations

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

Diet

No special diet is needed.

Activity

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.

Medication Summary

Beta-blocker and calcium antagonist therapy retard the aortic growth rate in children and adolescents with Marfan syndrome (MFS). Atenolol is a beta blocker that is longer acting and more cardioselective than others; it has largely replaced propranolol as the beta blocker of choice. Experience with calcium antagonists is limited.

An ARB regimen is now recommended as first-line treatment and should be emphasized. Some cardiologists who specialize in MFS also have their patients on beta blockers, to cover both arms of the pathway.

Atenolol (Tenormin)

Clinical Context:  Selective beta1-adrenergic antagonist.

Propranolol hydrochloride (Inderal)

Clinical Context:  Nonselective beta-adrenergic antagonist. Has membrane-stabilizing activity and decreases automaticity of contractions.

Class Summary

These drugs are used to delay aortic expansion and its subsequent progression to dissection or rupture. They inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation.

Verapamil hydrochloride (Calan, Isoptin)

Clinical Context:  Calcium ion influx inhibitor. Prevents aortic growth in Marfan syndrome.

Class Summary

These drugs inhibit the transport of calcium ions across cell membranes.

Further Outpatient Care

Ensure long-term cardiac follow-up, including regular blood pressure measurements and echocardiography. Patients also need lifelong cardiovascular surveillance to detect new or recurrent disease. After aortic surgery, follow-up is necessary to monitor for the possible development of lesions involving different segments and for pseudoaneurysms at the anastomosis site, which cause nearly 40% of late deaths postoperatively.

Further Inpatient Care

Provide care for postoperative complications in patients with Marfan syndrome (MFS), including dysrhythmias, thromboembolism, endocarditis, coronary dehiscence, congestive heart failure, renal failure, and respiratory failure. Observe the patient for postoperative hemorrhage and pseudoaneurysm formation.

Inpatient & Outpatient Medications

Patients with mitral valve prolapse require prophylactic antibiotics before dental or invasive procedures.

All patients should receive treatment with long term beta-adrenergic blockade if they have no medical contraindications.

Transfer

Transfer may be required for further diagnostic evaluation and surgical intervention.

Deterrence/Prevention

Patients should avoid strenuous activities and sports, such as basketball, volleyball, football, racquetball, squash, boxing, track, diving, and weightlifting.

Patients should wear eye protection to guard their eyes from injury during work and sports.

In general, athletes should be referred to a cardiologist if physical evidence of Marfan syndrome (MFS) is noted.[57] The following studies are indicated:

Complications

Complications that affect the aorta are the primary cause of death in Marfan syndrome (MFS). Aortic dissection can result in lethal hemorrhage, acute aortic valvular insufficiency, mitral insufficiency, pericardial tamponade, or visceral ischemia.

Complications can also include the following:

Prognosis

The patient's prognosis depends on the severity of cardiovascular complications and is mainly determined by progressive dilation of the aorta, which potentially leads to aortic dissection and death at a young age.

In the 1970s, the average life expectancy for a patient with MFS was 45 years old. Life expectancy has since increased to about 70 years.[58] Awareness, early and improved detection skills, timely and improved surgical techniques, and the prophylactic use of beta blockers have all contributed to increased survival. 

Patient Education

Lifestyle adaptations, such as avoidance of strenuous exercise and contact sports, are often necessary to reduce the risk of aortic dissection.

Patients should wear a Medic-Alert bracelet in case of an emergency.

The Marfan Foundation is an excellent resource for information about Marfan syndrome (MFS) (phone: 1-800-8-MARFAN, email: staff@marfan.org).

Author

Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

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

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

Disclosure: Nothing to disclose.

Additional Contributors

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

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

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Dural ectasia in the lumbosacral region.

Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.

Arachnodactyly.

Pectus excavatum of moderate severity.

Positive wrist (Walker) sign.

Positive thumb (Steinberg) sign.

Hypermobility of finger joints.

Stretch marks (striae atrophicae) in the lower back.

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.