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Marfan Syndrome

, MD.

Author Information

Initial Posting: ; Last Update: October 12, 2017.

Summary

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.

Diagnosis

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)

Table 1.

Calculation of the Systemic Score

FeatureValueEnter Value if Feature is Present
Wrist AND thumb sign3
Wrist OR thumb sign1
Pectus carinatum deformity2
Pectus excavatum or chest asymmetry1
Hindfoot deformity2
Plain flat foot (pes planus)1
Pneumothorax2
Dural ectasia2
Protrusio acetabulae2
Reduced upper segment / lower segment AND increased arm span/height ratios1
Scoliosis or thoracolumbar kyphosis1
Reduced elbow extension1
3 of 5 facial features1
Skin striae1
Myopia1
Mitral valve prolapse1
Total

A Systemic Score calculator and a complete description of each component evaluation can be found at the National Marfan Foundation Web site.

Click here for a printable copy (pdf) of this table.

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).

Option 1

When the clinical findings suggest the diagnosis of Marfan syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence and deletion/duplication analysis of FBN1 are performed.
  • A multigene Marfan syndrome/Loeys-Dietz syndrome/familial thoracic aortic aneurysms and dissections panel that includes FBN1 as well as a number of other genes associated with disorders that include aortic aneurysms and dissections (see Differential Diagnosis) may be offered by clinical laboratories. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from other inherited disorders with features observed in Marfan syndrome, molecular genetic testing approaches can include comprehensive genomic testing (exome sequencing and genome sequencing).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in Marfan Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
FBN1Sequence analysis 3~90%-93% 4
Gene-targeted deletion/duplication analysis 5~5% 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

In individuals with classic Marfan syndrome an FBN1 pathogenic variant was identified by sequence analysis in 86 (93%) of 93 [Loeys et al 2004] and 76 (91%) of 87 individuals [Baetens et al 2011]. Subsequently, a number of these individuals have subsequently were found to have FBN1 deletions that had not been detected by sequencing [Bart Loeys, personal communication].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Deletions and duplications ranging in size from one to multiple exons as well as full-gene deletions have been described (www​.hgmd.cf.ac.uk, www​.umd.be/FBN1). In one systematic study, 4/86 individuals with classic Marfan syndrome had a large deletion or duplication [Baetens et al 2011].

Clinical Characteristics

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.

Differential Diagnosis

Loeys-Dietz syndrome (LDS) is an autosomal dominant condition that includes many features of Marfan syndrome (long face, downslanted palpebral fissures, highly arched palate, malar hypoplasia, micrognathia, retrognathia, pectus deformity, scoliosis, arachnodactyly, joint laxity, dural ectasia, and aortic root aneurysm with dissection). Some features of Marfan syndrome are either less common or prominent (dolichostenomelia) or absent (ectopia lentis). Unique features can include widely spaced eyes, broad or bifid uvula, cleft palate, hydrocephalus (rare), Chiari I malformation, blue sclerae, exotropia, craniosynostosis, cervical spine instability, talipes equinovarus, soft and velvety skin, translucent skin, easy bruising, generalized arterial tortuosity and aneurysms, and dissection throughout the arterial tree. Individuals with LDS are at risk for cervical spine malformation and/or instability, food allergy, asthma, eosinophilic esophagitis, and inflammatory bowel disease (rare).

Aortic aneurysms behave very differently from those in Marfan syndrome, with frequent dissection and rupture at small dimensions and in early childhood.

LDS results from a heterozygous pathogenic variant in one of five genes (see Table 4).

Table 4.

Loeys-Dietz Syndrome: Associated Genes and Subtypes

GeneLDS Subtype 1CommentReference
TGFBR1LDS1 2Loeys et al [2005], Loeys et al [2006]
TGFBR2LDS2 2
SMAD3LDS3Strong predisposition for osteoarthritisvan de Laar et al [2011]
TGFB2LDS4Lindsay et al [2012], Bertoli-Avella et al [2015]
TGFB3LDS5
1.

Subtypes are ordered from most to least severe.

2.

Note: LDS1 and LDS2 are equal in severity.

Hemizygous loss-of-function pathogenic variants in the X-linked gene BGN are characterized by early-onset thoracic aortic aneurysm and dissection, as well as hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia [Meester et al 2017].

Other connective tissue disorders. Many of the skeletal features of Marfan syndrome are common in the general population. When severe and found in combination, such findings usually indicate a disorder of connective tissue, including the following:

  • Congenital contractural arachnodactyly (CCA), an autosomal dominant disorder characterized by a Marfan-like appearance and long, slender fingers and toes, is caused by a heterozygous pathogenic variant in FBN2 (encoding fibrillin-2). Most affected individuals have "crumpled" ears, with a folded upper helix, and most have contractures of knees and ankles at birth that usually improve with time. The proximal interphalangeal joints also have flexion contractures (i.e., camptodactyly), as do the toes. Hip contractures, adducted thumbs, and clubfoot may occur. Kyphosis/scoliosis, present in approximately half of all affected individuals, begins as early as infancy and is progressive. The majority of affected individuals have muscular hypoplasia. Mild dilatation of the aorta is present in rare cases. Rare infants have been observed with a severe/lethal form characterized by multiple cardiovascular and gastrointestinal anomalies in addition to the typical skeletal findings.
  • Heritable thoracic aortic disease (HTAD) refers to thoracic aortic disease caused by mutation of a gene that confers a high risk for thoracic aortic aneurysms and aortic dissections (TAAD). Up to 20% of individuals with TAAD who do not have features of Marfan syndrome, vascular Ehlers Danlos syndrome, or Loeys-Dietz syndrome have a family history of TAAD. Approximately 30% of families with HTAD who do not have a clinical diagnosis of Marfan syndrome or another syndrome have a causative pathogenic variant in one of the 13 known HTAD-related genes. HTAD is primarily inherited in an autosomal dominant manner.
  • Ehlers-Danlos syndrome (EDS) is a group of disorders that have joint hypermobility as a common feature.
    • EDS, classic type is an autosomal dominant disorder characterized by skin hyperextensibility, abnormal wound healing, smooth, velvety skin, and joint hypermobility. Approximately 50% of individuals with classic EDS have an identifiable heterozygous pathogenic variant in COL5A1 or COL5A2.
    • EDS, kyphoscoliotic form (previously known as EDS VI) is an autosomal recessive disorder characterized by friable, hyperextensible skin, thin scars, and easy bruising; generalized joint laxity; severe muscular hypotonia at birth; progressive scoliosis, present at birth or within the first year of life; and scleral fragility with increased risk of rupture of the globe. Intelligence is normal; life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries and respiratory compromise if kyphoscoliosis is severe. EDS kyphoscoliotic form is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1, resulting from biallelic pathogenic variants in PLOD1.
    • EDS, vascular type (previously known as EDS IV) is an autosomal dominant disorder characterized by joint laxity (often limited to small joints), translucent skin with easily visible underlying veins, easy bruising, wide and dystrophic scars, characteristic facies (prominent eyes and a tight or "pinched" appearance), organ rupture (spleen, bowel, gravid uterus), and a tendency for aneurysm and/or dissection of any medium to large muscular artery throughout the body. Unlike in Marfan syndrome, there is no particular tendency for involvement of the aortic root, although this location is not spared from risk. The tissues can be extremely friable, often contributing to surgical catastrophe. EDS, vascular type is caused by a heterozygous pathogenic variant in COL3A1.
  • Homocystinuria caused by cystathionine β-synthase deficiency, an autosomal recessive disorder, is characterized by variable intellectual disability, ectopia lentis and/or severe myopia, skeletal abnormalities (including excessive height and limb length), and a tendency for intravascular thrombosis and thromboembolic events. Overlap with Marfan syndrome can be extensive and includes an asthenic (long and lean) body habitus, pectus deformity, scoliosis, mitral valve prolapse, highly arched palate, hernia, and ectopia lentis. Thromboembolic events can be life threatening. Approximately half of affected individuals are responsive to pharmacologic doses of vitamin B6, highlighting the need to consider this diagnosis. Biallelic pathogenic variants in CBS are causative.
  • Stickler syndrome can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial hypoplasia and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. The diagnosis of Stickler syndrome is clinically based. Stickler syndrome caused by a heterozygous pathogenic variant in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner; Stickler syndrome caused by biallelic pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner.
  • Fragile X syndrome is an X-linked disorder characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Males may have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears) and connective tissue findings (joint laxity) that suggest the Marfan syndrome phenotype. They also have large testes (postpubertally). Behavior abnormalities, sometimes including autism spectrum disorder, are common. More than 99% of individuals with fragile X syndrome have a full mutation in FMR1 caused by an increased number of CGG trinucleotide repeats (>200 typically) accompanied by aberrant methylation of FMR1.

Management

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 www.ClinicalTrialsRegister.eu 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 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.

Prenatal Testing and Preimplantation Genetic Diagnosis

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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Genetic Aortic Disorders Association (GADA) Canada
    Centre Plaza Postal Outlet
    128 Queen Street South
    PO Box 42257
    Mississauga Ontario L5M 4Z0
    Canada
    Phone: 866-722-1722 (toll free); 905-826-3223
    Email: info@gadacanada.ca
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • National Marfan Foundation (NMF)
    22 Manhasset Avenue
    Port Washington NY 11050
    Phone: 800-862-7326 (toll-free); 516-883-8712
    Fax: 516-883-8040
    Email: staff@marfan.org
  • NCBI Genes and Disease
  • Medline Plus

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Marfan Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FBN115q21​.1Fibrillin-1FBN1 @ LOVDFBN1FBN1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Marfan Syndrome (View All in OMIM)

134797FIBRILLIN 1; FBN1
154700MARFAN SYNDROME; MFS

Gene structure. FBN1 is large (>600 kb) and has 65 exons. The promoter region is large and poorly characterized. High evolutionary conservation of intronic sequence at the 5' end of the gene suggests the presence of intronic regulatory elements. Three exons at the extreme 5' end of the gene are alternatively utilized and do not appear to contribute to the coding sequence. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 1,000 FBN1 pathogenic variants that cause Marfan syndrome or related phenotypes (see Genetically Related Disorders) have been described [Vollbrandt et al 2004, Faivre et al 2007] (for more information, see Table A.).

Nonsense, frameshift, splice site, and missense changes have been reported. As a general rule, a variant that causes the in-frame loss or gain of central coding sequence through deletions, insertions, or splicing errors is associated with more severe disease. Pathogenic variants that create a premature termination codon have been associated with clinical presentations that range from mild (not meeting criteria for Marfan syndrome) to classic Marfan syndrome.

Of note, missense changes associated with disease include:

  • Missense variant that creates or destroys a cysteine residue;
  • Missense variant affecting conserved residues in the EGF-like domain consensus sequence (D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) (m and n represent variable numbers of residues);
  • Missense variants that prevent C-terminal propeptide processing, which have been mainly associated with skeletal manifestations. More recent reports suggest that this variant can be phenotypically neutral.

No common (i.e., recurrent) pathogenic variants have been described.

Normal gene product. Fibrillin-1 is an extracellular matrix protein that contributes to large structures called microfibrils that are found in both elastic and non-elastic tissues. They participate in the formation and homeostasis of the elastic matrix, in matrix-cell attachments, and possibly in the regulation of selected growth factors.

Studies in animal models of Marfan syndrome have demonstrated that microfibrils regulate the matrix sequestration and activation of the growth factor TGFβ. Excess TGFβ signaling has been observed in the developing lung, the mitral valve, the skeletal muscle, the dura, and the ascending aorta [Neptune et al 2003, Ng et al 2004, Jones et al 2005, Loeys et al 2005, Habashi et al 2006, Cohn et al 2007]. TGFβ antagonism in vivo has been shown to attenuate or prevent pulmonary emphysema, myxomatous changes of the mitral valve, skeletal muscle myopathy, and progressive aortic enlargement seen in fibrillin-1-deficient mice. Recent evidence suggests particular relevance of non-canonic TGFβ signaling in Marfan mouse models, prominently including the ERK cascade [Habashi et al 2011, Holm et al 2011]. The relevance of this mechanism to other manifestations of Marfan syndrome is currently being explored. Other studies have highlighted the potential role of matrix-degrading enzymes in the pathogenesis of aortic disease in Marfan syndrome [Bunton et al 2001, Booms et al 2005].

Abnormal gene product. The pathogenesis of Marfan syndrome is complex. Abnormal forms of fibrillin-1 are believed to have dominant-negative activity. In affected individuals, the residual level of protein is generally far below the 50% level predicted by the presence of a wild type copy of FBN1. A hallmark feature of the Marfan syndrome is a severe reduction of microfibrils in explanted tissues and in the matrix deposited by cultured dermal fibroblasts.

Marfan syndrome and related disorders can also be caused by loss-of-function alleles, demonstrating a haploinsufficiency mechanism of disease.

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  • van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collée M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43:121–6. [PubMed: 21217753]
  • Vollbrandt T, Tiedemann K, El-Hallous E, Lin G, Brinckmann J, John H, Batge B, Notbohm H, Reinhardt DP. Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1. J Biol Chem. 2004;279:32924–31. [PubMed: 15161917]
  • Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol. 2005;95:1125–7. [PubMed: 15842990]

Suggested Reading

  • Dietz HC, Pyeritz RE. Marfan syndrome and related disorders. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 206.
  • Eagle KA. GenTAC Consortium. Rationale and design of the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Am Heart J. 2009;157:319–26. [PMC free article: PMC2840718] [PubMed: 19185640]

Chapter Notes

Author Notes

Harry (Hal) Dietz is the Victor A McKusick Professor of Medicine and Genetics in the Institute of Genetic Medicine at the Johns Hopkins University School of Medicine and an Investigator in the Howard Hughes Medical Institute. He directs the William S Smilow Center for Marfan Syndrome Research and serves on the Professional Advisory Board of the National Marfan Foundation. His research focuses on the development of rational therapeutic strategies for Marfan syndrome and related conditions through elucidation of disease pathogenesis using animal models of disease. He directs a multidisciplinary clinic for the diagnosis and management of Marfan syndrome and other connective tissue disorders affecting the cardiovascular system.

Revision History

  • 12 October 2017 (bp) Comprehensive update posted live
  • 12 June 2014 (me) Comprehensive update posted live
  • 1 December 2011 (me) Comprehensive update posted live
  • 30 June 2009 (me) Comprehensive update posted live
  • 26 October 2005 (me) Comprehensive update posted live
  • 22 September 2003 (me) Comprehensive update posted live
  • 18 April 2001 (pb) Review posted live
  • January 2001 (hd) Original submission
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