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Marfan Syndrome

, MD
Victor A McKusick Professor, Pediatrics, Medicine, and Molecular Biology & Genetics
Institute of Genetic Medicine
Director, Smilow Center for Marfan Syndrome Research
Investigator, Howard Hughes Medical Institute
Johns Hopkins University School of Medicine
Baltimore, Maryland

Initial Posting: ; Last Update: June 12, 2014.

Summary

Disease characteristics. Marfan syndrome is a systemic disorder of connective tissue with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. FBN1 pathogenic variants associate with a broad phenotypic continuum, ranging from isolated features of Marfan syndrome to neonatal presentation of severe and rapidly progressive disease in multiple organ systems. Myopia is the most common ocular feature; displacement of the lens from the center of the pupil, seen in approximately 60% of affected individuals, is a hallmark feature. People with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation. The skeletal system involvement is characterized by bone overgrowth and joint laxity. The extremities are disproportionately long for the size of the trunk (dolichostenomelia). Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Scoliosis is common and can be mild or severe and progressive. The major sources of morbidity and early mortality in the Marfan syndrome 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 with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.

Diagnosis/testing. Marfan syndrome is a clinical diagnosis based on family history and the observation of characteristic findings in multiple organ systems. Ectopia lentis and aortic aneurysm are given special significance in the diagnosis of Marfan syndrome because of their relative specificity or frequency and clinical significance, respectively. Marfan syndrome is caused by mutation of FBN1. The sensitivity of molecular genetic testing of FBN1 is substantial yet incomplete for unknown reasons; it may be explained by atypical location or character of FBN1 pathogenic variants in some individuals (e.g., large deletions or promoter mutations) or to locus heterogeneity.

Management. Treatment of manifestations: Comprehensive management by a multidisciplinary team including a geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon is strongly recommended. Eyeglasses for most eye problems; rare need for surgical removal of a dislocated lens with implantation of an artificial lens (preferably after growth is complete). Surgical stabilization of the spine for scoliosis and repair of pectus deformity (largely for cosmetic indications). Orthotics and arch supports can lessen leg fatigue and muscle cramps associated with pes planus. Surgical repair of the aorta when the maximal measurement approaches 5.0 cm in adults or older children, the rate of increase of the aortic root diameter approaches 1.0 cm per year, or progressive and severe aortic regurgitation occurs. For younger children, aortic root surgery should be considered once: (1) the rate of increase of the aortic root diameter approaches 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 beta blockers, are generally initiated at diagnosis or for progressive aortic dilatation. Other antihypertensive agents can be used if beta blockers 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 centimeters in adults, rates of aortic dilation exceed approximately 0.5 cm per year, and significant aortic regurgitation is present; intermittent surveillance of the entire aorta with CT or MRA scans beginning in young adulthood.

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 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: Echocardiography in relatives suspected of having Marfan syndrome and in apparently unaffected relatives if findings are subtle in the index case.

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, beta blockers should be continued, but some other classes of medications such as ACE inhibitors or angiotensin receptor blockers 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. Monitoring should continue in the immediate postpartum period due to an increased risk for aortic dissection.

Therapies under investigation: Use of angiotensin receptor blockers such as losartan is under intensive investigation because of the dramatic protection against aortic growth seen in mouse models. Multiple prospective trials have shown that the combination of beta blockers and losartan affords better protection against aortic root enlargement than beta blockers alone in both children and adults with Marfan syndrome.

Genetic counseling. Marfan syndrome is inherited in an autosomal dominant manner. Approximately 75% of individuals with Marfan syndrome have an affected parent; approximately 25% of probands with Marfan syndrome have a de novo mutation. The risk to the sibs of the proband depends on the status of the parents. If a parent is affected, the risk is 50%. If an affected child is born to clinically unaffected parents, it is likely that the child has a de novo mutation, and the risk to sibs is far less than 50% but above the population risk because of reported (but rare) cases of somatic and germline mosaicism. The children of an individual with Marfan syndrome are at 50% risk of inheriting the mutant allele and the disorder. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Diagnosis

Marfan syndrome is a clinical diagnosis based on family history and the observation of characteristic findings in multiple organ systems.

Diagnostic Criteria

The revised diagnostic criteria for Marfan syndrome [Loeys et al 2010a] integrate information from multiple sources including family history, personal medical history, physical examination, slit lamp evaluation, and echocardiography or other forms of cardiovascular imaging. Features other than aortic root enlargement or ectopia lentis are weighted and grouped to derive a “systemic score” that can contribute to diagnosis. See Table 1 (printable copy).

Note: Given autosomal dominant inheritance for this disorder, the number of physical findings needed to establish a diagnosis for someone with an established family history of Marfan syndrome is reduced (since many entities in the differential diagnosis for Marfan syndrome would be effectively excluded).

In the absence of a family history of Marfan syndrome, the diagnosis can be established for a proband in four scenarios:

  • Aortic root enlargement (Z-score ≥2.0) 1 and one of the following:
    • Ectopia lentis
    • A pathogenic FBN1 variant 2
    • A systemic score ≥7 3
  • Ectopia lentis and an FBN1 pathogenic variant previously associated with aortic enlargement

In the presence of a family history of Marfan syndrome (using these criteria), the diagnosis can be established for a first-degree relative of the proband in three scenarios:

  • Ectopia lentis
  • Systemic score ≥7 3
  • Aortic root enlargement (Z-score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) 3

Notes:

1. Aortic size must be standardized to age and body size for accurate interpretation. A Z-score ≥2.0 infers a value at or above the 95th percentile, while a Z-score ≥3.0 infers a value at or above the 99th percentile. References and calculators for this determination are available at the National Marfan Foundation Web site.

2. Any of the following findings in FBN1 molecular genetic testing should infer causality in making the diagnosis of Marfan syndrome (see Molecular Genetic Testing):

  • Pathogenic variant previously shown to segregate with Marfan syndrome in families (ideally n≥6 meioses)
  • De novo mutation (with proven paternity and absence of disease in parents) in one of the five following categories:
    • Nonsense mutation
    • In-frame or out-of-frame deletion/insertion
    • Splice site mutation that alters the splice consensus sequence or is shown to alter splicing
    • Missense mutation that creates or destroys a cysteine residue
    • Missense mutation 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, D = aspartic acid, N = asparagine, E = glutamic acid, Q = glutamine, Y = tyrosine, F = phenylalanine]
  • Other missense mutations:
    • Segregation in family and/or absence in 400 ethnically matched control chromosomes
    • If no family history, absence in 400 ethnically matched control chromosomes
  • Linkage analysis can be used to infer inheritance of a disease-associated FBN1 allele if segregation with disease is seen for n≥6 meioses. Given the widespread availability and high sensitivity of FBN1 sequencing, it is anticipated that use of this approach will be rare.

3. In the absence of discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome, collagen biochemical testing and/or molecular genetic testing of TGFBR1, TGFBR2, SMAD3, TGFB2, or COL3A1 may be indicated.

Table 1. Calculation of the Systemic Score

FeatureValueEnter Value if Present
Wrist AND thumb sign 3
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 of this table.

Given that many manifestations of Marfan syndrome can 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 authors suggest the use of tentative diagnostic designations:

  • If the systemic score is <7 and/or borderline aortic root measurements (Z-score <3) are present (without an FBN1 pathogenic variant), use of the term “nonspecific connective tissue disorder” is suggested until follow-up echocardiographic evaluation shows aortic root dilation (Z-score ≥3).
  • If an FBN1 pathogenic variant is identified in simplex or familial cases but aortic root Z-score is below 3.0, the term “potential Marfan syndrome” should be used until the aorta reaches this threshold.

Testing

Protein-based methods. Immunohistochemical or pulse-chase analysis of the fibrillin-1 protein expressed from cultured dermal fibroblasts can detect abnormalities in most samples from individuals with Marfan syndrome. Both methods require specialized laboratories with expertise in test execution and interpretation.

Note: Sequencing of FBN1 has emerged as the preferred method for molecular diagnosis.

Molecular Genetic Testing

Gene. FBN1 is the only gene in which pathogenic variants are known to cause classic Marfan syndrome.

Evidence for locus heterogeneity. While Mizuguchi et al [2004] reported identification of variants in TGFBR2 in individuals with Marfan syndrome (designated Marfan syndrome type II), a number of findings characteristic of Marfan syndrome, including ectopia lentis and prominent dolichostenomelia, were not observed. Loeys et al [2005] subsequently reported heterozygous variants in either TGFBR1 or TGFBR2 in a novel aortic aneurysm syndrome (Loeys-Dietz syndrome) that included some features of Marfan syndrome (arachnodactyly, aortic root aneurysms, pectus deformity, scoliosis, and dural ectasia) but also many distinguishing features (see Differential Diagnosis).

Genotyping of 93 individuals presenting with classic Marfan syndrome identified FBN1 pathogenic variants in 86 (93%); none of the remainder had pathogenic variants in either TGFBR1 or TGFBR2 [Loeys et al 2004, Loeys et al 2005]. A number of these individuals have subsequently been found to have FBN1 deletions [Bart Loeys, personal communication].

Stheneur et al [2008] reported additional individuals with a TGFBR2 variant and a clinical diagnosis of Marfan syndrome. Two individuals with a TGFBR2 variant reportedly showed evidence of ectopia lentis, a finding not reported by other groups. While more information and experience is needed, this finding raises the possibility that ectopia lentis in the context of a Marfan-like presentation may not be unique to individuals with FBN1 pathogenic variants. (See also Nomenclature.)

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Marfan Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
FBN1Sequence analysis 2~70%-93% 3
Deletion/duplication analysis 4Unknown 5
Linkage analysisNot applicable 6

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

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

3. Influenced by: (1) the accuracy of the clinical diagnosis of Marfan syndrome (i.e., individuals fulfilling the established clinical diagnostic criteria with positive family histories are much more likely to have a detectable FBN1 pathogenic variant); (2) mutation type (certain genetic alterations may preclude detection by various testing techniques); and (3) the ability of the testing methodology to detect pathogenic variants [Korkko et al 2002]

4. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Mátyás et al [2007]. The yield in persons with Marfan syndrome without a defined coding sequence or splice site mutation remains to be fully elucidated but appears to be approximately 30% [Baetens et al 2011].

6. Linkage analysis may be informative in some families. Given the expense associated with the genotyping of many family members and the increased availability and efficiency of gDNA sequencing, the current utility of linkage analysis is greatly limited.

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Arslan-Kirchner et al 2011 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of Marfan syndrome is established in a proband based on clinical diagnostic criteria.

Note: Even in the presence of an FBN1 pathogenic variant known to be associated with Marfan syndrome, establishing the diagnosis of Marfan syndrome relies on documentation of significant clinical findings (see Diagnostic Criteria and Table 1).

Single gene testing. The most common strategy for molecular diagnosis of a proband suspected of having Marfan syndrome is sequence analysis of exons and flanking intronic regions followed by deletion/duplication analysis if a pathogenic variant is not identified..

Multi-gene testing. Clinical laboratories may offer a multi-gene 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). These panels vary by methods used and genes included; thus, the ability of a panel to detect a pathogenic variant or pathogenic variants in any given individual also varies.

Note: In most circumstances a comprehensive clinical evaluation and imaging studies will point to a specific diagnosis (or subset of diagnoses) that has the highest probability, and thus should be pursued first for molecular confirmation. In the absence of such hypothesis-driven testing, there is an increased risk of erroneous interpretation of variants of uncertain significance when multi-gene panels are applied, especially if the physician requesting testing is not familiar with the specific diagnoses and/or genes under consideration.

Clinical Description

Natural History

Marfan syndrome is a systemic disorder of connective tissue with a high degree of clinical variability as reviewed in Judge & Dietz [2005]. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. FBN1 pathogenic variants associate with a broad phenotypic continuum, ranging from isolated features of Marfan syndrome to neonatal presentation of severe and rapidly progressive disease in multiple organ systems. The diagnosis of Marfan syndrome is clinically defined and does not include this whole spectrum, especially the milder overlap phenotypes. As a general rule, conditions run true within families, suggesting that the FBN1 genotype 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. This finding is most reliably diagnosed by slit-lamp examination after maximal pupillary dilatation. 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. Most often the eye problems of Marfan syndrome can be managed with the use of eyeglasses. Other problems can be mitigated using surgical techniques, including the implantation of artificial lenses.

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 a decrease in the arm span-to-height and the upper-to-lower segment ratios. 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 by their genetic background (excluding the FBN1 pathogenic variant) [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 of aortic dissection or rupture occurs when the maximal dimension reaches approximately 5.0 centimeters. 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.

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 aort0ic dissection or rupture during pregnancy, delivery, and the postpartum period.

Self-image. The vast majority of affected individuals over 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 a pathogenic variant in a proband thus has little prognostic value and has not been proven to reliably guide individual management.

The following are some generalizations:

  • In those with identified pathogenic variants, most individuals with the most severe and rapidly progressive form of Marfan syndrome, sometimes termed "neonatal Marfan syndrome," have alterations in a center portion of the gene between exons 24 and 32. It must be stressed that some individuals with this severe presentation have not had identifiable pathogenic variants in this region, and that many other individuals with pathogenic variants in this region have classic or even mild presentations of Marfan syndrome.
  • As a general rule, mutations causing the in-frame loss or gain of central coding sequence through deletions, insertions, or splicing errors are associated with more severe disease.
  • Pathogenic variants that create a premature termination codon and result in rapid degradation of mutant transcripts can be associated with mild conditions that may fail to meet diagnostic criteria for Marfan syndrome. Classic Marfan syndrome can also result from variants that create a premature termination codon.
  • Individuals harboring a pathogenic variant preventing C-terminal propeptide processing have shown predominantly skeletal manifestations.
  • Substitution of amino acids with intuitive functional significance, such as cysteines that participate in intramolecular linkages and residues that dictate the calcium binding affinity of epidermal growth factor-like domains, tend to cause Marfan syndrome of variable severity.
  • Substitution of residues without obvious functional importance can be phenotypically neutral or can cause mild disease presentations such as mitral valve prolapse syndrome.

Penetrance

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

Anticipation

Anticipation has not been observed in Marfan syndrome.

Nomenclature

“Neonatal Marfan syndrome.” Although many have adopted the use of 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 course of disease in these children.

Loeys-Dietz syndrome. Although Mizuguchi et al [2004] reported identification of pathogenic variants in TGFBR2 in individuals with “Marfan syndrome type 2,” a number of characteristic findings, including ectopia lentis and prominent dolichostenomelia, were not observed. Loeys et al [2005] subsequently reported heterozygous pathogenic variants in either TGFBR1 or TGFBR2 in a novel aortic aneurysm syndrome (Loeys-Dietz syndrome) that included some features of Marfan syndrome (arachnodactyly, aortic root aneurysms, pectus deformity, scoliosis, and dural ectasia) but also many distinguishing features (see Differential Diagnosis).

In a subsequent report, Loeys et al [2006] described individuals with TGFBR1 or TGFBR2 mutations who lacked the typical craniofacial manifestations of Loeys-Dietz syndrome, but had many features that distinguished the disorder from Marfan syndrome (e.g., easy bruising, dystrophic scars, cervical spine instability, club foot deformity, and/or arterial tortuosity).

In the authors’ experience and that of others [Eloisa Arbustini, personal communication], individuals with TGFBR1 or TGFBR2 pathogenic variants routinely show a propensity for diffuse and aggressive vascular disease with vessel rupture at young ages and small vessel dimensions. Given important differences in the performance of the vasculature and the risk for other life-threatening manifestations, the designation “Loeys-Dietz syndrome” better informs patients and clinicians regarding the need for individualized counseling and management than the term Marfan syndrome type 2.

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

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.

Marfan syndrome multi-gene panels may include testing for a number of the disorders discussed in this section. Note: The genes involved and methods used vary by laboratory.

Genetically related disorders caused by FBN1 pathogenic variants:

  • MASS phenotype is an autosomal dominant condition that can be caused by heterozygous pathogenic variants in FBN1. The acronym MASS stands for mitral valve prolapse, myopia, borderline and non-progressive aortic enlargement, and nonspecific skin and skeletal findings that overlap with those seen in Marfan syndrome. One is most confident in this diagnosis when concordant manifestations are seen in multiple generations in a given family. Still, it remains unclear whether some individuals in such a family may be predisposed to more severe vascular involvement, and a regimen of intermittent cardiovascular imaging should be maintained. It is difficult to distinguish MASS phenotype from "emerging" Marfan syndrome when assessing an isolated individual, especially during childhood. This phenotypic designation is appropriate if the aortic root Z-score is less than 2.0, there is no ectopia lentis, and the systemic score is at least 5. This diagnosis can only be established for individuals age 20 years or older [Loeys et al 2010a].
  • Mitral valve prolapse syndrome, an autosomal dominant condition that associates mitral valve prolapse and (often subtle) skeletal features reminiscent of the Marfan syndrome, can be caused by mutation of FBN1. This phenotypic designation is appropriate in the presence of MVP if the aortic root Z-score is less than 2.0, there is no ectopia lentis, and the systemic score is less than 5. This diagnosis can only be established for individuals age 20 years or older [Loeys et al 2010a].
  • Ectopia lentis syndrome is an autosomal dominant condition that associates ectopia lentis and variable skeletal manifestations that are reminiscent of the Marfan syndrome. The condition is often caused by heterozygous pathogenic variants in FBN1. It remains unclear whether some individuals in affected families are destined to show later onset of progressive aortic enlargement. A regimen of intermittent cardiovascular imaging should be maintained. This phenotypic designation is appropriate if the aortic root Z-score is less than 2.0 and the patient does not have an FBN1 pathogenic variant previously associated with aortic enlargement irrespective of the systemic score. This diagnosis can only be established for individuals age 20 years or older [Loeys et al 2010a].

    Autosomal recessive inheritance of isolated ectopia lentis can be caused by pathogenic variants in ADAMTSL4 and is not associated with other manifestations of Marfan syndrome [Ahram et al 2009]; see ADAMTSL4-Related Eye Disorders.
  • Shprintzen-Goldberg syndrome (SGS) is a condition that associates many features of Marfan syndrome (dolichostenomelia, arachnodactyly, pectus deformity, scoliosis, aortic root enlargement [rare], highly arched palate) with other discriminating features (craniosynostosis, developmental delay, Chiari malformation, hypertelorism, proptosis, rib anomalies, equinovarus deformity). While two individuals with many of these unique features had an FBN1 pathogenic variant, it is clear that the majority of cases are not caused by mutation of FBN1. More recently, it has been demonstrated that the vast majority of individuals with SGS have a heterozygous inherited or de novo mutation in SKI, which encodes a negative regulator of transforming growth factor-β signaling [Doyle et al 2012].
  • Loeys-Dietz syndrome (LDS) is an autosomal dominant condition that includes many features of Marfan syndrome (long face, downward slant of the 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 hypertelorism, broad or bifid uvula, cleft palate, learning disability (rare), 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. Loeys-Dietz syndrome types 1 and 2 designate those with and without severe craniofacial involvement, respectively [Loeys et al 2006].

    Aortic aneurysms behave very differently from those in Marfan syndrome, with frequent dissection and rupture at small dimensions and in early childhood. Surgical repair has not been complicated by the tissue friability observed in Ehlers-Danlos syndrome, vascular type. The condition results from pathogenic variants in either TGFBR1 or TGFBR2 [Loeys et al 2005, Loeys et al 2006]. Pathogenic variants in SMAD3 have been reported to cause a condition with complete phenotypic overlap with Loeys-Dietz syndrome, but with a strong predisposition for osteoarthritis [van de Laar et al 2011]. Pathogenic variants in TGFB2 also cause a condition with substantial phenotypic overlap with Loeys-Dietz syndrome [Lindsay et al 2012].

Other connective tissue disorders. Marfan syndrome shows limited overlap with other connective tissue disorders including the following:

  • Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder characterized by a Marfan-like appearance and long, slender fingers and toes. The condition is caused by heterozygous pathogenic variants 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 club foot 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 rarely present. Rare infants have been observed with a severe/lethal form characterized by multiple cardiovascular and gastrointestinal anomalies in addition to the typical skeletal findings.
  • Familial thoracic aortic aneurysms and aortic dissection (TAAD) is an autosomal dominant cardiovascular disorder without other phenotypic manifestations. The aortic disease observed is similar to that observed in the Marfan syndrome and includes dilatation of the aorta and dissections either at the level of the sinuses of Valsalva or the ascending thoracic aorta.
    • TGFBR2, TGFBR1, MYH11, ACTA2, MYLK, SMAD3, and two loci on other chromosomes, AAT1 (FAA1) and AAT2 (TAAD1), are associated with familial TAAD.
    • It appears that in some families a small subset of pathogenic variants in TGFBR2 may associate with predominant vascular disease in the absence of overt features of Loeys-Dietz syndrome. However, some individuals with a TGFBR2 pathogenic variant have features of a systemic connective tissue disorder, and some TGFBR2 pathogenic variants associated with TAAD have been seen in classic Loeys-Dietz syndrome.
  • Ehlers-Danlos syndrome (EDS) is a group of disorders that have joint hypermobility as a common feature.
    • EDS, classic type is autosomal dominant and is characterized by skin hyperextensibility, abnormal wound healing, smooth, velvety skin, and joint hypermobility. Approximately 50% of individuals with classic EDS have an identifiable 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. The kyphoscoliotic form is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1: lysyl hydroxylase 1). The diagnosis of EDS, kyphoscoliotic form relies on the demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC (a highly sensitive and specific test) and/or assay of lysyl hydroxylase enzyme activity in skin fibroblasts. Mutation of PLOD (encoding the enzyme lysyl hydroxylase 1) is causative.
    • 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. The diagnosis of EDS, vascular type is based on clinical findings and confirmed by identification of a causative pathogenic variant in COL3A1, the only gene in which mutation is known to cause EDS, vascular type. Analysis of collagens produced by cultured fibroblasts from affected individuals can demonstrate abnormalities of type III procollagen production, intracellular retention, reduced secretion, and/or altered mobility in cells from some individuals in whom no mutation was detected by genomic sequencing.
  • Homocystinuria is an autosomal recessive disorder caused by cystathionine β-synthase deficiency resulting from pathogenic variants in CBS. The 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 aesthenic (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.
  • 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 mutations in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner; Stickler syndrome caused by mutations in COL9A1 or COL9A2 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). Behavioral 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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:

  • Evaluation by an ophthalmologist with expertise in Marfan syndrome, including:
    • Slit lamp examination through a maximally dilated pupil to see lens subluxation
    • Refraction and visual correction, 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.
    • 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).
  • Medical genetics consultation

Treatment of Manifestations

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

Eye

  • The ocular manifestations should be managed by an ophthalmologist with expertise in Marfan syndrome.
  • Most often, eye problems can be adequately controlled with eyeglasses 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 artificial lens can be implanted once growth is complete. While this procedure is currently considered quite safe when performed in specialized centers, major complications, including retinal detachment, can occur.
  • Careful and aggressive refraction and visual correction is 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 medically (rather than cosmetically) indicated.
  • 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 who is familiar with Marfan syndrome.
  • Surgical repair of the aorta is indicated once: (1) the maximal measurement approaches 5.0 cm in adults or older children, (2) the rate of increase of the aortic root diameter approaches 1.0 cm per year, or (3) 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.
  • Surgical guidelines for young children with Marfan syndrome are based upon 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: (1) the rate of increase of the aortic root diameter approaches 1.0 cm per year, or (2) there is progressive and severe aortic regurgitation. While there is no agreed upon absolute size threshold for the aortic root, 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, are routinely prescribed. This therapy should be managed by a cardiologist or 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 needs to be titrated to effect, keeping heart rate after submaximal exercise or agitation lower than 110 in young children or lower than 100 in older children or adults.

  • Verapamil or other calcium channel blockers have been suggested if beta-blockers cannot be used (e.g., in individuals with asthma) or are not tolerated (e.g., prolonged lethargy, depression). 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 beta-blockers. Of note, the treatments were not randomized and the dose of beta-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 beta-blockers) have not previously been reported to provide notable protection from progressive aortic enlargement.
  • There is at least some theoretic concern that reducing afterload without a concomitant reduction in inotropy (as provided by a beta-blocker) could increase hemodynamic stress in the ascending aorta. Currently, afterload-reducing agents are only commonly used in conjunction with a beta-blocker to manage volume overload in the setting of valve dysfunction.

Prevention of Secondary Complications

Judicious use of subacute bacterial endocarditis (SBE) 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 at frequent intervals to monitor the status of the ascending aorta is indicated:

  • Yearly examinations when the aortic dimension is relatively small and the rate of aortic dilation is relatively slow
  • More frequent examinations when the aortic root diameter exceeds approximately 4.5 centimeters in adults, the rate of aortic dilation exceeds approximately 0.5 cm per year, and 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 correction of visual deficits
  • 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

Relatives of an individual with Marfan syndrome should be evaluated for signs of the disorder. Molecular genetic evaluation of relatives at risk is possible if the FBN1 pathogenic variant has been identified in the proband.

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. 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.

Note: 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

Pregnancy should only be considered after appropriate counseling from a medical 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 either during pregnancy or 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 <5.0cm) before becoming pregnant.

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, beta blockers should be continued, but some other classes of medications such as ACE inhibitors or angiotensin receptor blockers should be stopped because of the risk for fetal loss and birth defects.

Effort 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 due to an increased risk for aortic dissection.

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

Therapies Under Investigation

Studies in animal models of Marfan syndrome have demonstrated excessive activation of and signaling by the growth factor TGFβ. Systemic administration of TGFβ antagonists can attenuate or prevent many disease manifestations in fibrillin-1-deficient mice including emphysema, skeletal muscle myopathy, myxomatous valve disease, and aortic aneurysm. Losartan, an angiotensin II type 1 receptor blocker, can also decrease TGFβ signaling. Losartan has shown the ability to halt abnormal aortic root growth in mouse models of Marfan syndrome [Habashi et al 2006]. This effect associates with both a reduction in hemodynamic stress and antagonism of TGFβ signaling in the vessel wall. A small observational study of losartan in children with severe Marfan syndrome showed a reduction in aortic root growth with the combination of beta blockers and losartan, when compared to prior medical monotherapy including both beta-blockers and ACE inhibitors [Brooke et al 2008]. Subsequently, multiple prospective trials have shown that the combination of beta blockers and losartan affords better protection against aortic root enlargement than beta blockers alone in both children and adults with Marfan syndrome [Chiu et al 2013, Groenink et al 2013, Pees et al 2013]. A large multicenter clinical trial of losartan versus atenolol in Marfan syndrome is ongoing in the United States [Lacro et al 2007].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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 de novo mutation.
  • It is appropriate to evaluate both parents for manifestations of Marfan syndrome by performing a comprehensive clinical examination and echocardiogram. Molecular genetic testing of both parents is possible if the FBN1 pathogenic variant has been identified in the proband.

Note: 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.

Sibs of a proband

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 mutant allele from a parent will have Marfan syndrome, although the severity cannot be predicted.

Other family members of a proband. 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 pathogenic variant in the family.

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or 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

Molecular genetic testing. Prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

The pathogenic variant in an affected family member must be identified or linkage established in the family before prenatal testing can be performed. Linkage analysis should be used with caution unless FBN1 marker alleles can be shown to cosegregate with disease in a large family.

Ultrasound examination. Ultrasound examination in the first two trimesters is insensitive in detecting manifestations of Marfan syndrome [Burke & Pyeritz 1998].

Requests for prenatal testing for Marfan syndrome are uncommon [Loeys et al 2002]. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

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.

  • Canadian Marfan Association (CMA)
    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
    Fax: 905-826-2125
    Email: info@marfan.ca
  • 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
  • National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)
    Phone: 800-334-8571 ext 24640
    Email: gentac-registry@rti.org

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FBN115q21​.1Fibrillin-1FBN1 @ LOVDFBN1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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 Symbol.

Pathogenic allelic variants. More than 1,000 FBN1 pathogenic variants that cause Marfan syndrome or related phenotypes have been described [Vollbrandt et al 2004, Faivre et al 2007]. No common pathogenic variant exists in any population. (For more information, see Table A.)

Normal gene product. Fibrillin-1 is an extracellular matrix protein that contributes to large structures called microfibrils. Microfibrils 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-canonical 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. Mutant forms of fibrillin-1 are believed to have dominant-negative activity. That is, the mutant forms can interfere with the utilization of the normal protein derived from the opposite allele. 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. The residual level of protein is generally far below the 50% level predicted by the presence of a wild-type copy of FBN1 in all affected individuals.

Marfan syndrome and related disorders can also be caused by premature termination codon mutations or gene deletions that reduce expression from the mutant allele. Thus, haploinsufficiency also contributes to the pathogenesis of disease. Animal studies suggest that half-normal amounts of fibrillin-1 (i.e., haploinsufficiency) may be insufficient to initiate productive microfibrillar assembly [Judge et al 2004]. Polymorphic variation regulating the output of the wild-type allele can contribute to the severity of disease in the haploinsufficient state [Hutchinson et al 2003].

References

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Suggested Reading

  1. Dietz HC, Pyeritz RE. Marfan syndrome and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 206. Available online. 2014. Accessed 6-10-14.
  2. Eagle KA. 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 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 to live Web site
  • 22 September 2003 (me) Comprehensive update posted to live Web site
  • 18 April 2001 (pb) Review posted to live Web site
  • January 2001 (hd) Original submission
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