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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Marfan syndrome is a clinical diagnosis based on family history and the observation of characteristic findings in multiple organ systems. The four major diagnostic findings include dilatation or dissection of the aorta at the level of the sinuses of Valsalva, ectopia lentis, dural ectasia, and four of eight specific skeletal features. Molecular genetic testing of FBN1 is available in clinical laboratories. It remains unclear whether the lack of full sensitivity of this test relates to an atypical location or character of FBN1 mutations in some individuals (e.g., large deletions or promoter mutations) or to locus heterogeneity.
Management. Treatment of manifestations: Comprehensive management requires a team approach, including a geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon. 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 exceeds 5.0 cm in adults or older children, the rate of increase of the aortic diameter approaches 1.0 cm per year, or progressive aortic regurgitation occurs. 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; verapamil or other antihypertensive agents can be used if beta blockers are not tolerated. Prevention of secondary complications: subacute bacterial endocarditis prophylaxis for dental work. 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 in beginning in young adulthood. Testing 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. 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; LASIK correction of refractive errors; breathing against resistance or positive pressure ventilation in those with a documented predisposition for pneumothorax.
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 disease-causing mutation in the family is known.
Once the diagnosis of Marfan syndrome has been established in a proband, the requirements for diagnosis of a first-degree family member include major involvement of one organ system with minor involvement of a second. These criteria also apply if an individual has an FBN1 mutation that has previously been associated with Marfan syndrome or an FBN1 haplotype, inherited by descent, which segregates with disease within the extended family. Thus, even in the presence of a documented genetic predisposition for disease, one must document significant clinical findings for the positive diagnosis of Marfan syndrome.
Major and minor criteria. The four findings with major diagnostic significance:
Dilatation or dissection of the aorta at the level of the sinuses of Valsalva
Ectopia lentis
Dural ectasia
Four of eight specific skeletal features
Accurate diagnosis requires a specialized examination including anthropometric measurements.
| System | Diagnostic Criteria | |
|---|---|---|
| Major | Minor | |
| Skeletal | ≥4 of the following components: Pectus carinatum OR pectus excavatum requiring surgery Reduced upper-to-lower segment ratio for age (<0.85 for older children or adults) OR arm span-to-height ratio (>1.05) 1 Wrist (Walker-Murdoch) and thumb (Steinberg) signs 2 Scoliosis of >20° OR spondylolisthesis Elbow extension <170° Medial rotation of the medial malleolus causing pes planus Protrusio acetabuli (abnormally deep acetabulum with accelerated erosion) of any degree (on x-ray) | 2 major components OR1 major component and ≥2 of the following: Pectus excavatum of moderate severity Joint hypermobility Highly arched palate with tooth crowding Facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures) |
| Ocular | Ectopia lentis | ≥2 of the following: Abnormally flat cornea (measured by keratometry) Increased axial length of the globe (measured by ultrasound) Hypoplastic iris or hypoplastic ciliary muscle causing decreased pupillary miosis |
| Cardio-vascular | ≥1 of the following: Dilatation of the ascending aorta involving the sinuses of Valsalva Dissection of the ascending aorta | ≥1 of the following: Mitral valve prolapse ± mitral regurgitation Dilatation of the main pulmonary artery without obvious cause at age <40 yrs Calcification of the mitral annulus at age <40 yrs Dilatation/dissection of descending thoracic/abdominal aorta at age <50 yrs |
| Pulmonary | ≥1 of the following: Spontaneous pneumothorax Apical blebs (on chest x-ray) | |
| Skin and Integument | ≥1 of the following: Striae atrophicae without obvious cause Recurrent or incisional herniae | |
| Dura | Lumbosacral dural ectasia (ascertained by CT or MRI) | |
| Family/ Genetic History | ≥1 of the following: Parent, child, or sib who meets diagnostic criteria independently FBN1 mutation known to cause Marfan syndrome Haplotype around FBN1, inherited by descent, known to be associated with Marfan syndrome in the family (ascertained by linkage analysis) | |
1. The lower segment (LS) is measured from the top of the symphysis pubis to the floor; the LS is subtracted from the height to obtain the upper segment (US). The arm span is measured between the tips of the middle fingers with the arms outstretched.
2. Walker-Murdoch wrist sign is the overlapping of the complete distal phalanx of the thumb and fifth finger when wrapped around the opposite wrist. The thumb sign (Steinberg) is extension of the entire distal phalanx of the thumb beyond the ulnar border of the hand when apposed across the palm.
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 the FBN1 gene has emerged as the preferred method for molecular diagnosis.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. FBN1 is the only gene known to be associated with classic Marfan syndrome.
Other loci. While Mizuguchi et al [2004] reported identification of mutations 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 mutations 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 mutations in 86 (93%); none of the remainder had mutations 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 patients with TGFBR2 mutations and a clinical diagnosis of Marfan syndrome. Two individuals with TGFBR2 mutations reportedly showed evidence of ectopia lentis, a finding not reported by other groups. While more information and experience is needed, this raises the possibility that ectopia lentis in the context of a Marfan-like presentation may not be unique to individuals with FBN1 mutations (See also Nomenclature).
Clinical testing
Sequence analysis and mutation scanning. The mutation detection rate of FBN1 mutation scanning and cDNA sequence analysis ranges from approximately 70% to 93% and is 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 detectable FBN1 mutations); (2) mutation type (certain genetic alterations may preclude detection by various testing techniques); and (3) the ability of the testing methodology to detect mutations [Korkko et al 2002].
Sequence analysis of cDNA. Screening of cDNA (DNA reverse transcribed from RNA), rather than genomic DNA (gDNA) allows time-efficient screening of the full FBN1 coding region and permits identification of certain splice mutations undetectable by sequence analysis of gDNA. Mutation detection frequencies may be as high as 90% [V Schaefer, personal communication, 2003] in individuals meeting Marfan syndrome diagnostic criteria. The widespread availability and enhanced efficiency of screening of all the fibrillin-1 coding sequence using genomic DNA (see following) has diminished the utility of cDNA-based screening that requires establishment of patient cell lines.
Sequence analysis/mutation scanning using gDNA. Direct sequencing (of all 65 FNB1 exons) or mutation scanning using a variety of techniques can detect mutations resulting in rapid RNA degradation which are undetectable by cDNA sequence analysis. Mutation detection rates range from 70% to 93% in individuals meeting Marfan syndrome clinical diagnostic criteria [Halliday et al 2002, Korkko et al 2002, Loeys et al 2004, Arbustini et al 2005, Stheneur et al 2009].
Deletion analysis. Experience with animal models suggested that functional haploinsufficiency is sufficient to cause features of Marfan syndrome [Judge et al 2004]. This hypothesis was validated by the identification of persons with Marfan syndrome with large genomic deletions of regulatory elements that abolish transcription from the mutant allele [Mátyás et al 2007]. On this basis, multiple clinical laboratories will perform additional assays aimed at detecting large deletions if sequence analysis or mutation scanning are negative. The yield in persons with Marfan syndrome without a defined coding sequence or splice site mutation remains to be elucidated.
Linkage analysis. Linkage analysis may be used to determine if an individual has inherited an FBN1 allele that is associated with Marfan syndrome in family members. The markers used for Marfan syndrome linkage are highly informative and are within the FBN1 gene; they can be used in nearly 100% of families. However, caution should be applied in the application of linkage analysis for small families or atypical presentations of Marfan syndrome. 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.
Note: (1) Linkage testing is not available to families in which only a single member is affected. (2) Linkage analysis should be used with great caution particularly in families exhibiting atypical phenotypes because multiple phenotypes with some clinical overlap with Marfan syndrome are not caused by mutations in FBN1 and locus heterogeneity for Marfan syndrome has not been definitely excluded. (3) Linkage analysis has the greatest predictive value when a particular allele is shown to consistently cosegregate with disease in a large family.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method 1 | Test Availability |
|---|---|---|---|---|
| FBN1 | Mutation scanning/sequence analysis | Sequence variants | ~70%-93% | Clinical
 |
| Complementary DNA sequence analysis | ||||
| Deletion/duplication analysis 2 | Exonic and whole-gene deletions | Unknown |
1. Proportion of affected individuals with a mutation detected by this test method [Halliday et al 2002, Korkko et al 2002, Loeys et al 2004, Arbustini et al 2005, Loeys et al 2005, Stheneur et al 2009]
2. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), or array GH may be used.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirming the diagnosis in a proband. The diagnosis of Marfan syndrome is established in a proband based on clinical diagnostic criteria.
Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.
Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
Other phenotypes associated with mutations in FBN1:
Mitral valve prolapse syndrome (with or without skeletal features)
MASS phenotype – Myopia, mitral valve prolapse, borderline and non-progressive aortic enlargement, and nonspecific skin and skeletal features
Predominant aortic aneurysm with other subdiagnostic features of Marfan syndrome
Predominant or isolated skeletal features of Marfan syndrome
Familial ectopia lentis – associates the eye and skeletal features of Marfan syndrome and can only be differentiated from "emerging" Marfan syndrome with prolonged clinical follow-up including frequent echocardiograms
Shprintzen-Goldberg syndrome – associates many skeletal findings of Marfan syndrome with ocular hypertelorism, craniosynostosis, other craniofacial abnormalities and cognitive impairment. While aortic root enlargement can be seen, it is both rare and mild when compared to Marfan syndrome and Loeys-Dietz syndrome. Two persons with findings consistent with this diagnosis have been shown to have FBN1 mutations [Sood et al 1996, Kosaki et al 2006]. Interestingly, the two mutations are in close physical proximity (Cys1223Tyr and Cys1221Tyr) suggesting a potential phenotype-genotype correlation. There is documented locus heterogeneity, with many patients shown not to have a mutation in FBN1 [Robinson et al 2005].
One family with apparent autosomal dominant Weill-Marchesani syndrome [Faivre et al 2003]
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 mutations 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.
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 mutation) [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 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 hypotension 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 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.
Few genotype-phenotype correlations exist in the Marfan syndrome; none is definitive [Dietz & Pyeritz 2001]. Identification of a mutation 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 mutations, all 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 mutations in this region, and that many other individuals with mutations in this region have classic or even mild variants 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.
Mutations 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.
Individuals harboring a mutation 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 variants such as mitral valve prolapse syndrome.
While intrafamilial clinical variability can be extensive, no examples of non-penetrance in classic Marfan syndrome have been published.
Anticipation has not been observed in Marfan syndrome.
“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 mutations 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 mutations 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 mutations 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 of 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.
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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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.
Genetically related disorders caused by FBN1 mutations:
MASS phenotype is an autosomal dominant condition that can be caused by heterozygous mutations 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.
Mitral valve prolapse syndrome is an autosomal dominant condition that associates mitral valve prolapse and skeletal features (often subtle) that are reminiscent of the Marfan syndrome. This condition can be caused by mutations in FBN1.
Familial ectopia lentis is an autosomal dominant condition that associates ectopia lentis and variable skeletal manifestations that are reminiscent of the Marfan syndrome. The condition is caused by heterozygous mutations 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.
Shprintzen-Goldberg syndrome (SGS) is a condition with an unclear inheritance pattern 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 individual with many of these unique features had an FBN1 mutation, it is clear that the majority of cases are not caused by mutations in FBN1.
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 is caused by mutations in either the TGFBR1 or TGFBR2 gene [Loeys et al 2005, Loeys et al 2006].
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 mutations in the FBN2 gene (encoding fibrillin-2). Most affected individuals have "crumpled" ears, with a folded upper helix, and most have contractures of knees and ankles at birth, which 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. Dilatation of the aorta is occasionally 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). Familial 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.
Mutations in MYH11 and ACTA2 have been described in individuals with TAAD [Zhu et al 2006, Guo et al 2007].
It appears that in some families a small subset of mutations in TGFBR2 may associate with predominant vascular disease in the absence of overt features of Loeys-Dietz syndrome. However, some individuals with aTGFBR2 mutation have features of a systemic connective tissue disorder, and some TGFBR2 mutations associated with TAAD have been seen in classic Loeys-Dietz syndrome.
Additional locus heterogeneity is evident in TAAD, and additional loci have been described.
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, and smooth, velvety skin. Approximately 50% of individuals with classic EDS have an identifiable mutation in the COL5A1 or COL5A2 gene.
EDS, kyphoscoliotic form (previously known as EDS VI) is an autosomal recessive disorder characterized by kyphoscoliosis, joint laxity, muscle hypotonia, and, in some individuals, ocular problems. 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. Assay of lysyl hydroxylase enzyme activity in skin fibroblasts is also available. Molecular genetic testing of the PLOD gene that encodes the enzyme lysyl hydroxylase 1 is available on a research basis.
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 condition is caused by mutations in COL3A1; the diagnosis can be confirmed by observation of abnormal type III collagen biosynthesis by cultured dermal fibroblasts.
Homocystinuria is an autosomal recessive disorder caused by cystathionine β-synthase deficiency resulting from mutations in the CBS gene. The disorder is characterized by variable mental retardation, 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 is an autosomal dominant connective tissue disorder that 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. Mutations affecting one of three genes (COL2A1, COL11A1, and COL11A2) have been associated with Stickler syndrome.
Fragile-X syndrome is an X-linked disorder characterized by moderate mental retardation in affected males and mild mental retardation 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 the FMR1 gene caused by an increased number of CGG trinucleotide repeats (>200 typically) accompanied by aberrant methylation of the FMR1 gene.
To establish the extent of disease 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 to see nomograms. 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).
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 orthodonture 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 exceeds 5.0 cm in adults or older children, (2) the rate of increase of the aortic diameter approaches 1.0 cm per year, or (3) there is progressive 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.
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.
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 less than 110 in young children or less than 100 in older children or adults.
Verapamil is commonly used if beta-blockers cannot be used (e.g., in individuals with asthma) or are not tolerated (e.g., prolonged lethargy, depression).
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 theoretical 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.
Judicious use of subacute bacterial endocarditis (SBE) prophylaxis is indicated for dental work or other procedures expected to contaminate the bloodstream with bacteria.
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:
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.
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.
LASIK correction of visual deficits
For individuals at risk for recurrent pneumothorax, breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving)
Relatives of an individual with Marfan syndrome should be evaluated for signs of the disorder.
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 testing of at-risk relatives for genetic counseling purposes.
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 showed the ability to prevent aneurysm in Marfan mice. A small observational study showed an apparent protective effect of losartan in a subset of children with severe Marfan syndrome [Brooke et al 2008]. A large multicenter clinical trial of losartan in Marfan syndrome is ongoing and will be needed to definitively assess the efficacy of this treatment [Lacro et al 2007].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
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. Pregnancy can be associated with the risk of more rapid dilation of the aorta or aortic dissection, either during pregnancy or in the immediate postpartum period. This is especially relevant to women who begin pregnancy with a maximal aortic dimension that exceeds 4.0cm.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Marfan syndrome is inherited in an autosomal dominant manner.
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 gene mutation.
It is appropriate to evaluate both parents for manifestations of Marfan syndrome by performing a comprehensive clinical examination and echocardiogram.
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
The risk to the sibs of the proband depends on the genetic status of the parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
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) cases of somatic and germline mosaicism.
Offspring of a proband
Each child of an individual with Marfan syndrome has a 50% chance of inheriting the mutation and the disorder.
The penetrance of disease-causing FBN1 mutations 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.
See Management for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation 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 (i.e., 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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk for Marfan syndrome is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation is analyzed. The disease-causing allele of 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.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| FBN1 | 15q21.1 | Fibrillin-1 | The FBN1 Gene Mutations Database The FBN1 mutations database |
FBN1 |
Normal allelic variants. The FBN1 gene is large (>600 kb) and the coding sequence is highly fragmented (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.
Pathologic allelic variants. More than 200 FBN1 mutations that cause Marfan syndrome or related phenotypes have been described [Vollbrandt et al 2004]. No common mutation exists in any population. (For more information, see Table A: locus-specific databases and HGMD.)
Normal gene product. Fibrillin-1 is an extracellular matrix protein that contributes to large structures called microfibrils. Microfibrils are found in both elastic and nonelastic 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. 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].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
No specific guidelines regarding genetic testing for this disorder have been developed.
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.
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
