DiagnosisClinical DiagnosisMarfan syndrome is a clinical diagnosis based on family history and the observation of characteristic findings in multiple organ systems. Diagnostic CriteriaThe recently 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 (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 lentisA pathogenic FBN1 mutation ^{2A systemic score ≥7 3Ectopia lentis and a FBN1 mutation previously associated with aortic enlargementIn 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 lentisSystemic score ≥7 3Aortic root enlargement (Z-score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years) 3Notes: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): Mutation 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 mutationIn-frame or out-of-frame deletion/insertionSplice site mutation that alters the splice consensus sequence or is shown to alter splicingMissense 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 if possible + absence in 400 ethnically matched control chromosomesIf no family history, absence in 400 ethnically matched control chromosomesLinkage 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 mutation testing of TGFBR1, TGFBR2, SMAD3, or COL3A1 may be indicated.Table 1. Calculation of the Systemic ScoreView in own windowFeatureValueEnter Value if PresentWrist AND thumb sign  3 Wrist OR thumb sign 1 Pectus carinatum deformity 2 Pectus excavatum or chest asymmetry 1 Hindfoot deformity 2 Plain flat foot (pes planus) 1 Pneumothorax 2 Dural ectasia 2 Protrusio acetabulae 2 Reduced upper segment / lower segment AND increased arm span/height ratios 1 Scoliosis or thoracolumbar kyphosis 1 Reduced elbow extension 1 3 of 5 facial features 1 Skin striae 1 Myopia 1 Mitral valve prolapse 1 TotalA 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 with compatible but insufficient physical manifestations of Marfan syndrome under age 20 years. 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 FBN1 mutation), use of the term “non-specific connective tissue disorder” is suggested until follow-up echocardiographic evaluation shows aortic root dilation (Z-score ≥3). If an FBN1 mutation 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.TestingProtein-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 TestingGene. FBN1 is the only gene in which mutations are known to cause 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 individuals with a TGFBR2 mutation and a clinical diagnosis of Marfan syndrome. Two individuals with a TGFBR2 mutation 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 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 a detectable FBN1 mutation); (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/duplication 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 perform assays aimed at detecting large deletions if sequence analysis or mutation scanning does not detect a mutation. 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 in the range of approximately 30% [Baetens et al 2011]. 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 FBN1; 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 possible in 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. Table 2. Summary of Molecular Genetic Testing Used in Marfan SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFBN1Mutation scanning / sequence analysisSequence variants 2~70%-93%ClinicalComplementary DNA sequence analysisDeletion / duplication analysis 3Exonic and whole-gene deletionsUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. 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. Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).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 a FBN1 mutation 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). Alternative 1 – single gene testing. The most common strategy for molecular diagnosis of a proband suspected of having Marfan syndrome is gDNA sequencing followed by deletion/duplication analysis if a mutation is not identified by sequence analysis.Alternative 2 – 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 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 causative mutation or mutations 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 have the highest probability; that 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. Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing FBN1 mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the FBN1 disease-causing mutation in the family. Genetically Related (Allelic) DisordersOther 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 (p.Cys1223Tyr and p.Cys1221Tyr) suggesting a potential phenotype-genotype correlation. There is documented locus heterogeneity, with many affected individuals shown not to have a mutation in FBN1 [Robinson et al 2005].Autosomal dominant Weill-Marchesani syndrome; includes ectopia lentis in the context of microspherophakia, short stature, brachydactyly and the absence of vascular manifestations of Marfan syndrome [Faivre et al 2003]Stiff skin syndrome. Four families showing autosomal dominant inheritance of congenital scleroderma were found to harbor heterozygous missense mutations in the fourth 8-cysteine domain of fibrillin-1 encoded by exon 38 of FBN1 [Loeys et al 2010b]. This is the only domain in fibrillin-1 that encodes an RGD sequence that mediates cell attachment via integrin binding. Individuals with stiff skin syndrome are relatively short and do not show any phenotypic manifestations of Marfan syndrome.Geleophysic dysplasia-2 and acromicric dysplasia: related skeletal dysplasias found to be caused by heterozygous mutations in the fifth 8-cysteine domain of fibrillin-1 [Le Goff et al 2011]}

Natural HistoryMarfan 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. 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 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 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.OtherDura. Stretching of the dural sac in the lumbosacral region (dural ectasia) can lead to bone erosion and nerve entrapment. Symptoms include low back pain, proximal leg pain, weakness and numbness above and below the knees, and genital/rectal pain. Leaking of CSF from a dural sac can cause postural drop in CSF pressure and headache [Foran et al 2005]. Skin. Manifestations in the skin and integument include hernias and skin stretch marks (striae distensae). Individuals can show a paucity of muscularity and fat stores despite adequate caloric intake.Lung bullae can develop, especially of the upper lobes, and can predispose to spontaneous pneumothorax. Increased total and residual lung volume and reduced peak oxygen uptake have been demonstrated, with reduced aerobic capacity [Giske et al 2003]. Pregnancy can be dangerous for women with Marfan syndrome, especially if the aortic root exceeds 4.0 cm. Complications include rapid progression of aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, and the postpartum period. Self-image. The vast majority of affected individuals 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 CorrelationsFew 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, 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 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 presentations such as mitral valve prolapse syndrome.

Differential DiagnosisMany 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 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. 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 mutations in 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 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. This phenotypic designation is appropriate if the aortic root Z-score is less than 2.0 and the patient does not have an FBN1 mutation 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 mutations 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 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 individuals 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 TGFBR1 or TGFBR2 [Loeys et al 2005, Loeys et al 2006]. Mutations 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].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 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. Mutations in MYH11, ACTA2, and MYLK have been described in individuals with TAAD [Zhu et al 2006, Guo et al 2007, Wang et al 2010]. 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 COL5A1 or COL5A2.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 possible. Mutations in PLOD (encoding the enzyme lysyl hydroxylase 1) are 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 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 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 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 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Classic Marfan syndromeEarly-onset Marfan syndrome

ManagementEvaluations Following Initial DiagnosisTo 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 amblyopiaSpecific assessment for glaucoma and cataract Evaluation for skeletal manifestations that may require immediate attention by an orthopedist (e.g., severe scoliosis) EchocardiographyAortic 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). Medical genetics consultationTreatment of ManifestationsManagement 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 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. Prevention of Primary ManifestationsMedications 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 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). Very little data exist that document either the efficacy or safety of this approach in people with Marfan syndrome. 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 ComplicationsJudicious 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. SurveillanceEye. 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. Agents/Circumstances to AvoidThe 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)Evaluation of Relatives at RiskRelatives 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 mutation 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. 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 when compared to prior medical therapy including both beta-blockers and ACE inhibitors [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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFBN115q21​.1Fibrillin-1FBN1 @ LOVDFBN1Data 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) View in own window 134797FIBRILLIN 1; FBN1 154700MARFAN SYNDROME; MFSNormal allelic variants. FBN1 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 1,000 FBN1 mutations that cause Marfan syndrome or related phenotypes have been described [Vollbrandt et al 2004, Faivre et al 2007]. No common mutation 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 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. 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].