Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders

INTRODUCTION — One of the most common inherited disorders of connective tissue, Marfan syndrome (MFS, MIM #154700) is a predominantly autosomal dominant condition with a reported incidence of 1 in 3000 to 5000 individuals [1,2]. There is a broad range of clinical severity associated with MFS and related disorders, ranging from isolated features of MFS to neonatal presentation of severe and rapidly progressive disease involving multiple organ systems [3]. Although many clinicians view the disorder in terms of classic ocular, cardiovascular, and musculoskeletal abnormalities (picture 1), manifestations also include involvement of the lung, skin, and central nervous system.

The genetics, pathogenesis, clinical manifestations, and diagnosis of MFS and related disorders will be reviewed here. The management of patients with MFS and related disorders and issues related to pregnancy are discussed separately. (See "Management of Marfan syndrome and related disorders" and "Heritable thoracic aortic diseases: Pregnancy and postpartum care".)

GENETICS

Overview — MFS is a highly variable systemic tissue disorder with clinical characteristics similar to a variety of other hereditary disorders from which it should be distinguished. MFS is almost exclusively inherited in an autosomal dominant manner, although rare case reports have described recessive fibrillin 1 gene (FBN1) mutations [4]. While most individuals with MFS have an affected parent, 25 percent or more of probands have MFS as the result of a de novo mutation.

Most patients with the typical Marfan phenotype harbor mutations involving the gene (FBN1) encoding the connective tissue protein fibrillin-1 [5-7]. However, FBN1 mutations also cause a wide range of milder phenotypes that often show at least some overlap with the classic Marfan phenotype. (See 'Genotypes and phenotypes' below.)

In a minority of cases (less than 10 percent) with typical Marfan phenotype, no mutation in FBN1 is identified [3]. Studies have suggested that at least some of these cases are due to a complete allele deletion, more complex rearrangements, or alterations in regulatory sequences involving the FBN1 gene. In some of these individuals with atypical presentations reminiscent of MFS, an inactivating mutation in a gene encoding for transforming growth factor-beta receptor (TGFBR) may be responsible. (See 'TGFBR mutations' below.)

Mutations involving a second fibrillin protein, fibrillin-2 (encoded by the FBN2 gene located on chromosome 5), have been linked to a phenotype different from MFS, congenital contractural arachnodactyly (Beals syndrome). (See 'Congenital contractural arachnodactyly' below.)

FBN1 mutations

Genotypes and phenotypes — Since the first report of an FBN1 mutation in 1991, more than 1800 different mutations involving this protein have been registered for MFS and associated disorders in the Universal Mutation Database for FBN1 (UMD-FBN1). FBN1 is a large gene (65 exons) located at chromosome 15q21.1. The fibrillin-1 protein contains many cysteine-rich domains homologous to those observed in epidermal growth factor (EGF) and the latent transforming growth factor beta binding proteins (LTBPs) [8,9]. Fibrillin-1 is an important matrix component of both elastic and nonelastic tissues. It is the main constituent protein of extracellular microfibrils that are thought to contribute to the formation and maintenance of elastic fibers [10,11].

The majority of FBN1 mutations are nonrecurrent and distributed throughout the gene without striking phenotype-genotype correlations. One possible exception involves apparent clustering of mutations between exons 24 and 32 associated with cases of severe rapidly progressive MFS (previously known as “neonatal MFS”) [12]. However, some patients with severe MFS lack mutations in this region and many patients with mutations in this region have classic or mild variants of MFS [3].

As a general rule, patients with exon skipping tend to have more severe disease, while those showing premature termination causing reduced levels of mutant transcript and protein can show milder disease, often with absence of ectopia lentis [13]. Some families have members with both classic MFS and a milder but related phenotype without aortic involvement [14]. Rare patients with FBN1 mutations have one predominant manifestation such as isolated ectopia lentis syndrome, isolated ascending aortic aneurysm and/or dissection, or isolated skeletal features and do not meet criteria for MFS [15,16]. These phenotypic differences may be due to presence of a combination of genetic alterations rather than single FBN1 mutations and/or the influence of genetic modifiers.

Causal FBN1 mutations — Criteria have been developed to identify FBN1 mutations that are likely causal and thus can contribute to the diagnosis of MFS when used together with other criteria [17] (see 'Approach to diagnosis of MFS' below):

●A mutation previously shown to segregate with disease in a family with MFS; the degree of confidence in the association is proportional to the size of the family and the number of affected individuals that were genotyped.

●De novo mutation in association with sporadic disease (proven paternity and absence of disease in parents) in one of five categories:

•Nonsense variant.

•In-frame and out-of-frame deletion/insertion.

•Splice site mutation affecting canonical splice sequence or shown to alter splicing on the mRNA/cDNA level.

•Missense mutation substituting/creating cysteine residues.

•Missense mutation affecting conserved residues of the EGF consensus sequence (D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) with m and n representing variable numbers of residues; D aspartic acid, N asparagine, E glutamic acid, Q glutamine, Y tyrosine, and F phenylalanine.

●Hereditary missense mutation which is exceedingly rare or absent from databases of variation in an unselected population (eg, Exome Variant Server [EVS] or the Genome Aggregation Database [Gnomad]), with segregation in family, if possible to determine.

The potential pathogenicity of other de novo or hereditary missense variants that substitute evolutionarily conserved residues should not be excluded, but would require additional evidence.

TGFBR mutations

Genotypes and phenotypes — A minority of patients with the Marfan phenotype have no identifiable mutation in the FBN1 gene. Mutations in TGF-beta receptor 2 (TGFBR2) and TGFBR1 genes have been linked to the Marfan phenotype in some patients and may be responsible for up to 10 percent of cases with the Marfan phenotype [7,18,19].

A spectrum of clinical features and outcomes are seen in patients with TGFBR1 or TGFBR2 mutations [20,21]. Some individuals with TGFBR1 or TGFBR2 mutations have clinical features consistent with MFS, while others have features of one of two other syndromes: Loeys-Dietz syndrome (LDS) or familial thoracic aortic aneurysm (FTAA) syndrome. Autosomal dominant inheritance with variable penetrance has been observed in families with a variety of TGFBR mutations [20]. There are no apparent phenotype-genotype correlations and the identical mutations described as causing MFS are observed in patients and families with classic and severe LDS, including widespread and aggressive vascular disease. Some experts have proposed that patients with the Marfan phenotype and TGFBR1 or TGFBR2 mutations be classified as having LDS (rather than MFS) as a means of highlighting the potential for more aggressive vascular disease than seen in MFS with an FBN1 mutation [3,17].

The degree of aortic dilatation in individuals with TGFBR1 or TGFBR2 mutations is highly variable, and aortic dissection in patients with normal aortic diameters has been reported in some series but not others [20,21]. Skeletal features are also variable.

Most patients with a TGFBR1 or TGFBR2 mutation have Loeys-Dietz syndrome which is described below. (See 'TGFBR1 or TGFBR2 mutation: Loeys-Dietz syndrome' below.)

HISTOPATHOLOGY — Histologic features of the medial layer of the aortic root in patients with MFS include fragmentation of elastic lamellae, cystic medial necrosis, fibrosis, and loss of smooth muscle cells [22-26]. The term cystic medial necrosis was coined by Erdheim to describe the lacunar appearance of medial degeneration in MFS; however no actual cysts or overt necrosis is present [22,23]. Cystic medial necrosis and the other histologic findings are not specific for MFS, although greater elastin fragmentation has been described in patients with aortic root aneurysms with MFS compared to those without a connective tissue diagnosis; this distinction may not apply in patients with other vascular connective tissue disorders [22,23,26]. The histologic changes are thought to reflect injury and repair [23].

PATHOGENESIS — How FBN1 or TGFBR mutations lead to disease is not well understood at a molecular level. Proposed mechanisms include the following:

●A structural role of microfibrils in coordinating tissue morphogenesis, homeostasis, and/or response to hemodynamic stress [27].

●Increased bioavailability of transforming growth factor (TGF)-beta [28].

Support for the importance of TGF-beta signaling comes from study of an animal model of an FBN1-targeted mouse model of MFS as well as clinical studies in which inhibition of TGF-beta attenuated the clinical manifestations of the disease [29-32]. The administration of the angiotensin II type 1 receptor blocker losartan (an antagonist of TGF-beta signaling) in a mouse model prevented aortic dilation and improved disease manifestations in the aortic wall and the lungs [29]. This effect was not due to altered hemodynamics since a similar benefit was not seen with a beta blocker, which is used clinically to slow the rate of aortic growth. (See "Management of Marfan syndrome and related disorders", section on 'Beta blocker'.) Clinical evidence for this mechanism was provided by two randomized controlled trials in which losartan therapy reduced the rate of aortic root dilatation [31,32]. In addition, many conditions with pronounced clinical overlap with MFS are caused by primary mutations in genes encoding direct effectors and/or regulators of TGF-beta signaling, including Loeys-Dietz syndrome caused by heterozygous mutations in TGFBR1, TGFBR2, SMAD3, or TGFB2 (LDS1-4, respectively); and Shprintzen-Goldberg syndrome (SGS) caused by heterozygous loss-of-function mutations in SKI that encode a prototypical repressor of TGF-beta signaling. (See "Management of Marfan syndrome and related disorders", section on 'Renin-angiotensin system antagonist'.)

CLINICAL MANIFESTATIONS OF MFS

Aortic disease — Aortic root disease, leading to aneurysmal dilatation (figure 1), aortic regurgitation, and dissection, is the main cause of morbidity and mortality in MFS (movie 1 and image 1A-D) [33]. There can be poor correlation between the severity of the cardiovascular and the ocular or skeletal manifestations [34]. Although dilated, the aorta in MFS tends to be stiffer and less distensible than in controls, and these changes increase with age [35-38].

Dilatation of the aorta is found in approximately 50 percent of young children with MFS (characterized by abnormal Z-score) and progresses with time. Approximately 60 to 80 percent of adult patients with MFS have dilatation of the aortic root (with normal range adjusted for patient body surface area and age) by echocardiography [39], often accompanied by aortic regurgitation [34]. Importantly, all patients diagnosed with MFS using the revised criteria [17] must have aortic root dilatation, a family history of aortic root dilatation, or an FBN1 mutation previously associated with aortic root dilatation, highlighting the strong predisposition for emergence of vascular disease. Dilatation may also involve other segments of the thoracic aorta, the abdominal aorta, the root of the pulmonary artery or even the carotid and intracranial arteries, although this is much less frequent than observed in LDS.

As recommended in the 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery thoracic aorta guidelines, echocardiography is recommended at initial diagnosis and at six months to assess the aortic root and ascending aorta in patients with MFS [40]; the six-month echocardiogram is performed to confirm stability of the aortic dimension. The normal range for aortic diameter varies with body size and age, so nomograms and Z-scores are used to identify aortic dilatation [17,41]. Monitoring should be performed at least annually as discussed separately. Most centers perform cross-sectional aortic imaging with computed tomography (CT) or magnetic resonance imaging (MRI) at the first visit to confirm that the size of the ascending aorta measured by echocardiography is not underestimated, and also to identify aortic or vascular disease that is not appreciated by echocardiography. (See "Management of Marfan syndrome and related disorders", section on 'Monitoring MFS'.)

Undiagnosed and untreated MFS is frequently associated with aortic dissection (image 2 and image 1D). The dissection generally begins just above the coronary ostia and can extend the entire length of the aorta; it is a type I dissection in the DeBakey classification or a type A in the Dailey scheme. Approximately 10 percent of dissections begin distal to the left subclavian (type III or type B) but dissection is rarely limited to just the abdominal aorta. Many patients with MFS and aortic dissection have a family history of dissection. (See "Clinical features and diagnosis of acute aortic dissection".)

The frequency with which MFS is responsible for aortic dissection was addressed in a review from the International Registry of Aortic Dissection (IRAD) [42]. The frequency varied with age. MFS was present in 50 percent of those under age 40, compared to only 2 percent of older patients with aortic dissection and, in another report from IRAD, no patient over age 70 [43]. The potential for these observations to be influenced by age-specific ascertainment bias should be considered.

The degree of aortic disease also has implications for women who would like to become pregnant and for management during pregnancy. These issues are discussed separately. (See "Heritable thoracic aortic diseases: Pregnancy and postpartum care".)

Cardiac disease — Mitral valve prolapse (MVP) is frequently identified in patients with MFS (eg, 40 and 54 percent in two series of MFS patients [44,45]). However, only one point in the systemic score is assigned for MVP since it is a nonspecific feature and most patients with MVP do not have MFS [39]. The frequency of MVP in MFS increases with age and is greater in women. Tricuspid valve prolapse may also occur. (See "Mitral valve prolapse: Clinical manifestations and diagnosis".)

On echocardiography, the mitral leaflets have an elongated and redundant appearance and either or both leaflets may prolapse. Patients with MFS and MVP have mitral regurgitation ranging from none to severe, with most having mild or less regurgitation [44]. Approximately 25 percent of patients with MVP have progressive disease as defined by the appearance or worsening of clinical symptoms of mitral regurgitation or worsening on echocardiography. In some of these cases, worsening of mitral regurgitation is due to spontaneous rupture of the chordae tendineae or the result of infective endocarditis. Heart failure attributable to mitral valve prolapse and regurgitation represents a major source of morbidity and mortality in young children with the most extreme and rapidly progressive presentation of MFS. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet", section on 'Natural history of mitral valve prolapse'.)

Care should be taken to distinguish MFS from MVP syndrome, which is defined as MVP associated with a limited systemic features score (<5), as discussed below. (See 'Mitral valve prolapse syndrome' below.)

Some reports suggest that a subset of patients with MFS may have a cardiomyopathy with biventricular enlargement and systolic dysfunction that is usually mild, asymptomatic, and unrelated to valvular disease [46]. However, rare patients with MFS may develop progressive heart failure requiring mechanical circulatory support or heart transplantation [47].

Skeletal findings — Individuals with MFS have excess linear growth of the long bones and joint laxity [3]. Individuals with MFS are taller than predicted by their genetic background (aside from the FBN1 mutation), which is generally, but not necessarily, tall compared to general population standards [48].

Paradoxically, some individuals with MFS have reduced joint mobility, particularly of the elbow and digits [3]. The presence of reduced elbow extension (≤170 degrees with full extension) contributes one point to the systemic score [17].

Among patients with MFS, pain is common (reported in 89 percent in one series), is a presenting symptom in nearly one-third of patients, and is a significant cause of disability [49].

●Arachnodactyly – Patients with MFS typically have arachnodactyly with positive thumb and wrist signs. A positive thumb sign indicates that the entire distal phalanx protrudes beyond the ulnar border of a clenched fist with or without the assistance of the patient or examiner to achieve maximum adduction (picture 2). A positive wrist sign means that the top of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist (picture 3). Three points are assigned if both thumb and wrist signs are positive; only one point is assigned if only one of these signs is positive.

Generalized joint hypermobility also may occur, producing findings that overlap with the much more common benign joint hypermobility syndrome. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

●Pectus deformity – Pectus carinatum is assigned two points since it is thought to be more specific for MFS than pectus excavatum or chest asymmetry, which is assigned one point [17]. (See "Pectus carinatum and arcuatum" and "Pectus excavatum: Etiology and evaluation".)

●Hindfoot valgus – Hindfoot valgus is assigned two points. It occurs with forefoot abduction and lowering of the midfoot and should be evaluated from anterior and posterior views. Pes planus (flat foot) without hindfoot valgus is assigned one point.

●Abnormal US/LS and arm span/height – Individuals with MFS have disproportionately long extremities in comparison to the length of the trunk (dolichostenomelia), so the upper segment to lower segment (US/LS) ratio is decreased and the arm span to height ratio is increased. In determining the US/LS ratio, the lower segment is defined as the distance from the top of the symphysis pubis to the floor in the standing position and the upper segment is the height minus the lower segment [17]. Thresholds for abnormal US/LS and arm span/height vary with age and ethnicity. Reduced US/LS is <0.85 for White adults and <0.78 for Black adults. For children, reduced US/LS is <1 for age 0 to 5 years, <0.95 for 6 to 7 years, <0.9 for 8 to 9 years, and <0.85 above age 10 years. Increased arm span to height ratio is >1.05 for White adults. Scoliosis can artifactually influence body measurements and hence ratios.

●Scoliosis and kyphosis – Presence of either of the following findings is diagnostic for scoliosis [17]:

•With the patient bending forward, observation of a vertical difference of ≥1.5 cm between the ribs of the left and right hemithorax.

•A Cobb’s angle (on an anterior-posterior radiographic view of the spine, the angle between a line drawn along the superior end plate of the superior end vertebra and a second line drawn along the inferior end plate of the inferior end vertebra of the scoliosis) of at least 20 degrees.

If scoliosis is absent, one point can be attributed to kyphosis if there is exaggerated kyphotic thoracolumbar spinal curvature.

●Protrusio acetabuli – Acetabular protrusion can be diagnosed by plain radiograph, CT, or MRI. On an anterior-posterior pelvic film, medial protrusion of the acetabulum ≥3 mm beyond the ilio-ischial (Kohler) line is diagnostic. Criteria on CT or MRI are not as precisely defined but involve loss of the normal oval shape of the pelvic inlet at the level of the acetabulum.

●Facial features – One point is added to the systemic score if at least three of the following five facial features are present: dolichocephaly (reduced cephalic index or head width/length ratio), enophthalmos, downslanting palpebral fissures, malar hypoplasia, and retrognathia.

Ocular abnormalities — Annual ophthalmologic evaluation is recommended for all patients with MFS. Urgent assessment is recommended for patients with sudden change in vision.

Ectopia lentis occurs in 50 to 80 percent with MFS [50]. The finding of iridodonesis (vibration of the iris with eye movement) on external inspection of the eye should raise the concern for ectopia lentis. Ectopia lentis is detected on slit-lamp examination after maximal dilatation of the pupil and the lens is usually displaced upward and temporally (picture 4). It is caused by failure of the supporting ciliary zonules.

Ectopia lentis is the only cardinal ocular criterion for MFS. (See 'Approach to diagnosis of MFS' below.) However FBN1 mutations have been identified in some patients with ectopia lentis who do not have MFS [51], so the ectopia lentis syndrome should be carefully distinguished from MFS. (See 'Ectopia lentis syndrome' below and "Ectopia lentis (dislocated lens) in children".)

The finding of myopia >3 diopters contributes one point to the systemic score. Patients with MFS develop secondary myopia due to increased axis globe length. Other ocular findings in MFS include flat cornea (measured by keratometry) [52], hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis, retinal detachment, glaucoma, and early cataract formation [3]. Retinal tears and detachment are commonly bilateral in MFS and may be associated with proliferative retinopathy [53].

Dural ectasia — Dural ectasia results from enlargement of the spinal canal owing to progressive ectasia of dura and neural foramina and to erosion of vertebral bone (image 3). This abnormality usually involves the lumbosacral spine and was identified in 63 and 92 percent of patients with MFS in case series using CT and MR scanning [54,55]. Dural ectasia is a sensitive but not specific sign of MFS and is commonly seen in Loeys-Dietz syndrome and Shprintzen-Goldberg syndrome and has been reported in the vascular form of Ehlers-Danlos syndrome. (See 'Differential diagnosis' below.)

Several modalities have been utilized to help identify dural ectasia, including CT scanning and MRI. The latter technique appears to be the most sensitive [55]. No correlation appears to exist between the severity of dural ectasia and the degree of aortic dilatation.

Pulmonary disease — Some patients with MFS develop emphysematous changes with lung bullae predominantly in the upper lobes, which can predispose to spontaneous pneumothorax (this finding contributes two points to the systemic score) (image 1B and image 2) [3,17,56]. Sleep disordered breathing has also been reported with increased frequency in patients with MFS [57].

Skin striae — The presence of striae atrophicae contributes one point to the systemic score if they are not associated with pronounced weight changes or pregnancy and if they have an uncommon location such as the mid back, lumbar region, upper arm, axillary region, or thigh [17].

Other — Recurrent or incisional herniae, joint hypermobility, and high arched palate may occur but are not included in the systemic score since these clinical features are considered nonspecific [17].

DIAGNOSIS OF MFS

Approach to diagnosis of MFS — MFS is most commonly diagnosed using the 2010 revised Ghent Criteria [17]. These are based on the presence or absence of family history, physical examination, imaging of the aorta, and genetic testing in some cases. (See 'Role of genetic testing' below.)

The revised Ghent nosology puts greater weight on aortic root dilatation/dissection and ectopia lentis as the cardinal clinical features of MFS and on testing for mutations in FBN1. For the aortic criteria, aortic root Z score calculators are available for children and adults.

In the absence of family history of MFS — For individuals without a family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:

•Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and ectopia lentis.* (See 'Ocular abnormalities' above.)

•Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and a causal FBN1 mutation as defined above. (See 'Causal FBN1 mutations' above.)

•Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and a systemic score ≥7.* (See 'Systemic score' below.)

•Ectopia lentis and a causal FBN1 mutation as defined above (see 'Causal FBN1 mutations' above) that has been identified in an individual with aortic aneurysm.

In the presence of family history of MFS

Criteria with family history — In the presence of family history of MFS (as defined by presence of the above criteria in a first-degree or second-degree relative), the presence of one of any of the following criteria is diagnostic for MFS:

•Ectopia lentis.

•Systemic score ≥7 points.*

•Aortic criterion (aortic diameter Z ≥2 above 20 years old, Z ≥3 below 20 years, or aortic root dissection).*

For criteria with an asterisk (*), the diagnosis of MFS can be made only after exclusion of other causes by the following evaluation:

●Examination for discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome (table 1).

●If testing for vascular Ehlers-Danlos is clinically indicated, COL3A1 testing is performed (with or without analysis of type III procollagen from fibroblasts). (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Vascular EDS'.)

●Loeys-Dietz syndrome and Shprintzen-Goldberg syndrome should be excluded through a comprehensive aneurysm panel that comprises TGFBR1/2, SMAD2/3, TGFB2/3, and SKI.

Systemic score — The revised Ghent nosology includes the following scoring system for systemic features in patients with a family history [17]:

●Wrist (picture 3) AND thumb sign (picture 2): 3 points (wrist OR thumb sign: 1 point). (See 'Skeletal findings' above.)

●Pectus carinatum deformity: 2 (pectus excavatum or chest asymmetry: 1 point). (See 'Skeletal findings' above.)

●Hindfoot deformity: 2 points (plain pes planus:1 point). (See 'Skeletal findings' above.)

●Pneumothorax: 2 points. (See 'Pulmonary disease' above.)

●Dural ectasia: 2 points. (See 'Dural ectasia' above.)

●Protrusio acetabuli: 2 points. (See 'Skeletal findings' above.)

●Reduced upper segment/lower segment ratio AND increased arm span/height AND no severe scoliosis: 1 point. (See 'Skeletal findings' above.)

●Scoliosis or thoracolumbar kyphosis: 1 point. (See 'Skeletal findings' above.)

●Reduced elbow extension (≤170 degrees with full extension): 1 point. (See 'Skeletal findings' above.)

●Facial features (at least three of the following five features: dolichocephaly [reduced cephalic index or head width/length ratio], enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia): 1 point. (See 'Skeletal findings' above.)

●Skin striae: 1 point. (See 'Skin striae' above.)

●Myopia >3 diopters: 1 point. (See 'Ocular abnormalities' above.)

●Mitral valve prolapse (all types): 1 point. (See 'Cardiac disease' above.)

A systemic score ≥7 indicates major systemic involvement.

Additional testing needed in children and young adults — Application of diagnostic criteria to individuals <20 years old, particularly those with sporadic disease, requires special care since additional clinical features may subsequently emerge.

The revised Ghent nosology recommends the following categories for individuals <20 years old with features of MFS who do not meet diagnostic criteria for MFS [17]:

●“Nonspecific connective tissue disorder” applies if the systemic score is less than 7 and/or aortic root measurements are borderline (Z <3) in the absence of an FBN1 mutation.

●“Potential MFS” applies if an FBN1 mutation is identified in a sporadic or familial cases but the aortic root Z-score is less than 3.

Individuals under 20 years of age with systemic findings suggestive of MFS but without cardiovascular involvement should have annual echocardiograms until they are at least 20 years old or have completed growth, whichever is later, due to the potential risk of development of aortic disease [17].

Role of genetic testing — Not all patients with suspected MFS require genetic testing given the cost and potential limitations. As discussed above, over 90 percent of patients with MFS have an identifiable FBN1 mutation [58]. Even in the presence of an FBN1 mutation, the diagnosis of MFS requires fulfillment of clinical diagnostic criteria. (See 'Genetics' above and 'Diagnosis of MFS' above.)

Genetic testing may be beneficial in the following circumstances:

●Identification of FBN1 mutation will change medical management of the affected patient.

●Identification of FBN1 mutation will change follow-up frequency of the affected patient.

●Identification of FBN1 mutation will help identify potentially affected family members.

●Identification of FBN1 mutation will facilitate prenatal diagnostic testing.

●Identification of another disorder (eg, Loeys-Dietz or familial aortic aneurysmal disease) will change medical or surgical management or follow-up for the affected patient.

Prenatal genetic testing is discussed separately. (See "Heritable thoracic aortic diseases: Pregnancy and postpartum care".)

Critique of the revised Ghent nosology — Among 180 adult patients with MFS according to the original Ghent criteria, 164 (91 percent) met criteria for MFS using the revised Ghent criteria [59]. In 13 of the 16 patients in which the diagnosis of MFS was rejected using the revised criteria, the reason for rejection was a Z-score of the aortic root <2, although the aortic diameter was greater than 40 mm in six of them. Although Z-score data are based on assuming a linear relationship between body surface area (BSA) and aortic root size [41], subsequent studies suggest that all aortic roots with diameter ≥ 40 mm are dilated [59]. In contrast to this position, however, other studies have documented aortic measurements in excess of 40 mm in unselected individuals with larger body size and age >40 years. Further work in this area should help to clarify this important issue.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for MFS includes a variety of conditions with phenotypic features that partially overlap the Marfan phenotype including other disorders associated with FBN1/2 or TGFBR1/2 mutations as well as a variety of other disorders (table 1). As noted above, exclusion of MFS is particularly difficult in individuals <20 years old and thus repeated testing is required. (See 'Additional testing needed in children and young adults' above.)

Genetically similar disorders

FBN1 phenotypes — Although most patients with MFS have an identifiable FBN1 mutation, some patients with an FBN1 mutation have one or more features of MFS (eg, autosomal dominant form of ectopia lentis syndrome) but do not meet criteria for MFS. Other diseases associated with FBN1 mutations are Shprintzen-Goldberg syndrome, Weill-Marchesani syndrome, and stiff skin syndrome. As described above, follow-up testing is required to exclude MFS in individuals <20 years old with an FBN1 mutation who have an aortic root Z-score <3. (See 'Additional testing needed in children and young adults' above.)

TGFBR1 or TGFBR2 mutation: Loeys-Dietz syndrome — Most patients with a TGFBR1 or TGFBR2 mutation have Loeys-Dietz syndrome, which is often characterized by hypertelorism (widely spaced eyes), a split uvula or cleft palate, tortuous arteries, and aortic aneurysms [19,20]. Associated findings may include premature fusion of the skull, cervical spine deformity and instability [60], structural heart disease, and aneurysms affecting vessels other than the aorta. LDS-like phenotypes have also been reported in patients with heterozygous mutations in SMAD3, TGFB2, and TGFB3.

The prognosis in patients with LDS is variable and appears to depend upon clinical disease expression as well as treatment [20,21]. Initial reports documented more widespread and aggressive vascular disease, earlier ages of surgery and dissection, and earlier mortality in patients with the full clinical spectrum of LDS, when compared to MFS. However, different observations were made in 71 individuals who were diagnosed with TGFBR2 mutations in adulthood, when compared with 50 age- and sex-matched unaffected family members (controls) and 243 patients with FBN1 mutations [21]. Seven (10 percent) patients with TGFBR2 mutations met diagnostic criteria for MFS, including two who had equivocal features suggestive of ectopia lentis.

●The frequency of aortic dilation was similar in the TGFBR2 and FBN1 groups (78 and 79 percent).

●The two groups also had a similar incidence and average age for both thoracic aortic surgery (31 versus 27 percent and 35 versus 39 years) and aortic dissection (14 versus 10 percent and 38 versus 39 years).

●The TGFBR2 group had a lower rate of mitral valve disease (myxomatous, prolapse, or regurgitation).

●The mortality rate was higher in TGFBR2 than FBN1 families if patients who were not treated were included; the difference in mortality rate disappeared if only treated patients were included.

These observations highlight the importance of considering ascertainment bias when considering the natural history of disease.

Disorders that may be genetically similar — The ectopia lentis syndrome, MASS phenotype, and mitral valve prolapse syndrome each include some features of MFS but do not meet diagnostic criteria for MFS [17]. These should be distinguished from MFS with care since emerging MFS may include similar features.

Ectopia lentis syndrome — An autosomal dominant form of familial ectopia lentis syndrome (ELS) is caused by FBN1 mutations and recessive forms are caused by LTBP2 and ADAMTSL4 mutations [17]. The revised Ghent criteria for ELS are ectopia lentis with or without systemic features and either an FBN1 mutation not known to be associated with aortic dilatation/dissection or no FBN1 mutation.

Thus, the syndrome includes some skeletal features of MFS as well as ectopia lentis but does not include aortic aneurysm. MFS rather than ELS should be diagnosed if the patient has aortic dilation, family history of aortic dilation or aneurysm, or an FBN1 mutation previously associated with aortic dilation [17]. It can be difficult to distinguish ELS from emerging MFS since aortic aneurysm may emerge later, so vigilance for aortic aneurysm is required and the diagnosis of ELS cannot be made before the patient is 20 years of age.

MASS phenotype — MASS phenotype is a familial disorder that includes the following features that partially overlap with MFS: mitral valve prolapse, borderline but no progressive aortic dilatation, striae atrophica, and at least one skeletal feature [61]. The revised Ghent criteria for diagnosis of MASS are an aortic diameter Z <2 and systemic score ≥5 including at least one skeletal feature and absence of ectopia lentis [17].

The MASS phenotype is most difficult to distinguish from emerging MFS in a young individual without a contributory family history and careful follow-up is required for appropriate diagnosis [2]. FBN1 mutations have been found in some patients with the MASS phenotype [62] but the potential risk of progression to aortic complications has not been characterized.

Mitral valve prolapse syndrome — The revised Ghent criteria for mitral valve prolapse syndrome (MVPS) are mitral valve prolapse and systemic features (score <5) and aortic diameter Z <2 and absence of ectopia lentis [17]. Some common systemic features are pectus excavatum, scoliosis, and mild arachnodactyly.

Other disorders with similar phenotypes

Congenital contractural arachnodactyly — Mutations in the FBN2 gene, the gene encoding the extracellular matrix protein fibrillin-2, have been described in patients with congenital contractural arachnodactyly (CCA, MIM# 121050, Beals-Hecht or Beals syndrome), which is an autosomal dominant disorder characterized by a marfanoid habitus with arachnodactyly, kyphosis/scoliosis, contractures of knees and ankles, flexion contractures of the proximal interphalangeal joints of the fingers and toes (camptodactyly), and crumpled ears (folded upper helix) [17,50,63,64]. Rare individuals with this syndrome have mild enlargement of the sinuses of Valsalva that does not progress to aortic dissection.

Homocystinuria — Homocystinuria is associated with a Marfanoid body habitus and severe myopia and/or ectopia lentis, although the lens is typically dislocated downward rather than upward as in MFS [17]. Distinguishing features of homocystinuria include intellectual disability and thrombotic events. The diagnosis of homocystinuria can be established or excluded by measuring homocystine levels [65]. (See "Ectopia lentis (dislocated lens) in children", section on 'Genetic causes'.)

Certain Ehlers Danlos types — A number of forms of Ehlers Danlos syndrome (EDS) are associated with joint hypermobility. Arterial aneurysms and dissection are seen particularly in EDS vascular type. EDS is discussed in detail separately. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes" and "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Differential diagnosis'.)

Stickler syndrome — Type II and type XI collagen mutations have been identified in the Stickler syndrome [66,67].

Additional disorders in the differential diagnosis

●Congenital bicuspid aortic valve disease with associated aortopathy. Aortic dilation may involve primarily the aortic root or the mid-ascending aorta.

●Aortic coarctation with associated ascending aortic enlargement.

●Familial thoracic aortic aneurysm or aortopathy.

EVALUATION FOLLOWING DIAGNOSIS OF MFS OR RELATED DISORDERS

Imaging those at risk for aortic enlargement — The differential diagnosis for MFS includes other conditions associated with aortic complications. Patients with Loeys-Dietz syndrome (LDS) or a genetic mutation known to predispose to aortic aneurysms/dissections (TGFBR1, TGFBR2, FBN1, ACTA2, or MYH11) should undergo complete aortic imaging at initial diagnosis and six months thereafter to establish if enlargement is occurring, as recommended in the 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery guidelines [40]. Monitoring is discussed separately. (See "Management of Marfan syndrome and related disorders", section on 'Aortic monitoring'.)

As noted above, individuals under 20 years of age with systemic findings suggestive of MFS but without cardiovascular involvement should also have annual echocardiograms until they reach at least 20 years of age or have stopped growing, whichever is later due to the potential risk of rapid development of aortic disease [17]. Adults with repeatedly normal aortic root measurements can be seen at two- to three-year intervals.

Long-term aortic monitoring of patients with MFS or related disorders is discussed separately. (See "Management of Marfan syndrome and related disorders", section on 'Aortic monitoring'.)

Screening relatives — Recommendations for screening relatives are also included in the 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery guidelines [40]. First-degree relatives of patients with a gene mutation associated with aortic aneurysms and/or dissection (eg, FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) should undergo counseling and genetic testing. Those found to have the genetic mutation should then undergo aortic imaging. (See "Genetic testing".)

The risk of Marfan syndrome (MFS) in the siblings of an individual with MFS depends upon whether a parent has MFS [3]. If a parent has MFS, the risk of MFS in a sibling is 50 percent. If neither parent has MFS, the risk of MFS in a sibling is far less than 50 percent (since the mutation in the proband is likely de novo) but greater than general population risk since there are rare cases of somatic and germline mosaicism which could lead to MFS in siblings without manifestation of MFS in the parents.

For patients with aortic aneurysm and/or dissection without a known mutation, aortic imaging is recommended for first-degree relatives to identify those with asymptomatic disease. If one or more first-degree relatives are found to have thoracic aortic dilatation, aneurysm, or dissection, then imaging of second-degree relatives is reasonable.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Aortic dissection and other acute aortic syndromes" and "Society guideline links: Marfan syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Marfan syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Genetics – Marfan syndrome (MFS) is caused by a variety of mutations in the FBN1 gene.

•FBN1 mutations – These have been identified in over 90 percent of patients with MFS. (See 'FBN1 mutations' above.)

However, some patients with FBN1 gene mutations do not have MFS and instead have a related disorder such as ectopia lentis syndrome or other diseases such as Shprintzen-Goldberg syndrome, Weill-Marchesani syndrome, or stiff skin syndrome (table 1). (See 'FBN1 phenotypes' above.)

•Absence of defined FBN1 mutation – About 10 percent of individuals with suspected MFS have no defined FBN1 mutation. Some of these individuals may have TGFBR1 or TGFBR2 mutations. TGFBR1/TGFBR2 mutations more typically cause Loeys-Dietz syndrome (LDS), with rare reports in association with familial thoracic aortic aneurysm (FTAA) syndrome. We suggest categorizing individuals with the Marfan phenotype with a TGFBR1 or TGFBR2 mutation as LDS since they may be at risk for more aggressive vascular disease than seen in MFS. (See 'TGFBR mutations' above and 'Differential diagnosis' above.)

●Diagnosis – The presence of a likely causal FBN1 mutation in combination with certain clinical features lends strong support to the diagnosis of MFS. The diagnosis of MFS in familial and sporadic cases is based upon the presence of characteristic manifestations, particularly aortic root dilatation/dissection and ectopia lentis, as well as other systemic features including skeletal findings, mitral valve prolapse, dural ectasia, pneumothorax, and skin striae. (See 'Approach to diagnosis of MFS' above.)

•Identifying aortic dilation – The aortic root Z-score is used to identify aortic dilatation since aortic size varies with body size. However, use of Z-scores may underestimate aortic size, particularly in individuals with large body surface area. (See 'Aortic disease' above and 'Critique of the revised Ghent nosology' above.)

●Young individuals – Application of diagnostic criteria to individuals <20 years old requires special care since some clinical features may have not yet emerged. (See 'Additional testing needed in children and young adults' above.)

●Differential diagnosis – The differential diagnosis for MFS includes a variety of conditions with phenotypic features that partially overlap the Marfan phenotype, including disorders associated with FBN1/2 or TGFBR1/2 mutations, as well as a variety of other genetic disorders (table 1). (See 'Differential diagnosis' above.)

●Screening relatives (see 'Screening relatives' above)

•Of those with a known mutation – First-degree relatives of patients with a gene mutation associated with aortic aneurysms and/or dissection (eg, FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) should undergo counseling and genetic testing. Those found to have the genetic mutation should then undergo aortic imaging.

•Of those with aortic disease – For patients with aortic aneurysm and/or dissection without a known mutation, aortic imaging is recommended for first-degree relatives to identify those with asymptomatic disease. If one or more first-degree relatives are found to have thoracic aortic dilatation, aneurysm, or dissection, then imaging of second-degree relatives is reasonable.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Catherine M Otto, MD, who contributed to earlier versions of this topic review.