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  Disease summary:

  
  
  
  
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    Marfan syndrome (MFS) is a relatively common heritable disorder of connective tissue that affects many tissues and organs, most prominently the ocular, cardiovascular, and musculoskeletal systems. The natural history predicts early demise, typically from aortic dissection. However, advances in medical and surgical management over the past three decades have extended life expectancy to near normal.

  
  

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  Hereditary basis:

  
  
  
  
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    MFS is an autosomal dominant condition found in all populations. Reproduction is affected in the most severe cases, so sporadic cases represent one-quarter to one-third of all cases. Most cases (>95%) are due to mutations in FBN1, the product of which is a large glycoprotein in the extracellular matrix, especially elastic fibers. The molecule also functions to stabilize the latent transforming growth factor beta (TGFβ) complex, so the pathogenesis to an important extent involves excess canonical and noncanonical signaling.

    
    
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    MFS shows no ethnic predilection and occurs at a prevalence of at least 1 per 3 to 5000.

  
  

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  Differential diagnosis:

  
  
  
  
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    A number of syndromes include ectopia lentis, including an autosomal dominant form due to mutations in FBN1 with mild MFS-like skeletal features but no involvement of the aorta.

    
    
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    Isolated dilatation of the aortic root can occur in the absence of other features of MFS. Dilatation of the ascending aorta, typically of the mid portion more than the sinuses, often accompanies a bicuspid aortic valve. Dilatation, dissection, or both of any portion of the aorta can be inherited as an autosomal dominant trait and can be due to mutations in a growing list of genes (FBN1, TGFBR1, TGFBR2, ACTA2, MY11, SMAD3, COL3A1).

    
    
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    Many individuals have some features of MFS but fail to meet the revised Ghent criteria. If the individual is a child, then features sufficient to diagnose MFS may emerge with time, and a diagnosis of emerging MFS is useful to ensure that routine follow-up is maintained. Other individuals never warrant a diagnosis of MFS, despite having numerous, mild features. A diagnosis of MASS phenotype is appropriate for the individual with several of the following: mitral valve prolapse (MVP), myopia, an aortic root at the upper limits of normal, mild skeletal features, and striae distensae. This phenotype is of unclear molecular cause, can be inherited as an autosomal dominant trait, and, importantly, is not generally associated with progressive aortic dilatation or dissection.

    
    
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    In the Loeys-Dietz syndrome (LDS), the aorta and its branches are tortuous from an early age and the aorta tends to dissect at a smaller diameter than in MFS. The craniofacial characteristics include cleft palate or bifid uvula, craniosynostosis, and increased head circumference. The lens of the eye does not dislocate in LDS. Molecular testing for mutations in TGFBR1 and TGFBR2 can distinguish LDS from MFS.

  
  

Diagnostic Criteria for MFS

The revised Ghent criteria have been expanded to include molecular genetic testing. MFS can be diagnosed by

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  A family history of documented MFS and presence of ectopia lentis or dilatation of the aortic root.

  
  
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  In the absence of a family history, presence of ectopia lentis, and dilatation of the aortic root.

  
  
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  Presence of either ectopia lentis or dilatation of the aortic root and a positive systemic score (a combination of multiple features, including elongated limbs, anterior chest deformity, dural ectasia, pneumothorax, craniofacial features, and MVP: see Management and Treatment section).

  
  
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  Having a pathogenic mutation in FBN1 known to cause MFS in either the patient’s family of another individual with documented MFS qualifies for a diagnosis of MFS.

Clinical Characteristics

Patients present to medical attention with any of a variety of clinical issues. Occasionally infants are diagnosed because of severe skeletal features; they typically have severe mitral regurgitation as their major cardiovascular issue. At the other end of the phenotypic spectrum, adults with MFS can first present with acute aortic dissection. An ophthalmologist may suggest the diagnosis based on detection of lens subluxation.

Children with the most severe forms of MFS have poorly developed skeletal muscle and a paucity of subcutaneous adipose tissue. However, some people with MFS are robust, and there is a propensity for developing central adiposity in adulthood.

Screening

When MFS is suspected, such as in a relative of a person with documented MFS or in a person with one, a protocol for establishing or discarding the diagnosis of MFS is as follows:

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