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Marfan syndrome. Part 1: pathophysiology and diagnosis

Abstract

Marfan syndrome is a connective-tissue disease inherited in an autosomal dominant manner and caused mainly by mutations in the gene FBN1. This gene encodes fibrillin-1, a glycoprotein that is the main constituent of the microfibrils of the extracellular matrix. Most mutations are unique and affect a single amino acid of the protein. Reduced or abnormal fibrillin-1 leads to tissue weakness, increased transforming growth factor β signaling, loss of cell–matrix interactions, and, finally, to the different phenotypic manifestations of Marfan syndrome. Since the description of FBN1 as the gene affected in patients with this disorder, great advances have been made in the understanding of its pathogenesis. The development of several mouse models has also been crucial to our increased understanding of this disease, which is likely to change the treatment and the prognosis of patients in the coming years. Among the many different clinical manifestations of Marfan syndrome, cardiovascular involvement deserves special consideration, owing to its impact on prognosis. However, the diagnosis of patients with Marfan syndrome should be made according to Ghent criteria and requires a comprehensive clinical assessment of multiple organ systems. Genetic testing can be useful in the diagnosis of selected cases.

Key Points

  • Marfan syndrome is an autosomal-dominant connective-tissue disorder usually caused by mutations in the gene that encodes fibrillin-1

  • Fibrillin-1 is the major constituent of extracellular microfibrils and has structural and regulatory functions in the extracellular matrix

  • Marfan syndrome phenotype is thought to be the result of structural abnormalities and dysregulation of transforming growth factor β signaling

  • Marfan syndrome typically affects cardiovascular, skeletal, ocular, and neural systems and its diagnosis is based on clinical (Ghent) criteria

  • Aortic root dilatation in the leading cause of morbidity and mortality in patients with Marfan syndrome

  • Many connective-tissue disorders share phenotypic features with Marfan syndrome and should, therefore, be considered in the differential diagnosis

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Figure 1: Typical phenotypic manifestations associated with Marfan syndrome.
Figure 2: Echocardiography of the aortic root.
Figure 3: Normal range of aortic root dimensions.
Figure 4: Dural ectasia.

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Dianna M. Milewicz, Alan C. Braverman, … Reed E. Pyeritz

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Cañadas, V., Vilacosta, I., Bruna, I. et al. Marfan syndrome. Part 1: pathophysiology and diagnosis. Nat Rev Cardiol 7, 256–265 (2010). https://doi.org/10.1038/nrcardio.2010.30

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