Genetics of Marfan Syndrome

Updated: Jan 04, 2017
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Overview

Background

Marfan syndrome (MFS) is an inherited connective tissue disorder noteworthy for its worldwide distribution, relatively high prevalence, and clinical variability. This autosomal dominant syndrome has pleiotropic manifestations involving primarily the ocular, cardiovascular, and skeletal systems. Classic MFS (MFS type 1, MFS1) has been considered a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1; however, studies of Marfan mouse models and Marfan-related conditions have expanded our current understanding to a pathogenic model that involves dysregulation of cytokine-transforming growth factor beta (TGFβ) signaling. [1, 2] . Patients who have clinical findings of MFS, as well as genetic variants in the transforming growth factor-beta receptor-1 gene (TGFβR1) and the transforming growth factor-beta receptor-2 gene (TGFβR2), are designated as having MFS type 2 (MFS2).

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Pathophysiology

Marfan syndrome (MFS) results from heterozygous mutations in the fibrillin-1 gene (FBN1; OMIM #134797), located on chromosome 15 at band q21.1 (15q21.1), which encodes for the glycoprotein fibrillin. Fibrillin is a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the ocular lens and serve as substrates for elastin in the aorta and other connective tissues. Abnormalities involving microfibrils weaken the aortic wall. Progressive aortic dilatation and eventual aortic dissection occur due to the tension caused by left ventricular ejection impulses. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.

Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the abnormal fibrillin-1 disrupts microfibril formation (although other fibrillin genes still encode normal fibrillin). Evidence of this mechanism is shown in studies of cultured skin fibroblasts from patients with MFS who produce greatly diminished and abnormal microfibrils.

FBN1 mutations cause several Marfan-like disorders, such as the MASS (myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, nonspecific skin and skeletal findings) phenotype and isolated ectopia lentis.

Studies have suggested that abnormalities in the transforming growth factor-beta (TGFβ)-signaling pathway may represent a common pathway for the development of the Marfan phenotype. [3] This gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix.

The identification of mutations in TGFβR2 in patients with MFS type 2 (MFS2 mapped at 3p24.2-p25) provided direct evidence of abnormal TGFβ signaling in the pathogenesis of MFS.

Abnormalities in TGFβR1 and TGFβR2 were also reported to cause a new dominant syndrome similar to MFS1; it was associated with aortic aneurysm and congenital anomalies, including Loeys-Dietz syndrome (LDS). LDS is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement (LDS; OMIM #609192). [3] These results define a new group of Marfan syndrome–related connective tissue disorders, namely, TGFβ signalopathies, and include LDS1 and LDS2 (TGFβR1 and TGFβR2) and the SMAD3 and TGFβ2 disorders, with the latter two being classified as Loeys-Dietz-like (or as LDS3 and LDS4).

Shprintzen-Goldberg syndrome (SGS) has been found to be caused by a pathogenic variant in the SKI gene, which encodes a negative regulator of TGFβ signaling. There is phenotypic overlap with MFS and LDS. 

A variant of the fibrillin-2 gene, FBN2, causes congenital contractural arachnodactyly, known as Beals syndrome. [4]

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Epidemiology

Frequency

United States

MFS is one of the most common single-gene malformation syndromes. MFS1 affects about 1:5000 to 1:10,000 individuals. [5, 6]  Estimates suggest that at least 200,000 people in the United States have MFS or a related connective-tissue disorder.

International

No geographic predilection is known. 

Mortality/Morbidity

Cardiovascular disease (aortic dilatation and dissection) is the major cause of morbidity and mortality in MFS. Without proper medical management, MFS can be lethal in young adulthood, with death occurring at an average age of 30-40 years.

Infant morbidity, as related to cardiovascular disease, is due to progression of mitral valve prolapse to mitral regurgitation and often occurs in conjunction with tricuspid prolapse and regurgitation. Progression to congestive heart failure is a leading cause of cardiovascular morbidity and mortality, as well as the leading indicator for cardiovascular surgery.

Death later in life is usually due to chronic aortic regurgitation and ascending aortic dissection. Dissection generally occurs at the aortic root and is uncommon in childhood and adolescence. 

Race

Marfan syndrome is panethnic.

Sex

No sex predilection is known.

Age

MFS may be diagnosed prenatally, at birth, in childhood, during adolescence, or in adulthood. Neonatal presentation is associated with a severe clinical course.

Many clinical features are specific to age. Some features may not present until later in life, a situation that may make early diagnosis in childhood difficult.

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