Marfan's syndrome

Editors-In-Chief: William James Gibson, C. Michael Gibson, M.S., M.D.

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1] ; Assistant Editor-In-Chief: Cassandra Abueg, M.P.H. [2]

Marfan syndrome (or Marfan’s syndrome) is a connective tissue disorder most often caused by defects in the Fibrillin-1 gene (FBN1). Patients with Marfan’s syndrome are at significant risk of skeletal, cardiovascular and ocular complications. People with Marfan’s are typically tall, with long limbs and long thin fingers.

Template:WH Template:WS

Editors-In-Chief: William James Gibson, C. Michael Gibson, M.S., M.D.

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1] ; Assistant Editor-In-Chief: Cassandra Abueg, M.P.H. [2]

In 1896, French pediatrician Antoine-Bernard Jean Marfan described a five year old girl, Gabrielle P, with skeletal features characteristic of Marfan Syndrome ^[1], pieds d’aragne (French, spider feet) and dolichostenomalie (French, longheadedness meaning long limbs). In 1902, Emile Charles Achard described a similar syndrome, reporting scoliosis and arachnodactyly (abnormally long and slender fingers) as essential features ^[2]. Salle contributed the observation in 1912 that patients with arachnodactyly had thickened mitral leaflets, ocular abnormalities and increase in eosinophilic cells in the pituitary ^[3], ^[4]. The observation that ectopic lens was associated with other symptoms was first made by Boerger in 1914 ^[5]. Weve established the autosomal dominant inheritance of the disease, still known as arachnodactyly, in 1931 ^[6]. We have postulated that the syndrome arose from a defect in mesenchymal tissue and thus designated the syndrome dystrophia mesodermalis congenita typus Marfanis. Association of the syndrome with aortic dilation and dissection, the major causes of mortality in individuals with Marfan Syndrome were identified in 1943 by RW Baer et al. as well as Etter and Glover ^[7], ^[8]. Harry C Deitz finally established the molecular basis of Marfan Syndrome in his landmark 1991 Nature paper, showing that mutations in the FBN1 gene are responsible for the disease ^[9].

Template:WH Template:WS

Editors-In-Chief: William James Gibson, C. Michael Gibson, M.S., M.D.

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1] ; Assistant Editor-In-Chief: Cassandra Abueg, M.P.H. [2]

Marfan syndrome has been linked to a defect in the FBN1 gene on chromosome 15,^[1] which encodes a glycoprotein called fibrillin-1. Fibrillin is essential for the formation of the elastic fibers found in connective tissue, as it provides the scaffolding for tropoelastin.^[2] Elastic fibers are found throughout the body but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye, consequently these areas are among the worst affected. Without the structural support provided by fibrillin many connective tissues are weakened, which can have severe consequences for support and stability.

Marfan syndrome is inherited as a dominant trait. In so far as the pattern of inheritance is dominant, people who have inherit just one affected FBN1 gene from either parent will develop Marfan syndrome. This expression of the syndrome can range from mild to severe.

A related disease has been found in mice, and the study of mouse fibrillin synthesis and secretion, and connective tissue formation, has begun to further our understanding of Marfan syndrome in humans. It has been found that simply reducing the level of normal fibrillin-1 is associated with a Marfan-related disease in mice.^[3]

High levels of Transforming growth factor beta (TGFβ) are associated with inflammation and also play an important role in Marfan syndrome. Ordinarily, Fibrillin-1 binds TGFβ and inactivates it. In Marfan syndrome, reduced levels of fibrillin-1 allow activated TGFβ to damage the lungs and heart. Researchers now believe that the inflammatory effects of TGF-β, on the lungs, heart valves, and aorta weaken the connective tissues and cause the features of Marfan syndrome. In so far as angiotensin II receptor blockers (ARBs) reduce TGF-β, these agents have been administered to young Marfan syndrome patients, and the expansion of the aorta was indeed reduced.^[4]

A defect in the gene TGFβR2 on chromosome 3, a receptor protein of TGFβ, has also been related to Marfan syndrome.^[5] Marfan syndrome can often be confused with Loeys-Dietz syndrome, a similar connective tissue disorder resulting from mutations in the TGFβ receptor genes TGFβR1 and TGFβR2.^[6]

Marfan syndrome is an autosomal dominant disorder caused by mutations in the Fibrillin-1 gene encoding an extracellular matrix protein which constitutes an essential component of microfibrils, critical in formation of elastin. Engvall first isolated the protein from human fibroblast cell culture in 1986, demonstrated its function as a component of extracellular microfibrils and its widespread expression through connective tissue in many organ systems ^[7]. Early linkage studies of families with Marfan syndrome mapped the gene to 15q21.1 ^[8], surprising some investigators who suspected defects in the Elastin gene were causal. Subsequent mutational analysis of FBN1 in patients with Marfan system revealed identical missense mutations in two unrelated patients9. Many linkage studies have been performed and demonstrate that most families have private mutations. The FBN1 gene is very large, consisting of 65 exons. It encodes a 350 kiloDalton protein and is highly conserved between different species.

Familial mutations of the FBN1 gene account for 75% of cases of Marfan syndrome and their corresponding phenotype is inherited in a dominant fashion. Over 500 different FBN1 mutations have been detected in Marfan syndrome patients ^[9]. 56% of these mutations are missense mutations, most often by creating or substituting a cysteine in a cbEGF domain critical for calcium binding ^[10]. Missense mutations are clustered in loci with cbEGF domains and typically cause moderate to severe phenotype ^[11]. Other documented mutations include nonsense, frameshift and splice site mutations. Complete deletions of a FBN1 allele are very rare. 90% of FBN1 mutations are private to an individual or family10. The incredibly diverse set of mutations that cause the syndrome suggest that these mutations generally reflect loss-of-function cause a dominant negative phenotype. Haploinsufficiency and other theories have been proposed to account for the dominant negative phenomenon which will be detailed later.

No FBN1 mutation can be identified in 10% of Marfan syndrome patients ^[12]. In this subset of patients, mutations in the transforming growth factor-beta receptor 2 (TGFBR2) are causal. Families with TGFBR2 mutations display autosomal dominant inheritance with variable penetrance.

How FBN1 and TGFBR2 mutations cause the syndrome is not well understood. Early data suggests that the mechanism of pathogenesis may involve altered calcium binding FBN1 proteins, as suggested by the predominance of mutations in putative calcium binding regions of the FBN1 gene. The gene contains 47 tandemly repeated calcium binding epidermal growth factor-like domains (cbEGF). These domains contain six cysteine residues that are spaced in a conserved fashion and function to both coordinate calcium binding and form disulfide linkages which govern protein folding. Mutations in cbEGF domains make the Fibrillin-1 proteins more vulnerable to proteolytic degradation and cleavage ^[13],^[14].

The dominant negative inheritance of the disorder suggests mechanisms for molecular pathogenesis. Indeed, other diseases of connective tissue have an established pathway of dominant negative pathology such as osteogenesis imperfecta, a disorder caused by defects in the collagen-1 gene. Because collagen assembles from several monomers, a defect in one protein can disrupt the folding and thus function of the entire assembly, a phenomenon called interference. Similarly, microfibrils are composed of several fibrillin monomers and it is suspected that interference may occur in Marfan syndrome. More complex interactions may be at play as well. Many patients show dramatically decreased expression of FBN1, far below a simple halving that would be expected from loss of one allele. Further, patients with a mild phenotype have been identified who express very low levels of the mutant allele.

Conversely, there is a great deal of evidence suggesting that haploinsufficiency of FBN1 causes the disease. In a mouse model, transgenic expression of a missense mutant FBN1 gene which caused vascular hallmarks of disease with only one normal allele did not cause disease in mice with two normal alleles ^[15]. A second mouse study showed that mice with loss of one FBN1 allele displayed aortic manifestations of the disease, and transgenic expression of a wild-type FBN1 in these same mice was able to rescue the normal phenotype ^[16]. Finally, a 2010 report of 10 patients with full deletions of one copy of the FBN1 gene showed that seven of these patients fulfilled the Ghent criteria, while the others were quite young at examination but still displayed facial and skeletal manifestations of the disease ^[10]. Thus, haploinsufficiency can account for the dominant negative effect of mutations in one FBN1 alllele. Various genetic modifiers of expression of the normal FBN1 allele are thought to account for the observed variance in disease severity. Modulating expression of the normal FBN1 gene is therefore an attractive therapeutic target.

Fibrillin-1 defects are thought to manifest in two pathways, abnormal construction of microfibrils directly causing disease and altered cytokine signaling resulting from microfibrilar misregulation of these molecules.

Mouse models have showed that fibrillin-1 is not required for the construction of elastic fibers, instead suggesting that fibrillin-1 is required for the maintenance of elastic fibers. Elastic fibers connect to vascular smooth muscle cells in fibrillin-1 dependent ways. When these connections are disrupted, the smooth muscle cells begin secreting matrix metalloproteinases 2 and 9. Following this misregulation of extacellular matric degrading enzymes, elastic fibre calcification, inflammation and smooth muscle proliferation follow, occasionally causing collapse of the vessel wall. This pathology is not unique to mice, indeed it accurately reflects pathologic changes observed from human specimens. Marfan syndrome thus reflects an inability to maintain structural integrity of the vessel wall rather than an instrinsic inability to create sound vessel architecture and subsequent weakening by mechanical forces.

FBN1 was observed to have a high degree of homology with latent Transforming Growth Factor beta binding proteins. TGF-β is known to be secreted as a complex bound to a latency peptide and a latent TGF-β binding protein which is in turn bound by extracellular matrix. These two observations led investigators to examine the possibility that fibrillin-1 mediates the sequestration of TGF-β molecules in the extracellular matrix. The role of TGF-β is thought to explain the disease phenotype in tissues not composed largely of elastic fibers. This hypothesis has been confirmed in the setting of atrioventricular valve complications with a mouse model showing that increased TGF-β signaling causes myoxamatous degeneration of atrioventricular valves in FBN1 deficient mice. Injecting mice with an anti-TGF-β antibody was sufficient to rescue the normal phenotype with respect to valvular disease ^[17].

Increased TGF-β signaling is reflected by higher concentrations of the cytokine in both Marfan syndrome patients (6 fold increase in concentration) and mice with FBN1 mutations. Marfan syndrome mice treated with losartan, an angiotensin II type I blocker which attenuates TGF-β activation, experienced a significant reduction in plasma TGF-β concentration. This finding was also replicated in Marfan Sydrome patients. Promisingly, aortic root diameter was also significantly reduced in mice receiving losartan ^[18].

Current efforts aim at identifying molecular events occurring downstream of TGF-β signaling as possible therapeutic targets. TGF-β dependent activation of matrix metalloproteinases 2 and 9 has been implicated in disease pathogenesis. Data from mouse models shows that the matrix metalloproteinase antagonist doxycycline can slow aortic root growth ^[19].

The following conditions that can result from having Marfan’s syndrome and may also occur in people without any known underlying disorder. what leads doctors to a diagnosis of Marfan syndrome is family history and a combination of major and minor indicators of the disorder that occur in one individual which is a rare manifestation in general population. Example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual.

• Aortic aneurysm or dilatation
• Arachnodactyly
• Bicuspid aortic valve
• Cysts
• Craniosynostosis
• Cystic medial necrosis
• Dural ectasia
• Ectopia lentis
• Flat feet
• Gigantism
• Glaucoma
• Hernias
• Hypermobility of the joints
• Malocclusion
• Mitral valve prolapse
• Myopia
• Obstructive lung disease
• Osteoarthritis
• Pectus carinatum or excavatum
• Pneumothorax
• Retinal detachment
• Scoliosis
• Sleep apnea
• Stretch marks

Template:WH Template:WS

Please help WikiDoc by adding more content here. It’s easy! Click here to learn about editing.

Editors-In-Chief: William James Gibson, C. Michael Gibson, M.S., M.D.

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1] ; Assistant Editor-In-Chief: Cassandra Abueg, M.P.H. [2]

The following disorders have similar signs and symptoms of Marfan syndrome:

• Congenital Contractural Arachnodactyly (CCA) or Beals Syndrome
• Ehlers-Danlos syndrome
• Homocystinuria
• Loeys-Dietz syndrome
• MASS phenotype
• Stickler syndrome

Template:WH Template:WS

Editors-In-Chief: William James Gibson, C. Michael Gibson, M.S., M.D.

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1] ; Assistant Editor-In-Chief: Cassandra Abueg, M.P.H. [2]

Populations of certain athletes such as basketball and volleyball players have been shown to have an increased incidence of Marfan syndrome (~0.5%) ^[1], perhaps due to skeletal abnormalities associated with the syndrome.

The prevalence of Marfan syndrome is 1 case per 3000 to 5000 individuals or .033 % (upper estimate) ^[2].

Marfan syndrome affects males and females equally,^[3] and the mutation shows no geographical bias.

Neither location nor ethnicity appear to impact the statistics.

Estimates indicate that approximately 60 000 (1 in 5000, or 0.02% of the population)^[3] to 200 000^[4] Americans have Marfan syndrome. Each parent with the condition has a 50% chance of passing it on to a child due to its autosomal dominant nature. Most individuals with Marfan syndrome have another affected family member, but approximately 15-30% of all cases are due to de novo genetic mutations^[5] — such spontaneous mutations occur in about 1 in 20 000 births. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.^[6][7] It is associated with variable expressivity. Incomplete penetrance, has not been definitively documented.

Template:WH Template:WS

Please help WikiDoc by adding content here. It’s easy! Click here to learn about editing.

Please help WikiDoc by adding more content here. It’s easy! Click here to learn about editing.

Editors-In-Chief: William James Gibson, C. Michael Gibson, M.S., M.D.

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1] ; Assistant Editor-In-Chief: Cassandra Abueg, M.P.H. [2]

While patients now have nearly normal life expectancies, in previous decades, patients’ life expectancies were significantly shortened by the risks of aortic dissection, valvular failure and congestive heart failure. Together, these cardiovascular complications accounted for 90% of the mortality associated with Marfan syndrome such that in the 1970s, an affected individual would be expected to live only two-thirds as long as his unaffected counterparts ^[1].

Template:WH Template:WS