The material covered in this review is based on extensive review of published works, including journals and textbook articles, as well as our ongoing investigation in this area. For PubMed searches we used the search term “Marfan”. We did not restrict our search by language, and, when possible, references within the past 5 years were chosen.
SeminarMarfan's syndrome
Section snippets
Epidemiology
The incidence of classic Marfan's syndrome is about 2–3 per 10 000 individuals, although this estimate depends on complete recognition of all affected and genetically predisposed individuals. Gray reported the incidence in Scotland as one in 9802 livebirths.2 Various factors could have contributed to an underestimate of disease prevalence. First, the phenotype becomes more apparent with increasing age in most families. Second, many of the outward manifestations are common in the general
Clinical manifestations
Marfan's syndrome is a multisystem disorder with manifestations typically involving the cardiovascular, skeletal, and ocular systems. A consensus opinion regarding diagnostic criteria was outlined at the International Nosology of Heritable Disorders of Connective Tissue Meeting in Berlin in 1986.8 However, the recognition that many individuals diagnosed with the disorder do not carry the FBN1 mutation identified in more severely affected family members led to revised criteria several years
Differential diagnosis
Several disorders are included in the differential diagnosis of Marfan's syndrome on the basis of similar skeletal, cardiac, or ophthalmological manifestations (table). Many individuals referred for possible Marfan's syndrome are shown to have evidence of a systemic disorder of the connective tissue, including long limbs, deformity of the thoracic cage, striae atrophicae, mitral valve prolapse, and mild and non-progressive dilatation of the aortic root, but do not meet diagnostic criteria for
Molecular genetics and pathophysiology
Both skin and aorta from patients with Marfan's syndrome show decreased elastin content and fragmentation of elastic fibres.40, 41, 42 However, phenotypic manifestations in tissues without elastin, such as ciliary zonules and bone, helped to exclude the elastin gene as the primary site of mutations causing the disorder. Additionally, linkage analysis mapped the Marfan's syndrome locus to 15q21.1, distant from the chromosomal locus of elastin at 7q11.2.43, 44
Sakai and colleagues45 first
Clinical genetic testing
The role of genetic testing in establishing a diagnosis remains limited. To date, over 500 mutations resulting in the disorder have been catalogued in an international database.68 Over 90% are private mutations unique to an individual or family. Even within families where all affected individuals share the same mutation, phenotypic variation is prominent. Thus, it is difficult to derive significant genotype–phenotype correlations.69 Due to the large size of FBN1 (65 exons), the cost of routine
Management
The diagnosis of Marfan's syndrome requires a multidisciplinary assessment that generally includes a geneticist for general assessment and anthropomorphic measurements, an ophthalmologist for a slit-lamp examination, and a cardiologist for cardiovascular imaging. After establishing a clinical diagnosis of Marfan's syndrome, routine monitoring of aortic growth is essential to decrease the risk of aortic dissection. Yearly assessment by transthoracic echocardiography allows serial measurements of
New developments
The prevailing view had been that people with Marfan's syndrome are born with a structural weakness of the tissues that imposes an obligate risk of tissue failure later in life. Strategies to strengthen the connective tissue throughout the body were difficult to conceive much less implement. The new realisation that Marfan's syndrome manifests postnatally acquired tissue pathology, and that this may largely indicate a failed regulatory (as opposed to structural) role of the extracellular
Conclusions
Progress in the past century has led to an improved understanding of the cause, pathophysiology, and treatment of Marfan's syndrome. As our knowledge of the consequences of fibrillin-1 deficiency develops, we anticipate that treatment will continue to advance, allowing improved length and quality of life for patients with the disorder. Indeed, Marfan's syndrome represents a paradigm success that foreshadows future challenges and opportunities that will derive from the human genome project and
Search strategy and selection criteria
References (109)
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Aortic root dilatation among young competitive athletes: echocardiographic screening of 1929 athletes between 15 and 34 years of age
Am Heart J
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Life expectancy in the Marfan syndrome
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The Marfan syndrome in early childhood: analysis of 15 patients diagnosed at less than 4 years of age
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Mitral valve dysfunction in the Marfan syndrome. Clinical and echocardiographic study of prevalence and natural history
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(1965)
Pulmonary function in the Marfan syndrome
Chest
Importance of dural ectasia in phenotypic assessment of Marfan's syndrome
Lancet
Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome
Am J Hum Genet
Familial congenital bicuspid aortic valve: secondary calcific aortic stenosis and aortic aneurysm
Chest
Elastin and collagen in the aortic wall: changes in the Marfan syndrome and annuloaortic ectasia
Exp Mol Pathol
Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5′ end
Genomics
Revised genomic organization of FBN1 and significance for regulated gene expression
Genomics
Calcium determines the shape of fibrillin
J Biol Chem
Calcium stabilizes fibrillin-1 against proteolytic degradation
J Biol Chem
Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome
Genomics
Cell signaling events: a view from the matrix
Matrix Biol
Latent transforming growth factor-beta binding proteins (LTBPs)—structural extracellular matrix proteins for targeting TGF-beta action
Cytokine Growth Factor Rev
A novel mutation of the fibrillin gene causing ectopia lentis
Genomics
ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome
Am J Hum Genet
Outcome of pectus excavatum in patients with Marfan syndrome and in the general population
J Pediatr
Cardiorespiratory function before and after corrective surgery in pectus excavatum
J Pediatr
Pulmonary function and exercise response in patients with pectus excavatum after Nuss repair
J Pediatr Surg
Midterm evaluation of cardiopulmonary effects of closed repair for pectus excavatum
J Pediatr Surg
Impact of pectus excavatum on pulmonary function before and after repair with the Nuss procedure
J Pediatr Surg
Chest wall constriction after too extensive and too early operations for pectus excavatum
Anns Thorac Surg
Effect of beta-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome
Am J Cardiol
Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome
Am J Cardiol
Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the marfan syndrome
Am J Cardiol
Remodeling of the aortic valve anulus
J Thorac Cardiovasc Surg
Results of surgery for aortic root aneurysm in patients with Marfan syndrome
J Thorac Cardiovasc Surg
Results of aortic valve-sparing operations: Experience with remodeling and reimplantation procedures in 65 patients
Ann Thorac Surg
One-year appraisal of a new aortic root conduit with sinuses of Valsalva
J Thorac Cardiovasc Surg
Un cas de deformation congenitale des quarte membres plus prononcee aux extremites caracterisee par l'allongement des os avec un certain degre d'amincissement
Bull Mem Soc Med Hop Paris
Ascertainment and severity of Marfan syndrome in a Scottish population
J Med Genet
Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene
Nature
Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome
Hum Mutat
Life expectancy and causes of death in the Marfan syndrome
N Engl J Med
International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986
Am J Med Genet
Revised diagnostic criteria for the Marfan syndrome
Am J Med Genet
Orthopedic aspects of the Marfan phenotype
Clin Orthop Relat Res
The eye in the Marfan syndrome
Trans Am Ophthalmol Soc
The cardiovascular aspects of Marfan's syndrome
Circulation
Ventricular dysrhythmias in children with Marfan's syndrome
Am J Dis Child
Abnormal ambulatory electrocardiographic findings in patients with the Marfan syndrome
J Intern Med
Replacement of the aortic root in patients with Marfan's syndrome
N Engl J Med
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