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
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