Elsevier

The Lancet

Volume 366, Issue 9501, 3–9 December 2005, Pages 1965-1976
The Lancet

Seminar
Marfan's syndrome

https://doi.org/10.1016/S0140-6736(05)67789-6Get rights and content

Summary

Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth. Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with genetically defined mouse models to elucidate the pathogenetic sequence that is initiated by fibrillin-1 deficiency. The new understanding is that many aspects of the disease are caused by altered regulation of transforming growth factor β (TGFβ), a family of cytokines that affect cellular performance, highlighting the potential therapeutic application of TGFβ antagonists. Insights derived from studying this mendelian disorder are anticipated to have relevance for more common and non-syndromic presentations of selected aspects of the Marfan phenotype.

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

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.

References (109)

  • EA Streeten et al.

    Pulmonary function in the Marfan syndrome

    Chest

    (1987)
  • R Fattori et al.

    Importance of dural ectasia in phenotypic assessment of Marfan's syndrome

    Lancet

    (1999)
  • RA Montgomery et al.

    Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome

    Am J Hum Genet

    (1998)
  • AN Gale et al.

    Familial congenital bicuspid aortic valve: secondary calcific aortic stenosis and aortic aneurysm

    Chest

    (1977)
  • T Halme et al.

    Elastin and collagen in the aortic wall: changes in the Marfan syndrome and annuloaortic ectasia

    Exp Mol Pathol

    (1985)
  • GM Corson et al.

    Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5′ end

    Genomics

    (1993)
  • NJ Biery et al.

    Revised genomic organization of FBN1 and significance for regulated gene expression

    Genomics

    (1999)
  • DP Reinhardt et al.

    Calcium determines the shape of fibrillin

    J Biol Chem

    (1997)
  • DP Reinhardt et al.

    Calcium stabilizes fibrillin-1 against proteolytic degradation

    J Biol Chem

    (1997)
  • HC Dietz et al.

    Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome

    Genomics

    (1993)
  • F Ramirez et al.

    Cell signaling events: a view from the matrix

    Matrix Biol

    (2003)
  • J Saharinen et al.

    Latent transforming growth factor-beta binding proteins (LTBPs)—structural extracellular matrix proteins for targeting TGF-beta action

    Cytokine Growth Factor Rev

    (1999)
  • L Lonnqvist et al.

    A novel mutation of the fibrillin gene causing ectopia lentis

    Genomics

    (1994)
  • N Dagoneau et al.

    ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome

    Am J Hum Genet

    (2004)
  • PH Arn et al.

    Outcome of pectus excavatum in patients with Marfan syndrome and in the general population

    J Pediatr

    (1989)
  • PM Quigley et al.

    Cardiorespiratory function before and after corrective surgery in pectus excavatum

    J Pediatr

    (1996)
  • D Borowitz et al.

    Pulmonary function and exercise response in patients with pectus excavatum after Nuss repair

    J Pediatr Surg

    (2003)
  • OA Bawazir et al.

    Midterm evaluation of cardiopulmonary effects of closed repair for pectus excavatum

    J Pediatr Surg

    (2005)
  • ML Lawson et al.

    Impact of pectus excavatum on pulmonary function before and after repair with the Nuss procedure

    J Pediatr Surg

    (2005)
  • J Haller et al.

    Chest wall constriction after too extensive and too early operations for pectus excavatum

    Anns Thorac Surg

    (1996)
  • MA Salim et al.

    Effect of beta-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome

    Am J Cardiol

    (1994)
  • R Rossi-Foulkes et al.

    Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome

    Am J Cardiol

    (1999)
  • AT Yetman et al.

    Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the marfan syndrome

    Am J Cardiol

    (2005)
  • MA Sarsam et al.

    Remodeling of the aortic valve anulus

    J Thorac Cardiovasc Surg

    (1993)
  • NC de Oliveira et al.

    Results of surgery for aortic root aneurysm in patients with Marfan syndrome

    J Thorac Cardiovasc Surg

    (2003)
  • BT Bethea et al.

    Results of aortic valve-sparing operations: Experience with remodeling and reimplantation procedures in 65 patients

    Ann Thorac Surg

    (2004)
  • R De Paulis et al.

    One-year appraisal of a new aortic root conduit with sinuses of Valsalva

    J Thorac Cardiovasc Surg

    (2002)
  • AB Marfan

    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

    (1986)
  • JR Gray et al.

    Ascertainment and severity of Marfan syndrome in a Scottish population

    J Med Genet

    (1994)
  • HC Dietz et al.

    Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene

    Nature

    (1991)
  • B Loeys et al.

    Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome

    Hum Mutat

    (2004)
  • JL Murdoch et al.

    Life expectancy and causes of death in the Marfan syndrome

    N Engl J Med

    (1972)
  • P Beighton et al.

    International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986

    Am J Med Genet

    (1988)
  • A De Paepe et al.

    Revised diagnostic criteria for the Marfan syndrome

    Am J Med Genet

    (1996)
  • KN Joseph et al.

    Orthopedic aspects of the Marfan phenotype

    Clin Orthop Relat Res

    (1992)
  • IH Maumenee

    The eye in the Marfan syndrome

    Trans Am Ophthalmol Soc

    (1981)
  • VA McKusick

    The cardiovascular aspects of Marfan's syndrome

    Circulation

    (1955)
  • S Chen et al.

    Ventricular dysrhythmias in children with Marfan's syndrome

    Am J Dis Child

    (1985)
  • A Savolainen et al.

    Abnormal ambulatory electrocardiographic findings in patients with the Marfan syndrome

    J Intern Med

    (1997)
  • VL Gott et al.

    Replacement of the aortic root in patients with Marfan's syndrome

    N Engl J Med

    (1999)
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