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Special Feature
August 2005

Picture of the Month—Diagnosis

Arch Pediatr Adolesc Med. 2005;159(8):721-723. doi:10.1001/archpedi.159.8.722
Denouement and Discussion: Marfan Syndrome

Marfan syndrome (MFS), an autosomal dominant disorder of connective tissue, was first described by Antonine-Bernard Marfan in 1896 when he presented to the Medical Society of Paris a 5-year-old girl with long limbs and fingers and a variety of other features that have come to be associated with the syndrome bearing his name.1 In 1991, MFS was linked to chromosome 15q, and reduced levels of a relatively newly described glycoprotein, fibrillin, were found in the fibroblasts of patients with MFS.2,3 Fibrillin, an essential component of extracellular connective tissue, interacts with elastin in the aorta and ligaments and anchors nonelastic tissue such as ciliary zonules, tendons, and periosteum. In patients with MFS, fibrillin aggregation into microfibrils is disturbed,4 leading to the typical phenotypic expression. Subsequent studies2,57 have demonstrated that all patients with MFS have a mutation in the large gene encoding fibrillin 1 (FBN1) at 15q21.1.

The diagnosis of MFS is primarily based on clinical history and examination findings. Although initial diagnostic criteria were established in 1986 and known as the Berlin nosology,8 revision of the criteria was undertaken in 1996 to address some shortcomings, particularly the overdiagnosis of MFS in relatives of patients with MFS.9 These new criteria, called the Ghent criteria, emphasize major and minor criteria in the following 6 domains: ocular, cardiovascular, pulmonary, skin and integument (including the dura mater), family or genetic history, and skeletal. Requirements for the diagnosis of MFS in the index patient include:

  1. Major criteria present in at least 2 different organ systems with involvement of a third system. This presumes no family history of MFS.

  2. Detection of a mutation in FBN1 known to cause MFS in other family members, plus 1 major criterion in an organ system with involvement of a second organ system.9 The diagnosis of MFS in a relative of an index patient requires the presence of a major criterion in the family history and 1 major criterion in an organ system with involvement of a second organ system.9

Major criteria in each of the domains include9:

  • Ocular: ectopia lentis

  • Cardiovascular system: dilation of the ascending aorta, with or without aortic regurgitation, and involving at least the sinuses of Valsalva; or dissection of the ascending aorta

  • Pulmonary system: no major criteria

  • Skin and integument: lumbosacral dural ectasia, confirmed by computed tomography or magnetic resonance imaging

  • Family or genetic history: having a parent, child, or sibling who meets the criteria independently; presence of a mutation in FBN1 known to cause MFS; or presence of a haplotype around FBN1, inherited by descent and known to be associated with unequivocally diagnosed MFS in the family

  • Skeletal (the presence of ≥4 of the following manifestations is necessary to satisfy a major criterion): pectus carinatum; pectus excavatum requiring surgery; reduced upper-segment–lower-segment ratio or arm span–height ratio greater than 1.05; wrist and thumb signs; scoliosis of more than 20° or spondylolisthesis; reduced extension of the elbow (<170°); medial displacement of the medial malleolus causing pes planus; protrusio acetabuli of any degree (ascertained on radiographs)

  • Differential diagnosis: Conditions with features similar to MFS include homocystinuria, congenital contractural arachnodactyly, familial ectopia lentis, familial aortic dissection, and MASS phenotype.9,10 The MASS phenotype (myopia, mitral valve prolapse, mild aortic dilation, skin [striae atrophicae], and skeletal [manifestations similar to MFS, including long limbs and deformity of the thoracic cage]) also is caused by a mutation in the FBN1 gene. Familial Marfan-like habitus (MFS, type II), however, is due to a mutation in the gene encoding transforming growth factor β receptor 2 at gene locus 3p24.2-p25.11,12

In the case described herein, the patient was a direct descendant of Abraham Lincoln, who has long been thought to have had MFS.

Submissions

The Editors welcome contributions to Picture of the Month. We would like to get common problems presenting uncommonly, rather than total zebras. These cases should be of interest to practicing pediatricians, problems that they are likely to at least occasionally encounter in the office or hospital setting. Submissions must be high-quality photographs in either 35-mm slide or electronic format. Parent or patient permission to use photographs must accompany the submission. The discussion should be no more than 750 words. Articles and photographs accepted for publication will bear the contributor’s name. There is no charge for reproduction and printing of color illustrations.

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Article Information

Correspondence: Basil J. Zitelli, MD, Department of Pediatrics, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2583.

Accepted for Publication: February 15, 2005.

References
1.
Marfan  AB Un cas de déformation congénitale des quatre membres plus prononcée aux extrémités caractérisée par l’allongemont des os avec un certain degré d’amincissement. Bull Mém Soc Méd Hôp (Paris) 1896;13220- 226
2.
Kainulainen  KPulkkinen  LSavolainen  AKaitila  IPeltonen  L Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990;323935- 939
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Hollister  DWGodfrey  MSakai  LYPyeritz  RE Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome. N Engl J Med 1990;323152- 159
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Kielty  CMDavies  SJPhillips  JEJones  CJShuttleworth  CACharles  SJ Marfan syndrome: fibrillin expression and microfibrillar abnormalities in a family with predominant ocular defects. J Med Genet 1995;321- 6
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 Marfan syndrome; MFS. Online Mendelian Inheritance in Man Web site. Available at:http://www.ncbi.nih.gov/entrez/dispomim.cgi?id=154700Accessed May 27, 2005
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Dietz  HCPyeritz  REHall  BD  et al.  The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3. Genomics 1991;9355- 361
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Tsipouras  PSarfarazi  MDevi  AWeiffenbach  BBoxer  M Marfan syndrome is closely linked to a marker on chromosome 15q1.5→q2.1. Proc Natl Acad Sci U S A 1991;884486- 4488
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8.
Beighton  Pde Paepe  ADanks  D  et al.  International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986. Am J Med Genet 1988;29581- 594
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de Paepe  ADevereux  RBDeitz  HCHennekam  RCPyeritz  RE Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62417- 426
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Glesby  MJPyeritz  RE Association of mitral valve prolapse and systemic abnormalities of connective tissue: a phenotypic continuum. JAMA 1989;262523- 528
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11.
Boileau  CJondeau  GBabron  M-C  et al.  Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin genes. Am J Hum Genet 1993;5346- 54
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12.
Collod  GBabron  M-CJondeau  G  et al.  A second locus for Marfan syndrome maps to chromosome 3p24.2-p25. Nat Genet 1994;8264- 268
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