Introduction
Marfan syndrome (MFS) is a spectrum disorder caused by a heritable genetic defect of connective tissue that has an autosomal dominant mode of transmission.1,2,3,4 The defect itself has been isolated to the FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin.1,5 Abnormalities in this protein cause a myriad of distinct clinical problems, of which the musculoskeletal, cardiac, and ocular system problems predominate.2,6,7
The skeleton of patients with MFS typically displays multiple deformities including arachnodactyly (ie, abnormally long and thin digits), dolichostenomelia (ie, long limbs relative to trunk length), pectus deformities (ie, pectus excavatum and pectus carinatum), and thoracolumbar scoliosis.8,9
In the cardiovascular system, aortic dilatation, aortic regurgitation, and aneurysms are the most worrisome clinical findings.1,3,4 Mitral valve prolapse that requires valve replacement can occur as well. Ocular findings include myopia, cataracts, retinal detachment, and superior dislocation of the lens.
For excellent patient education resources, visit eMedicine's Heart Center and Eye and Vision Center. Also, see eMedicine's patient education articles Mitral Valve Prolapse and Cataracts.
History of the Procedure
Bernard Marfan was born in Castelnaudary, Aude, France on June 23, 1858. In 1892, he was appointed assistant professor of pediatrics in the Paris faculty. Marfan described the disease that still bears his name at a meeting of the Medical Society of Paris in 1896. He presented the case of a 5-year-old girl named Gabrielle, who had disproportionately long limbs.
In later studies, further anomalies were documented, including arachnodactyly (long digits), cardiovascular abnormalities, and dislocation of the ocular lens. A common and often lethal complication of MFS is dissection of the aorta, and the genetic inheritance is now known to be autosomal. Marfan gained an international reputation and was widely recognized as a pioneer of pediatric medicine in France. This was very much the case in Britain, too, where he received an honorary fellowship of the Royal Society of Medicine in 1934.
Problem
The abnormality of the connective tissue protein fibrillin causes a variety of problems in the affected individual. The most severe problems include aortic root dilatation and dissection, which have historically been the causative factors in early patient demise.10 Skeletal deformities such as thoracolumbar scoliosis, thoracic lordosis, and pectus excavatum, may lead to pulmonary difficulties that include restrictive airway disease and cor pulmonale if the deformities are progressive and untreated. Finally, blindness may result from unrecognized and untreated glaucoma, retinal detachment, and cataracts.
Frequency
The estimated incidence of MFS ranges from 1 in 5,000 to 2-3 in 10,000 persons.1 The mutation in the fibrillin gene causes pleiotropic effects; thus, a wide range of phenotypic features is derived from a single gene mutation. Several other diseases have presentations similar to MFS, making it exceedingly difficult to determine the exact incidence.
Etiology
Mutations in the FBN1 locus of the fibrillin gene on chromosome 15 have been linked to MFS and other distinct clinical entities with similar findings.
Pathophysiology
Over many years, several investigators have studied various molecules found in the extracellular matrix in attempts to elucidate the cause of MFS. These molecules have included collagen, elastin, hyaluronic acid, and, more recently, fibrillin. Sakai et al identified fibrillin, a 350-kd protein, by using monoclonal antibodies raised against myofibrils.11 Immunofluorescence studies were then used to compare the reactivity in both healthy subjects and those with MFS. During this period, similar technology was used to construct a genetic exclusion map that led to the localization of the defect to chromosome 15 (bands q15-q23).
Several point mutations have now been identified in the fibrillin gene, most of which affect cysteine residues within the microfibril. Thus, these mutations are thought to cause defective fibrillin to be produced. Fibrillin's structure and function are altered by abnormal protein folding due to the alteration of bonding between cysteine residues, which in turn causes defective microfibril production.
Presentation
No single sign is pathognomic for MFS, given its variable expressivity. The diagnosis is made on clinical grounds based upon typical abnormalities. The cardiac, skeletal, and ocular systems are generally more focused upon for MFS diagnostic criteria; however, other tissues, including skeletal muscle, fat, skin, fascia, and the respiratory tract, may be affected in this condition as well.
The following list describes the most common clinical findings and the revised Berlin criteria (1986) for diagnosis of MFS. The Ghent criteria (1996) updated the previous guidelines to include greater emphasis on the skeletal findings, as well as those of the family and genetic history.12,13 (See also the eMedicine article Marfan Syndrome in the Pediatrics section for a more detailed description of the Ghent criteria.)
Skeletal system
For the skeletal system involvement to be used as criteria for the diagnosis, at least 2 major criteria or 1 major criterion plus 2 minor criteria must be present.
Major skeletal system criteria are as follows:
- Pectus carinatum
- Pectus excavatum requiring surgery
- A reduced upper-to-lower segment ratio (ie, the distance from the head to the pubic symphysis divided by the distance of the pubic symphysis to the sole) of less than 0.85
- An increased arm span–to–height ratio that is greater than 1.05
- A positive wrist sign (ie, the thumb and index fingers overlap when encircling the contralateral wrist.)
- A positive thumb (Steinberg) sign (ie, the thumb extends beyond the ulnar border of the hand when the digit is held flexed in the palm.)
- A thoracolumbar scoliosis of more than 20º or spondylolisthesis
- Progressive collapse of the hindfoot, leading to pes planovalgus deformity
- A protrusio acetabuli of any degree (seen on anteroposterior (AP) radiographs of the pelvis)
Minor skeletal system criteria are as follows:
- Pectus excavatum of moderate severity
- Joint hypermobility
- High arched palate, with dental crowding
- Facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)
Ocular system
For ocular system involvement to be used as diagnostic criteria, the major criterion or at least 2 minor criteria must be present.
The ocular system major criterion is ectopia lentis (lens dislocation).
Minor ocular system criteria are as follows:
- An abnormally flat cornea
- An increased axial length of the globe, as measured by ultrasound
- A hypoplastic iris or hypoplastic ciliary muscle, causing myopia
Cardiovascular system
For cardiovascular system involvement to be considered diagnostic criteria, only one of the major or minor criteria must be present.
Major cardiovascular system criteria are as follows:
- Dilatation of the ascending aorta, with or without regurgitation, and involving at least the sinuses of Valsalva
- Dissection of the ascending aorta
Minor cardiovascular system criteria are as follows:
- Mitral valve prolapse, with or without regurgitation
- Dilatation of main pulmonary artery in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause in patients younger than 40 years
- Calcification of the mitral valve annulus in patients younger than 40 years
- Dilatation or dissection of the descending thoracic or abdominal aorta in patients younger than 50 years
Pulmonary system
For pulmonary system involvement to be considered diagnostic criteria, one of the minor criteria must be present.
No major pulmonary system criteria exist.
Minor pulmonary system criteria are as follows:
- Spontaneous pneumothorax
- Apical blebs
Skin and integument
For skin and integument involvement to be considered diagnostic criteria, the major criteria or one of the minor criteria must be present.
The major skin and integument criterion is lumbosacral dural ectasia, as depicted by computed tomography (CT) scanning or magnetic resonance imaging (MRI).
The minor skin and integument criteria are as follows:
- Striae atrophicae that are not associated with pregnancy or repetitive stress
- Recurrent or incisional hernia
Family history
For the family history to be considered contributory to a diagnosis of MFS, one of the major criteria must be present.
The major family history criterion is a parent, child, or sibling who meets the following diagnostic criteria independently:
- Presence of a mutation in FBN1 known to cause MFS
- Presence of a haplotype around FBN1, inherited by descent that is known to be associated with unequivocally diagnosed MFS in the family
No minor family history criteria exist.
Requirements for a diagnosis of MFS
- Index case – Major criteria in at least 2 different organ systems and involvement in a third organ system
- Family member – Presence of a major criterion in the family history, one major criterion in an organ system, and involvement of a second organ system
Indications
No specific surgical procedure exists to cure this systemic disease. Rather, specific medical and surgical interventions may ameliorate certain aspects of MFS. System-specific treatment options are discussed in the Treatment section.
Relevant Anatomy
MFS is a systemic disease with various clinically significant abnormalities that require the medical and surgical intervention described in the Treatment section. The disease is not specific to one anatomic location.
Contraindications
Any evidence of aortic dilatation must be treated medically or surgically, before any spinal reconstruction is attempted for scoliosis.
Any evidence of imminent cardiac compromise would preclude surgical intervention until that issue is addressed.
More on Marfan Syndrome |
 Overview: Marfan Syndrome |
| Workup: Marfan Syndrome |
| Treatment: Marfan Syndrome |
| Follow-up: Marfan Syndrome |
| References |
| Next Page » |
References
Ammash NM, Sundt TM, Connolly HM. Marfan syndrome-diagnosis and management. Curr Probl Cardiol. Jan 2008;33(1):7-39. [Medline].
Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. Jul 25 1991;352(6333):337-9. [Medline].
Tachdjian MO. Marfan's syndrome. In: Herring JA, ed. Tachdjian's Pediatric Orthopaedics. 3rd ed. Philadelphia, Pa: WB Saunders; 1990:829-37.
McKusick VA. The cardiovascular aspects of Marfan's syndrome: a heritable disorder of connective tissue. Circulation. Mar 1955;11(3):321-42. [Medline]. [Full Text].
Judge DP, Dietz HC. Therapy of Marfan syndrome. Annu Rev Med. Feb 18 2008;59:43-59. [Medline].
Matt P, Habashi J, Carrel T, et al. Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan?. J Thorac Cardiovasc Surg. Feb 2008;135(2):389-94. [Medline].
Demetracopoulos CA, Sponseller PD. Spinal deformities in Marfan syndrome. Orthop Clin North Am. Oct 2007;38(4):563-72, vii. [Medline].
Sponseller PD, Hobbs W, Riley LH 3rd, Pyeritz RE. The thoracolumbar spine in Marfan syndrome. J Bone Joint Surg Am. Jun 1995;77(6):867-76. [Medline]. [Full Text].
Robins PR, Moe JH, Winter RB. Scoliosis in Marfan's syndrome. Its characteristics and results of treatment in thirty-five patients. J Bone Joint Surg Am. Apr 1975;57(3):358-68. [Medline]. [Full Text].
Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med. Apr 13 1972;286(15):804-8. [Medline].
Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol. Dec 1986;103(6 pt 1):2499-509. [Medline]. [Full Text].
National Heart, Lung and Blood Institute. Marfan syndrome. Available at http://www.nhlbi.nih.gov/health/dci/Diseases/mar/mar_diagnosis.html. Accessed February 15, 2008.
Porter RS, Kaplan JL, Homeier BP, Beers MH, eds. Diagnostic criteria for Marfan syndrome (Ghent nosology) [table]. The Merck Manuals Online Medical Library. Available at http://www.merck.com/media/mmpe/pdf/Table_284-1.pdf. Accessed February 15, 2008.
Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. N Engl J Med. May 12 1994;330(19):1335-41. [Medline]. [Full Text].
Gott VL, Cameron DE, Pyeritz RE, et al. Composite graft repair of Marfan aneurysm of the ascending aorta: results in 150 patients. J Card Surg. Sep 1994;9(5):482-9. [Medline].
Giacheti CM, Zanchetta S, Maranhe E, et al. A newly recognized syndrome of Marfanoid habitus; long face; hypotelorism; long, thin nose; long, thin hands and feet; and a specific pattern of language and learning disabilities. Am J Med Genet A. Dec 15 2007;143(24):3137-9. [Medline].
Maumenee IH. The eye in the Marfan syndrome. Trans Am Ophthalmol Soc. 1981;79:684-733. [Medline]. [Full Text].
Mommertz G, Sigala F, Langer S, et al. Thoracoabdominal aortic aneurysm repair in patients with Marfan syndrome. Eur J Vasc Endovasc Surg. Feb 2008;35(2):181-6. [Medline].
Pepe G, Lapini I, Evangelisti L, et al. Is ectopia lentis in some cases a mild phenotypic expression of Marfan syndrome? Need for a long-term follow-up. Mol Vis. 2007;13:2242-7. [Medline]. [Full Text].
Further Reading
Keywords
MFS, Marfan's syndrome, arachnodactyly, long and thin digits, dolichostenomelia, long limbs, pectus deformities, pectus excavatum, pectus carinatum, thoracolumbar scoliosis, aortic dilatation, aortic regurgitation, aortic dissection, aneurysm, mitral valve prolapse, myopia, cataracts, retinal detachment, superior lens dislocation
