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Marfan syndrome consists of connective tissue anomalies resulting in ocular, skeletal, and cardiovascular abnormalities (eg, dilation of ascending aorta, which can lead to aortic dissection). Diagnosis is clinical. Treatment may include prophylactic β-blockers to slow dilation of the ascending aorta and prophylactic aortic surgery.
Inheritance is autosomal dominant. The basic molecular defect results from mutations in the gene encoding the glycoprotein fibrillin-1 (FBN1), which is the main component of microfibrils and helps anchor cells to the extracellular matrix. The principal structural defect involves the cardiovascular, musculoskeletal, and ocular systems. The pulmonary system and CNS are also affected. There are many different manifestations of the genetic mutation that causes Marfan syndrome; however, it is typically recognized by the constellation of long limbs, aortic root dilation, and dislocated lenses.
Symptoms and Signs
Cardiovascular system
Findings include valvular prolapse and aortic aneurysm. A diastolic murmur may be heard over the aortic valve. Those with mitral valve prolapse may have a systolic click and a late systolic murmur or, in severe cases, a holosystolic murmur. Most severe complications result from pathologic changes in the aortic root and ascending aorta. The aortic media is affected preferentially in areas subject to the greatest hemodynamic stress. The aorta progressively dilates or acutely dissects, beginning in the coronary sinuses, sometimes before age 10 yr. The aortic root dilates in 50% of children and in 60 to 80% of adults and can cause aortic regurgitation. Bacterial endocarditis may develop. Redundant cusps and chordae tendineae may lead to mitral valve prolapse or regurgitation.
Musculoskeletal system
Severity varies greatly. Patients are taller than average for age and family; arm span exceeds height. Arachnodactyly (disproportionately long, thin digits) is noticeable, often by the thumb sign (the distal phalanx of the thumb protrudes beyond the edge of the clenched fist). Sternum deformity—pectus carinatum (outward displacement) or pectus excavatum (inward displacement)—is common, as are joint hyperextensibility, genu recurvatum (backward curvature of the legs at the knees), pes planus (flat feet), kyphoscoliosis, and diaphragmatic and inguinal hernias. Subcutaneous fat usually is sparse. The palate is often high-arched.
Ocular system
Findings include ectopia lentis (subluxation or upward dislocation of the lens) and iridodonesis (tremulousness of the iris). The margin of the dislocated lens can often be seen through the undilated pupil. High-grade myopia may be present, and spontaneous retinal detachment sometimes occurs.
Pulmonary system
Cystic lung disease and recurrent spontaneous pneumothorax may occur. These disorders can cause pain and shortness of breath.
CNS
Dural ectasia is a common finding and most frequently occurs in the lumbosacral spine. It is widening of the dural sac surrounding the spinal cord and may cause headache, lower back pain, or neurologic deficits manifested by bowel or bladder weakness.
Diagnosis
Diagnosis can be difficult because many patients have few typical symptoms and signs and no specific histologic or biochemical changes. Considering this variability, diagnostic criteria are based on constellations of clinical findings and family and genetic history (see Table 1: Connective Tissue Disorders in Children: Diagnostic Criteria for Marfan Syndrome (Ghent Nosology)  ). Nonetheless, diagnosis is uncertain in many partial cases of Marfan syndrome. Homocystinuria can partially mimic Marfan syndrome but can be differentiated by detecting homocystine in the urine. Prenatal diagnosis by linkage analysis of the FBN1 gene mutation is hampered by poor genotype/phenotype correlation. Standard imaging of the skeletal, cardiovascular, and ocular systems is done to detect any clinically relevant structural abnormalities and to provide information contributing to the diagnostic criteria (eg, echocardiography to identify aortic root enlargement). In addition to the criteria established within organ systems, family history (1st-degree relative with Marfan syndrome) and genetic history (presence of the FBN1 mutation known to cause Marfan syndrome) are considered major criteria.
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Table 1
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| Diagnostic Criteria for Marfan Syndrome (Ghent Nosology) |
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Organ System
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Major Criteria
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Minor Criteria
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Needed for Involvement
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Cardiovascular
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1 of the following:
- Dilation of the ascending aorta and sinuses of Valsalva
- Aortic dissection
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Mitral valve prolapse
Annulus mitralis calcification in patients < 40 yr
Pulmonary artery dilation
Descending or abdominal aorta dilation or dissection in patients < 50 yr
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1 major or 1 minor criterion
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CNS
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Lumbosacral dural ectasia (detected by MRI or CT)
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N/A
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1 major criterion
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Musculoskeletal
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4 of the following:
- Pectus carinatum
- Pectus excavatum requiring surgery
- Arm span/height ratio > 1.05 or upper segment/lower segment ratio < 0.86 (in adults)
- Wrist and thumb signs
- Scoliosis > 20° or spondylolisthesis
- Elbow extension < 170°
- Pes planus (flat feet)
- Protrusio acetabuli
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Typical facies (eg, dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)
Joint hypermobility
Pectus excavatum not requiring surgery
High-arched palate with crowded teeth
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2 of the 8 components comprising the major criteria or 1 of those criteria plus 2 minor criteria
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Ocular
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Ectopia lentis (lens dislocation)
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Myopia
Flat cornea
Iris or ciliary muscle hypoplasia
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2 minor criteria
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Pulmonary
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N/A
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Pneumothorax
Apical blebs (seen on chest x-ray)
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1 minor criterion
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Skin
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N/A
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Atrophic striae not secondary to pregnancy or weight change
Recurrent or incisional hernia
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1 minor criterion
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If family/genetic history is not contributory, index case diagnosis requires major criteria in 2 organ systems and involvement in a 3rd. Alternatively, if a mutation known to cause Marfan syndrome is present, index case diagnosis requires 1 major criterion in 1 organ system and involvement in a 2nd. Diagnosis of an index case's relative requires 1 major criterion in family history, 1 major criterion in 1 organ system, and involvement in a 2nd. Minor criteria are used only to score organ system involvement and do not count toward the diagnosis.
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N/A = not applicable.
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Adapted from De Paepe A, Devereux RB, Dietz HC, et al: Revised criteria for Marfan syndrome. American Journal of Medical Genetics 62:417–426, 1996; Loeys B, Nuytinck L, Delvaux I, et al: Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Archives of Internal Medicine 161:2447–2454, 2001.
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Prognosis
Advancements in therapy and regular monitoring have improved quality of life and reduced mortality. Median life expectancy increased from 48 yr in 1972 to 72 yr as of 1992. However, life expectancy is still reduced for the average patient, primarily because of the cardiac and vascular complications. This decreased life expectancy can take an emotional toll on an adolescent and the family.
Treatment
Treatment focuses on prevention and treatment of complications. For very tall girls, inducing precocious puberty by age 10 with estrogens and progesterone may reduce potential adult height. All patients should routinely be given β-blockers (eg, atenolol, propranolol) to help prevent cardiovascular complications. These drugs lower myocardial contractility and pulse pressure and reduce progression of aortic root dilation and risk of dissection. Prophylactic surgery is offered if aortic diameter is > 5 cm (less in children). Pregnant women are at especially high risk of aortic complications; elective aortic repair before conception should be discussed. Severe valve regurgitation is also surgically repaired. Bacterial endocarditis prophylaxis before certain invasive procedures (see see Endocarditis: Prevention) is not indicated except in patients who have prosthetic valves or who previously had infective endocarditis (see see Endocarditis: Procedures Requiring Antimicrobial Endocarditis Prophylaxis in High-Risk Patients and see Endocarditis: Recommended Endocarditis Prophylaxis During Oral-Dental or Respiratory Tract Procedures*). Scoliosis is managed with bracing as long as possible, but surgical intervention is encouraged in patients with curves of 40 to 50°.
Cardiovascular, skeletal, and ocular findings should be reevaluated annually. Appropriate genetic counseling is indicated.
Last full review/revision February 2008 by Frank Pessler, MD, PhD; David D. Sherry, MD
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