Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete)

Condition: Marfan Syndrome
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of Marfan syndrome (MFS) has been estimated in the range of 1/5000 to 1/20,000.
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Clinical Features
(Signs / symptoms)
The diagnosis of MFS is based on clinical features, even in the presence of a known FBN1 mutation. The cardinal features of MFS involve the cardiovascular, ocular, and skeletal systems. Patients are highly predisposed to thoracic aortic aneurysm and/or dissection, and may also have valvular disease, primarily mitral valve prolapse and regurgitation. Skeletal manifestations are the result of excessive linear growth of the long bones and connective tissue abnormalities, and include long extremities, pectus deformities, scoliosis, and joint laxity. The most common ocular manifestation is myopia, while ectopia lentis is the hallmark feature. Some patients develop progressive lung disease.
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Natural History
(Important subgroups & survival / recovery)
Virtually all patients have evidence of aortic disease at some point in their life, with these cardiovascular features being the major source of morbidity and early mortality, specifically aortic dilation, dissection, and rupture. Symptoms can appear at any age and vary greatly between individuals even within the same family. Without treatment, patients with MFS with aortic dissection have a reduced long-term survival, 50-70% at 10 years after diagnosis of aortic dissection. Survival in patients with MFS has been significantly improved with medical and surgical management of the aortic disease and may approach that of the general population. There are no ethnic/racial or gender differences observed. Pregnancy can be dangerous for women and complications include rapid progression of aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, and the postpartum period.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Pregnant patients with MFS are at an increased risk for aortic dissection at aortic diameters >4cm. Thus, for women contemplating pregnancy, aortic prophylactic surgery is recommended for aortic diameters >4.0 cm. (Tier 2)
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Prophylactic surgical repair of the aorta is recommended for aortic diameters >5.0 cm, though some guidelines indicate repair at >4.0 or >4.5 cm with special consideration for the rate of aortic diameter expansion, progressive aortic regurgitation, family history of aortic dissection, and the height of the patient. Timely repair of aortic aneurysms among patients with MFS prolongs survival such that it approaches that of age-matched controls. (Tier 2)
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A systematic review of observational studies, beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers concluded that these medications slowed the progression of aortic dilation in MFS. Three of the included studies showed that the treatment group's aortic dilation progressed by roughly 1mm/year less than the non-treatment group, though no information was provided on how this impacted clinical outcomes. (Tier 1)
Use of prophylactic antibiotics in any invasive procedure such as tooth extraction and surgery is recommended in the presence of valvular disease. (Tier 2)
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At the time of diagnosis, an echocardiogram of the entire aorta is recommended to determine the aortic root and ascending aortic diameters followed by a second echocardiogram 6 months later to determine rate of aortic enlargement. (Tier 2)
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Patients with documented stable aortic diameters are recommended to have annual echocardiograms. More frequent imaging should be considered for those with diameters >4.5 cm or those that show significant aortic diameter growth. (Tier 2)
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MRI or CT of the entire aorta is recommended starting in young adulthood. Repeat annually for patients with a history of aortic root replacement or dissection, less frequently for those without. (Tier 2)
Annual ophthalmological exams are recommended, including monitoring for glaucoma. Removal of lenses may be indicated if vision is poor. (Tier 2)
Orthopedic referral may be indicated for progressive scoliosis, followed by corrective bracing or surgery if needed. (Tier 2)
Pre-pregnancy counselling should include full discussion of the risks and benefits of pregnancy and the alternatives (adoption, surrogate, etc.). Pregnant women should be followed by a high risk obstetrician both during pregnancy and through the immediate postpartum period. Women should undergo cardiovascular imaging with echocardiography prior to pregnancy and at least every three months during pregnancy. 4.4% of carefully monitored patients developed aortic dissection and in unmonitored patients, the risk is likely higher. (Tier 2)
Circumstances to Avoid
Stent graphs to repair type B aortic dissection should be avoided in patients with MFS. (Tier 1)
Patients should avoid strenuous physical exercise, competitive, contact, and isometric sports, though specific recommendations for appropriate types of sports varies depending on degree of aortic enlargement, severity of mitral regurgitation, and family history of dissection or sudden death. (Tier 2)
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Patients should avoid activities that cause joint injury or pain; agents that stimulate the cardiovascular system such as decongestants and caffeine; LASIK correction of visual deficits; and breathing against a resistance or positive pressure ventilation for individuals at risk for recurrent pneumothorax. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
The prevalence of FBN1 mutations is unknown, but should be similar to MFS prevalence as FBN1 mutations account for nearly 100% of MFS cases. (Tier 4)
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Mutation screening of FBN1 should yield a result in up to 97% of patients with MFS who meet the Ghent criteria. (Tier 4)
(Include any high risk racial or ethnic subgroups)
Penetrance is high, with nearly all patients having evidence of aortic disease during their lifetime. (Tier 4)
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75-85% of patients have aortic root dilations. (Tier 3)
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60% of patients have ectopia lentis. (Tier 4)
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on relative risk was available.
The onset and rate of aortic dilation is highly variable. MFS demonstrates both intra- and inter-familial variability. (Tier 4)
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4. What is the Nature of the Intervention?
Nature of Intervention
The identified interventions involve invasive prophylactic surgery, which is likely associated with some risk for mortality and morbidity.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
The major source of morbidity and mortality is aortic disease, with most cases of MFS presenting with a dilation of the aortic root or the ascending aorta or a Type A dissection (Tier 4), which would likely not be detected through routine clinical care. (Tier 4)
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Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Clinically Significant Aortic Aneurysms / Surveillance
Aortic Dilation Progression / Beta-blockers
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. HC Dietz. Marfan syndrome. 2001 Apr 18 [Updated 2014 Jun 12]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from:
2. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task force 4: hcm and other cardiomyopathies, mitral valve prolapse, myocarditis, and marfan syndrome. J Am Coll Cardiol. (2005) 45(8):1340-5.
3. Arslan-Kirchner M, Arbustini E, Boileau C, Child A, Collod-Beroud G, De Paepe A, Epplen J, Jondeau G, Loeys B, Faivre L. Clinical utility gene card for: marfan syndrome type 1 and related phenotypes [fbn1]. Eur J Hum Genet. (2010) 18(9).
4. Guidelines for diagnosis and treatment of aortic aneurysm and aortic dissection (jcs 2011): digest version. Circ J. (2013) 77(3):789-828.
5. Guidelines for the diagnosis and management of marfan syndrome. Other. (2011) Website:
6. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A report of the american college of cardiology foundation/american heart association task force on practice guidelines, american association for thoracic surgery, american college of radiology,american stroke association, society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, society of interventional radiology, society of thoracic surgeons,and society for vascular medicine. J Am Coll Cardiol. (2010) 55(14):e27-e129.
7. Pyeritz RE. Evaluation of the adolescent or adult with some features of marfan syndrome. Genet Med. (2012) 14(1):171-7.
8. Pacini D, Parolari A, Berretta P, Di Bartolomeo R, Alamanni F, Bavaria J. Endovascular treatment for type b dissection in marfan syndrome: is it worthwhile?. Ann Thorac Surg. (2013) 95(2):737-49.
9. Marfan syndrome. Orphanet encyclopedia,
10. Svensson LG, Adams DH, Bonow RO, Kouchoukos NT, Miller DC, O'Gara PT, Shahian DM, Schaff HV, Akins CW, Bavaria JE, Blackstone EH, David TE, Desai ND, Dewey TM, D'Agostino RS, Gleason TG, Harrington KB, Kodali S, Kapadia S, Leon MB, Lima B, Lytle BW, Mack MJ, Reardon M, Reece TB, Reiss GR, Roselli EE, Smith CR, Thourani VH, Tuzcu EM, Webb J, Williams MR. Aortic valve and ascending aorta guidelines for management and quality measures. Ann Thorac Surg. (2013) 95(6 Suppl):S1-66.
11. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. (2012) 33(19):2451-96.
12. Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC. Canadian cardiovascular society position statement on the management of thoracic aortic disease. Can J Cardiol. (2014) 30(6):577-89.
13. Thakur V, Rankin KN, Hartling L, Mackie AS. A systematic review of the pharmacological management of aortic root dilation in marfan syndrome. Cardiol Young. (2013) 23(4):568-81.
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