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) Curation Status (Adult): Released Status (Pediatric): Passed (Consensus scoring is Complete) P

Condition: Marfan Syndrome
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
FBN10007947 (marfan syndrome; mfs)
Assertion Pending
Actionability Rationale
This report was generated prior to the implementation of the process for making actionability assertions. An actionability assertion will be made, but may take time due to the substantial backlog of topics that need assertions.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: FBN10007947
Clinically significant aortic aneurysm / Aortic surveillance
Aortic dilation progression / Pharmacotherapy

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 1/3300 to 1/20,000.
1 2 3 4 5 6 7
Clinical Features
(Signs / symptoms)
The diagnosis of MFS is based on clinical features, even in the presence of a pathogenic variant in FBN1. MFS is a connective tissue disorder with a broad phenotypic continuum that ranges from mild (one or a few systems impacted) to severe (rapidly progressive multiorgan disease in neonates). The cardinal features of MFS involve the cardiovascular, ocular, and skeletal systems. Progressive aortic root dilation is the most frequent cardiovascular manifestation predisposing patients to aortic aneurysm and/or dissection. Patients may also have valvular disease, mitral valve prolapse, and regurgitation. Skeletal manifestations are due to excessive linear growth of long bones and connective tissue abnormalities, and include tall stature, long extremities, arachnodactyly, pectus deformities, scoliosis, and joint laxity. Ocular features include myopia (the most common), ectopia lentis (a hallmark feature), and an increased risk for retinal detachment, lens subluxation, glaucoma, and early cataracts. Pulmonary issues include spontaneous pneumothorax, reduced pulmonary reserve, and sleep apnea. Most individuals often develop dural ectasia that can lead to bony erosion and nerve entrapment. Chronic pain, fatigue, reduced physical capacity and endurance, psychosocial challenges, and depression and anxiety are also reported.
1 3 8 9 10 4 5 6 7 11 12 13 14 15
Natural History
(Important subgroups & survival / recovery)
Age at onset of symptoms is variable and can appear from birth to adulthood. Ectopia lentis is often the presenting feature and occurs commonly before age 10 years. The cardiovascular features are the major source of morbidity and early mortality, specifically aortic dilation, dissection, and rupture and mitral valve prolapse with congestive heart failure. Aortic dilation progresses over time, on average 0.5-1 mm per year, with the vast majority of cases becoming evident before age 18 years. Prognosis depends on the degree of aortic involvement. A long-term survival study of MFS in the 1970s showed the mean age of death of 32 years for individuals without surgery; however, survival in patients with MFS has significantly improved with medical and surgical management of aortic disease and may approach that of the general population. There are no ethnic/racial or gender differences observed, though some evidence indicates greater survival in females. Pregnancy can be dangerous for women; complications include rapid progression of aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, and the postpartum period.
1 8 10 4 16 5 6 11 12 13 15 17
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with MFS, the following evaluations are recommended at diagnosis:
• Evaluation by an ophthalmologist with expertise in MFS
• Evaluation for skeletal manifestations that may require immediate attention by an orthopedist (e.g., severe scoliosis)
• Echocardiography
• Consultation with a clinical geneticist and/or genetic counselor. (Tier 4)
Management is most effectively accomplished through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon. (Tier 4)
Prophylactic surgical repair of the aorta is recommended for aortic diameters >5.0 cm, though some guidelines indicate repair at >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)
3 8 9 16 18 7 17 19 20
Pregnant patients with MFS are at an increased risk for aortic dissection at aortic diameters > 4.0 cm. Thus, for women contemplating pregnancy, aortic prophylactic surgery is recommended for aortic diameters > 4.0-4.5 cm, taking into account aortic growth and family history. (Tier 2)
3 8 16 18 19 20
A meta-analysis of five cohort studies among children and adolescents with MFS indicated that beta-blocker treatment decreased the rate of aortic dilation compared to no treatment (standardized mean difference: -1.30; 95% CI: -2.11 to -0.49; p=0.002). A randomized trial of 70 patients with MFS aged 12-50 years showed that beta-blocker vs. no treatment slowed the rate of aortic dissection (aortic ratio mean slope: 0.084 vs. 0.023, respectively). However, none of the studies demonstrated an impact on mortality, occurrence of aortic dissection, or the need for elective repair of the aorta and/or aortic valve, though these studies were likely underpowered. (Tier 1)
11 14
A meta-analysis of six randomized clinical trials among children and adults with MFS indicated that losartan, an angiotensin II receptor antagonist, significantly decreased the rate of aortic dilation compared to no losartan treatment (standardized mean difference: -0.13; 95% CI: -0.25 to 0.00; p=0.04). However, improvements in mortality, cardiovascular surgery, or aortic dissection or rupture were assessed but not observed. Follow-up time in these studies ranged from 35 months to 3.5 years, which may have limited the ability to assess these 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)
3 16 7
Pregnancy and the post-partum period confer a higher risk for aortic complications. Aortic dissection and/or rupture has the highest incidence in the third trimester (about 50%) and peripartum period (33%). Women should be managed closely throughout the pregnancy, ideally in a high-risk obstetric clinic with a multidisciplinary team. Pregnant women should have strict blood pressure control to prevent stage II hypertension. 4.4% of carefully monitored patients with MFS developed aortic dissection and in unmonitored patients, the risk is likely higher. (Tier 2)
8 20
Hypertension should be promptly identified and treated. (Tier 2)
Because of the defect in connective tissue, individuals with MFS are at risk for hernias. Many will have inguinal herniation that will require surgical repair. Recurrent hernias or hernias at the site of surgical incisions are a more distinctive hallmark of a connective tissue disorder. Primary hernia repair should use a synthetic mesh (or similar artificial construct) to minimize the risk of recurrence. (Tier 2)
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)
3 8 16 18
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)
3 6 8 9 16 18 20
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)
7 9 20
Individuals with MFS should be followed closely by an ophthalmologist familiar with MFS at least yearly with slit lamp examinations for lens subluxation and evaluations for glaucoma and cataracts. Careful and aggressive refraction and visual correction are mandatory in young children at risk for amblyopia. (Tier 2)
Close monitoring for scoliosis by using the forward-bending test at yearly intervals and management by an orthopedist is preferred because surgical stabilization of the spine may be required. (Tier 2)
Circumstances to Avoid
Stent grafts to repair type B aortic dissection, frequently used in non-MFS patients, should not be used routinely in patients with MFS given the substantial risk of early and late complications. Their use should be considered with the greatest of caution, and pros and cons evaluated patient-by-patient. (Tier 1)
Though individuals with MFS are encouraged to participate in recreational activities, they should not participate in low and moderate static/low dynamic competitive sports if they have more than one of the following:
• Aortic root dilation
• Moderate to severe mitral regurgitation
• Left ventricular systolic dysfunction
• Family history of aortic dissection. (Tier 2)
3 6 7
Individuals with MFS should not participate in any competitive sports, contact sports, or isometric exercises that involve intense physical exertion, require straining (e.g., heavy weight lifting), or the potential for bodily collision. (Tier 2)
6 20
Sports in which ocular trauma is likely, such as boxing or full-contact karate, should be discouraged. (Tier 2)
Individuals with MFS should avoid agents that stimulate the cardiovascular system, including routine use of decongestants. Caffeine can aggravate a tendency for arrhythmia. The use of psychostimulant medications for chronic fatigue or attention-deficit/hyperactivity disorder should be used with caution and approved by the cardiologist. (Tier 2)
Individuals with MFS should avoid breathing against a resistance (e.g., playing a brass instrument), scuba diving, or high-altitude sports (e.g., skydiving, mountaineering). (Tier 2)
Corneal refractive surgery for myopia is generally contraindicated in individuals with MFS given the risk of additional eye complications. (Tier 2)
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 up to 95% of cases meeting diagnosis criteria. (Tier 3)
(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) (Tier 4)
1 8
75-85% of patients have aortic root dilations. (Tier 3)
10 14
60% of patients have ectopia lentis. (Tier 3)
Emphysematous lung disease occurs in approximately 10-15% of those with MFS. (Tier 4)
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on relative risk was available.
The clinical symptoms of MFS vary within and between families. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
The interventions identified in this report include beta-blockers, an angiotensin II receptor antagonist (losartan), and prophylactic surgery, which is likely associated with some risk for mortality and morbidity. Side effects of beta-blockers include exercise intolerance, fatigue, bronchospasm or wheezing, and depression. Side effects of losartan include dizziness, syncope, angioedema, and renal dysfunction.
13 14
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, which would likely not be detected through routine clinical care. In addition, 25% of patients do not have a family history and represent new cases due to sporadic variants for the condition. (Tier 4)
1 8
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.

Gene Disease Associations
Disease Associations
Primary MONDO Identifier
Additional MONDO Identifiers
OMIM Identifier
Reference List
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4. Marfan syndrome. Orphanet encyclopedia,
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9. Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. (2012) 14(1):171-7.
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11. Koo HK, Lawrence KA, Musini VM. Beta-blockers for preventing aortic dissection in Marfan syndrome. Cochrane Database Syst Rev. (2017) 11:CD011103.
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13. Gao L, Chen L, Fan L, Gao D, Liang Z, Wang R, Lu W. The effect of losartan on progressive aortic dilatation in patients with Marfan's syndrome: a meta-analysis of prospective randomized clinical trials. Int J Cardiol. (2016) 217:190-4.
14. Gao L, Mao Q, Wen D, Zhang L, Zhou X, Hui R. The effect of beta-blocker therapy on progressive aortic dilatation in children and adolescents with Marfan's syndrome: a meta-analysis. Acta Paediatr. (2011) 100(9):e101-5.
15. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MARFAN SYNDROME; MFS. MIM: 154700: 2017 Mar 06. World Wide Web URL:
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17. Erbel R, Aboyans V, Boileau C, Bossone E, Di Bartolomeo R, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwoger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, von Allmen RS, Vrints CJ. [2014 ESC Guidelines on the diagnosis and treatment of aortic diseases]. Kardiol Pol. (2014) 72(12):1169-252.
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19. Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez Munoz D, Rosenhek R, Sjogren J, Tornos Mas P, Vahanian A, Walther T, Wendler O, Windecker S, Zamorano JL. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. (2017) 38(36):2739-2791.
20. D. Zentner, M. West, L. Ades. Update on the diagnosis and management of inherited aortopathies, including Marfan Syndrome. Publisher: The Cardiac Society of Australia and New Zealand. (2016) Website:
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