Stage I: Rule-Out Dashboard
Incidental Findings in Adults
GENE/GENE PANEL: FBN1
DISORDER: Marfan Syndrome
PENETRANCE
ACTIONABILITY
1. Is there a qualifying resource, such as a practice guideline
or systematic review, for the genetic condition?
YES
NO
2. Does the practice guideline or systematic review indicate
that the result is actionable in one or more of the following
ways?
Yes
4. Is there at least one known pathogenic variant with at least
moderate penetrance (≥40%) or moderate relative risk (≥2)
in any population?
YES
NO
SIGNIFICANCE/BURDEN OF DISEASE
5. Is this condition an important health problem?
No
Patient Management
YES
Surveillance or Screening
NEXT STEPS
Family Management
6. Are Actionability (Q2-3), Penetrance (Q4), and Significance
(Q5) all “YES”?
Circumstances to Avoid
YES (≥ 1 of above)
NO
3. Is the result actionable in an undiagnosed adult with the
genetic condition?
YES
NO
NO
YES (Proceed to Stage II)
NO (Consult Actionability Working Group)
Exception granted, proceed to Stage II
Exception not granted, STOP
1
Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
GENE/GENE PANEL: FBN1
Topic
Narrative Description of Evidence
DISORDER: Marfan Syndrome
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the
genetic disorder
Signif/Burden of Condition
Clinical Features
(Signs/symptoms)
Natural History
(Important
subgroups &
survival/recovery)
The prevalence of Marfan syndrome (MFS) has been estimated in the range of 1/5000 to
1/20,000.
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.
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.
(1-5)
(1;2;4-8)
(1;5;6;9)
2. How effective are interventions for preventing the harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
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)
(4;6;10-12)
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)
(4-7;10-12)
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 nontreatment group, though no information was provided on how this impacted clinical
outcomes. (Tier 1)
(13)
Patient
Management
Surveillance
Use of prophylactic antibiotics in any invasive procedure such as tooth extraction and
surgery is recommended in the presence of valvular disease. (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)
(4;10)
(4;6;10;12)
Patients with documented stable aortic diameters are recommended to have annual
2
Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
Family
Management
echocardiograms. More frequent imaging should be considered for those with diameters
>4.5 cm or those that show significant aortic diameter growth. (Tier 2)
(4-7;10-12)
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)
Annual ophthalmological exams are recommended, including monitoring for glaucoma.
Removal of lenses may be indicated if vision is poor. (Tier 2)
(5)
Orthopedic referral may be indicated for progressive scoliosis, followed by corrective
bracing or surgery if needed. (Tier 2)
(5)
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)
First-degree relatives should undergo imaging of the thoracic aorta. (Tier 2)
(5)
(10-12)
If a familial FBN1 mutation has been identified, predictive testing in children will identify
those at risk of MFS and those in whom no annual surveillance is necessary. Annual clinical
examination is indicated in asymptomatic family members with or without screening
investigations, depending on the clinical context. (Tier 2)
(5)
All family members potentially at risk should receive genetic counselling, lifestyle
modification advice, and where appropriate, counseling with regard to carrier options. (Tier
2)
Stent graphs to repair type B aortic dissection should be avoided in patients with MFS. (Tier
1)
Circumstances to
Avoid
(5)
(8)
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)
(5;11)
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)
(1)
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
3
Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
GENE/GENE PANEL: FBN1
Topic
Narrative Description of Evidence
DISORDER: Marfan Syndrome
Ref
3. What is the chance that this threat will materialize?
Mode of Inheritance Autosomal dominant
Prevalence of
Genetic Mutations
Penetrance
OR
Relative Risk
(include high risk racial
or ethnic subgroups)
Expressivity
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)
Mutation screening of FBN1 should yield a result in up to 97% of patients with MFS who meet
the Ghent criteria. (Tier 4)
Penetrance is high, with nearly all patients having evidence of aortic disease during their
lifetime. (Tier 4)
(1;3)
(5)
(1;6)
75-85% of patients have aortic root dilations. (Tier 3)
(1;8;13)
60% of patients have ectopia lentis. (Tier 4)
No information on relative risk was available.
The onset and rate of aortic dilation is highly variable. MFS demonstrates both intra- and interfamilial variability. (Tier 4)
(1)
(1;5)
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
setting 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.
(1;6)
Date of Search (MM.DD.YYYY): 06.12.2014 (updated 03.20.2015)
Reference List
1. Dietz HC. Marfan Syndrome. GeneReviews. 2011.
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 Apr
19;45(8):1340-5.
3. Arslan-Kirchner M, Arbustini E, Boileau C, Child A, Collod-Beroud G, De PA, et al. Clinical utility gene card for:
Marfan syndrome type 1 and related phenotypes [FBN1]. Eur J Hum Genet 2010 Sep;18(9).
4. JCS Joint Working Group. Guidelines for diagnosis and treatment of aortic aneurysm and aortic dissection (JCS
2011): digest version. Circ J 2013;77(3):789-828.
5. Ades L. Guidelines for the diagnosis and management of Marfan Syndrome. The Cardiac Society of Australia and
New Zealand; 2011.
4
Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
6. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE, Jr., et al. 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 Apr 6;55(14):e27-e129.
7. Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med 2012
Jan;14(1):171-7.
8. Pacini D, Parolari A, Berretta P, Di BR, Alamanni F, Bavaria J. Endovascular treatment for type B dissection in
Marfan syndrome: is it worthwhile? Ann Thorac Surg 2013 Feb;95(2):737-49.
9. OrphaNet. Marfan Syndrome. 2010.
Ref Type: Online Source
10. Svensson LG, Adams DH, Bonow RO, Kouchoukos NT, Miller DC, O'Gara PT, et al. Aortic valve and ascending aorta
guidelines for management and quality measures. Ann Thorac Surg 2013 Jun;95(6 Suppl):S1-66.
11. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, et al. Guidelines on the
management of valvular heart disease (version 2012). Eur Heart J 2012 Oct;33(19):2451-96.
12. Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, et al. Canadian Cardiovascular Society
position statement on the management of thoracic aortic disease. Can J Cardiol 2014 Jun;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 Aug;23(4):568-81.
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