Marfan Syndrome

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: FBN1 (HGNC:3603)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 03/01/2019
• Curation Status: Released - Under Revision (1.1.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
FBN1	N/A (0007947)	154700	Definitive Actionability

Actionability Assertion Rationale

• The assertion was unanimously definitive. This is based on decades of systematic collection of evidence and analysis. Although there were concerns about the fact that there is not strong evidence regarding the penetrance in an unselected population, the condition can lead to sudden death if unidentified, and the initial intervention is relatively benign.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Clinically significant aortic aneurysm / Aortic surveillance	3	3C	3B	3	12CB
Aortic dilation progression / Pharmacotherapy	3	3C	2A	3	11CA

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of Marfan syndrome (MFS) has been estimated in the range of 1/3300 to 1/20,000.

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.

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.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 5000

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

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Penetrance is high, with nearly all patients having evidence of aortic disease during their lifetime. (Tier 4)

Tier 4

>= 40 %

75-85% of patients have aortic root dilations.

Tier 3

>= 40 %

60% of patients have ectopia lentis.

Tier 3

>= 40 %

Emphysematous lung disease occurs in approximately 10-15% of those with MFS.

Tier 4

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was available.

Expressivity

The clinical symptoms of MFS vary within and between families.

Tier 3

Intervention Effectiveness

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

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

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

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

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

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

Surveillance

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

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

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

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

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

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

Nature of 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.

Context: Adult Pediatric

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.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			FBN1			154700	0007947

References List

Arslan-Kirchner M, Arbustini E, Boileau C, Child A, Collod-Beroud G, De Paepe A, Epplen J, Jondeau G, Loeys B, Faivre L. (2010) Clinical utility gene card for: Marfan syndrome type 1 and related phenotypes [FBN1]. European journal of human genetics : EJHG. 18(9).

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) 2017 ESC/EACTS Guidelines for the management of valvular heart disease. European heart journal. 38(36):2739-2791.

Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC. (2014) Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. The Canadian journal of cardiology. 30(6):577-89.

Braverman AC, Harris KM, Kovacs RJ, Maron BJ. (2015) Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 7: Aortic Diseases, Including Marfan Syndrome: A Scientific Statement From the American Heart Association and American College of Cardiology. Journal of the American College of Cardiology. 66(21):2398-2405.

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) URL: https://www.csanz.edu.au/

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) [2014 ESC Guidelines on the diagnosis and treatment of aortic diseases]. Kardiologia polska. 72(12):1169-252.

Gao L, Chen L, Fan L, Gao D, Liang Z, Wang R, Lu W. (2016) The effect of losartan on progressive aortic dilatation in patients with Marfan's syndrome: a meta-analysis of prospective randomized clinical trials. International journal of cardiology. 217(1874-1754):190-4.

Gao L, Mao Q, Wen D, Zhang L, Zhou X, Hui R. (2011) The effect of beta-blocker therapy on progressive aortic dilatation in children and adolescents with Marfan's syndrome: a meta-analysis. Acta paediatrica (Oslo, Norway : 1992). 100(9):e101-5.

HC Dietz. Marfan Syndrome. (2001) [Updated Jun 12 2014]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1335/

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) 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. Journal of the American College of Cardiology. 55(14):e27-e129.

JCS Joint Working Group. (2013) Guidelines for diagnosis and treatment of aortic aneurysm and aortic dissection (JCS 2011): digest version. Circulation journal : official journal of the Japanese Circulation Society. 77(3):789-828.

Koo HK, Lawrence KA, Musini VM. (2017) Beta-blockers for preventing aortic dissection in Marfan syndrome. The Cochrane database of systematic reviews. 11(1469-493X):CD011103.

MARFAN SYNDROME; MFS. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 154700, (2017) World Wide Web URL: http://omim.org/

Marfan syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=558

Pacini D, Parolari A, Berretta P, Di Bartolomeo R, Alamanni F, Bavaria J. (2013) Endovascular treatment for type B dissection in Marfan syndrome: is it worthwhile?. The Annals of thoracic surgery. 95(2):737-49.

Pyeritz RE. (2012) Evaluation of the adolescent or adult with some features of Marfan syndrome. Genetics in medicine : official journal of the American College of Medical Genetics. 14(1):171-7.

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. (2013) Aortic valve and ascending aorta guidelines for management and quality measures. The Annals of thoracic surgery. 95(6 Suppl):S1-66.

Tinkle BT, Saal HM. (2013) Health supervision for children with Marfan syndrome. Pediatrics. 132(4):e1059-72.

Velvin G, Bathen T, Rand-Hendriksen S, Geirdal AO. (2015) Systematic review of the psychosocial aspects of living with Marfan syndrome. Clinical genetics. 87(2):109-16.

Velvin G, Bathen T, Rand-Hendriksen S, Geirdal AO. (2016) Systematic review of chronic pain in persons with Marfan syndrome. Clinical genetics. 89(6):647-58.