Author(s): Rachel Berger, Nancy Moran, MD, Eric Weidert, DO, MS
Originally published: December 17, 2025 Last updated: December 17, 2025
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Disease/Disorder

Definition

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that is caused by variations in the fibrillin-1 (FBN1) gene. Major systems affected include skeletal, ocular, and cardiac connective tissue, though the clinical characteristics are highly variable.1

Etiology

The gene FBN1 on chromosome 15q21.1 encodes fibrillin-1. A mutation in this gene causes a defect in fibrillin protein. The majority of MFS is due to an FBN1 variation inherited in an autosomal dominant manner with high penetrance. About 25% of cases are due to de novo mutations.

Epidemiology including risk factors and primary prevention

MFS affects approximately 1 out of every 5,000 to 15,000 individuals.2 With new genetic markers, studies show that prevalence is likely closer to 5,000.3 There is no sex or ethnic predilection. There is no standard primary prevention for MFS, but recent studies have shown promising results for in vitro gene editing as a form of primary prevention.4 There can be some variation in skeletal features across populations.5

Patho-anatomy/physiology

The pathogenesis of MFS is not fully understood. Proposed mechanisms include the role of FBN1 and TGFBR variants in the structural role of microfibrils and increased bioavailability of transforming growth factor-beta, respectfully.6,7 Individuals with MFS are susceptible to thoracic aortic disease due to aortic fragmentation and loss of elastin fibers. The disruption in aortic function is thought to be due to dysfunction between microfibrils in the elastin fibers and the smooth muscle cell contractile units. Fibrillin-1 and microfibril also play major roles in normal skeletal and ocular development and dysfunction results in skeletal and ocular abnormalities.1

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Skeletal features are often the earliest signs of MFS. Cardiovascular involvement typically emerges around adolescence and the risk of aortic dissection increases significantly after age 20.8,9 Without appropriate surveillance and treatment, MFS leads to a reduced lifespan and death in the 3rd to 5th decade of life. Life expectancy can be near-normal with prophylactic surgery and current surveillance recommendations.10  

Specific secondary or associated conditions and complications

MFS is associated with skeletal, ocular, and cardiovascular conditions. Cardiovascular conditions include aortic root aneurysm, aortic dissection, mitral valve prolapse, aortic regurgitation, and left ventricular dysfunction. Aortic pathology is a major cause of morbidity and mortality in MFS. Ectopia lentis and myopia are common ocular manifestations. Skeletal manifestations include dolichostenomelia, arachnodactyly, pes planus, scoliosis, pectus excavatum or carinatum, protrusion acetabuli, joint pain, and joint contractures.

Essentials of Assessment

History

As MFS affects many different organ systems, individual history requires a comprehensive review of systems with particular emphasis on family history. Musculoskeletal inquiries include joint pain, scoliosis, flat feet. Pain can be a significant problem in MFS and at times is the presenting complaint. It is important to ask about cardiovascular symptoms (palpitations, syncope, family history of aneurysms or sudden death). Other systems include Pulmonary (spontaneous pneumothorax), Skin (striae), Ocular (nearsightedness, retinal detachment, strabismus, early-onset cataracts). When discussing family history, many people may not know they had/have a relative with MFS so it is important to ask about signs and symptoms associated with MFS. It is important to explore cardiac history and any sudden onset deaths, or early deaths that were related to a cardiac event. Also ask about family members with increased height, arm span, and finger length.

Physical examination

A detailed orthopedic exam is warranted. Inspection includes marfanoid habitus (tall stature, long limbs, long fingers), pectus excavatum or carinatum, and scoliosis/thoracolumbar kyphosis. Careful examination of the feet is warranted as hindfoot deformity is scored differently than plain pes planus in the GHENT criteria. Any joint contractures should be noted, especially the elbows. Important special exam tests include the Steinberg thumb sign and the Walker-Murdock sign. Hip exam is warranted as protrusio acetabuli is associated with limited hip internal rotation and abduction and often accompanied with a positive FADIR and FABER test. Detailed musculoskeletal exams should be performed for specific areas of joint pain. A detailed cardiac and pulmonary exam to assess for signs of cardiac insufficiencies or pneumothorax. Skin should be inspected for striae. Detailed neurologic exams are warranted for complaints of low back pain or radicular symptoms given dural ectasia association. If the provider has ophthalmologic training, it is recommended to perform a detailed ophthalmologic examination.

Functional assessment

Visual testing should include initial evaluation of refraction, intraocular pressure, lens status, peripheral retina status, and changes to the optic nerve. Annual testing should evaluate for subluxation, glaucoma, and early cataract formation. Chest and spine deformity may result in alterations in pulmonary function which can impact exercise capacity and tolerance. The highest risk is for restrictive lung disease and upper lobe blebs. Evaluation with spirometry and DLCO annually is recommended for preventative care.11

Laboratory studies

There are no specific laboratory exams necessary for treatment or surveillance. Laboratory testing can be used for diagnostic molecular genetic testing.

Due to recent advances in genetic testing, free testing is available via multiple commercial entities that have gene panels including the FBN1 gene for analysis. The type of sample that needs to be submitted (e.g. saliva, blood) depends on the panel so please check with the specific company for their requirements.

Imaging

The main imaging modalities for diagnosis and surveillance include 2D-transthoracic echocardiography (2D-TTE), CT scans, and MRI. Echocardiography is used to assess the aortic root and the proximal ascending aorta. CT and MRI are used for complete vascular imaging of the thorax, abdomen, and neck.11

Specific imaging guidelines include

  • 2D-TTE at initial diagnosis with measurements taken from the parasternal long-axis view at end-diastole. Follow-up every 6 months for children or adults with rapid aortic growth and annually for stable cases.
  • CT or MRI for complete vascular imaging starting at age 18 and every 2-5 years thereafter. MRI is preferred when possible.
  • Special Populations: monthly or bi-monthly echocardiography in pregnant women with aortic dilation

Other helpful imaging modalities for associated conditions with MFS

  • Spontaneous pneumothorax: Chest X-ray
  • Protrusio acetabuli: Hip X-rays
  • Hindfoot deformity/pes planus: Foot X-rays
  • Dural ectasia: MRI lumbar spine

Supplemental assessment tools

The Ghent criteria is used to diagnose MFS

  • Wrist AND thumb sign (+3), Wrist OR thumb sign (+1)
  • Pectus carinatum deformity (+2), Pectus excavatum or chest asymmetry (+1)
  • Hindfoot deformity (+2), plain pes planus (+1)
  • Spontaneous pneumothorax (+2)
  • Dural ectasia (+2)
  • Protrusio acetabuli (+2)
  • Reduced Upper segment (US)/Lower segment (LS) ratio AND increased arm/height AND no severe scoliosis (+1)
  • Scoliosis or thoracolumbar kyphosis (+1)
  • Reduced elbow extension –(+1)
  • 3 of 5 facial features (+1) – (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia)
  • Skin striae (+1)
  • Myopia > 3 diopters (+1)
  • Mitral valve prolapse (all types) (+1)

Maximum total: 20 points; score ≥7 is considered diagnostic for MFS

Early predictions of outcomes

Life expectancy can be near-normal with prophylactic surgery and current surveillance recommendations.11

Environmental

N/A

Social role and social support system

Psychological studies have highlighted a decrease in the level of satisfaction among the MFS population with an impact on quality of life and social relationships. Moreover, patients with MFS are also associated with having increased levels of stress, anxiety and depression. It is important to consider the role that psychological support can play in MFS. A multidisciplinary approach that considers the psychological implications of MFS is recommended.11  

Professional issues

Given the significant morbidity and mortality risk of aortic pathology associated with MFS, genetic testing and counseling for patients and families is an essential component of MFS management. It is important to be aware of varying opinions regarding genetic testing as you counsel patients on genetic recommendations.

If patient is an athlete and recently diagnosed with MFS, it is important to have discussions with them about the risks associated with competitive sports and how they are contraindicated for people with MFS.

Rehabilitation Management and Treatments

Available or current treatment guidelines

While exercise is potentially associated with increased risk of aortic dilatation and/or dissection, it is still recommended to individualize physical activity based on aortic diameter, family history of aortic dissection, and pre-existing fitness.12 Regular moderate aerobic exercise with a level of intensity informed by aortic diameter is recommended in most patients with MFS.

There are currently no evidence-based rehabilitation guidelines for Marfan Syndrome. For patients who have undergone aortic surgery, post-operative cardiac rehabilitation is generally recommended.12

At different disease stages

There are no consistent disease stages. Treatment plans aim to strengthen muscles, improve stability, and maintain cardiovascular health, all while avoiding excessive strain on weakened connective tissue. A personalized approach dependent on the severity of symptoms is crucial due to the variable presentation of the condition.13,14

In general, the intensity of exercise and physical activity should be in the low to moderate metabolic equivalent task (METs) range (<6 METs). High-intensity and high-impact activities, such as contact sports, intense isometric exercise, extreme environmental conditions, and burst exertion, should be avoided due to the strain on the aorta and joints.15

Coordination of care

An interdisciplinary approach is recommended. The team should include physiatrists, orthopedic surgeons, cardiologists, ophthalmologists, and other specialists, as necessary, as well as nurses, wound care specialists, social workers, psychologists, and physical and occupational therapists.14

Patient & family education

Patients and families should be educated on activities to avoid and become confident in gauging the level of exertion required to perform tasks to preserve function. In general, contact sports and activities with rapid changes in atmospheric pressure, like scuba diving, should be avoided.15

Measurement of treatment outcomes

N/A

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

As pain can often be the presenting complaint, it is important for PM&R physicians to recognize the signs associated with MFS (marfanoid habitus, cardiac family history, pectus excavatum or carinatum, Steinberg thumb sign and the Walker-Murdock sign) 

It is important to recognize MFS early as aortic pathology is a major cause of morbidity and mortality. Life expectancy is near-normal with current management.

The GHENT criteria are diagnostic for MFS

Competitive sports are contraindicated in people with MFS

Cutting Edge/Emerging and Unique Concepts and Practice

N/A

Gaps in the Evidence-Based Knowledge

  • Limited evidence on rehabilitation protocols and safe exercise intensity and duration
  • Limited data on optimal management strategies during pregnancy
  • Limited evidence for effective management of the non-cardiovascular conditions associated with MFS

References

  1. Milewicz, D.M., Braverman, A.C., De Backer, J. et al. Marfan syndrome. Nat Rev Dis Primers 7, 64 (2021). https://doi.org/10.1038/s41572-021-00298-7
  2. Groth KA, Hove H, Kyhl K, Folkestad L, Gaustadnes M, Vejlstrup N, Stochholm K, Østergaard JR, Andersen NH, Gravholt CH. Prevalence, incidence, and age at diagnosis in Marfan Syndrome. Orphanet J Rare Dis. 2015 Dec 2;10:153. doi: 10.1186/s13023-015-0369-8. PMID: 26631233; PMCID: PMC4668669.
  3. Klemenzdottir EO, Arnadottir GA, Jensson BO, Jonasdottir A, Katrinardottir H, Fridriksdottir R, Jonasdottir A, Sigurdsson A, Gudjonsson SA, Jonsson JJ, Stefansdottir V, Danielsen R, Palsdottir A, Jonsson H, Helgason A, Magnusson OT, Thorsteinsdottir U, Bjornsson HT, Stefansson K, Sulem P. A population-based survey of FBN1 variants in Iceland reveals underdiagnosis of Marfan syndrome. Eur J Hum Genet. 2024 Jan;32(1):44-51. doi: 10.1038/s41431-023-01455-0. Epub 2023 Sep 8. PMID: 37684520; PMCID: PMC10772070.
  4. Deng Y, Ou Z, Li R, Chen Z, Liang P, Sun L. Affected-embryo-based SNP haplotyping with NGS for the preimplantation genetic testing of Marfan syndrome. Syst Biol Reprod Med. 2021 Aug;67(4):298-306. doi: 10.1080/19396368.2021.1926574. Epub 2021 May 30. PMID: 34053377.
  5. Akutsu K, Morisaki H, Takeshita S, Ogino H, Higashi M, Okajima T, Yoshimuta T, Tsutsumi Y, Nonogi H, Morisaki T. Characteristics in phenotypic manifestations of genetically proved Marfan syndrome in a Japanese population. Am J Cardiol. 2009 Apr 15;103(8):1146-8. doi: 10.1016/j.amjcard.2008.12.037. Epub 2009 Mar 4. PMID: 19361604.
  6. Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest. 2004 Jul;114(2):172-81. doi: 10.1172/JCI20641. PMID: 15254584; PMCID: PMC449744.
  7. Harry C. Dietz, Iain McIntosh, Lynn Y. Sakai, Glen M. Corson, Stephen C. Chalberg, Reed E. Pyeritz, Clair A. Francomano, Four Novel FBN1 Mutations: Significance for Mutant Transcript Level and EGF-like Domain Calcium Binding in the Pathogenesis of Marfan Syndrome, Genomics, Volume 17, Issue 2, 1993, Pages 468-475, ISSN 0888-7543, https://doi.org/10.1006/geno.1993.1349.
  8. Stheneur C, Tubach F, Jouneaux M, Roy C, Benoist G, Chevallier B, Boileau C, Jondeau G. Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition. Genet Med. 2014 Mar;16(3):246-50. doi: 10.1038/gim.2013.123. Epub 2013 Sep 5. PMID: 24008997.
  9. Milleron O, Arnoult F, Delorme G, Detaint D, Pellenc Q, Raffoul R, Tchitchinadze M, Langeois M, Guien C, Beroud C, Ropers J, Hanna N, Arnaud P, Gouya L, Boileau C, Jondeau G. Pathogenic FBN1 Genetic Variation and Aortic Dissection in Patients With Marfan Syndrome. J Am Coll Cardiol. 2020 Mar 3;75(8):843-853. doi: 10.1016/j.jacc.2019.12.043. PMID: 32130918.
  10. Pyeritz RE. Recent progress in understanding the natural and clinical histories of the Marfan syndrome. Trends Cardiovasc Med. 2016 Jul;26(5):423-8. doi: 10.1016/j.tcm.2015.12.003. Epub 2016 Jan 13. PMID: 26908026.
  11. Marelli, S.; Micaglio, E.; Taurino, J.; Salvi, P.; Rurali, E.; Perrucci, G.L.; Dolci, C.; Udugampolage, N.S.; Caruso, R.; Gentilini, D.; et al. Marfan Syndrome: Enhanced Diagnostic Tools and Follow-up Management Strategies. Diagnostics 2023, 13, 2284. https://doi.org/10.3390/ diagnostics13132284
  12. Mazzolai L, Teixido-Tura G, Lanzi S, Boc V, Bossone E, Brodmann M, Bura-Rivière A, De Backer J, Deglise S, Della Corte A, Heiss C, Kałużna-Oleksy M, Kurpas D, McEniery CM, Mirault T, Pasquet AA, Pitcher A, Schaubroeck HAI, Schlager O, Sirnes PA, Sprynger MG, Stabile E, Steinbach F, Thielmann M, van Kimmenade RRJ, Venermo M, Rodriguez-Palomares JF; ESC Scientific Document Group. 2024 ESC Guidelines for the management of peripheral arterial and aortic diseases. Eur Heart J. 2024 Sep 29;45(36):3538-3700. doi: 10.1093/eurheartj/ehae179. PMID: 39210722.
  13. Benninghoven D, Hamann D, von Kodolitsch Y, Rybczynski M, Lechinger J, Schroeder F, Vogler M, Hoberg E. Inpatient rehabilitation for adult patients with Marfan syndrome: an observational pilot study. Orphanet J Rare Dis. 2017 Jul 12;12(1):127. doi: 10.1186/s13023-017-0679-0. PMID: 28701211; PMCID: PMC5508759.
  14. von Kodolitsch Y, Rybczynski M, Vogler M, Mir TS, Schüler H, Kutsche K, Rosenberger G, Detter C, Bernhardt AM, Larena-Avellaneda A, Kölbel T, Debus ES, Schroeder M, Linke SJ, Fuisting B, Napp B, Kammal AL, Püschel K, Bannas P, Hoffmann BA, Gessler N, Vahle-Hinz E, Kahl-Nieke B, Thomalla G, Weiler-Normann C, Ohm G, Neumann S, Benninghoven D, Blankenberg S, Pyeritz RE. The role of the multidisciplinary health care team in the management of patients with Marfan syndrome. J Multidiscip Healthc. 2016 Nov 3;9:587-614. doi: 10.2147/JMDH.S93680. PMID: 27843325; PMCID: PMC5098778.
  15. The Marfan Foundation. Physical Activity Guidelines. Nov 2017.  https://marfan.org/wp-content/uploads/2021/09/FINAL-Physical-Activity-Guidelines-11_17.pdf

Author Disclosure

Rachel Berger
Nothing to Disclose

Nancy Moran, MD
Nothing to Disclose

Eric Weidert, DO, MS
Nothing to Disclose