Marfan syndrome

Background

  • Marfan syndrome (MFS) is a heritable connective tissue disorder with multi-system involvement[1]
    • First characterized as a syndrome by French pediatrician Antoine Marfan in 1896
    • Clinical features vary along a spectrum typical of autosomal-dominant disorders
  • Autosomal-dominant mutation in FBN1 gene (encodes collagen matrix protein fibrillin-1) on chromosome 15[1]
    • This results in cystic medial degeneration of the aortic tunica media (leading to increased risk of aortic aneurysm / dissection)
    • This also interferes with elastin deposition during extracellular matrix formation implicates in the elasticity of multiple tissue types
    • Majority of cases (75%) are familial / inherited vs. minority (25%) are de novo mutations
  • Estimated prevalence of 1/5000 individuals worldwide (equal between men and women)[1]
  • Life expectancy for those diagnosed and treated is now close to that of non-MFS population (previously expected increase in patient mortality by third and fourth decades of life)

Clinical Features

Pectus excavatum in a person with Marfan syndrome.
Marfan Patient.jpeg
Ectopia lentis in Marfan syndrome with Zonular fibers seen.

Physical Findings

Not all may be present

  • Tall stature, long extremities
  • Reduce upper-to-lower segment ratio, increased arm span-to-height ratio
  • Arachnodactyly (“wrist sign, thumb sign), reduced elbow extension
  • Scoliosis or thoracolumbar kyphosis
  • Pectus excavatum or carinatum
  • Ligamentous laxity, hyperextensibility
  • Protrusio acetabuli
  • Hindfoot deformity, plain flat foot
  • Ectopia lentis
  • Myopia (often severe); retinal detachment
  • Lumbrosacral dural ectasia
  • Dolichocephaly, downward slanting palpebral fissures, enophthalmos, retrognathia, malar hypoplasia, high arched palate
  • Skin striae

Increased Risk[2]

Differential Diagnosis

  • Classic vs. Kyphoscoliotic vs. Vascular Ehlers-Danlos Syndrome (vEDS)[4]
  • Loeys-Dietz Syndrome (LDS)
  • Familial Thoracic Aortic Aneurysm and Dissection (FTAAD)
  • Familial Ectopia Lentis Syndrome
  • MASS Phenotype (Myopia, Mitral Valve Prolapse, Aortic Root Dilatation, Aortic Aneurysm Syndrome, Striae, Skeletal Findings)
  • Shprintzen-Goldberg Syndrome
  • Beals Syndrome
  • Stickler Syndrome
  • Non-Specific Connective Tissue Disorder

Evaluation

TOP: Flowchart of ADvISED Trial Algorithm. BOTTOM: flowchart of AORTAs Algorithm[5].
Summary of currently published clinical tools for acute aortic syndrome in the ED, with respective components and scoring systems.[6]

Workup

  • Initial evaluation often occurs in the outpatient setting and involves a thorough physical exam for identification of classically associated features, review of family medical history, slit lamp dilated pupil eye exam (to evaluate for ectopia lentis), and echocardiogram.
  • Advancement to specialist involvement, review of transthoracic echocardiography for aortic root dilation / aneurysm / heart valve involvement, potential genetic testing and/or medical genetics consultation per current guidelines.[7]

Acute Aortic Syndrome (AAS)

  • A high index of suspicion for AAS in the ED setting is critical in MFS when symptoms or signs of this life-threatening complication occur.
  • Key Elements:
    • Sudden onset of severe, “thunderclap” quality, potentially “tearing” and/or migratory chest, neck, abdominal, and/or back pain
    • Young patients with few traditional cardiovascular risk factors
    • Current or recent pregnancy
    • Family history of aortic aneurysm/dissection or unexplained sudden death
    • Typical “Marfanoid” features may not always be present, especially in non-white patients
  • Clinical decision-making tools and algorithms are available (e.g., ADvISED Trial ADD-RS + D-dimer, AORTAs Algorithms), but are not yet externally validated (see images).[8]
  • Basic labs, troponin, D-dimer
    • Important Note: D-dimer is not 100% sensitive and cannot exclude all acute aortic syndromes
  • EKG, CXR
  • CTA / MRA aortic protocol (with IV contrast)
  • Bedside POCUS (Left ventricular outflow tract, aortic root, aortic valve, pericardium, abdominal aorta survey)
  • Formal TTE / TEE

Other Emergencies

  • Standard workup as with non-MFS patients

Diagnosis

Revised Ghent Nosology (2010)[4]

In the absence of family history:

  • Aortic Root Dilatation Z Score > 2 and Ectopia Lentis
  • Aortic Root Dilatation Z Score > 2 and FBN1 Mutation
  • Aortic Root Dilatation Z Score > 2 and Systemic Score > 7 points
  • Ectopia Lentis and FBN1 Mutation (associated with aortic root dilatation)

In the presence of family history:

  • Ectopia Lentis and Family History of MFS
  • Systemic Score > 7 points and Family History of MFS
  • Aortic Root Dilatation Z Score > 2 (above 20 years old), > 3 (below 20 years old) and Family History of MFS

Aortic Dissection Classification

  • Stanford
    • Type A: Involves any portion of ascending aorta
    • Type B: Isolated to descending aorta
  • De Bakey
    • Type I: Involves the ascending and descending aorta
    • Type II: Involves only the ascending aorta
    • Type III: Involves only the descending aorta
Classification of aortic dissection
Image AoDissect DeBakey1.png AoDissect DeBakey2.png AoDissect DeBakey3.png
Percentage 60% 10–15% 25–30%
Type DeBakey I DeBakey II DeBakey III
Classification Stanford A (Proximal) Stanford B (Distal)

Management

Medications

  • Beta-Blocker and/or Angiotensin II Type 1 Receptor Blocker (ARB) Therapy
    • Beta-blockade lowers blood pressure / heart rate and reduces aortic wall shearing forces to reduce the rate of aortic aneurysm growth and risk of dissection
    • Inhibition of ATII Type 1 Receptor-mediated TGF-beta signaling may reduce elastic tissue degeneration based upon mouse models.[9]
  • Other Pharmacologic Considerations
    • Avoid fluoroquinolones (FQs) due to matrix metalloproteinase activation and increased risk of aortic aneurysm/dissection
      • Chen S-W et al. (2023) did not show a significant increase in aortic aneurysm/dissection (OR 1.000) in MFS and other high-risk patients after FQ administration.[10]
      • Gopalakrishnan et al. (2020) showed a significant increase in aortic aneurysm/dissection in patients receiving FQs for pneumonia (HR 2.57, p<0.01%), but not UTIs (HR 0.99, p<0.01%). This suggests intrathoracic inflammation from the primary disease pathology, not FQs themselves, increase the risk of aneurysm or dissection.[11]
    • Antibiotic prophylaxis is no longer recommended for MFS patients before dental procedures, except in those with artificial heart valves

Lifestyle Modifications [12]

  • Regular blood pressure measurement, lifestyle modification, and titration of antihypertensive therapies with goal BP < 120/80 mmHg
  • Avoidance of high-intensity, high-impact sports and intensive isometric activities / weightlifting
  • Low- to moderate-intensity aerobic activities are encouraged after discussion with a cardiologist or specialist
  • Avoidance of Valsalva and other maneuvers that increase intrathoracic or abdominal pressure (risk of acute dissection)
  • Avoidance/cessation of tobacco, smoking, vaping, or stimulant abuse (e.g., cocaine, methamphetamines)
  • Psychiatric evaluation, resources, and support groups (e.g., Marfan Foundation, oeys-Dietz Syndrome Foundation) as appropriate to help address psychosocial sequelae (e.g., body dysmorphia, anxiety, depression, PTSD, suicidal ideation)

Emergency Management [13] [14]

  • Evidence-based management of acute aortic dissection:
    • IV medications to reduce blood pressure (< 100–120 mmHg) and heart rate (< 60 bpm) (e.g., esmolol, labetalol, nitroprusside)
    • Emergent vascular, cardiothoracic, or other surgical consultations
    • Definitive management per current guidelines based on Stanford Type A vs. B dissection, location, extent, and branch involvement
  • Standard-of-care treatment for other associated pathologies

Disposition

  • Disposition depends upon the chief complaint, clinical gestalt, and objective findings from physical exam and workup.

See Also

External Links

References

  1. ↑ 1.0 1.1 1.2 Milewicz DM, Braverman AC, De Backer J, et al. Marfan syndrome. Nat Rev Dis Primers. 2021;7(1):64. doi:10.1038/s41572-021-00298-7.
  2. ↑ Dean, J. Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet. 2007;15:724-733. doi.org/10.1038/sj.ejhg.5201851
  3. ↑ 4. Kim JH, Woo Kim J, Song S-W, et al. Intracranial aneurysms are associated with Marfan Syndrome: Single cohort retrospective study in 118 patients using brain imaging. Stroke. 2020;52(1):331-334. doi:10.1161/STROKEAHA.120.032107
  4. ↑ 4.0 4.1 The Marfan Foundation. (2025, May 21). The Marfan Foundation | Know the Signs | Fight for Victory. Marfan Foundation. https://marfan.org/
  5. ↑ Pena RCF, Hofmann Bowman MA, Ahmad M, et al. An assessment of the current medical management of thoracic aortic disease: A patient-centered scoping literature review. Seminars in Vasc Surg. 2022;25(1):16-34. doi:10.1053/j.semvascsurg.2022.02.007
  6. ↑ Pena RCF, Hofmann Bowman MA, Ahmad M, et al. An assessment of the current medical management of thoracic aortic disease: A patient-centered scoping literature review. Seminars in Vasc Surg. 2022;25(1):16-34. doi:10.1053/j.semvascsurg.2022.02.007
  7. ↑ Isselbacher EM, Preventza O, Black JH, et al. 2022 ACC/AHA Guideline for the diagnosis and management of aortic disease: A report of the American Heart Association / American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2022;146(24):e334-482. doi.org/10.1161/CIR.0000000000001106
  8. ↑ Pena RCF, Hofmann Bowman MA, Ohle R, et al. Algorithms and clinical-decision-making tools for ruling out acute aortic syndrome in the Emergency Department: A narrative review. Italian Journal of Vascular Surgery. 2024;31(1):42-53. doi:10.23736/S1824-4777.23.01623-6
  9. ↑ Pena RCF, Hofmann Bowman MA, Ahmad M, et al. An assessment of the current medical management of thoracic aortic disease: A patient-centered scoping literature review. Seminars in Vasc Surg. 2022;25(1):16-34. doi:10.1053/j.semvascsurg.2022.02.007
  10. ↑ Chen S-W, Lin C-P, Chan Y-H, et al. Fluoroquinolones and risk of aortic aneurysm or dissection in patients with congenital aortic disease and Marfan Syndrome. Circ J. 2023;87(9):1164-1172. doi:10.1253/circj.cj-22-0682
  11. ↑ Gopalakrishnan C, Bykov K, Fischer MA, et al. Association of fluoroquinolones with the risk of aortic aneurysm or aortic dissection. JAMA Intern Med. 2020;180(12):1596-1605. doi:10.1001/jamainternmed.2020.4199
  12. ↑ The Marfan Foundation. (2017). Physical Activity Guidelines. https://marfan.org/wp-content/uploads/2021/09/FINAL-Physical-Activity-Guidelines-11_17.pdf
  13. ↑ Reed MJ. Diagnosis and management of acute aortic dissection in the emergency department. Brit J of Hosp Med. 2024;85(4). doi:10.12968/hmed.2023.0366
  14. ↑ Isselbacher EM, Preventza O, Black JH, et al. 2002 ACC/AHA Guideline for the diagnosis and management of aortic disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. JACC. 2022;80(24):e223-e393. doi:10.1016/j.jacc.2022.08.004
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