Marfan syndrome

Background

• Marfan syndrome (MFS) is a heritable connective tissue disorder with multi-system involvement
  • 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
  • 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)

• 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 & Diagnostic Criteria

Revised Ghent Nosology (2010)

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 Marfan Syndrome (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

Source: https://step1.medbullets.com/msk/113055/marfan-syndrome

Clinical Features (not all may be present) (Figure 1)

• 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 of the Following

• Acute Aortic Syndrome (AAS)
  • Thoracic aortic aneurysm
  • Stanford Types A and B Aortic Dissection
  • Intramural Hemotoma (IMH)
• Mitral valve prolapse (present in up to 60%) and mitral regurgitation
• Spontaneous pneumothorax (associated with bullae, 4-11%)
• Subarachnoid hemorrhage (SAH)^[4]
  • Controversial link between Marfan Syndrome and intracranial aneurysms (more clearly associated with vEDS and LDS)
• Ocular Lens dislocation, retinal detachment
• Spinal conditions (scoliosis; lumbosacral disease; dural ectasia)
• Musculoskeletal injuries due to joint laxity (laxity in 85% of children, 56% of adults)
• Complications during pregnancy (risk of aortic dissection)
  • Type A dissection risk increases with aortic dilation; Type B risk poorly understood. (aortic dissection in up to 4.5%, primarily peripartum)

Figure 2. Classification of Aortic Dissection using Stanford and DeBakey systems. Source: ResearchGate

Management

Medications

• Beta-Blocker (BB) 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.

• Other Pharmacologic Considerations
  • Avoidance of fluoroquinolones (FQs) due to matrix metalloproteinase (MMP) 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
    • 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
  • Antibiotic prophylaxis is no longer recommended for MFS patients before dental procedures, except in those with artificial heart valves

Lifestyle Modifications

• 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, GenTAC) as appropriate to help address psychosocial sequelae (e.g., body dysmorphia, anxiety, depression, PTSD, suicidal ideation)

Emergency Management

• 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

DIFFERENTIAL DIAGNOSIS

• Classic vs. Kyphoscoliotic vs. Vascular Ehlers-Danlos Syndrome (vEDS)
• 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

• 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.

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 Figure 3, Table 1)
• 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

Figure 3. TOP: (Figure 1 from Peña et al. (2022) – flowchart of ADvISED Trial Algorithm). BOTTOM: (Figure 2 from Peña et al. (2022) – flowchart of AORTAs Algorithm).

Table 1. Summary from Peña et al. (2022) of currently published clinical tools for acute aortic syndrome in the ED, with respective components and scoring systems.

Disposition

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

See Also

• Connective Tissue Disease
• Non-Traumatic Thoracic Aortic Dissection
• Ehlers-Danlos Syndrome
• IRAD

References

1. 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.org/10.1161/STROKEAHA.120.032107

External Links

• Marfan Foundation
• Marfan Foundation (Resources for Physicians)
• GenTAC Alliance
• International Registry of Acute Aortic Dissection (IRAD)