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)[2]

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 (if age > 20 years)
 * Z Score > 3 (if age < 20 years)
 and Family History of MFS

File:Marfan Syndrome Clinical Features.jpg.jpg

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

Clinical Features (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 of:

• 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)
  • 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

Disposition

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

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:

• • 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)
  • 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.