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A. Definitionnavigator

  1. Skeletal abnormalities
    1. Usually tall
    2. Moderate joint hypermobility
    3. Arachnodactyly ("spider fingers")
    4. Kyphoscoliosis
    5. Pectus excavatum
    6. High arched palate
  2. Eyes - lens dislocations (subluxation)
  3. Cardiovascular
    1. Mitral valave prolapse and aortic dilatation (± regurgitation)
    2. Aortic aneurysms
  4. Autosomal dominant

B. Pathophysiologynavigator

  1. Systemic disorder of connective tissue
  2. Caused by mutations of Fibrillin-1 [6,7]
    1. Fibrillin-1 (FBN1) on chromosome 15 codes for an extracellular matrix protein
    2. FBN1 is a major component of microfibrils associated with elastin fibers
    3. Dominant negative FBN1 mutations cause Marfan Syndrome indicates that abnormal fibrillin incorporated into elastin with normal fibrillin causes structurally inferior connective tissue
    4. Abnormal FBN1 explains cardiovascular, ophthalmological, and joint laxity abnormalities
    5. Normal fibrillin also binds transforming growth factor (TGF) ß and latent TGFß binding proteins (LTBP)
    6. TGFß is a key stimlator of connective tissue production
    7. TGFß normally exists in inactive complexes in various tissues bound to LTBP
    8. Mutated FBN1 does not regulate TGFß-LTBP activity well, leading to elevated TGFß activity
    9. Overactivity of TGFß may be final pathway for several manifestations of Marfan Syndrome
    10. TGFß overactivity leads to cystic lungs, myxomatous mitral-valve laflets and aortic dilatation
    11. Overactivity of TGFß leads to increases in angiotensin production and action [3]
    12. Angiotensin II binding to angiotensin receptor 1 also increases TGFß production [7]
    13. Blockade of TGFß (and/or angiotensin recpetor 1) in mice with Marfan Syndrome prevents most of the symptoms and signs
  3. Missense mutations in TGFß receptor 2 have been found in a subset of Marfan Syndrome
  4. Procollagen type I gene anomalies have also been reported in some Marfan Syndrome patients
  5. Mutations in TGFß receptor 2 also found in Loeys-Dietz Syndrome [8]
  6. Fibrillin 2 (FBN2) mutations cause related congenital contractural arachnodactyly or Beals' syndrome

C. Diagnostic Criteria [1]navigator

  1. Skeletal System
    1. Pectius carinatum
    2. Pectus excavatum, needing surgery
    3. Scoliosis of >20° or spondylolithesis
    4. Joint hypermobility
    5. Various other major and minor criteria
  2. Ocular System
    1. Major criterion: ectopia lentis
    2. Minor criteria: abnormally flat cornea, increased axial length of bloe, hypoplastic iris or ciliary muscle, causing ecreased miosis
  3. Cardiovascular System
    1. Dilatation of ascending aorta, with or without aortic regurgiation, involving at least the sinuses of Valsalva
    2. Dissection of ascending aorta
    3. Minor criteria: mitral valve prolapse (MVP), dilatation of main pulmonary artery, dilatation or disssectin of aorta in age <50 years, calcification of mitral annulus in <40 years
    4. Either major criteria and one minor criteria
  4. Pulmonary System: spontaneous pneumothorax, apical blebs (emphysematous changes)
  5. Skin and Integument: idiopathic striae atrophicae (strech marks), recurrent hernia
  6. Dura: lumbosacral dural ectasia
  7. Family / Genetic History
    1. parent, child or sibling hwo meets diagnostic criteria
    2. Presence of FBN1 mutation known to cause Marfan syndrome
    3. Haploytpe around FBN1, known to be associated with unequivocal case of Marfan's

D. Evaluationnavigator

  1. Family members affected
  2. Presence of lens disease
    1. Slit lamp exam is critical
    2. Intraocular pressure measurements as some patients can develop glaucoma
  3. Skeleton
    1. Tall patients, especially for age
    2. Ratio of tips of fingers to knuckles (PIP) : knuckles to wrist >1.5 is fairly specific
    3. Thumb Sign - thumb protrudes from clenched fist
  4. Cardiovascular Anomalies
    1. Proximal aortic dilatation - often seen on chest radiograph
    2. Thoracic aortic aneurysm formation is very common (including root dilatation)
    3. Echocardiography is preferred study for evaluation
    4. High risk in pregnancy
  5. Striae over shoulders and buttocks may occur
  6. High arched palate and high pedal arches frequent
  7. Dural Ectasia (Dilation) [2]
    1. MRI of spinal cord performed (spin-echo sequence)
    2. Dural ectasia found in 92% (76 of 83) of Marfan patients
    3. Dural ectasia found in none of control patients
  8. Pregnant women should undergo thorough evaluation for aortic dilatation

E. Treatment navigator

  1. Regular ocular exams with corrections as needed
  2. Scoliosis treatment with mechanical bracing and physical therapy; surgery as needed
  3. ß-Adrenergic Blockers
    1. Very effective in reducing risk of aortic aneurysm formation and rupture
    2. ß-blockers and surgery prolong life
    3. ß-blockers should likely be used in pregnant women to prevent dilatation
    4. Propranolol (non-specific) or atenolol (ß1-specific) are used
  4. Angiotensin Blockade [7,9]
    1. Blockade of angiotensin action in Marfan syndrome likely beneficial
    2. Perindopril, an ACE inhibitor with TGFß reducing activity, reduced large artery stiffness and aortic root diameter in Marfan patients taking standard ß-blockers [3]
    3. Losartan (Cozaar®), an angiotensin II receptor blocker (ARB) with TGFß reducing activity, has prevented disease progression in animal models of Marfan Syndrome [6]
    4. Young patients with progressive, severe Marfan syndrome despite ß-blockers who switched to losartan showed significantly reduced progression of aortic root dilatation [9]
    5. Use ARB in ß-blocker intolerant persons and consider adding on top of ß-blockers
  5. Prophylactic repair of aortic root should be considered in patients with Marfan's Syndrome and an aortic root diameter of 6.5cm or more [4]
  6. Overall survival has increased mean lifespan from 32 to 41 years [5]

References navigator

  1. Judge DP and Dietz HC. 2005. Lancet. 366(9501):1965 abstract
  2. Fattori R, Nienaber CA, Descovich B, et al. 1999. Lancet. 354(9182):910 abstract
  3. Ahimastos AA, Aggarwal A, D'Orsa KM, et al. 2007. JAMA. 298(13):1539 abstract
  4. Gott VL, Greene PS, Alejo DE, et al. 1999. NEJM. 340(17):1307 abstract
  5. Silverman DI, Burton KJ, Gray J, et al. 1995. Am J Cardiol. 75:157 abstract
  6. Gelb BD. 2006. NEJM. 355(8):841 abstract
  7. Pyeritz RE. 2008. NEJM. 358(26):2829 abstract
  8. Loeys BL, Schwarze U, Holm T, et al. 2006. NEJM. 355(8):788 abstract
  9. Brooke BS, Habashi JP, Judge DP, et al. 2008. NEJM. 358(26):2787 abstract