Lecture 17 Part II: Marfan Syndrome

What is Marfan syndrome and how is it inherited?

• Autosomal dominant connective tissue disorder.

• Caused by a mutation in the FBN1 gene on chromosome 15q21.1.

• Affects 1 in 5,000–10,000 individuals (~200,000 in the US).

• No sex predilection; occurs worldwide.

What is the genetic breakdown of Marfan syndrome cases?

• ~75% inherited from an affected parent.

• ~25% are de novo mutations.

• <1% are mosaic.

• 10% of individuals have no FBN1 mutation (some have FBN2 mutations on chromosome 5).

What types of mutations cause Marfan and what are they called?

• Most severe mutations are in exons 24–32.

• Called Type 1 fibrillinopathies; Marfan is the most common type.

What is fibrillin-1 and what does it do?

• Large glycoprotein that maintains the extracellular matrix.

• Forms microfibrils; provides structure, elasticity, and strength to connective tissue.

• Functions in:

  • Eyes: holds the lens in place.

  • Aorta & ligaments: forms elastic fiber networks.

  • Releases growth factors throughout the body.

What are the two molecular mechanisms by which FBN1 mutations cause disease?

• Haploinsufficiency: one mutant allele → insufficient fibrillin for microfibrils.

• Dominant negative effect: mutant fibrillin monomers impair normal monomers.

• Both lead to: weakened elastic fibers + overactivation of TGF-β.

How does fibrillin relate to TGF-β regulation?

• Fibrillin-1 sequesters TGF-β; loss of fibrillin → overactivation of TGF-β.

• Mouse models: TGF-β neutralizing antibodies prevent valve thickening and dysfunction.

• Overactive TGF-β contributes to cardiovascular phenotypes.

What is variable expressivity in Marfan syndrome?

• Over 1,850 mutations in FBN1 can cause Marfan; usually family-specific.

• Members of the same family with the same mutation can have different phenotypes.

• 10% have no FBN1 mutation; some have FBN2 mutations instead.

What are the major phenotypes of Marfan syndrome by system?

• Skeletal: disproportionately long limbs (arm span:height >1.05; normal <1.05), reduced upper:lower body ratio (0.85 vs. 0.93), arachnodactyly, dolicocephaly, scoliosis (50–60%), pectus excavatum/carinatum.

• Hands: wrist sign (1st & 5th digits overlap around wrist) and thumb sign (thumb projects past ulnar surface when fist clenched).

• Cardiovascular: aortic dilation (universal), leaky valve murmur, aortic dissection/rupture (leading cause of death).

• Ocular: ectopia lentis, lens dislocation in 50%, usually displaced superiorly.

• Lungs: restrictive lung disease (70%), spontaneous pneumothorax; dural ectasia in nervous system; stretch marks on skin.

What are the signs of scoliosis in Marfan and how is it managed?

• 50–60% of Marfan patients develop scoliosis; caused by loosening of spinal ligaments.

• <20° curve: monitor; >40° curve: surgery needed.

• Between extremes: back brace can halt progression in growing children.

How is Marfan syndrome diagnosed?

• Clinical findings in two of three systems: ocular, musculoskeletal, cardiovascular.

• Additional mutational analysis of FBN1.

• Must distinguish from: Weill-Marchesani, Ehlers-Danlos, Loeys-Dietz, and MASS phenotype (Mitral, Aortic, Skin, Skeletal).

What are the Ghent / Revised Ghent Criteria?

• Scoring system used to formally diagnose Marfan syndrome.

• Places heavy weight on: aortic root dilation, ectopia lentis, and FBN1 mutation.

• Helps distinguish Marfan from overlapping syndromes.

What is Neonatal Marfan Syndrome?

• Very rare, very severe; phenotypes present within first 3 months of life.

• Most caused by mutations in exon 25 of FBN1; often de novo.

• Features: congestive heart failure, mitral/tricuspid insufficiency, loose/senile-appearing skin.

• Most die within first 2 years; detectable prenatally via ultrasound at ~22 weeks.

What is the life expectancy with Marfan syndrome?

• Without treatment: ~37 years.

• With modern intervention: ~78 years.

• Leading cause of death: hemorrhage from acute aortic dissection.

What are the treatment options for Marfan syndrome?

• Activity restriction: strenuous/contact sports dangerous due to aortic dissection risk.

• β-blockers: standard of care to delay/prevent aortic aneurysm and dissection.

• Surgery: for aortic root, cardiac valves, scoliosis, pectus deformities.

• Emerging: boosting fibrillin-1 expression; TGF-β inhibition.

Reproduction concerns in Marfan syndrome

• Neither men nor women experience fertility problems.

• Women need medical clearance before pregnancy.

• Aortic root diameter >4 cm is a contraindication; mother may not survive.

• Babies at birth need monitoring for extreme mitral valve regurgitation.