Marfan syndrome

From Iusmgenetics

Contents 1 Marfan syndrome 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.6.1 Ocular Abnormalities 1.6.2 Cardiovascular Abnormalites 1.6.3 Skeletal Abnormalities 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

Marfan syndrome

General background information

• 1 of 10k-20k
• 1 in 5,000 **10,000 live births
• Flo Hyman
  • Died of aortic rupture in the middle of a volleyball match.

Mode of inheritance

• Autosomal Dominant Inheritance
• 75% are inherited
• 25% de novo mutations
• No Documented Cases of Non‐Penetrance
• Many different missense mutations have been observed (allelic heterogeneity).
• At least one known splicing mutation: IVS63+373 mutation creates an intronic GT sequence as a new acceptor site at the 5’ terminus and results in generation of a pseudoexon.
  • This resulted in a 93bp insertion between 8,379 & 8,380 (junction between exons 63 & 64)

Single important gene

• 15q21.1: FBN1 gene codes for Fibrillin‐1
• Fibrillin is present in the suspensory ligament, eleastic connective tissue (aorta & ligaments) and periosteum
• 320 kDa glycoprotein, 2,871 AA
• Has 3 types of repeating modules
• Epidermal Growth Factor (EGF) like module
  • Occurs 47 times, 43 are Calcium binding EGF like modules
  • Each has 6 cysteine residues
• TGF‐Beta Binding Protein (TGFBP) like module
  • Occurs 7 times
  • Each has 8 cysteine residues that form 4 disulfide bonds
• Hybrid Module
  • Occurs twice

Etiology

• Ca2+ binding fails in EGF-like domain mutations
  • Most common domain in the protein
  • Ca2+ binding required for protein‐protein interactions
• TGF‐β Binding Protein motif mutations
  • TGF‐β is important for ECM remodelling, matrix deposition, and MMP regulation.
  • Upregulated TGF‐β may result in:
    • poor ECM remodeling
    • lack of matrix deposition
    • decreased matrix proteins
    • elevated matrix degrading enzymes (MMPs)
  • http://salamano‐giovanni.blogspot.com/2009/06/collagenopathies‐and‐marfan‐syndrome.html

Pathogenesis

Phenotypic information

Ocular Abnormalities

• Ectopia Lentis
  • Lens subluxation
  • Glaucoma
• Myopia in 60%
• Retinal Detachment
• Premature Cataract Formation
• 
• http://www.medstudents.com.br/original/revisao/marfan/marfan.htm

Cardiovascular Abnormalites

• Mitral valve prolapse
  • Regurgitation
• Aortic Diliatation
  • Enlargement
• 
  • Regurgitation
  • Aneurysm
• 

Skeletal Abnormalities

• Dolichostenomelia
• Pectus Excavatum
• Pectus Carinatum
• Scoliosis http://www.medicaltourismco.com/general‐surgery/pectus‐excavatum‐surgery‐abroad.
• http://www.nytimes.com/imagepages/2007/08/01/health/adam/9011Bowedchestpigeonbreast.html
• Thoracic Lordosis
• Narrow & highly arched Palate
• Joint laxity
• Arachnodactyly
• Walker Murdoch http://yogatmanbarcelona.wordpress.com/2009/11/24/tu‐medula‐espinal‐ii‐lordosis/ Walker‐(wrists)
• Steinberg (thumbs)

Diagnosis

• Ghent criteria: Major findings in 2 systems (3 systems w/out family history) and a minor feature in a 3rd
• Systems
  • Ocular
  • Skeletal
  • Cardiovascular
• MFS Genetic Test
  • bidirectional sequence analysis of 65 exons & splice sites in the FBN1 gene
  • Does not detect mutations in introns or large deletions
  • 99.9% accurate at detecting mutations in the 65 exons & splice sites
  • 70‐90% Sensitive
  • Won’t find mutation ~ 10% who meet Ghent criteria
  • Cost: $1800

Treatment

• Ocular: Ophthalmic lens correction for myopia, monitor for glaucoma & retinal detachment. Ectopic lens may need surgical intervention
• Cardiovascular: monitor mitral valves and aorta through echocardiography; β blockers
• Counseling: Advise against isometric exercises and impact sports. Pregnancy & aorta dilatation.

Recent research

5 important facts

1. Autosomal Dominant 75% & 25% de novo mutations
2. Allelic Heterogeneity
3. Mutation in the Fibrillin‐1 (FBN1 found at 15q24.1)
4. Fibrillin is found in the periosteum, Connective Tissues, and suspensor ligaments.
5. TGF‐β signaling is upregulated in some forms of Marfan Syndrome

Not to be confused with

Questions and answers

• What are the requirements for a clinical diagnosis of Marfan Syndrome?
• What signaling pathway is affected in Marfan Syndrome?