Marfan Syndrome

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Marfan Syndrome
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Description

• Heritable disorder of the connective tissue
• Connective tissue affects
• Growth and development
• Cushioning of joints
• Vital organs
• Not tied to any particular sex, race, or ethnic
  group
• 1 in 5,000 people in US have disorder

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Symptoms

• affects many body systems including
• Skeleton
• Eyes
• Heart and Blood Vessels
• Nervous System
• Lungs
• Skin

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Skeleton

• Tall and slender
• Disproportionately long appendages
• Indented or protruding sternum
• Arched palate, overcrowded teeth, receding
  mandible
• Curvature of spine

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Eyes

• Off-center or dislocated lenses
• Nearsightedness
• Development of cataracts at a younger age
• 30s to 50s
• Retinal detachment
• Holes or tears in
• inner lining

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Heart and Blood vessels

• Abnormally large mitral valve leaflets
• Causes prolapse
• Present in 75 of cases
• Mitral regurgitation
• Heart murmurs
• Long-term damage to heart
• Can lead to breathless, extreme exhaustion,
  irregular pulse

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Heart and Blood vessels

• Weakened middle layer of aortic wall
• Stretched aortic valve leaflets
• Aneurysm may form
• Aortic regurgitation
• Left ventricle must compensate
• Chest pain, heart failure
• Tears in inner and middle aortic layers
• Middle layer separates
• New channels for blood flow

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Nervous System

• Stretching and enlargement of dura membrane
• Pushes on and wears down vertebrae
• Can protrude through vertebral column and into
  abdomen
• Dural cysts
• Increased susceptibility to learning disabilities

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Lungs

• Diminished alveoli elasticity
• Susceptibility to asthma, bronchitis, pneumonia
• In rare cases, develop emphysema
• 5 experience spontaneous lung collapse
• Sleep disordered breathing
• Snoring most common
• Caused by partial obstruction of airway by
  connective tissue

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Skin

• Stretch marks
• Shoulders, hips, lower back
• Increased risk for abdominal hernias

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Basic Genetic Information

• Autosomal Dominant
• Dominant Negative Mutation the altered gene
  product antagonizes the product of the normal
  gene
• Haploinsufficiency when a diploid organism has
  only one functional copy of a gene, the other
  copy being mutated
• Affects FBN-1 Gene

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FBN-1 Gene

• Located on chromosome 15
• Codes instructions for the creation of protein
  Fibrillin 1
• Marfans is caused by over 500 different
  mutations on FBN1
• 60 mutations are change in one protein building
  block.
• 40 mutations produce small protein that cant
  function

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Fibrillin 1 protein

• Connect with other Fibrillin 1 proteins to make
  microfibrils, which become connective tissue.
• Microfibrils mainly trap transforming growth
  factor-beta (TGF-beta) and keeps them inactive.

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Defective Fibrillin 1 Protein

• Amount of fibrillin 1 protein produced by cells
  is reduced
• Structure and stability of protein is affected
• Transport of fibrillin 1 protein out of the cell
  is impaired
• Amount of fibrillin 1 reduced means decreased
  microfibril production
• Less microfibril leads to more active TGF-beta,
  which leads to Marfans symptoms

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Testing and Diagnosis

• Genetic
• Types
• Complete bi-directional DNA sequencing
• Familial known mutation test
• Prenatal
• If parent or close relative has FBN1 or TGFBR
  mutation
• Costs
• FBN1 gene sequencing 1,599
• TGFBR gene sequencing 599
• Familial mutation test 250

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Testing and Diagnosis

• No definitive genetic tests available
• Accuracy
• 99.9 accuracy in detecting mutations
• 70-90 mutation detection rate in individuals
  with clinical diagnosis

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Testing and Diagnosis

• Other
• Imaging tests
• Chest x-ray
• MRI
• Symptoms checklist
• Family history 2 affected body systems
• At least 3 affected body systems

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Diagnostic Checklist

• OCULARMajor__ ectopia lentisMinor__ flat
  cornea__ increased axial length of the globe__
  hypoplastic iris OR hypoplastic ciliary muscle
  causing decreased miosisCARDIOVASCULARMajor__
  dilatation of the ascending aorta with or without
  aortic regurgitationand involving at least the
  sinuses of Valsalva__ dissection of the
  ascending aortaMinor__ mitral valve prolapse
  with or without mitral valve regurgitation__
  dilatation of the main pulmonary artery, in the
  absence of valvular orperipheral pulmonic
  stenosis below the age of 40 years__
  calcification of the mitral annulus below the age
  of 40 years__ dilatation or dissection of the
  descending thoracic or abdominal aortabelow age
  of 50 yearsPULMONARYMinor (only)__
  spontaneous pneumothorax__ apical blebsSKIN
  AND INTEGUMENTMinor (only)__ striae
  atrophicae__ recurrent or incisional
  herniaDURAMajor__ lumbosacral dural ectasia
  by CT or MRIFAMILY/GENETIC HISTORYMajor__
  first degree relative who independantly meets the
  diagnostic criterian.__ presence of mutation in
  FBN1 known to cause Marfan syndrome__ presence
  of haplotype around FBN1 inherited by descent and
  unequivocallyassociated with diagnosed Marfan
  syndrome in the family

• Index caseMajor criteria in 2 different organ
  systems AND involvement of a third organ system.
  Relative of index case1 major criterion in
  family historyAND 1 major criterion in an organ
  systemAND involvement in second organ
  system.SKELETALMajor (Presence of at least 4
  of the following manifestations)__ pectus
  carinatum__ pectus excavatum requiring
  surgery__ reduced upper to lower segment ratio
  (Note 1) OR arm span to height ratio
  gt1.05Height ____ Arm span ____ Upper segment
  ____ Lower segment ______ wrist (Note 2) and
  thumb (Note 3) signs__ scoliosis of gt20 or
  spondylolisthesis__ reduced extension at the
  elbows (lt170)__ medial displacement of the
  medial malleolus causing pes planus__ protrusio
  acetabulae of any degree (ascertained on
  radiographs)Minor__ pectus excavatum of
  moderate severity__ joint hypermobility__ high
  arched palate with crowding of teeth__ facial
  appearance__ dolichocephaly,__ malar
  hypoplasia,__ enophthalmos,__ retrognathia,__
  down-slanting palpebral fissures

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• Positive Walker
• Wrist Sign

• Positive Steinburg Thumb Sign

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Treatment

• Require a multidisciplinary team
• Symptoms, not disorder, must be treated
• Yearly echocardiograms
• Emotional support
• Healthy Diet

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General

• Chronic
• Progressive
• Typically not detected until adulthood
• Life expectancy 70-80
• Variable expression

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Heart

• Enlargement of the aorta
• Aortic Dissection
• Aortic Dilation
• Aortic Valve regurgitation
• Mitral valve prolapse
• Medications
• Lower blood pressure
• Angiotensin receptor blockers
• Beta blockers
• Regular Echocardiograms

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Skeleton

• Physiotherapy
• Pain Clinics
• Loose joints
• Bracing
• Back
• Ankle
• Surgery
• Pectus excavatum

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Dural Ecstasia

• 60 of Marfan patients affected
• Causes pain
• Identified through MRI
• Treatment
• Spinal shunting
• medication

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Eyes

• Glasses
• and/or
• Contact
• Lenses
• Surgery
• Removal
• or replacement
• of lenses
• Reattachment
• of retinas
• Cataract surgery

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Lungs

• Surgery to correct pectus abnormalities
• Pulmonary function tests
• Pneumothorax
• Chest tube evacuation
• Supplemental oxygen
• Emphysema
• Supplemental oxygen
• Antibiotics

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Dental

• Treatment individualized
• Crowding
• Palate misshape
• Dental implants
• Dangers

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Physical Activity

• Avoid contact and strenuous sports because of the
  risk of damaging the aorta and injuring the eyes
• Individual restrictions based on severity and
  discussed with physician

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Testing in High Schools

• Desirable Traits
• Laws
• Ethics?

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Flo Hyman

• July 31, 1954-Jan. 24, 1986
• Olympic Volleyball Player
• 6 foot 5 inches
• Died on court from Marfan