Welcome, Applicants!

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Welcome, Applicants!
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Marfan Syndromeand related disorders

• Sara Faber, MP3
• Morning Report
• 1/8/10

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Overview

• Epidemiology
• Genetics/Pathophysiology
• Diagnosis/Clinical Features
• Management
• Differential Diagnosis

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Epidemiology

• First described in 1896 named in 1902.
• Common inherited connective tissue disorder
• Incidence 1 in 3000-5000 approximately 200,000
  Americans affected
• M F men with shorter life expectancy
• Races affected equally

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Genetics

• Autosomal dominant variable expression
• 25 spontaneous mutations
• Genes involved in Marfan Syndrome phenotype
• Fibrillin-1 (MFS)
• Microfibril glycoprotein in both elastic and non
  elastic tissues
• gt 97 different mutations
• TGFBR (MFS type II or Loeys-Dietz)
• Works through apoptosis and cell cycle
  regulation prevents proper incorporation of
  fibrillin into tissue
• Also with triad hypertelorism, bifid uvula or
  cleft palate, generalized arterial tortuosity
• Other gene mutations may lead to similar
  phenotypes

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Abraham Lincoln
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Diagnosis

• Clinical diagnosis the Ghent criteria
• physical exam 6 organ systems involved
• family history
• genetic testing
• If () family history, additionally you need
• Involvement of 2 organ systems including 1 major
  criterion
• If () family history, additionally you need
• Major criterion from 2 systems and involvement of
  a 3rd system

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Clinical Features

• HEENT
• Eye superior lens dislocation (ectopia lentis)
• Oropharynx high palate and crowded dentition
• Cardiac
• Mitral valve prolapse
• Aortic root dilation
• Pulmonary Spontaneous pneumothorax
• Neurologic Dural ectasia
• Skin Stretch marks

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Clinical Features

• Musculoskeletal
• Tall stature (dolichostenomelia)
• Long digits (arachnodactyly)
• Thumb sign (distal phalanx protrudes beyond
  border of clenched fist)
• Wrist sign (thumb and fifth digit overlap when
  around the wrist)
• Sternal deformity (prominent pectus)
• Scoliosis gt 20 degrees
• Joint hypermobility
• Arm span exceeding height (ratio gt1.05)
• Reduced elbow extension (lt170 degrees)
• Medial displacement of medial malleolus

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Jonathan Larson, playwright/composer
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Cardiovascular Complications

• Most common cause of MM (80)
• Aortic root disease ? aneurysms, AR, dissection
• In 50 children
• In up to 80 of adults
• May lead to neurovascular complications
• AR murmur decrescendo, diastolic
• Mitral valve prolapse (minor criterion)
• In 60-80 patients most common valve disorder
• Worsens with time, complicated by rupture
• MVP murmur ejection click, holosystolic
• Arrhythmias

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MKSAP Question

• A 22-year-old man is evaluated as part of a
  routine examination...He is 171.5 cm (78 in) tall
  and weighs 72.8 kg (185 lb) with pectus
  excavatum. Blood pressure is 134/65 mm Hg
  bilaterally, and pulse rate is 76/min and
  regular. He has a high arched palate. There is a
  2/6 decrescendo diastolic murmur at the right
  upper sternal border while in the upright
  posture. There is moderate scoliosis, joint
  hypermobility, and the patient's thumb and fifth
  digit overlap when circling the opposite wrist
  (wrist sign).
• Whats the most appropriate next step in
  management?
• A Chest radiograph
• B Transthoracic echocardiogram
• C Aortic magnetic resonance angiogram
• D Transesophageal echocardiogram

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Management screening/counseling

• Annual echocardiogram
• Annual ophtho exam and orthopedic involvement as
  needed
• Counseling regarding physical activities
• Genetic counseling

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Management medications

• Beta blockade
• Standard of care for adult patients (no data on
  children)
• Based on studies of propranolol versus placebo
• Slower rate of aortic dilatation with beta
  blockade
• Survival at 10 yrs not significantly improved
• Calcium channel blockers?
• ARBs
• Recent animal study models of FBN1 mutants
  demonstrated decreased rate of aortic dilatation
• Mechanism is via TGFBR
• One randomized trial of 17 patients is complete
  larger study is now ongoing

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Management surgical intervention

• Better survival with elective repair
• Variable recommendations for aortic root diameter
  at which intervention warranted
• ACC/AHA diameter gt 5.0 cm
• ESC diameter gt 4.5 cm
• Rate of increase gt 0.5 cm/year
• Earlier intervention indicated in women desiring
  pregnancy
• Annual imaging post-op still necessary

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Similar phenotypes

• Congenital contractual arachnodactyly FBN2
• MASS (Mitral valve prolapse, aortic dilation,
  skin and skeletal abnormalities) FBN1
• Joint hypermobility syndrome
• Ehlers-Danlos mutation of type V collagen
• Stickler syndrome mutation of type II and XI
  collagen

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Take home points

• Marfan Syndrome is relatively common
• If you have a patient lt 40 with evidence of
  aortic root changes, think MFS
• No cure, so cardiovascular management is key
• Annual echo
• Beta blockade
• Counseling on physical activity

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References

• Lacina, S. Whats new in outpatient cardiology.
  Curr Opin in Ped. 2009 21605-610.
• Midla, G. Diagnosis and management of patients
  with Marfan syndrome. JAAPA 2008 21(2) 21-25.
• Attias, D, et al. Comparison of Clinical
  Presentations and Outcomes Between Patients with
  TGFBR2 and FBN1 Mutations in Marfan Syndrome and
  Related Disorders. Circulation 2009 120
  2541-2549.
• Loeys, B, et al. Aneurysm Syndromes Caused by
  Mutations in the TGF-B Receptor. NEJM
  2006355788-798.