DOMMR Week of March 2, 2009 Rozina Mithani

1. DOMMR Week of March 2, 2009 Rozina Mithani Marfan’s Syndrome

2. Learning Objectives Identify risks and presentation of Marfan’s Review of Aortic Dissection Treatment options Pharmacologic Aortic surgery

3. Everyone’s Doing It! Bradford Cox frontman of the bands Deerhunter and Atlas Sound Flo Hyman silver medal in Women's Volleyball (1984 Olympics) Robert Johnson blues singer and guitarist Jonathan Larson author and composer of the hit musical Rent Sir John Tavener contemporary British composer

4. What is Marfan’s Syndrome Fibrillin ? formation of extracellular matrix Main protein of CT Microfibils including elastic fibers Abundant in the aorta, ligaments, cilliary body of the eye MFS: mutation in the fibrillin-1 gene (FBN1) chromosome 15

5. Epidemiology Incidence at least 1 in 5,000 in the US Inheritance AD, Variable Penetrance Gender men, women, children Risk Child of parent with MFS: 50% chance Prenatal testing available but given unpredictable phenotype not widely used Two unaffected parents: 1 in 10,000 ~ 25% from a spontaneous mutation

6. Work-up H&P including family history Eye Exam slit lamp lens dislocation Echo looking for Aortic root dilation

7. Differential Diagnosis Homocystinuria marfanoid habitus, ectopia lentis, mental retardation, osteoporosis MASS phenotype MVP, mild aortic dilatation, striae atrophica, skeletal involvement Congenital contractural arachnodactyly arachnodactyly, joint contractures, scoliosis, crumpled ear malformation Ehlers-Danlos syndromes types II & III marked joint hypermobility, paparaceous scars, mitral prolapse Klinefelter syndrome marfanoid habitus, small testes and genitalia, learning difficulty Congenital bicuspid aortic valve disease with associated aortopathy aortic dilation may involve primarily the aortic root or the mid-ascending aorta Aortic coarctation with associated ascending aortic enlargement Loeys-Dietz syndrome

8. Diagnostic Criteria Major criterion: highly specific & rarely occur in the general population aortic root enlargement (aortic aneurysm) aortic dissection lens dislocation dural ectasia at least 4 major skeletal features Chest wall deformities Long, thin arms/legs Scoliosis greater than 20 degrees Minor criterion: features with Marfan’s but may also occur in the general population Diagnosis requires: + FamHx: only 1 Major criteria – FamHx: at least 2 Major criteria

9. Diagnostic Criteria

11. Organ Systems Affected Skeletal Oral Cavity Eyes Cardiovascular CNS Skin Pulmonary

12. Skeletal Tall, slender stature Joint hypermobility Thumb sign Wrist sign Reduced elbow extension <170 degrees Affects long bones arms/legs/fingers/toes may be disproportionately long Arm span > Height ratio >1.05 Long, narrow face Sternal deformity Pectus escavatum (funnel chest) Pectus carinatum (pigeon’s chest) Scoliosis Pes plantus (flat feet)

13. Oral Cavity Arched palate crowded dentition Mandible malocclusion

14. Eyes Lens dislocation Superior lens disolocation (ectopia lentis) Lens position changes slightly higher/lower and may be shifted to one side Retinal detachment Myopia Early glaucoma or Cataracts

15. Cardiovascular System Heart Mitral Valve Prolapse 60-80% of pts SOB, fatigue, palpitations Vascular Ao dilation Ao dissection/rupture Type I or Type A

16. Types of Aortic Dissection

17. CNS Dura surrounds brain/spinal cord made of connective tissue Dural Ectasia … with age the dura weakens/stretches ? progressive ectasia of dura/neural foramina and erosion of verterbrae ? enlargement of the spinal canal Radiculopathy CT, plain films, MRI

18. Skin Stretch marks appear at sites subject to stress shoulders, hips, lower back Increased risk of an abdominal or inguinal hernia

19. Pulmonary Marfan fibrillin–1 deficiency: affects lung development & homeostasis Restrictive lung disease pectus abnormalities and/or scoliosis ~ 70% of people with MFS Spontaneous pneumothorax Early emphysema Sleep-related breathing disorders snoring and sleep apnea

20. Follow-up Annual Echo monitor the size and function of heart and aorta Periodic follow up with ophthamology Monitoring of the skeletal system chest and back x-rays  BB to lower BP and regulate heart rhythm ? reduced strain on the aorta and slowing the widening of the aorta  Physical exercise stay fit to improve muscle tone avoid strenuous exercises and activities, avoid contact sports or generally exhausting sports, to prevent injury to the Aorta

21. European Society of Cardiology Lifelong BB – Class I Periodic Imaging of the aorta – Class I Prophylactic replacement of the aortic root before > 5.0 cm diameter if FHx of dissection – Class IIa before > 5.5 cm diameter if no FHx – Class IIa Moderate restriction of physical activity – Class I

22. Treatment Beta Blockers TGFß Aortic Surgery

23. Beta Blockers Properties: Decrease myocardial contractility Decrease pulse pressure May also improve the elastic properties of the aorta Standard of Care in Adults open-label, randomized trial of 70 adults with classic MFS assigned to propanolol vs. no specific tx … 10yr data Propranolol group had a significantly slower rate of aortic dilatation Survival for the propranolol group was higher

24. TGFß TGFß – Cytokine involved in scarring controls proliferation, cellular differentiation acts as an antiproliferative factor in normal epithelial cells TGF-ß is a secreted protein part of a superfamily which includes inhibins, activin, anti-müllerian hormone, bone morphogenetic protein, decapentaplegic and Vg-1 Fibrillin-1 indirectly binds a latent form of TGFß Keeps TGFß sequestered and unable to exert its biological activity MFS: low levels of fibrillin-1 ? TGFß levels rise 2/2 inadequate sequestration ? inflammatory reaction releasing proteases ? degrade elastin fibers & other components of the ECM

25. TGFß and ARB ARB (losartan) inhibits TGF-ß signaling Attenuation pathologic changes in the aortic wall progressive dilation of the aortic root

27. Indications for Aortic Surgery Prefer elective vs. emergent Aortoc root diameter for surgery is unclear 2006 ACC/AHA Guidelines Elective surgery for an aortic root diameter =5.0 cm MFS pts with a FHx of Ao dissection or Rapid increase in Ao size should be considered at <5.0 cm Limitation: based on absolute aortic root diameters predicted aortic root diameter varies with body size ? may be smaller in women

28. Learning Objectives Identify risks and presentation of Marfan’s mutation in the fibrillin-1 gene (FBN1) We’re all at risk … esp. with family hx Affects multiple organ systems Review of Aortic Dissection Types of Aortic Dissection A & B vs. I, II, III Treatment options Pharmacologic: BB (propanolol) and ARB (losartan) Aortic surgery: elective, consider ~ 5.0cm

29. Questions? CPC TODAY! 4:30pm