Welcome, Applicants!

1. Welcome, Applicants!

2. Marfan Syndromeand related disorders Sara Faber, MP3 Morning Report 1/8/10

3. Overview • Epidemiology • Genetics/Pathophysiology • Diagnosis/Clinical Features • Management • Differential Diagnosis

4. 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

5. 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 • > 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

6. Abraham Lincoln

7. 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

8. 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

9. 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 > 20 degrees • Joint hypermobility • Arm span exceeding height (ratio >1.05) • Reduced elbow extension (<170 degrees) • Medial displacement of medial malleolus

10. Jonathan Larson, playwright/composer

11. Cardiovascular Complications • Most common cause of M&M (~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

12. 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 pectusexcavatum. 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”). What’s the most appropriate next step in management? A Chest radiograph B Transthoracic echocardiogram C Aortic magnetic resonance angiogram D Transesophageal echocardiogram

13. Management: screening/counseling • Annual echocardiogram • Annual ophtho exam and orthopedic involvement as needed • Counseling regarding physical activities • Genetic counseling

14. 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

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

16. 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

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

18. References • Lacina, S. What’s new in outpatient cardiology. Curr Opin in Ped. 2009; 21:605-610. • 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 2006;355:788-798.