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Welcome, Applicants!

Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

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Page 1: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Welcome, Applicants!

Page 2: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

SARA FABER, MP3MORNING REPORT

1/8/10

Marfan Syndromeand related disorders

Page 3: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Overview

EpidemiologyGenetics/PathophysiologyDiagnosis/Clinical FeaturesManagementDifferential Diagnosis

Page 4: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Epidemiology

First described in 1896; named in 1902.Common inherited connective tissue disorderIncidence: 1 in 3000-5000; approximately

200,000 Americans affectedM = F; men with shorter life expectancyRaces affected equally

Page 5: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Genetics

Autosomal dominant; variable expression~25% spontaneous mutationsGenes 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

Page 6: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Abraham Lincoln

Page 7: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

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

criterionIf (–) family history, additionally you need:

Major criterion from 2 systems and involvement of a 3rd system

Page 8: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Clinical Features

HEENT: Eye: superior lens dislocation

(ectopia lentis) Oropharynx: high palate and

crowded dentitionCardiac:

Mitral valve prolapse Aortic root dilation

Pulmonary: Spontaneous pneumothorax

Neurologic: Dural ectasiaSkin: Stretch marks

Page 9: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

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

Page 10: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Jonathan Larson, playwright/composer

Page 11: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

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

Page 12: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

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”).

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

Page 13: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Management: screening/counseling

Annual echocardiogram

Annual ophtho exam and orthopedic involvement as needed

Counseling regarding physical activities

Genetic counseling

Page 14: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

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

Page 15: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

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

Page 16: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Similar phenotypes

Congenital contractual arachnodactyly: FBN2MASS (Mitral valve prolapse, aortic dilation,

skin and skeletal abnormalities): FBN1 Joint hypermobility syndromeEhlers-Danlos: mutation of type V collagenStickler syndrome: mutation of type II and XI

collagen

Page 17: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

Take home points

Marfan Syndrome is relatively commonIf you have a patient < 40 with evidence of

aortic root changes, think MFSNo cure, so cardiovascular management is

key Annual echo Beta blockade Counseling on physical activity

Page 18: Welcome, Applicants!. SARA FABER, MP3 MORNING REPORT 1/8/10 Marfan Syndrome and related disorders

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.