Upload
gary-bridges
View
217
Download
3
Tags:
Embed Size (px)
Citation preview
Welcome, Applicants!
SARA FABER, MP3MORNING REPORT
1/8/10
Marfan Syndromeand related disorders
Overview
EpidemiologyGenetics/PathophysiologyDiagnosis/Clinical FeaturesManagementDifferential Diagnosis
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
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
Abraham Lincoln
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
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
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
Jonathan Larson, playwright/composer
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
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
Management: screening/counseling
Annual echocardiogram
Annual ophtho exam and orthopedic involvement as needed
Counseling regarding physical activities
Genetic counseling
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
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
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
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
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.