Welcome, Applicants!
Marfan Syndrome
and related disorders
SARA FABER, MP3
MORNING REPORT
1/8/10
Overview
 Epidemiology
 Genetics/Pathophysiology
 Diagnosis/Clinical Features
 Management
 Differential Diagnosis
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
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
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 criterion
 If (–) 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
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 > 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
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 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
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–
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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: 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
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
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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.