1. Welcome, Applicants!

2. Marfan Syndrome and 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 ; 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
Fibrillin-1 homologous to TGF binding protein
Transforming growth factor beta receptors 1 and 2: increased expression is associated with progression of various malignancies

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
Dural ectasia: enlargement of dural sac – seen in 60-80%

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
Untreated Marfan’s is a/w dissection: usually type 1 or type A. Often, there is family h/o dissection as well.
In patients under age of 40, approx 50% of those cases are related to Marfan’s dz (also in differential is cocaine)

12. MKSAP Question
A 22-year-old man is evaluated as part of a routine examination...He is 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

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
Studies out of Hopkins compared elective versus urgent versus emergent repair and found mortality to be 1.5%, 2.6% and 11.7%.
Variable recommendations, but thus far don’t take into account patient’s body size; should women have smaller diameters at time of repair. Some studies starting to look at diameter as a standard deviation from population mean.

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:
Midla, G. Diagnosis and management of patients with Marfan syndrome. JAAPA 2008; 21(2):
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:
Loeys, B, et al. Aneurysm Syndromes Caused by Mutations in the TGF-B Receptor. NEJM 2006;355: