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TRANSCRIPT
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Marfan Syndrome
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DescriptionHeritable disorder of the connective tissueConnective tissue affects:
•Growth and development•Cushioning of joints•Vital organs
Not tied to any particular sex, race, or ethnic group1 in 5,000 people in US have disorder
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Symptoms
affects many body systems including: Skeleton Eyes Heart and Blood Vessels Nervous System Lungs Skin
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Skeleton
Tall and slender Disproportionately long appendages Indented or protruding sternum Arched palate, overcrowded teeth, receding mandible Curvature of spine
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Eyes
Off-center or dislocated lenses Nearsightedness Development of cataracts at a younger age
30s to 50s Retinal detachment
Holes or tears in inner lining
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Heart and Blood vessels Abnormally large
mitral valve leaflets Causes prolapse Present in 75 % of
cases Mitral regurgitation
Heart murmurs Long-term damage to
heart Can lead to breathless,
extreme exhaustion, irregular pulse
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Heart and Blood vessels Weakened middle layer of
aortic wall Stretched aortic valve
leaflets Aneurysm may form
Aortic regurgitation Left ventricle must
compensate Chest pain, heart failure
Tears in inner and middle aortic layers Middle layer separates New channels for blood flow
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Nervous System
Stretching and enlargement of dura membrane Pushes on and wears down vertebrae Can protrude through vertebral column and into
abdomen Dural cysts
Increased susceptibility to learning disabilities
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Lungs Diminished alveoli elasticity Susceptibility to asthma,
bronchitis, pneumonia In rare cases, develop
emphysema 5% experience
spontaneous lung collapse Sleep disordered breathing
Snoring most common Caused by partial obstruction
of airway by connective tissue
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Skin
Stretch marks Shoulders, hips, lower back
Increased risk for abdominal hernias
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Basic Genetic Information Autosomal Dominant Dominant Negative Mutation – the altered
gene product antagonizes the product of the normal gene
Haploinsufficiency – when a diploid organism has only one functional copy of a gene, the other copy being mutated
Affects FBN-1 Gene
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FBN-1 Gene Located on chromosome
15 Codes instructions for the
creation of protein Fibrillin 1 Marfan’s is caused by over
500 different mutations on FBN1
60% mutations are change in one protein building block.
40% mutations produce small protein that can’t function
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Fibrillin 1 protein Connect with other Fibrillin 1 proteins to make
microfibrils, which become connective tissue. Microfibrils mainly trap transforming growth
factor-beta (TGF-beta) and keeps them inactive.
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Defective Fibrillin 1 Protein Amount of fibrillin 1 protein produced by cells
is reduced Structure and stability of protein is affected Transport of fibrillin 1 protein out of the cell is
impaired Amount of fibrillin 1 reduced means
decreased microfibril production Less microfibril leads to more active TGF-
beta, which leads to Marfan’s symptoms
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Testing and Diagnosis Genetic
Types Complete bi-directional DNA
sequencing Familial known mutation test Prenatal
If parent or close relative has FBN1 or TGFBR mutation
Costs FBN1 gene sequencing $1,599 TGFBR gene sequencing $599 Familial mutation test $250
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Testing and Diagnosis No definitive genetic tests available Accuracy
99.9% accuracy in detecting mutations 70-90% mutation detection rate in
individuals with clinical diagnosis
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Testing and Diagnosis Other
Imaging tests Chest x-ray MRI
Symptoms checklist Family history + 2 affected
body systems At least 3 affected body
systems
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Index case:Major criteria in 2 different organ systems AND involvement of a third organ system.
Relative of index case:1 major criterion in family historyAND 1 major criterion in an organ systemAND involvement in second organ system.
SKELETALMajor (Presence of at least 4 of the following manifestations)__ pectus carinatum__ pectus excavatum requiring surgery__ reduced upper to lower segment ratio (Note 1) OR arm span to height ratio >1.05Height ____ Arm span ____ Upper segment ____ Lower segment ______ wrist (Note 2) and thumb (Note 3) signs__ scoliosis of >20° or spondylolisthesis__ reduced extension at the elbows (<170°)__ medial displacement of the medial malleolus causing pes planus__ protrusio acetabulae of any degree (ascertained on radiographs)Minor__ pectus excavatum of moderate severity__ joint hypermobility__ high arched palate with crowding of teeth__ facial appearance__ dolichocephaly,__ malar hypoplasia,__ enophthalmos,__ retrognathia,__ down-slanting palpebral fissures
Diagnostic Checklist OCULARMajor__ ectopia lentisMinor__ flat cornea__ increased axial length of the globe__ hypoplastic iris OR hypoplastic ciliary muscle causing decreased miosis
CARDIOVASCULARMajor__ dilatation of the ascending aorta with or without aortic regurgitationand involving at least the sinuses of Valsalva__ dissection of the ascending aortaMinor__ mitral valve prolapse with or without mitral valve regurgitation__ dilatation of the main pulmonary artery, in the absence of valvular orperipheral pulmonic stenosis below the age of 40 years__ calcification of the mitral annulus below the age of 40 years__ dilatation or dissection of the descending thoracic or abdominal aortabelow age of 50 years
PULMONARYMinor (only)__ spontaneous pneumothorax__ apical blebs
SKIN AND INTEGUMENTMinor (only)__ striae atrophicae__ recurrent or incisional hernia
DURAMajor__ lumbosacral dural ectasia by CT or MRI
FAMILY/GENETIC HISTORYMajor__ first degree relative who independantly meets the diagnostic criterian.__ presence of mutation in FBN1 known to cause Marfan syndrome__ presence of haplotype around FBN1 inherited by descent and unequivocallyassociated with diagnosed Marfan syndrome in the family
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Positive Steinburg Thumb Sign
Positive Walker
Wrist Sign
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Treatment Require a multidisciplinary team Symptoms, not disorder, must be treated Yearly echocardiograms Emotional support Healthy Diet
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General Chronic Progressive Typically not detected until adulthood Life expectancy: 70-80 Variable expression
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Heart Enlargement of the aorta
Aortic Dissection Aortic Dilation
Aortic Valve regurgitation Mitral valve prolapse
Medications Lower blood pressure Angiotensin receptor blockers Beta blockers
Regular Echocardiograms
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Skeleton Physiotherapy Pain Clinics
Loose joints Bracing
Back Ankle
Surgery Pectus excavatum
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Dural Ecstasia 60% of Marfan patients affected Causes pain Identified through MRI Treatment
Spinal shunting medication
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Eyes Glasses
and/or Contact Lenses
Surgery Removal
or replacement of lenses
Reattachment of retinas
Cataract surgery
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Lungs Surgery to correct pectus abnormalities Pulmonary function tests Pneumothorax
Chest tube evacuation Supplemental oxygen
Emphysema Supplemental oxygen Antibiotics
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Dental Treatment individualized
Crowding Palate misshape
Dental implants Dangers
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Physical Activity Avoid contact and strenuous sports because of
the risk of damaging the aorta and injuring the eyes
Individual restrictions based on severity and discussed with physician
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Contact/collision high potential: strenuous
basketball,
boxing, field hockey, football, ice hockey, lacrosse martial arts, rodeo, skiing (water) soccer, wrestling
Limited contact: strenuous baseball, bicycling (intense) gymnastics, horseback riding, skating (ice & roller) skiing (downhill & cross-country) softball, squash, volleyball
Noncontact: strenuous aerobic dancing (high impact) crew, running (fast), weightlifting
Noncontact: moderately strenuous aerobic dancing (low impact), badminton bicycling (leisurely), jogging, swimming (leisurely) table tennis, tennis
Noncontact: nonstrenuous golf, bowling riflery, walking
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Testing in High Schools Desirable Traits Laws Ethics?
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Flo Hyman July 31, 1954-Jan. 24,
1986 Olympic Volleyball
Player 6 foot 5 inches Died on court from
Marfan