Marfan Syndrome

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

Symptoms

affects many body systems including: Skeleton Eyes Heart and Blood Vessels Nervous System Lungs Skin

Skeleton

Tall and slender Disproportionately long appendages Indented or protruding sternum Arched palate, overcrowded teeth, receding mandible Curvature of spine

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

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

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

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

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

Skin

Stretch marks Shoulders, hips, lower back

Increased risk for abdominal hernias

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

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

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.

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

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

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

Testing and Diagnosis Other

Imaging tests Chest x-ray MRI

Symptoms checklist Family history + 2 affected

body systems At least 3 affected body

systems

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

Positive Steinburg Thumb Sign

Positive Walker

Wrist Sign

Treatment Require a multidisciplinary team Symptoms, not disorder, must be treated Yearly echocardiograms Emotional support Healthy Diet

General Chronic Progressive Typically not detected until adulthood Life expectancy: 70-80 Variable expression

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

Skeleton Physiotherapy Pain Clinics

Loose joints Bracing

Back Ankle

Surgery Pectus excavatum

Dural Ecstasia 60% of Marfan patients affected Causes pain Identified through MRI Treatment

Spinal shunting medication

Eyes Glasses

and/or Contact Lenses

Surgery Removal

or replacement of lenses

Reattachment of retinas

Cataract surgery

Lungs Surgery to correct pectus abnormalities Pulmonary function tests Pneumothorax

Chest tube evacuation Supplemental oxygen

Emphysema Supplemental oxygen Antibiotics

Dental Treatment individualized

Crowding Palate misshape

Dental implants Dangers

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

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

Testing in High Schools Desirable Traits Laws Ethics?

Flo Hyman July 31, 1954-Jan. 24,

1986 Olympic Volleyball

Player 6 foot 5 inches Died on court from

Marfan