Marfan Syndrome

Question 1

a mutation in FBN1 gene in the long arm of chromosome 15 affecting CT

Answer 1

marfan syndrome (autosomal dominant disorder)

Question 2

responsible for encoding Fibrillin-1 glycoprotein

Answer 2

FBN-1 gene

Question 3

importance of Fibrillin-1 glycoprotein

Answer 3

a major component of microfibrils found in ECM

Question 4

roles of microfibrils

Answer 4

play a role in elastic fiber formation that allows skin, ligaments, & BVs to stretch

provides scaffolding framework into which tropoelastin gets deposited to make elastic fibers

Question 5

MFS mainly affects what systems in the body?

Answer 5

cardiovascular (heart, BVs), skeletal, and ocular

Question 6

Why is MFS mainly affecting the skeletal, CV, and ocular systems?

Answer 6

affected microfibrils are particularly abundant in the aorta, ligaments, and ciliary zonules, which suspend the lense of our eyes.

Question 7

what are the 2 mechanisms that lead to MFS?

Answer 7

1. loss of structural support in microfibril-rich CT

2. excessive activation of the important cytokine – Transforming GF-B

Question 8

how does missense mutation contribute to MFS?

Answer 8

it results in development of abnormal fibrillin-1 glycoprotein, which inhibits polymerization. This decreases fibrillin, which then leads to weakening of elastic fibers.

Question 9

why does the loss of structural support in microfibril-rich CT happen in MFS?

Answer 9

due to loss of microfibrils.

Normally, microfibrils sequester transforming GF-B, which enables them to control the bioavailability of the cytokine.

absence or lack of microfibrils allows these cytokines to accumulate, which has a damaging effect on smooth muscle cells of BVs. This also leads to the activation of METALLOPROTEASE (an enzyme responsible for destruction of ECM.)

Question 10

(an enzyme responsible for destruction of ECM

Answer 10

metalloprotease

Question 11

excessive activation of TGF-B

Answer 11

responsible for BONE OVERGROWTH and MYXOID CHANGES in mitral valve

Question 12

what are myxoid changes?

Answer 12

• mitral valve prolapse

- thickening of valve leaflets and fibrosis

Question 13

MFS ocular problem

Answer 13

• ectopia lentis (bilateral subluxation/dislocation of lens)

dislocation is upwards and outwards

Question 14

MFS CV problems

Answer 14

• mitral valve prolapse, aortic aneurysm (aortic dilation, dissection)

Question 15

in MFS, dilation of ascending aorta or aortic aneurysm is due to _______.

Answer 15

cystic medial necrosis or cystic medial degeneration

Question 16

causes of mitral valve prolapse

Answer 16

• elongation of chordae tendineae
• elongation of valve ring
• redundant valve tissues

Question 17

clinical features of MFS

Answer 17

• arachnodactyly
• arm span greater than height
• decreased ratio b/w upper and lower segments (torso is abnormally shorter compared to legs)
• hypermobile joints due to weakness of CT
• thumb can be hyperextended back to wrist
• prominent supraorbital ridges
• bossing on frontal eminence (protruding forehead)
• kyphosis, scoliosis
• pectus excavatum (pt at risk for pneumothorax)
• ectopic lentis
• floppy valve syndrome/mitral valve regurgitation
• aortic aneurysm/aortic dilation

Question 18

what can pectus excavatum lead to?

Answer 18

decreased lung capacity –> restrictive pulmonary deficit (4-5%) –> spontaneous pneumothorax

Question 19

why would patients with MFS also have sleep apnea?

Answer 19

due to laxity of pharyngeal tissues, blocking the airway

Question 20

early diagnosis of MFS leads to ______

Answer 20

better prognosis

Question 21

MFS and pregnancy

Answer 21

increased risk of aortic dissection

pt must be on frequent cardiovascular monitoring

Question 22

what meds can we give pts w/ MFS?

Answer 22

beta blockers (decreases strain or aorta = slows rate of dilation)
calcium channel blockers (if pt experiences sadness or nausea)
losartan (blocks action of TGF-B)

Question 23

When should we recommend aortic root surgery to patients w/ MFS?

Answer 23

• aortic root diameter greater than or equal to 50 mm
• rapide rate of enlargement (> 6-10 mm/yr)
• family hx of early aortic dissection

Question 24

indications for preventive or prophylactic surgery

Answer 24

diameter of the aorta reaches 5 centimeters in older children or adults

rate of widening reaches 1 centimeter a year, or when there is severe or progressive backflow (regurgitation) of blood through the aortic valve

for leakage of the mitral valve