Marfan syndrome

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Marfan syndrome is a genetic disorder that results in defective connective tissue, which can affect a person’s skeleton, heart, blood vessels, eyes, and lungs.
Normally, the interstitial space of various body tissues is full of microfibrils - which are strong ropelike structures that provide tissue integrity and form connective tissue.
The main component of microfibrils is a glycoprotein called fibrillin. In some structures microfibrils form a scaffold for additional proteins like elastin.
Elastin fibers are highly cross-linked, and that gives them a rubber-band-like quality, which allows tissues to stretch and then spring back to their original shape.
Tissues that have elastin fibers are tissues like the arteries, skin, and lungs, and tissues that have microfibrils but no overlying layer of elastin are like tendons and the ciliary zonules that hold the eye lens in place.
These tissues are less stretchable, but still have considerable tensile strength. In addition to being part of microfibrils, fibrillin also regulates tissue growth.
Fibrillin sequesters or removes transforming growth factor beta, or TGF-β, which stimulates tissue growth, so fibrillin therefore lowers how much TGF-β is available to stimulate growth.
Marfan syndrome is caused by mutations in a gene called FBN1, or fibrillin 1, on chromosome 15. It’s autosomal dominant, which means that even if there’s a normal copy of the gene, a single mutated copy of the gene – in other words a heterozygous mutation – is sufficient to cause the disease.
The FBN1 gene encodes Fibrillin-1 protein, one of three fibrillin subtypes. In Marfan syndrome, fibrillin-1 is either dysfunctional or less abundant.
As a result, there are fewer functioning microfibrils in the extracellular matrix, and that means there’s less tissue integrity and elasticity.
Connective tissue is found throughout the body, so this can affect nearly every body system. Additionally, TGF-β doesn’t get effectively sequestered, so TGF-β signaling is excessive in these tissues - meaning more growth.
The most obvious physical features of Marfan syndrome involve the skeleton. The long bones grow excessively, so individuals are tall with long arms and legs – this is called a Marfanoid body habitus.
They have long, thin fingers and toes too, called arachnodactyly, which is a reference to the long legs of spiders. Finally, overgrowth of ribs can cause pectus excavatum, where the chest sinks in, or pectus carinatum, where the chest points out.
Other bone and joint features include scoliosis where the spine has a sideways curve, an inability to extend the elbows all the way to 180 degrees, flexible joints, a downward slant to the eyes, and a narrow palate that crowds the teeth.
In the skin, Marfan syndrome can cause stretch marks, and in the lung it can cause bullae to form. Which are large spaces that replace the normal architecture of the lungs and can cause a pneumothorax to form.
In the eyes, Marfan syndrome is a risk factor for retinal detachment and a dislocation of the lens, which is usually in an upward direction.
The most serious features, though, of Marfan syndrome are cardiovascular. The aorta dilates over time, which is a risk for aortic valve insufficiency, where blood leaks back into the left ventricle during diastole.
The aorta also undergoes cystic medial necrosis, which is where there is degeneration of the tunica media, which is the central portion of the aortic wall.
Both dilation and cystic medial necrosis weaken the aorta, making it susceptible to aneurysm, dissection, and rupture. An aneurysm is an outpouching of a vessel, which weakens its wall even further.
A dissection is where the inner wall, or intima, gets a tear, and blood tracks into a false lumen in the vessel wall. And this can occlude normal blood flow.
An aortic rupture is a full-thickness tear, which allows blood to escape the vessel. And all of these complications can be fatal.
Finally, Marfan syndrome is a risk factor for mitral valve prolapse, where the mitral valve pouches into the left atrium during systole.
The features of Marfan syndrome, though, might not be present for everyone with Marfan syndrome, and any given feature can be more or less severe.
Also, Marfan syndrome isn’t usually noticeable at birth, so the symptoms show up over time as the child grows. Occasionally, though, features are present at birth, called early-onset or neonatal Marfan syndrome.
As for diagnosis, A person is diagnosed with Marfan syndrome if they have clinical features of Marfan syndrome like aortic disease, a dislocated lens, family history, and FBN1 mutations.
Now, although there is no cure for Marfan syndrome but there are treatments for some of the clinical features. For example, if an eye lens dislocates, it can be removed and replaced by an artificial lens.
If the aorta gets too wide, it can be repaired surgically so it doesn’t dissect or rupture. Beta blockers have been shown to slow aortic dilation, and the angiotensin receptor blocker losartan, which decreases TGF-β signaling, can slow dilation even more when given in conjunction with a beta blocker.
All right, as a quick recap -Marfan syndrome is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene.
This leads to fewer fibrillin microfibrils in certain connective tissues, which compromises their strength and elasticity, and upregulating TGF-β signaling.
The end result is an individual with a tall, thin body with symptoms of loose connective tissue, most importantly in the aorta.