Cytoskeleton and elastin disorders: Pathology review

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Case studies0:00–1:05

A 10 year old male, named Thomas, is brought to the clinic by his father because of a persistent fever, as well as a productive cough with dark, foul-smelling sputum.
Upon further questioning, his father states that, since birth, Thomas has had multiple bouts of sinusitis and pneumonia, which required antibiotics.
Upon chest auscultation, you realize that the heart sounds are heard on the right side of the chest! You then decide to order a chest X ray, which reveals that Thomas’ heart is in fact located on the right side of the chest!
Finally, you get a CT scan, which reveals abnormally dilated airways. Right after Thomas, you meet Sara, a 17 year old female who comes into the clinic complaining that her joints frequently slip out of place.
On physical examination, her height is at the 90th percentile and weight at the 60th percentile for her age. In addition, you notice that her fingers and toes are abnormally long.
Upon chest auscultation, you hear a diastolic murmur in the aortic area. Based on the initial presentation, Thomas seems to have some sort of a cytoskeletal disorder, whereas Sara most likely has an elastin-related disorder.Okay, before we start with cytoskeletal disorders, here’s a bit of physiology real quick!

Pathology1:05–1:15

Cytoskeletal disorders1:15–2:49

The cytoskeleton is an intracellular network of proteins, which allows each cell to maintain its shape, but also to move, contract, divide, and absorb or secrete molecules.
Now, one of the protein structures in the cytoskeleton is microtubules. These are tiny hollow rods found at the base of cilia, which are hair-like structures on the surface of epithelial cells lining the respiratory and reproductive tracts.
Specifically, each cilium has microtubules arranged in a 9+2 pattern, meaning there are 9 microtubules doublets on the periphery, as well as two single central microtubules.
Now, in between the microtubules, there’s the dynein arm ATPase protein, which uses ATP to make microtubules slide past each other.
This causes the cilium to bend and, thus, move back and forth in a wave-like motion, which is necessary to swipe out mucous secretions, debris, and foreign particles or pathogens.
This function is especially important in the middle ear, paranasal sinuses, airways, and lungs. Additionally in females, cilia transport a fertilized ovum along the fallopian tube to the uterus, where implantation occurs.
On the other hand, in males, sperm cells have a similar but longer motile structure called flagellum, which allows them to propel along the female reproductive tract and fertilize the ovum.All right, now, the most high yield cytoskeletal disorder is primary ciliary dyskinesia, which refers to a group of genetic disorders that occur due to a mutation in the gene coding for dynein arm ATPase protein.

Primary ciliary dyskinesia2:49–6:06

For your exams, remember that primary ciliary dyskinesia is autosomal recessive, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition.
Now, when the dynein arm ATPase is not functioning normally, cilia won’t be able to move effectively and swipe out mucus from the middle ear, paranasal sinuses, airways, and lungs.
As a consequence, mucus builds up and traps foreign particles like dust and pathogens, especially bacteria, which start to multiply and cause infection.
At the same time, fertilized ovum or sperm cells won’t be able to move along the reproductive tract. Symptoms of primary ciliary dyskinesia include recurrent bacterial infections, such as otitis media, which may lead to conductive hearing loss; as well as respiratory tract infections, such as chronic sinusitis and pulmonary infections.
Over time, this results in chronic lung inflammation, which may cause the bronchi and bronchioles to get damaged and dilate, leading to the development of bronchiectasis.
And that’s a high yield fact! In the reproductive tract, both male and female fertility will be impaired.
For your exams, keep in mind that individuals with primary ciliary dyskinesia are also at an increased risk for ectopic pregnancy.
That’s because the defective cilia won’t be able to transport the fertilized ovum to the uterus, so it may implant in the wall of the fallopian tube.Another high yield fact is that, for unknown reasons, primary ciliary dyskinesia can be associated with situs inversus, a condition in which chest and abdominal organs are positioned in a mirror image to their normal anatomical location.
For example, the heart is normally present on the left side of the chest, but in situs inversus, it would be on the right side, and the high yield term used to describe this is dextrocardia.
Now, in a test question, if primary ciliary dyskinesia presents with a clinical triad of chronic sinusitis, bronchiectasis, and situs inversus, it is called Kartagener syndrome.
And that’s a high yield fact! Diagnosis of primary ciliary dyskinesia starts by measuring nitrous oxide level in the nasal epithelium, which would be markedly low.
The diagnosis can be then confirmed with a biopsy from the nasal or bronchial epithelium, which can be examined via transmission electron microscopy to detect the absence of dynein arms.
In addition, bronchiectasis or situs inversus can be identified via imaging tests, such as X-rays or a CT scan.Treatment of primary ciliary dyskinesia focuses on addressing complications like infections with antibiotics, or managing bronchiectasis with daily chest physiotherapy, which can help expel bronchial secretions.
Finally, fertility issues can be treated with in vitro fertilization methods.All right, let’s switch gears and talk about elastin-related disorders!

Elastin-related disorders6:06–7:27

But first, a bit of physiology real quick! Within the extracellular matrix is a network that consists of several proteins and sugars, which provide support for the surrounding cells.
Zooming into this network, there’s a glycoprotein called fibrillin, which along with other molecules like cellulose, form strong rope-like structures called microfibrils.
These act as a scaffold for other proteins like elastin, forming elastic fibers, which are highly cross-linked. This gives elastic fibers a rubber-band-like quality, which allows them to stretch and then spring back to their original shape.
Tissues that have elastic fibers include the skin, arteries, and lungs, as well as the ligaments, in particular the ligamentum flavum, which supports the vertebrae.
Now, some tissues have microfibrils but no overlying layer of elastin, including tendons and the ciliary zonules that hold the eye lens in place.
As a result, these tissues are less stretchable, but still have considerable tensile strength. Now, in addition to being part of microfibrils, fibrillin also sequesters and removes transforming growth factor beta, or TGF-β, which normally stimulates tissue growth.
Therefore, fibrillin’s function results in decreased tissue growth.Okay, the first elastin-related disorder is Marfan syndrome, which is caused by a mutation in a gene called FBN1, or fibrillin 1, on chromosome 15, which encodes fibrillin.

Marfan syndrome7:27–13:26

For your exams, bear in mind that Marfan syndrome is autosomal dominant, which means that a single mutated copy of the gene is sufficient to cause the disease.Now, the FBN1 mutation results in an either less abundant or dysfunctional fibrillin.
This means that there are fewer functioning microfibrils in the extracellular matrix, so there’s less integrity and elasticity of the skin, arteries, lungs, and the ligamentum flavum.
At the same time, the lack of fibrillin means TGF-β doesn’t get effectively sequestered, leading to excessive and unregulated TGF-β signaling.
This results in excessive tissue growth, and particularly affects long bones, like the femur.Signs and symptoms of Marfan syndrome vary depending on the tissue affected.
The most obvious physical features involve the skeleton, since individuals are tall and have long arms and legs. For your exams, remember that this is called a Marfanoid body habitus.
They also have long, thin fingers and toes, which is called arachnodactyly. In addition, 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, as well as hypermobile joints that can move beyond a normal range, which may result in recurrent joint dislocations.
In the skin, Marfan syndrome can cause stretch marks; whereas in the lung it can cause bullae to form, which are large air-filled spaces.
What’s important to remember is that these bullae are prone to rupture and may lead to pneumothorax, where air collects in the pleural space, which impairs lung expansion.
In the mouth, Marfan syndrome causes a high-arched palate; while in the eyes it causes weakness of the suspensory ligaments of the lens, which may lead to lens dislocation, usually in an upward and lateral direction.
The most serious features of Marfan syndrome, though, are cardiovascular. The aorta often undergoes cystic medial necrosis, which is when the tunica media, or middle layer of the aortic wall, degenerates.
This makes the aorta susceptible to dilation and aneurysms, or outpouchings of the vessel, as well as dissection, where the intima, or inner wall, develops a tear, letting blood track into a false lumen in the vessel wall.
And that’s important to bear in mind since it may lead to aortic rupture, which is a full-thickness tear that causes internal bleeding, and can be life-threatening!
Now, as the aorta dilates over time, there’s a risk for aortic valve insufficiency, where blood leaks back into the left ventricle during diastole.
Marfan syndrome may also lead to mitral valve prolapse, which is when the mitral valve becomes floppy and bulges into the left atrium during systole.Now, if a test question describes an individual with a marfanoid habitus, pectus excavatum, or pectus carinatum, it’s extremely important to differentiate Marfan syndrome from homocystinuria.
This is an autosomal recessive disorder, most often caused by a mutation involving the enzyme cystathionine beta-synthase, which normally combines homocysteine and serine to create cystathionine.
In homocystinuria, cystathionine beta-synthase is defective, so homocysteine builds up in the body. Now, unlike Marfan syndrome, homocystinuria does not cause hypermobile joints.
Instead, the excess homocysteine accumulates in the brain, which causes neurons to undergo apoptosis or programmed cell death, leading to neurodegeneration and intellectual disability.
Homocysteine also builds up in the blood, where it binds to platelets, causing them to stick to one another, resulting in thrombosis, as well as stick to endothelial cells lining the blood vessels.
This leads to atherosclerosis or plaque build-up, which narrows the arteries and could lead to ischemia of their supplied tissues.
As a consequence, homocystinuria can increase the risk of strokes, myocardial infarctions, and thromboembolism. But what’s even more important to set it apart from Marfan syndrome is that in homocystinuria, the lens is dislocated down and inward, rather than up and outward.
Now, if a test question mentions hypermobile joints, scoliosis, and abnormalities involving the heart valves, make sure not to confuse Marfan syndrome with Ehler-Danlos syndrome, which is most often caused by an autosomal dominant mutation that leads to a defective collagen protein.
Now, the main difference with Marfan syndrome is that individuals with Ehler-danlos syndrome usually have normal height, as well as hyperextensible skin.
So be sure to keep an eye out for these clues!All right, to diagnose Marfan syndrome, echocardiography can be done to detect heart and aortic complications, while a slit-lamp examination can be performed to look for lens dislocation.
Finally, diagnosis can be confirmed via genetic testing, looking for FBN1 mutations. Treatment of Marfan syndrome depends on the associated clinical features.
For example, medications like beta blockers and angiotensin receptor blockers have been shown to slow aortic dilation, especially when used in combination.
If the aorta gets too wide, it can be repaired surgically to prevent dissection or rupture. In addition, if an eye lens dislocates, it can be removed and replaced by an artificial lens.
The last elastin-related disorder is alpha-1 antitrypsin deficiency, which is an autosomal codominant disorder caused by a mutation in the SERPINA1 gene coding for the protein alpha-1 antitrypsin.

Alpha-1 antitrypsin deficiency13:26–16:51

Some of these mutations completely abolish the gene, which means no alpha-1 antitrypsin is made; while other mutations result in a misfolded and defective alpha-1 antitrypsin protein.
Now, normally, in the lungs, alpha-1 antitrypsin inactivates neutrophil elastase. This is a protease capable of breaking down elastin, which gives elasticity and strength to lung tissues, so to allow lung expansion and elastic recoil when breathing.
But when there’s a deficiency of alpha-1 antitrypsin, this elastase remains excessively active, and can damage the alveoli in the lungs.
In addition, misfolded alpha-1 antitrypsin can build up in the liver, damaging and killing hepatocytes. As a result, individuals develop cirrhosis, a process in which normal liver tissue is replaced with scar tissue.So the main symptoms of alpha-1 antitrypsin deficiency usually involve the lungs and liver.
Starting with the lungs, individuals with panacinar emphysema typically experience shortness of breath, cough with sputum production, and wheezing, which is a whistling sound in the chest.
In addition, because the lung loses much of its elastic recoil, it will be less able to propel the air in the alveoli to the outside, leading to air trapping and hyperinflation of the lungs.
This causes individuals to develop panacinar emphysema, which means that the whole acinus is affected, and is typically associated with a barrel-shaped chest.
On the other hand, liver damage causes cirrhosis, a process in which normal liver tissue is replaced with scar tissue. Ultimately, cirrhosis can lead to a number of complications, including an inability to make coagulation factors; as well as inability to remove toxins, like ammonia, from the blood.
These toxins can build up and harm tissues like the brain, causing hepatic encephalopathy. Other complications include portal hypertension, which can lead to esophageal varices; as well as an increased risk of hepatocellular carcinoma.
So, in a test question, you should think of alpha-1 antitrypsin deficiency in a young person with cirrhosis and dyspnea without a history of smoking.For diagnosis of alpha-1 antitrypsin deficiency, blood tests can measure the low levels of alpha-1 antitrypsin, and genetic testing can confirm the mutations.
A chest X-ray or CT scan can be performed to look for hyperinflated lungs or evidence of damaged lung tissue. In addition, pulmonary function testing can be used to measure how quickly air exits the lung, which can be slower than normal.
Finally, cirrhosis can be diagnosed with a liver ultrasound or liver biopsy. In terms of treatment, intravenous infusions of normal alpha-1 antitrypsin protein may help slow or halt the progression of lung disease.
In addition, supplemental oxygen is often needed as well. Finally, standard treatments for cirrhosis are also required, such as lactulose, to prevent hepatic encephalopathy.All right, as a quick recap… Primary ciliary dyskinesia is caused by a defective dynein arm ATPase, and this results in abnormal ciliary motility in the respiratory and reproductive tracts.
Manifestations include recurrent sinopulmonary bacterial infections, as well as decreased fertility and increased risk of ectopic pregnancy.

Review16:51–19:11

When primary ciliary dyskinesia presents with a clinical triad of chronic sinusitis, bronchiectasis, and situs inversus, it is called Kartagener syndrome.
Next is Marfan syndrome, which is caused by mutations in the FBN1 gene. This leads to fewer fibrillin microfibrils in certain connective tissues, compromising their strength and elasticity, and upregulating TGF-β signaling.
The end result is an individual presenting with a Marfanoid body habitus, so tall and thin, as well as scoliosis, hypermobile joints, and stretch marks.
Individuals with Marfan syndrome are at higher risk of pneumothorax and aortic aneurysm, dissection, or rupture. Finally, alpha-1 antitrypsin deficiency is caused by mutations that result in absent or defective alpha-1 antitrypsin, which can cause excessive degradation of elastin in the lungs, leading to panacinar emphysema; and can build up in the liver, causing cirrhosis.
Okay, back to our cases! Thomas is the 10 year old boy who presented with a persistent fever and productive cough with dark, foul-smelling sputum.
His history of recurrent infections, along with the imaging findings of situs inversus and bronchiectasis, make up the characteristic clinical triad of Kartagener syndrome, which is a type of primary ciliary dyskinesia.
Diagnosis was confirmed by taking a biopsy from his nasal epithelium, which revealed absent dynein arms between the microtubules of cilia.
On the other hand, Sara, the 17 year old girl, came in with frequent joint dislocations. In addition, her diastolic murmur in the aortic area indicates aortic valve regurgitation.
These two findings combined should make you think of either Marfan syndrome or Ehler-Danlos syndrome. However, the additional findings of a marfanoid body habitus, as well as arachnodactyly, are characteristic of Marfan syndrome.
with frequent joint dislocations In addition her diastolic murmur in the aortic area indicates aortic valve regurgitation These two findings combined should make you think of either Marfan syndrome or Ehlers Danlos syndrome However the additional findings of a marfanoid body habitus as well as the arachnoid actually are characteristic