Cytoskeleton and elastin disorders: Pathology review

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! 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. 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! 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. 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.