Collagen disorders: Pathology review

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Case studies0:00–1:07

A 5 year old male, named Mateo, is brought by his father to the emergency department for right thigh pain. Past medical history reveals multiple fractures following minor traumas.
Upon further questioning, Mateo’s father states that Mateo has been experiencing progressive hearing loss. On physical examination, you notice that Mateo’s scleras appear bluish in color.
You then decide to order an X-ray, which shows a fracture of the right femur. Later that day, you see Mary, an 18 year old female, who comes in complaining of left shoulder pain after she tripped during a basketball game.
She mentions that she's had multiple joint dislocations since childhood, including two elbow dislocations in the past year.
Mary has also noticed that her skin is “stretchy” when pulled, and seems to bruise easily. You then order an X-ray, which reveals anterior dislocation of the left shoulder.
Based on the initial presentation, both Mateo and Mary seem to have some form of a collagen disorder. So let’s first start with a bit of physiology real quick!

Pathophysiology1:07–3:33

What’s high yield for your exams is that there are five major types of collagen. Type I collagen is mainly found in the skin, sclera, teeth, bones, tendons, and ligaments.
Type II collagen is abundant in cartilage. Type III collagen is mainly present in the walls of blood vessels, as well as hollow organs, like the intestines and the uterus.
Type IV collagen is found in the basement membrane of the glomeruli of the kidneys, as well as the lens of the eyes, and cochlea of the inner ears.
Finally, there’s type V collagen, which is found in cell surfaces, hair, and placenta, as well as in places where type I collagen is found.Now, collagen synthesis starts when the collagen genes get transcribed from DNA to mRNA, which gets translated into an alpha chain of amino acids, which mostly consists of repetitive sequences of glycine, proline, and lysine.
Some of these proline and lysine residues will then need to get hydroxylated, meaning that hydroxyl groups are added by the enzyme hydroxylase, resulting in the formation of hydroxyproline and hydroxylysine.
What’s high yield for your exams is that hydroxylase requires vitamin C, or ascorbic acid, as a cofactor. Afterward, glucose or galactose are added to the hydroxyproline residues in a process called glycosylation.
Next, hydrogen bonds form between the newly added hydroxyl groups of different alpha chains, and this ultimately results in cross-linking of three alpha chains together forming a pro-collagen triple helix.
The pro-collagen triple helix is then secreted into the extracellular space. In the extracellular space, the N and C terminal sequences are trimmed, forming tropocollagen.
Multiple molecules of tropocollagen are then cross-linked together by the enzyme lysyl oxidase, which uses copper as a cofactor, leading to the formation of collagen fibrils.Okay, now, one of the most high yield collagen disorders is osteogenesis imperfecta.

Osteogenesis imperfecta3:33–6:32

This is most commonly caused by an autosomal dominant mutation, meaning that an individual needs to inherit only one copy of the mutated gene from one parent to develop the condition.
Now, the mutation is usually found in COL1A1 or COL1A2 genes that code for type I collagen, resulting in decreased production of structurally normal collagen.
Less commonly, the mutation occurs in the gene coding for hydroxylase enzyme, which affects hydrogen bonding between alpha chains, leading to an unstable collagen triple helix.
In either case, the result is an overall weaker type I collagen. Signs and symptoms of osteogenesis imperfecta can be easily remembered with the memory trick “patients can’t BITE”.
Now, B stands for bone, as bones in osteogenesis imperfecta are so fragile that individuals experience recurrent and multiple fractures during childhood, which occur even with minimal trauma.
And that is why osteogenesis imperfecta is also known as brittle bone disease. For your exams, remember that in any case of a child with multiple fractures, you should also consider child abuse, and look for other clues like a history of sexually transmitted diseases or repeated injuries with inconsistent or inadequate explanations.
Also look for behavior of the child, like being scared of the caregiver, as well as the clinical examination, like bruises and burns in weird locations and patterns.
In contrast, osteogenesis imperfecta may also have bone deformities, like bowed legs. Alright, next, the I in BITE sounds like eye, where the sclera becomes thinner and more transparent.
This makes it easier to see the choroidal veins underneath, giving the sclera a blue color. And that’s extremely high yield!
Now, T stands for teeth, where dentin erosion leads to brittle teeth that are also brownish or yellow in color. Finally, E stands for ear, since abnormal growth of the bony ossicles in the middle ear can lead to conductive hearing loss.
For the diagnosis of osteogenesis imperfecta, an X-ray skeletal survey can be done to look for fractures. Confirmation comes with genetic testing, to look for mutations in COL1A1 and COL1A2 genes.
Treatment of osteogenesis imperfecta focuses on decreasing the risk of fractures, which could involve avoiding activities like contact sports.
In addition, medications like bisphosphonates can be used to decrease bone resorption and increase bone thickness. The next collagen disorder is Ehlers-Danlos syndrome, which is caused by mutations in certain genes that regulate the cross-linking process of tropocollagen molecules, and this results in unstable collagen fibrils.

Ehlers-Danlos syndrome6:32–10:31

For your tests, remember that most of these mutations are inherited in an autosomal dominant manner. But keep in mind that a few mutations can be inherited in an autosomal recessive manner, in which case the individual will need to inherit two copies of the mutated gene, one from each parent, to develop the condition.
Now, based on the specific mutation and the type of collagen affected, Ehlers-Danlos syndrome can be classified into several types.
For your exams, remember that the most common one is the hypermobile type, where the underlying genetic mutation and the type of collagen affected is unknown.
So the only thing you need to note is that it typically affects joints. Then, there’s the classical type of Ehlers-Danlos syndrome, which is caused by a mutation in COL5A1 or COL5A2 genes that code for type V collagen and thus affects the skin, bones, tendons, and ligaments.
Next is the vascular type, which results from a mutation in the COL3A1 gene that codes for type III collagen, so it mainly affects blood vessels, the intestines, and uterus.
Alright, depending on the specific type of Ehlers-Danlos, certain symptoms may predominate or vary in their severity. However, bear in mind that some symptoms can be seen in all types of Ehlers-Danlos syndrome, including musculoskeletal symptoms like scoliosis or increased curvature of the spine, as well as hypermobile joints that can move beyond a normal range, which may result in recurrent joint dislocations and joint injury, and ultimately lead to early osteoarthritis.
Another high yield finding is skin hyperextensibility, along with easy bruising and frequent skin lacerations. In addition, keep in mind that individuals with Ehlers-Danlos syndrome are more likely to develop abdominal hernias, where part of an abdominal organ protrudes through the abdominal wall, as well as pelvic organ prolapse, where the uterus or the rectum slide out of place and protrude out of the vagina or anus, respectively.
There’s also an increased risk of spontaneous rupture of internal organs, like the uterus or bowel. In the cardiovascular system, Ehlers-Danlos syndrome classically predisposes to mitral valve prolapse, which is when the mitral valve becomes floppy and bulges into the left atrium during systole.
There’s also an increased risk of aortic root dilation, which may progress to aortic aneurysms or abnormal outpouching, as well as aortic dissection, where the inner wall, or intima, 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!
On the other hand, the arteries in the brain may develop berry aneurysms, which are berry- or sack- shaped outpouchings of arteries in the brain, are also especially common among individuals with Ehlers-Danlos syndrome.
And what’s high yield is that berry aneurysms can be prone to rupture, potentially leading to subarachnoid hemorrhage, which is bleeding between the arachnoid mater and pia mater, the innermost layer of the meninges covering the brain.Diagnosis of Ehlers-Danlos syndrome can be confirmed via a genetic test, looking for the mutation in one of the collagen genes.
Unfortunately, there’s no cure for Ehlers–Danlos syndrome, so the main treatment is supportive, and may include physiotherapy, as well as orthopedic instruments like bracing, a wheelchair, and casting.Now moving on to Menkes disease, this is caused by a mutation in the ATP7A gene, which is found on the X chromosome.
So, Menkes disease is an X-linked recessive condition, meaning that biological males who carry an ATP7A gene mutation on their X chromosome will have the condition.

Menkes disease10:31–13:50

On the other hand, biological females generally have two X chromosomes, so even if they have a defective ATP7A gene on one chromosome, they still have another functional one.
Now, the ATP7A gene codes for a protein called copper-transporting ATPase, which is present on the basal surface of enterocytes lining the intestines.
So, normally, once copper gets absorbed into the enterocytes, this ATPase helps transport it through the enterocytes and into the blood.
In Menkes disease, the copper-transporting ATPase is defective, so the absorbed copper gets trapped in the enterocytes and can’t reach the blood, resulting in copper deficiency.
For your tests, make sure you don’t confuse Menkes disease with Wilson disease, which is caused by a mutated ATP7B gene.
This codes for a protein that’s responsible for copper excretion from the body, which instead leads to copper build-up in different organs, such as the liver and brain.
A clever way to remember this is to think that ATP7A causes absence of copper, while ATP7B causes build-up of copper.Okay, so copper deficiency affects several enzymes that depend on copper for proper functioning.
A high yield enzyme is lysyl oxidase, which normally cross-links multiple tropocollagen molecules into strong collagen fibrils.
When there’s not enough copper, lysyl oxidase can’t function normally, and the result will be a defective collagen synthesis.
And another high yield enzyme is tyrosinase, which is needed by melanocytes to produce melanin. Now, symptoms of Menkes disease most commonly appear early in infancy and include osteoporosis, or low bone density, as well as failure to thrive.
Other high yield symptoms can include skin hypopigmentation, where the skin appears lighter in color or completely white, as well as kinky and brittle hair.
Finally, individuals with Menkes disease can present with neurological symptoms, such as developmental delay, seizures, hypotonia or low muscle tone, and an increased risk of cerebral aneurysms, which could rupture, leading to intracranial hemorrhage.Diagnosis of Menkes disease begins with blood tests, which show low levels of copper and its carrier protein ceruloplasmin.
In addition, imaging tests like brain MRI can show brain atrophy, whereas an X-ray of the skeleton would show a generalized decrease in bone density.
Genetic testing can be also done to confirm the ATP7A gene mutation.Treatment of Menkes disease focuses on intravenous or subcutaneous copper supplementation, as well as managing neurological symptoms with medications and physical therapy.
Alright, moving on, Alport syndrome affects type IV collagen, which is mainly found in the basement membrane of the glomeruli of the kidneys, the lens of the eyes, and cochlea of the inner ears.
Now, Alport syndrome is caused by a mutation in the gene coding for type IV collagen. In most cases, the disease is X-linked dominant, meaning that both biological males and females who carry the mutation will have the condition.
Now, in the glomeruli of the kidneys, the defective type IV collagen leads to thinning and splitting of the basement membrane, which may allow red blood cells to pass right through from the capillaries to the urine, leading to hematuria.

Alport syndrome 13:50–16:50

Over time, the glomeruli continue to deteriorate, and excessive amounts of protein start to get through the filter, resulting in proteinuria.
Ultimately, individuals may develop progressive kidney failure, which may also predispose to hypertension or increased blood pressure.
For your exams, remember that these manifestations fit the nephritic syndrome pattern.At the same time, in the eyes, the defective type IV collagen in the anterior lens capsule affects its ability to maintain the shape of the lens, resulting in anterior lenticonus, where the central part of the lens starts to push into the anterior chamber.
Other ocular manifestations include lens dislocation, as well as retinopathy, which appears as white or yellow flecks around the macula.
As for the inner ear, the defective collagen in the cochlea progressively affects sound transmission to the brain. The main symptoms of Alport syndrome include hematuria, which can be gross, where blood in the urine can be seen with naked eyes, or microscopic, which can be seen only under the microscope.
Other symptoms include blurred vision, and progressive sensorineural hearing loss.Diagnosis of Alport syndrome is typically based on a kidney biopsy.
For your test, remember that on electron microscopy, the glomerular basement membrane will appear irregularly thin in some areas, but there are also areas where the glomerular basement membrane is thicker.
This creates a “basket weave” appearance. Diagnosis can be confirmed with genetic testing to look for the mutation of type IV collagen.Treatment for Alport syndrome includes medications, such as angiotensin converting enzyme or ACE inhibitors, or angiotensin receptor blockers or ARBs, which may help prevent progression to kidney failure.
In severe cases, though, dialysis or even kidney transplant might be necessary. Anterior lenticonus can be treated with lens replacement.Another disorder that affects type IV collagen is Goodpasture syndrome, but bear in mind that this is not genetic.
Instead, Goodpasture syndrome is a type II hypersensitivity reaction where autoantibodies are directed against the type IV collagen found in the basement membrane of the glomeruli of the kidneys, but also of the alveoli in the lungs.
In either case, this leads to the activation of the complement system, which results in a strong inflammatory response and widespread damage.The most characteristic symptoms of Goodpasture syndrome include a decline in kidney function leading to gross hematuria and hypertension, which again fit the pattern of nephritic syndrome.
But to set this apart from Alport syndrome, bear in mind that Goodpasture syndrome also presents with shortness of breath, cough, and hemoptysis or coughing up blood.

Goodpasture syndrome16:50–18:35

Diagnosis of Goodpasture syndrome is once again based on a kidney biopsy. So, what we’ll see under the light microscope is a crescent moon shape in Bowman's space, which is mostly made up of fibrin and plasma cells, as well as parietal epithelial cells, monocytes, and macrophages.
Another thing to keep in mind is that the immunofluorescence pattern will be linear, since antibodies bind to collagen of the glomerular basement membrane.For treatment of Goodpasture syndrome, immunosuppressive drugs might be useful, as well as plasmapheresis, which involves filtering out the plasma portion of blood to eliminate anti-glomerular basement membrane antibodies.
Alright, the last topic we’re gonna discuss is hypertrophic and keloid scars. Normally, wound healing starts with an inflammatory phase, where inflammatory cells like macrophages clear pathogens and debris.
This is followed by a proliferative phase, where vascular endothelial growth factor or VEGF causes new blood vessels to form, whereas transforming growth factor beta or TGF-β stimulates fibroblasts to proliferate and produce type III collagen.
Finally, there’s the remodeling phase, in which type III collagen is replaced by type I collagen and a scar is formed to increase the tensile strength of the wound.
Once the mission is done, fibroblasts decrease their activity and lessen their production of collagen.Now, in hypertrophic and keloid scars, there’s excessive tissue response to injury, leading to excessive fibroblasts proliferation and overproduction of collagen.

Hypertrophic and keloid scar18:35–21:38

The reason behind this is not exactly known, but it’s thought to be due to increased levels of VEGF and TGF-β. Now, hypertrophic scars have no genetic predisposition, so a high yield fact is that they can occur in all races.
In contrast, remember that in keloid scars, genetics also seem to play a role, and they tend to be more common in individuals of African and Asian descent.Alright, now hypertrophic scars typically develop due to overproduction of type IIl collagen in sites of surgical wounds, burns, or laceration.
What’s high yield is that hypertrophic scars typically remain confined to edges of the wound, and progress over a period of 6 months, which is often followed by spontaneous regression.On the other hand, in keloid scars, there’s massive overproduction of type I and III collagen, even after minor skin injuries like earlobe piercing.
What might help you set these apart from hypertrophic scars is that keloid scars typically extend beyond the wound's boundaries and don’t regress on their own.
Diagnosis is mainly clinical, but if a skin biopsy is done, hypertrophic scars will contain well organized type I collagen fibers, which are arranged parallel to each other, whereas in keloid scars, type I and III collagen fibers will appear in an unorganized pattern.Treatment of hypertrophic and keloid scars involves injection of steroids into the scar, which can reduce the pain and pruritus.
Scars can be removed by cryotherapy, which uses liquid nitrogen, as well as laser therapy, or surgery. Keep in mind that hypertrophic scars are unlikely to recur after treatment, but the risk of recurrence of keloid scars following treatment is high.
All right, as a quick recap … In osteogenesis imperfecta, there are mutations that result in decreased or weaker type I collagen, which presents with recurrent bone fractures, weak teeth, blue sclerae, and conductive hearing loss.
Ehler-danlos syndrome is caused by mutations that disrupt tropocollagen cross-linking, resulting in unstable collagen fibrils.
Symptoms include joint hypermobility, skin hyperextensibility and fragility, hernias and pelvic organ prolapse, mitral valve prolapse, and aneurysms.
Next, Menkes disease is caused by a mutation in ATP7A gene that codes for the copper-transporting ATPase, leading to deficiency of copper, which is important for collagen synthesis.
Manifestations include osteoporosis, failure to thrive, hypopigmented skin, and brittle hair, as well as neurological symptoms like developmental delay, seizures, and hypotonia.
Next is Alport syndrome, which occurs due to a mutation in type IV collagen, and leads to anterior lenticonus and progressive sensorineural hearing loss, as well as nephritic syndrome, which manifests as hematuria, progressive kidney failure, and hypertension.

Review21:38–24:29

On the other hand, Goodpasture syndrome results from autoantibodies directed against type IV collagen, causing nephritic syndrome, as well as shortness of breath, cough, and hemoptysis.
Moving on, hypertrophic and keloid scars result from overproduction of collagen during wound healing. Hypertrophic scars typically remain confined to wound edges, and often regress spontaneously.
On the other hand, keloid scars extend beyond the wound's boundaries, and don't regress on their own. Keloid scars are more common in individuals of african and asian descent.
Okay, back to our patients! Mateo is a 5 year old boy who presents with right femoral fracture, and has a history of multiple fractures after minor traumas.
These findings along with the fact that he’s experiencing progressive hearing loss should make you think of osteogenesis imperfecta.
However, the biggest clue is the blue-colored sclerae found on physical examination. Diagnosis was confirmed by genetic testing, which revealed mutations in the COL1A1.
On the other hand, Mary is an 18 year old girl who presents with anterior dislocation of the left shoulder, and has a history of multiple joint dislocations since childhood.
This indicates that Mary has hypermobile joints. In addition, Mary has skin hyperextensibility and easy bruising.
The combination of these factors makes this a pretty straightforward case of Ehler-Danlos syndrome. extend beyond the wound's boundaries and don't regress on their own Keloid scars are more common in individuals of African and Asian descent Ok Back to our patients Mateo is a five year old boy who presents with right femoral fracture and has a history of multiple fractures after minor traumas These findings along with the fact that he is experiencing progressive hearing loss should make you think of osteogenesis imperfecta However the biggest clue is the blue colored sclera found on physical examination Diagnosis was confirmed by genetic testing which revealed mutations in the col one a one On the other hand Mary is an 18 year old girl who presents with anterior dislocation of the left shoulder and has a history of multiple joint dislocations since childhood This indicates that Mary has hypermobile joints In addition Mary has skin hyperextensibility and easy bruising The combination of these factors makes this