Collagen disorders: Pathology review

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! 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. 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. 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. 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.