This is a mechanism of disease map for Down syndrome also called trisomy 21. I'll be talking about the etiology, the pathophysiology, and the manifestations for Down syndrome. And as in all of these flow charts, each of these boxes is color coded according to the legend that you see up at the top right. So I'll be clearing all of the boxes and talking through them one by one, explaining them as we go through it all. So let's go ahead and get started. At the center of the pathophysiology for Down syndrome is that the patient has excess genetic material from chromosome 21. Now there are a number of ways that this can happen. The most common by far, and the first that we'll talk about, is at the top here. It's called full trisomy 21 and it occurs in about 95% of patients with Down syndrome. In this case the patient has three complete copies of chromosome 21. There's a specific way that this happens. It's called nondisjunction. Nondisjunction is when the chromosomes fail to separate from their centers during meiosis. Remember that meiosis is the process of the cell cycle that germ cells go through, whereas mitosis is the process of the cell cycle that all the other body cells, all the other somatic cells go through. This is a problem when you're splitting your chromosomes during meiosis. And it happens more frequently on the maternal side during meiosis 1 at a chance of 70%, less frequently on the maternal side during meiosis 2, and even less frequently on the paternal side during spermatogenesis during meiosis 2. All of these are more likely to happen when you have high paternal age, when mom and dad get older when they're having the baby. So that's the most common full trisomy 21. And the karyotype looks like this. They'll have 47 chromosomes instead of 46 of course. In the male case, there'll be XY with an additional chromosome 21. In the female case, of course, there'll be XX with an additional chromosome 21. So this is the karyotype for full trisomy 21, the most common form of Down syndrome. Moving down, we'll have this translocation trisomy 21 as the next most common variant. This happens in three or four percent of patients with Down syndrome. In this case, you have a third copy of chromosome 21, but it's attached to another chromosome, usually chromosome 14. And in that case, it's called an unbalanced Robertsonian translocation. Now, as we try to understand this translocation trisomy 21, let's look at what a translocation actually is. So imagine you have two chromosomes like this, and they become reattached so that the large portions, the bulk of the chromosomes, attach to each other, and the small legs of the chromosome attach to each other, and we can kind of ignore that small leg portion. Now in translocation, you're keeping this big piece here. This is the large piece of chromosome 21 that's attached to another chromosome, most commonly chromosome 14. And it's possible to have a translocation of this large where you still have the same amount of genetic material across all of your chromosomes. That's called a balanced Robertsonian translocation. And in that case, the patient has a normal phenotype. You don't have Down syndrome. The problem is that when a person with a balanced Robertsonian translocation then has their own child, that can predispose them to having a translocation trisomy 21 with an unbalanced Robertsonian translocation. So imagine if you have this abnormal translocated chromosome with the addition of a normal chromosome, you'll have this extra piece here, this extra blue piece, and that's what makes the translocation unbalanced. So when you have a balanced Robertsonian translocation, it's also possible to have a child that still has that balanced Robertsonian translocation, and you can even have a child with a normal karyotype, which of course would also have a normal phenotype. But, in any case, when you have a balanced Robertsonian translocation, you are more predisposed to having miscarriages. So, it's not a completely normal condition, and they still have trouble having children, as shown here. These are the karyotypes for the balanced and the unbalanced translocations. You can see that the balanced translocation has less chromosomes than you would expect. It's 45, but that translocation is noted here. There's an extra piece of 21 on chromosome 14. In the unbalanced Robertsonian translocation, they have the normal number of chromosomes, but there's this extra piece again of 21 on chromosome 14. In addition to the other two parts of chromosome 21, so there's that additional chromosome 21, and that's what causes Down syndrome. They have that excess genetic material from chromosome 21. This was a little less, this was much less common than full trisomy 21, and this one is even less common down here. So moving down to mosaic trisomy 21, this is when a patient has both trisomy 21 cell lines and normal cell lines present throughout the body in a kind of mosaic pattern. So the phenotypes here are going to range according to which cells are affected and which cells are normal, and kind of that normal to affected cell ratio. This happens from non-disjunction during mitosis after fertilization. So this happens during mitosis whereas full trisomy 21 happens during meiosis. And the karyotype here for mosaic trisomy 21 depends on the cell. So some cells will be normal 46XX or 46XY. Other cells will have the same karyotype that you see up here 47XX with an additional 21 or 47XY with an additional 21. So, you can think of mosaic, it is quite literally a full trisomy 21 in some cells and normal karyotype in other cells. Okay, we got the etiology and the pathophysiology out of the way, now let's talk about the many manifestations of Down syndrome throughout many organ systems. So you can think of the manifestations of Down syndrome as belonging to these categories. They change the patient's appearance, they have a number of organ malformations, they have a few endocrine disorders, they have some mental, behavioral, intellectual disabilities, and they have an increased risk of blood cancers. So let's go through the characteristic appearance, and we have a drawing of the faces here as well as a picture of the feet for reference. So in the eyes in Down syndrome you'll have upslanting palpebral fissures and you can kind of see that where I'm pointing here on the face on this child. They'll also have epicantle folds and brush field spots. Brush field spots if you zoom in on this picture here are kind of grayish, sometimes white spots around the iris. So you can see that this eye isn't completely blue but there are kind of reddish, sorry, there are kind of whitish or gray spots inside the iris. Less common eye problems are strabismus, cataracts, and refractive errors in these kids. The mouth is also affected. Patients tend to have a small mouth with a large tongue, which gives the appearance of a protruding tongue. Their teeth also tend to be smaller than normal, and they tend to have gaps between their teeth. Some details on the ears and the nose. The patients have a hypoplastic nasal bone, so it won't be a hard nasal bone there. The nose also tends to be broad and flat with a flat nasal bridge. So if we were to look at the child in profile, we would see that their nose isn't prominent. It's kind of the opposite of a Roman nose. It doesn't stick out. It kind of dents inward. Ears are also affected. They have small, round, and low set ears, and they tend to have adherent ear lobes. And these patients also have a short neck, which predisposes them to obstructive sleep apnea. Their extremities are also affected. These patients have transverse palmar creases. So if you look at the palm of your hand, you might see a number of lines that kind of go across diagonally. In a patient with Down syndrome, they have one line that goes across their hand perpendicular to their fingers. They also have a sandal gap, which is where their big toe is kind of pointed medially, creating a gap between the big toe and the second toe, as shown in this image here. They have clinodactyly, which is an inward curvature of the fifth finger. So their pinky finger is kind of curved in toward the other fingers, and they tend to be shorter in stature. They have shorter limbs and tend to be shorter height. Next big category, organ malformations. The heart is one of the big ones that's affected. They have atrioventricular septal defects, also called endocardial cushion defects. This can include and additionally have atrial septal defects. They can have VSDs, ventricular septal defects. They can have a PDA, a patent ductus arteriosus, and they can also have tetralogy of flow. The GI tract is also affected. They can have duodenal atresia and duodenal stenosis in less severe cases. They can have an annular pancreas, anal atresia where the anal canal does not form, and rectal prolapse. Anal atresia can lead to megacolon and they can also have Hirschsprung's disease, which can also lead to megacolon. These patients are also predisposed to having celiac disease. The genitourinary tract is the next one that's affected. These patients have hypogonadism. They also have cryptorchism, that's when your testicles fail to descend, one or both fail to descend. They can also have impaired spermatogenesis in the boys, which leads to decreased fertility. Next, endocrine disorders. People with Down syndrome are predisposed to having hypothyroidism and type 1 diabetes. They also tend to have higher rates of obesity, and this is thought to be from decreased metabolism, high leptin levels, and decreased physical activity, among other things, leading to high obesity. Next are the behavioral and intellectual problems. These patients from a motor perspective have delayed development and they end up with muscle hypotonia. They have varying levels of intellectual disability but it's usually quite severe. The average IQ is 50, which is half of the mean IQ for the population. They have delayed developmental milestones. These kids usually meet their milestones like standing, walking, running at twice the normal age, so quite delayed. They also can have ADHD, attention deficit hyperactivity disorder, and in more severe cases can have conduct disorder if they're not able to be well controlled. They're predisposed to having early onset Alzheimer's, and the pathophys of that is worth knowing. The amyloid precursor protein is actually located on chromosome 21. And of course, because these patients have excess genetic material from chromosome 21, they have more of a chance to generate amyloid beta, which leads to early onset Alzheimer's. Lastly, they have social disabilities. They tend to be on the autism spectrum disorder. Lastly, they have an increased risk of acute lymphoblastic leukemia and acute myeloid leukemia. So that's their increased risk of malignancy. This has been an overview of Down syndrome. I hope this was helpful and thank you for listening.