Amit AminOctober 03rd, 2014

[General Pathology] [28&29] [Developmental Disorders III&IV] by [Dr Phelan]

Slide 68 Dominant vs. Recessive TraitsDr. Phelan So moving on, Ill just go back a little bit to where we were on, whatever day it was this week, Monday or so. I had gotten to the inheritance patterns and I had finished with the developmental abnormalities and you will see as we get to some examples of the developmental abnormalities that the genetic diseases that the developmental abnormalities are actually part of some of the developmental diseases. The developmental abnormalities that we looked at earlier can occur in isolated form related to environmental conditions such that we talked about the poly Ok; actually, what I really meant was this. I have one of those, thank you. Im sorry, I saw you run out and I realized I had told you the wrong thing. He was helping. I dont think I need that remote for this one. But anyway, so we talked about sequence anomalies in a number of different ways. Two different ways that the environment can affect or that fever* environment can affect developmental disorders. And then we got to those that are genetic and those that we understand the genetic transmission pattern for. And those have been studied over years and so we understand the genetic transmission pattern because these diseases have been studied and Ill show you some examples of those later. There are a number of them that are, that have head, neck, and oral manifestations. Most of those youll be responsible for next year, but I will give you some examples of those this year as well. So we talked about dominant and recessive traits and I described the difference between the two. And that the dominant trait requires only one allele, only one gene has to be effected for the pair of genes where the recessive trait, you have to have both in order for that condition or that trait to show itself. This is the same as the traits that make us look different than normal. The diseases work in the same manner. There are traits that are required only one allele and there are traits that require, that are recessive and require both. They arent causing diseases; theyre just making us who we are. But for this course, were talking about the pathology and the pathologic entities that are related to these genetic patterns.

Slide 69- Autosomal DominantDr. Phelan We talked about autosomal dominant. Both males and females are equally affected. Again, in a family, you cant say if you have four children youre going to have two and two. It doesnt work that way. Each child is 50-50. So a family with an autosomal dominant disorder could have all their children affected, or none of their children affected, or half of their children affected and one child out of many. So each child is the 50-50. In order to get males and females equally affected, our have to look at lots and lots and lots of individuals and eventually you will get up to 50-50, but the chance is 50-50. Again, because this is an inherited disorder, these are inherited disorders were talking about, theyre transmitted to successive generations in a pattern thats understood except that we have a little bit of a sidebar where we have possibilities of skipping a generation or possibilities of one of these genetic disease popping up new and we talked about that last time. Here again you have the proportions of male and female, but the proportions of normal and diseased individuals are on the average equal. Again, since each individual is 50-50, you cant look at that in a family, what in the pathology or the concern for genetic diseases. There are genetic counselors that work on this with families to help them understand what the risk is of a genetic disease being transmitted and also what the possibilities are for the disease. Genetic counselors work on that. You will have, I think I mentioned to somebody, you would have situations where you can figure this out yourselves. Some of you, last year, you were so nave you might not have known what were talking about. In one of our integrated case presentations. One of the students was able to work out a pedigree of a family with a genetic disorder. She worked it out from the proband, which was the individual patient that she was working with, worked back and forth from the parents and grandparents, and aunts and uncles and cousins, then the children in that family.

Slide 70 - DefinitionsDr. Phelan So we had two definitions, I think, that are important to remember because they mess us up a little bit. We talk about these patterns as being really well defined patterns and then we have a disease we know of that can form and develop in many, many ways. There are some genetic diseases where not every individual has a problem with mental development. The genetic counselor would advise the prospective parents about what the risk might be. Incomplete penetrance again is a problem because its possible in some of these genetic diseases where we know the transmission pattern, where it skips a generation. The concept of incomplete penetrance is the way thats described. Exactly how it happens thats a different problem altogether, we dont really know. We talked about the pedigree and I showed you the pedigree and we are going to look at a number of those. I expect you to be able to understand that. The proband is where you start the pedigree. Its the person youre working with that starts the pedigree and pedigree is worked was designed around.

Slide 71 Pedigree pattern for an autosomal dominant traitDr. Phelan I showed you with pedigree for autosomal dominant trait.

Slide 72 Locus vs. AllelesDr. Phelan - We talked about what a locus is and what alleles are. There are two alleles matching on two chromosomes and they are each at a locus on that chromosome.

Slide 73 - Pedigree pattern for an autosomal dominant traitDr. Phelan Did I go backwards?

Slide 74 Autosomal RecessiveDr. Phelan We talked about autosomal recessive. These are much less rarer. Usually the problem is apparent at birth or shortly after. With autosomal dominant problems, sometimes the disease does not show itself until later, but autosomal recessive almost always you see the disease a newborn or shortly after birth. Both parents have to have the gene, at least one gene, in order for this to occur. If you have a parent, one parent with one gene affected and one gene not, another parent with two affected genes. So for example, cystic fibrosis is an autosomal recessive condition and its really very common. I mentioned last time that people with cystic fibrosis now live into there 40s at least. It used to be that they didnt. They used to live into their teenage years. So its really possible for them to have children and they would have two affected genes. So that every one of their children would at least be a carrier of that gene. Does that make sense?

Slide 75 - Autosomal Recessive (continued)Dr. Phelan [skips]

Slide 76 - Pedigree for an autosomal recessive traitDr. Phelan I also showed you the pedigree pattern for an autosomal recessive trait. Here what were looking at with the double line are related individuals who mated. When you have related individuals mating, you increase the risk of there being a previously unidentified recessive gene for a disease that wasnt evident before. Its also possible that we see the same thing in cultures where theres close inter-marriage in that culture. You cant find the proband because it isnt on there. The pedigree pattern is developed from the proband. Good question, though. There is no proband indicated on this pedigree. A proband would be indicated usually with an arrow. [Goes to Slide 71] We had one here with a new mutant. You could say maybe that arrow was a proband. The proband is if you were developing your own pedigree, you would indicate the proband somehow. They didnt, so you couldnt figure out who was the first person they started with in order to develop this pedigree. It could have been the grandparents, but usually its one of the more recent generations. You have to be told. You cant figure it out form the pedigree. The only thing you can figure out from the pedigree is what the key tells you. So on here, the pedigree is telling you whos affected and whos not. [Returns to Slide 76] On here, they gave you the key for what that double line meant on this pedigree.

Slide 77 X-linked DisordersDr. Phelan We didnt get this far. This is new stuff for today, and that is the X-linked disorders. The sex-linked disorders are almost all x-linked. There are some Y-linked, but they are, for us in dentistry, they usually are problems where the individual would never get anywhere near our practices because usually they are much more severe and extraordinarily rare. If you are really interested in going into this deeper, your textbook does describe at least one Y-linked disorder and you can take a look at it. At this point, I think its most important that you understand the X-linked disorders and how they work because they are the ones that youre most likely to see and need to understand. The gene responsible for the disease is on the X chromosome. So what this means is that there are different possibilities for men and for women because of the number of X chromosomes. Women have two and men have one. The disease can show itself possibly in a man where it wouldnt show in a woman and they show differently in both. If the man has the trait on the X chromosome, its going to show. There is no other X involved. Females could be either homozygous or heterozygous because they happen to have two X chromosomes. Being homozygous for this is a little bit more difficult and the way I describe it is that you probably have to have people who met through some type of support program where there are a lot of people who happen to have this condition because this is pretty rare. Let me say it right the possibility of finding females who are homozygous is much rarer than people that are heterozygous. In this one, since the father does not transmit an X chromosome, you cant transport X-linked disorders from fathers to sons. The X chromosome can go form mothers to both daughters and sons, but the disease that emerges is going to show itself differently.

Slide 78 X-linked Dominant TraitsDr. Phelan There are X-linked dominant traits. So these are on the X chromosome and you only need one. You dont need a homologous pair for the disease to show itself. Females, if you look at the statistics in a family, females could be affected twice as frequently as males because theres two possibilities for the females. But again, when were talking about that, were talking about lots and lots of numbers, not one family. If you were the genetic counselor, then youre telling the family that theres twice as great of a risk for female babies than there are for male babies, for girls than the boys. A man with a dominant X-linked chromosome is only going to be able to transmit that to his daughters because thats who gets the X chromosome. Still clear? The disease tends to be less severe and more variable in heterozygous females than in hemizygous males. Now we have a new word. The word that is used for a man that has an X chromosome affected is hemizygous. There is no way for that male to ever be homozygous. We had to come with a different word. But it still describes a male who is affected and the term that is used is hemizygous.

Slide 79 - X-Linked DominantDr. Phelan Here is a pedigree on, no proband indicated, for an X-linked dominant trait. If you look down at the bottom, down in the bottom is our key. It is the keys that will help you figure out the pedigree. Dont try to figure out a pedigree unless youre given a key. You can make it up, but you are expected to have a key. There are pedigrees that are constructed with different symbols and its really essential that you have a key if youre trying to interpret a pedigree. If you look at what we have on the bottom with our key, the affected hemizygous male, thats an infected male. He is showing the disease, is as a red circle. And the affected heterozygous female is with the half-circle. I suppose if we had an affected homozygous female, wed have to fill in the circle, but we dont have that here because that female would have two genes and you would have to come up with a key that would describe that. But its not here so we dont have to worry about it. And you notice none of the circles are filled in completely because theyre illustrating a female that has one affected gene but its dominant. So we can start anywhere on this, but if you look at the very first generation that is identified, the great-grandparents, I guess here. The great-grandmother here was affected and had one gene and showed the disease because its dominant. Then we move down to the next generation and theres an affected girl in the generation and an affected male but theyre indicated differently because the female has only one gene. The male only has one gene too, but he doesnt have another X and whoever constructed this pedigree did it by filling in the box. And we move down to the next generation and we have two women that are affected in one gene. We have moved to the next generation, we have an affected male and an affected female but they are indicated differently. Then we move down to the last generation indicated here, there is two affected women because they are heterozygous or homozygous? Heterozygous. They only have one gene and its dominant. Its dominant, so the disease shows itself.

Slide 80- X-linked Recessive TraitsDr. Phelan Then there are X-linked recessive traits. These are actually conditions that you will know about because there are some famous examples of X-linked recessive traits. If you studied this in high school or in college these will be conditions that were described in pretty much in detail. So for X-linked recessive traits, sons of women who are carriers of the trait have a 50% chance of getting the disease because they have a 50% of getting the affected gene. The daughters are usually symptomatic unless there is some reason you have a mother and a father who were both affected and then the daughter was homozygous and then the daughter actually got the disease. This is sort of true. In many of these, the daughter that is the carrier and unaffected, has some very mild forms of the disease and Ill talk about that in a minute. All daughters of affected men are going to be asymptomatic carriers, because they dont have any choice. Unless you have a mother that also has the gene and you end up with a homozygous daughter and that daughter will have the disease. Sons of affected men are free of the trait and cannot transmit the disease to their children. So the sons, its done. If they dont get that affected gene, theres no way of them transmitting that disease any further in that line. Symptomatic, homozygous females, that would be a female that somehow got an affected gene from her mother and an affected gene from her father, very rare but possible. Again, I just explained how that would happen. The trait tends to occur in maternal uncles and male cousins that come from the mothers and sisters. If you look at this disease, if you look at the pedigree, you can see that the problem is emerging on the males side of the family.

Slide 81 Find the error in this pedigreeDr. Phelan Now what Id like you to do is see, this is an X-linked recessive pedigree and its designated affected males as a, which would be if you wanted to go back to the other one perhaps, hemizygous males. And then heterozygous females without the disease who would be silent carriers. Theres an error on this pedigree. Can you find it? See, in the second generation. What do we have? We have a woman, a female. See her? There is no way of that female not being heterozygous. This female, this pedigree missed the line. Because there is no other way. There is no other possibility for her. What Ive found is taking pedigrees from books is very dangerous because they very often have an error in them. So when you look at pedigrees in books, figure them out. Textbooks miss things. When I pulled this one, there was a missing line on the woman who only could have gotten an X from her father and there wasnt any choice. Question? I answered it. So I think this is kind of fun that most of the time you figure it out pretty fast.

Slide 82 - Single Gene DisordersDr. Phelan So from here, I want to talk about some single gene disorders. Some that exemplifies the problems that were talking about.

Slide 83 - Marfan syndromeDr. Phelan They are disorders that you may see. Theyre on, the ones we picked and the ones that are in the text are the ones that are a little bit more common. We have patients with these disorders here as part of our patient population. Marfan Syndrome, one of our students in the integrated case presentations, as indicated the patient with Marfan syndrome. So these are not so rare so that you wont see them. Marfan syndrome is an autosomal dominant disorder. It is known that if the patient has Marfan syndrome, it was transmitted as an autosomal dominant gene. We know the disease, we know how its transmitted so part of the understanding of these diseases, when we look about the cause and the pattern, is how theyre transmitted. In Marfan syndrome, the problem is that theres a defect in extracellular glycoprotein, fibrillin-1, which is a major component of microfibrils fond in the extracellular matrix. So this product, fibrillin-1, is particularly abundant in the aorta, ligaments, and ciliary zonules of the lens. So if thats the problem, you could figure out what the signs and possibly the symptoms might be. So these individuals have skeletal abnormalities. They usually are exceptionally tall. They are usually very thin. They have an elongated body. They have elongated legs, arms, fingers, and toes. So they looked quite stretched out people. There has been some discussion, which I think at this point as been pretty well debunked, but that Abraham Lincoln might have had Marfan Syndrome. I tell you that because thats the body type. Not everybody thats tall and thin and has elongated legs and elongated fingers has Marfan Syndrome. If you think about Abraham Lincoln- thats the image of an individual with Marfan syndrome. They may have a problem with the lens of their eyes. They are very prone to cardiovascular abnormalities. In our setting, the cardiovascular abnormalities are the abnormalities that we might worry about because they tend to have cardiovascular diseases.

Slide 84 - ImageDr. Phelan This is an example that I got from one of your textbooks of the elongated fingers in Marfan syndrome. Thats Marfan syndrome. Its a change in one component that has made a major change in the individuals appearance and also in making that person have an increased risk of cardiovascular disease.

Slide 85 Neurofibromatosis Type IDr. Phelan - Neurofibromatosis, there are a couple of different types. The one that is most common is Type I. When you recognize this disease, you will make the diagnosis on the subway. The signs of this disease are very prominent. We have a number of patients in our patient population here with neurofibromatosis Type I. Again an autosomal dominant disorder. The disorder involves multiple neural tumors that are usually on the skin, but they could also occur on mucosa. We occasionally find a biopsy of a neurofibroma when we ask the clinician, the patient has multiple lesions. Usually by the time the patient is an adult the diagnosis has been made in childhood. They have pigmentations on their skin that are cafe au lait macules, coffee with milk color. They are flat. So theyre not tumors, just a flat patch. There are two diseases and were going to get another one at another time, probably not until Systems Pathology. I did talk about it in the developmental diseases and thats something called fibrous dysplasia. In fibrous dysplasia, they also get caf au lait macules. Its a popular question on exams, not yet because you really havent done the differential diagnosis of the disease, of the diseases in which you find caf au lait macules. There are really only two: fibrous dysplasia- there is types of fibrous dysplasia- and neurofibromatosis. Its usually Type I where you get those macules. In neurofibromatosis, the macules can be very large. They are described to be larger than the macules that are in fibrous dysplasia. Again, I call this pathology trivia, but it is something you might want to tuck in your brains. Im not going to ask you that at this point because were not comparing fibrous dysplasia and neurofibromatosis, but you will get that comparison at some point in the future. You can sort of tuck it in - you probably ought to have a trivia list, assuming when you get ready to study for boards, you go over your trivia list. Its not going to make you a better dentist, but it will gain you a question answer correct on the exam. Its nice to get those points and bumps things up a little bit. It is a popular question. Right now we dont know whats on the boards because we dont get that kind of information that we used to. Again, its an easy question to ask so put it in your trivia pile. Lisch nodules are pigmented hamartomas, the melanodic hamartomas that are in the iris. These individuals also get skeletal abnormalities. They have a greater risk of developing some of the tumors, which is an important reason besides the cosmetics here for trying to deal with this autosomal dominant disorder. Some people have a mild mental impairment and sometimes its too mild to even be able to recognize that its below normal intelligence limits.

Slide 86 Neurofibromatosis Type I (von Recklinghausen Disease)Dr. Phelan These are some examples and the cosmetic problem is these multiple neurofibromas on the skin. They are really multiple, multiple, multiple and they are disfiguring. Some of them are much larger than the ones that are shown here. Over here are some small caf au lair spots. In neurofibromatosis, they can be much larger. This patient ahs a neurofibroma on the gingiva right here. Just a reminder that it is possible that we might see some neurofibromas intraorally. Usually intraorally, they are not they cosmetic problem that they are on skin. Okay? Thats neurofibromatosis. Another example of an autosomal dominant disorder. When an individual, the proband if thats whom youre dealing with, has neurofibromatosis, you can see the pattern in the previous generous generations and you can predict for future generations. Thats the way genetic counseling will work.

Slide 87 Ehlers-Danlos SyndromesDr. Phelan Ehlers-Danlos syndrome is a pretty rare syndrome. It follows multiple inheritance patterns. There are autosomal dominant examples. There are autosomal recessive examples. It is a defect in Type I collagen most of the time. Sometimes also Type III or Type IV. I think its important to put this in your trivia pile. For years when we had more specific information about the board exams, there was almost always question about Ehlers-Danlos syndrome. Trust me, I dont know why. I dont know why its that important, but its almost always on there in one-way or another either in a choice or actually in understanding the disease. So at this point, I dont know that Ehlers-Danlos syndrome is the most important thing for you to know for the rest of your career, but I am going to ask you questions about it because I think that we need to prepare you for those kinds of things. So the collagen is the defect. What happens here is that these are people with very hypermobile joints. They bruise easily. Why do they bruise easily? Because they dont have the collagen framework that are tacked around blood vessels. Their blood vessels are very easily disrupted. Theres a lot of elasticity of the skin. These people can actually take their skin and pick it up and separate it out in a different way form most of us. 50% of these people can touch the tip of their nose with their tongue. You can try it among the bunch of you an very few of us can do this. There are people who can do this who dont have Ehler-Dnalos syndrome. It is a trick that Ehlers-Danlos people can do. Its very common for them to have TMJ area problems because the collagen is weaker and the joint dislocates. If you work on dental treatment on patients with this disorder, it is very easily pliable tissue and bleeding during manipulation, so you need to be careful. Ruptures in the colon happen and ruptures in large arteries. Its a pretty serious disease.

Slide 88 - ImagesDr. Phelan These are some textbook pictures. This shows the skin flexibility. This shows the flexibility of the hand. I can do this. I dont have Ehlers-Danlos syndrome. Just because you have some hypermobility doesnt mean you have this syndrome. Or at least I used to be able to do this. Im not sure I can do it anymore. This shows the hypermobility of the foot.

Slide 89 Cystic FibrosisDr. Phelan Thats Ehlers-Danlos syndrome. Again, a good chance of seeing it is much rarer. You will probably see patients with neurofibromatosis either in your life or in your practice. Marfan syndrome, maybe. Ehlers-Danlos syndrome, maybe, but among all of you, one of the 300 and however many you are now, see it, I would be surprised. One might, but its really pretty rare. Cystic fibrosis is an autosomal recessive disorder. It is the most common autosomal recessive disorder. You will very likely see patients with cystic fibrosis. The disorder or the defect is related to epithelial transport and it affects fluid secretion in exocrine glands and also in the epithelial lining of the respiratory tract, in the gastrointestinal and reproductive tracts. These patients traditionally have lung problems because of the buildup of mucus in the lungs and the treatment has involved trying to prevent that buildup of mucus in the lungs and infection because of that stasis of mucus in the lungs. It is the most common and it used to be lethal in children and then it got to be more lethal in teenagers. I mentioned before that at this point children with cystic fibrosis are living much longer. If you have nothing else to do when you want to be entertained, my son is an actor and he was hired by Novartis who produces a drug for treating cystic fibrosis to do a video that shows the transition of a kind with cystic fibrosis from a teenager to an adult and trying to move from pediatric care into adult medical care. The name of the video and I think you can pick it up on YouTube is called Being Christopher. So if you want to be entertained at some time, it does show what the symptoms are cystic fibrous and how it is managed. Ive told students in the past and theyve kind of enjoyed the video. Christopher is Andy, and thats my son. It has changed and now you are very likely to treat patients with cystic fibrosis and it is important that you know about this disease. The problem as I mentioned earlier is the pulmonary disease and it is the obstruction of the pulmonary passages with mucus secretions and then the potential for infection because of this mucus secretion. There are problems with pancreas, function of the pancreas. It has sometimes been called cystic fibrosis of the pancreas as an old name for cystic fibrosis. There is dried up mucus that collects in the small intestine, the liver, and the reproductive tract and all of these are part of the problem of cystic fibrosis.

Slide 90 - Dr. Phelan This chart illustrates the problems that I just mentioned in chart form that relate to cystic fibrosis.

Slide 91 - Gaucher DiseaseDr. Phelan Another one Gaucher disease. Gaucher disease is an autosomal recessive disorder and you had it before in this course, do you remember when? In the first conference we talked about it. What was the category of diseases? The lysosomal storage diseases. The reason I include this one now is because it is the one in which people live to adult life that are part of, it may be rare, but they are part of dental practices. I think that Dr. Partridge mentioned this one last year as you were first year students because we talked about finding some pictures for her to illustrate Gaucher disease. It is the most common but it is also the one that people live to adulthood. It results in mutations from the gene that encodes glucocerbrosidase. It accumulates primarily in phagocytic cells and also in the central nervous system. We may see bone lesions because phagocytic cells might cause an increase in the amount of bone marrow and you might get a radiolucency in the mandible, usually not more than the maxilla, that when it is explored, the cells are these foamy, macrophages that are associated with this disease. Rare, certainly. The disease itself is not as rare as the possibility of us finding some bone lesions. We have seen this. It is rare, but I have seen it. Its probably the word for Gaucher disease. Having a patient with Gaucher disease in your practice is not so rare, but finding bone manifestations in the mandible is pretty rare.

Slide 92 Other Storage DiseasesDr. Phelan Ok there are two others that are included in the spectrum of pathology. One of them is Tay-Sachs Disease and the other is Niemann-Pick Disease. At this point, theyre both autosomal recessive. What I would like you to do, you can put it in your trivia package. You need to learn the accumulated substance in each one of these. In Tay-Sachs its gangliosidase and Niemann-Pick sphingomyelin. These children do not live past childhood. They dont live very long. Theyre very serious diseases. They are examples of other lysosomal storage disease. You need to memorize the accumulated substance in each of these. Theres certain things we include not to become a better dentist but so you can past exams that like these things. Gaucher Disease, I think thats different. I think you should know that one. These, learn them now, and before you study the board have your trivia list and bring it out and spend a little bit of time. You can always look them up.

Slide 93 Hemophilia ADr. Phelan Hemophilia A is very interesting. This one a Factor VIII deficiency. There are other hemophilias but this one is best-defined and best known. Its inherited as an X-linked recessive trait. This is best known b/c of its effect on the royal families in Europe who were continually passing their children from one family to another. As long as they were related and royal the were all right. Ended up having a serious problem w/ hemophilia. They were not the only people w/ hemophilia. In fact you will see patients in your practice that do have hemophilia A. It is not extremely rare. It occurs in hemizygous males and homozygous females. In order for a female to have the bleeding disorder, the woman should have the two matching genes that are coding for this problem. However, it seems that the females that are hemizygous have a little bit of bleeding disorder. ITs not nearly as severe. In terms of your practice, its probably not enough to cause any problems in your practice. If youre involved in surgery and you have a family w/ hemophilia, its wise to check the bleeding in females as the men. Its life threatening in the males but not the females. There are many people that develop hemophilia and you cant find the family history. It has to be a number of mutations. When that happens, you will pass the gene to the next generations. Even if you cant find it in previous generations, hemophilia A is an X-linked recessive trait and when we have it, you can be assured that the gene is there and it can be transmitted. There moderate forms of the disease and severe forms of the disease. In this situation where you need think about surgery, this is a work up that needs to be done carefully to know what kind of problem you might run into. When you get to Dr. Robbins course next year you will talk about the management of the patient with hemophilia and with other bleeding disorders. Thats something we will leave for later but by them you will know what it is and youll have a foundation to build on. Interesting in hemophilia b/c this is not trivia. Its a clinical issue. There are a number of bleeding disorders in which you get petechiae. Youve been talking about those w/ Dr. Vernillo. In hemophilia you dont get petechiae. Can you figure out why? Its a bleeding disorder. Why would you not get it? What is the classic problem in which you get petechiae? Thrombocytopenia. In thrombocytopenia whats the problem? You dont have enough platelets. If you have damage to a vessel and you have platelets youre not going to have bleeding. If you dont have platelets and theres a little damage to a blood vessel you will have bleeding and youll get petechiae. In hemophilia the problem isnt petechiae, its a factor VIII deficiency, which is a clotting factor. Its a different mechanism for having a bleeding problem. Its an issue when youre doing oral surgery. You will not see petechiae and so is thrombocytopenia. If you want to look for the disorder, you need to do different test in order to do it. Those you will work with in systems pathology and a lot more w/ Dr. Robinson next year.

Slide 94 Autosomal Dominant DisordersDr. Phelan Im going to give you a list here. B/c were going to talk about these later but I really dont think you need to memorize the list this year. I want you to recognize how many of the autosomal dominant disorders that youre going to bump into as you move through oral pathology. Cyclic neutropenia is a problem where once a month the neutrophils disappear. You dont have any protection against bacterial infections when you dont have the neutrophils and then they come back up again. You see in cylic neutropenia usually the clue is when you have a child you begins to get severe periodontal disease. There are a number of other reasons for children to get periodontal disease but this is one of them. In order to make the diagnosis you have to do a CBC, a completely blood count. You do that on a regular basis. You do that every couple days to find the pattern and the decrease is about at about 28 days. There is a much rarer disease focal palmoplantar gingival hyperkeratosis where the kids get keratosis on their hands and palms and soles but they also get keratosis on their gingiva. There is something called Laband syndrome where these individuals get a gingival enlargement. WE have lots of reasons to get gingival enlargement so this goes on the differential diagnosis list. Theres another one called gingival fibromatosis and multiple hyaline fibromas and again these individuals get a lot of bumps that are a little bit different when you look under the microscope. Cherubim is unusual b/c these children get bilateral enlargement of usually their mandibles. Sometimes also the maxilla but usually its mandible. The description of cherubim is b/c these kids look like cherubs since they have fat faces. The enlargement resolves as the children grow up.

Slide 95- Continuation of past slideDr. Phelan Cleidocranial dysplasia, the classic pattern is a person w/ absent clavicles. This is one of the diagnosis for multiple impacted and supernumerary teeth. When we see a child or adult with multiple supernumerary impacted teeth this goes on the differential diagnosis list. Gardner Syndrome is an important one b/c these individuals develop polyps in the colon that will become malignant. They are pretty much programmed to maligenciey. They get osteomas in the jaws. They also get some cysts on the skins. The osteomas and the supernumerary teeth can be a clue to Gardner syndrome a very important syndrome, to identify b/c of the high risk of malignancy and adenocarcinoma of the colon. There is something called hereditary hemorrhagic telangiectasia. These individuals get telangiectasisas on the mucosa and the skin. A telangiectatc lesion looks like petechiae. If you use your loops or magnify it, you can actually see an enlargement of these tiny little capillaries where in petechiae youre looking at a bleeding spot, you cant see the tiny vessels. Here the vessels are enlarged and more prominent. I think we can describe it as hyperemia in those vessels that are close to the surface. Because of those vessels these individuals might have gingival bleeding. Theres something called multiple musical neuroma syndrome. These neuromas we might make the diagnosis in a child in the oral cavity and they are high risk for thyroid cancer. Almost 100%. Usually the thyroid is removed b/c its so certain that they will get a thyroid carcinoma. We might be responsible for the diagnosis by doing a good oral exam and then actually examining the nodules. Peutz-Jeghers syndrome is where patients get pigmented lesions around their mouth on the skin, and also intraorally. Their major problem is some benign intestinal polyps. There are some malignancies associated w/ this as well. The one you will know really well by the time you finish next year is something called basal cell nevus, jawbone cysts syndrome. I gave you this as an example of the syndrome that has 60-70 different components and not everybody in the family gets the same thing. What do we call that? Whats the name? Its other one. Variable expressivity. Thats the one were going to know best by the time youre done.

Slide 96- Teeth issuesDr. Phelan Amelogensis, Osteogenesis, Dentinogensis Imperfecta, Radicular Dentin Dysplasia. All of these are teeth problems and you will get to know those. You will have to know them by the time you finish next year. Pegged or absent maxillary lateral incisors is an autosomal dominant trait, thats the one the student did a pedigree on. It appears that mandibular and palatal tori follow in some families an autosomal inheritance pattern.

Slide 97 - RicketsDr. Phelan Then we have a bunch. You dont have to know those. Im giving them this year so you can recognize that the kind of patterns we were talking about will occur in patients that have head and neck manifestations of syndrome. The more careful you are at doing your exam the better youre going to pick them up. You are going to have to go through these at a later date, I just want you to know that this is something that youre going to have to know as you begin to work on your foundations for your dental career. There is an X-linked dominant disorder that has an oral facial dental disorder thats called hypophosphatemic vitamin D resistant rickets and this well talk about Vitamin D and its problems associated w/ Vitamin D deficiency next week. It looks like a vitamin D deficiency but you cant treat it with vitamin D. Vit. D. doesnt work. The patients are resistant to Vit. D. The reason we get into this story is b/c these patients have abnormal teeth. Usually patients w/ Vit. D deficiencies have some sort of problems but they usually dont have the same kind of dental sign as this where the teeth have large pulp horns. Theres a very high prevalence of periapical inflammatory disease. Either periapical granuloma like lesions or periapical cysts.

Slide 98 Autosomal Recessive DisordersDr. Phelan Then we got some autosomal recessive disorders. Were going to go through this a bit quickly. Papillon-Lefevere syndrome. The kids lose all their teeth. I remember working with one prosthodontics where the child would come in every year or 6 months to make new dentures b/c this child had no teeth and the teeth had been lost very early. As the jaws grew, the dentures no longer fit. In order to keep this little girl in teeth there was a constant remaking of dentures. Hypophosphatasia, here there is a decrease in serum alkaline phosphatase levels. Theres a change in the development of cemenutm. When we get to see these, the tooth is extracted and we get to process the tooth and actually look at a tooth that is missing the cementum. You will get to know the amelogenesis spectrum quite well. These are changes in enamel that you need to sort out as you look at teeth so that you can recognize the genetic enamel disorders and those that are environmental. A baby that has high fever early in development will have changes in the enamel but they will follow the pattern of what was developing at the time the teeth were developing or what part of the tooth. Something like we talked about congenital syphilis last time.

Slide 99 Developmental and Genetic Disorders. Dr. Phelan Thats covering the developmental disorders. I think I can finish early if we dont take a break. Ill leave it up to you. Do you need a break? Lets start again. The next section that were going to talk about are a group of chromosomal disorders.

Slide 100 Causes of birth defectsDr. Phelan If you look in the percentages that I gave you early on in the course, these are considered cytogenic diseases. They account for the highest percentages of the causes of birth defects that are on the list. Were still a pretty small percentage in that 4% compared to hereditary diseases and then compared to those for which we cant figure out the cause. Its very frustrating to not figure out the cause of something and slowly that number will change.

Slide 101 Chromosomal abnormalitiesDr. Phelan When we talk about chromosomal abnormalities, there are two categories. One is the structural abnormalities and the other is numerical abnormalities. They are all related b/c the structural abnormalities can end up causing the numerical abnormalities. In the structural abnormalities, you actually get changes in the individual chromosomes. In numerical abnormalities you have missing or more than the correct number of chromosomes.

Slide 102 Structural ChromosomesDr. Phelan - When we look at the chromosomal disorders if the structural chromosomal abnormalities that originate during gametogenesis are going to be transmitted to all the somatic cells of the offspring but they only are going to result in heritable diseases if the germ cells are effected. You can have chromosomal abnormalities that are inherited and that are. It fits in both categories. It depends in the very early stages of development. What cells being the problem. They are probably whats responsible for those spontaneous occurrences of genetic diseases. They may be responsible for many of our developmental diseases.

Slide 103 Cytogenetics Dr. Phelan The term cytogenetics is going to be something thats going to be familiar to some of you. Its the discipline thats concerned w/ the study of chromosomes and chromosomal abnormalities and cytogenic analysis has been traditionally performed only on dividing cells. Usually its circulating lymphocytes or buccal epithelial cells. From the study of the dividing cells you make a karyotype.

Slide 104 Human male karyotype Dr. Phelan Then you can study some of the components of the karyotype. At this point, the ability to study chromosomes has become incredibly complex and the genetic makeup is being studied almost entirely developed is the human genome. Were going to talk about pretty large chromosomal disorders. Were not getting into multiple of the much rarer genetic disorders. You will see that the identifying location, there is a system for identify where the abnormal location is on the system.

Slide 105 Female karyotypeDr. Phelan This, we talked about this before. This is a normal female karyotype and this was a normal male.

Slide 106 No titleDr. Phelan In identifying chromosomes there are three different categories that are used. Metacentric means that the pinch in the chromosome is in the middle. Sub metacentric means that its closer to one end than the other. Acrocentric, you only see one part of the chromosome. Its right at the end of the chromosome.

Slide 107 Chromosomal bandingDr. Phelan In order to do this kind of study there are special banding techniques/ staining in order to band the chromosomes. The chromosomes of each one of the paired chromosomes will be exactly the same.

Slide 97 Chromosomal banding pictureDr. Phelan This illustrates what kind of chromosome? Thats metacentric. This is the banding. It happens to be Chromosome 1. Its identified based on its metacentric appearance and also that the banding is exactly the same. Its not the only metacentric chromosome.

Slide 108 Structural abnormalitiesDr. Phelan There are a number of abnormalities that occur either during meiosis in gametogenesis or in mitosis when the somatic cells are dividing. If it occurs in gametogenesis in meiosis youre going to have an inherited disease but if it occurs in mitosis youre usually going to get a developmental disease if its a problem of significance that can affect the disease. There a number of changes or rearrangements that can occur to effect chromosomes.

Slide 109 Reciprocal TranslocationDr. Phelan In an individual, this one is called reciprocal translocation and these are cartoons of chromosomes. Here you break off a part of one chromosome and it attaches to another chromosome. This individual has all of the genetic material. Its probably not going to cause a problem in this individual. If this occurs in meiosis, than one of theses chromosomes have the wrong material so then you can end up w/ a potential for a developmental disorder b/c the chromosome is different. If you can pass the abnormal chromosome youd have the problem occur in meiosis. In mitosis youre looking at somatic cells and overtime you can also see the potential for a problem when these cells divide b/c they dont have the same material. Most of the time w/ reciprocal translocation in the first individual when its not inherited, the individual gets the right chromosomal and genetic material and you dont see it.

Slide 110 Robertsonian Translocation Dr. Phelan Another kind of chromosomal translocation is something called robertsonian translocation. You dont need to know these names. Whats happening here, when two chromosomes are dividing, instead of getting two identical chromosomes you get one chromosome that has some material from one and some material from another. For this one, some material is lost. Depending on what material this is you can end up having a developmental abnormality or even in meiosis in an inherited abnormality.

Slide 111 Chromosomal DeletionsDr. Phelan There are situations where part of the chromosome is deleted. It just disappears. The resulting chromosome is missing some genetic material.

Slide 112 Chromosomal InversionsDr. Phelan You can invert them. Most of the time, meiosis and mitosis work fine. You end up duplicating what youre supposed to duplicate; however, biology isnt always perfect and sometimes chromosomes dont divide the way they are supposed to. Thats how we get these chromosomal abnormalities. This one is called an inversion where theres a break in two different points in the chromosomal material and its flipped. Whether or not it causes a problem is if its occurring in mitosis or meiosis.

Slide 113 - Ring ChromosomesDr. Phelan Ring chromosomes have been identified and they are chromosomes were actually the two ends of the chromosomes join and this appears that this exists is normal and doesnt seem to cause (now idea what she says at the end).

Slide 114 - IsochromosomesDr. Phelan In an isochromosome, you get a faulty division at the centromere, the pinched placed. Instead of getting two equal chromosomes you get two unequal ones. All of those abnormalities, at this point what I want you to know from this, is that chromosomes do not always equally divide and by having problems in the way the chromosome material is distributed b/w the two chromosomes you can either have inherited disorders or somatic disorders. Please dont go memorizing everyone of these different kind of disorders. If we were doing a course in it, perhaps. What is most important here is that you recognize that in the dividing chromosomes there are abnormalities that will lead to developmental or genetic disorders. It depends on if occurs in gametogenesis and meiosis or in the somatic cells and in these cells you wont have an inherited disorder. You may have a developmental disorder, but youre not going to be able to pass that from one generation to the next.

Slide 115 Number of chromosomesDr. Phelan There are some terminology in chromosomes that for some of you will be very familiar. Haploid refers to a single set of each of the chromosomes that are characteristics of a species. Different species have different haploid numbers. In humans the haploid number is 23. Its half of the final complement of the chromosomes. Diploid is a double set, the normal in humans is 46. Most somatic cells in humans is 46. Euploid is a number thats not used often. Any multiple of haploid is euploid.

Slide 116 Number of chromosomes Dr. Phelan Aneuploid is karyotypes that are not exact multiples of the haploid number. Many cancer cells are anueploid.

Slide 117 - PictureDr. Phelan This picture is not in your handout b/c I added it afterwards. These are cancer cells. This was taken from a squamous cell carcinoma. These are very abnormal cells. You had histology and you know that your epithelial cells never looked like this in your histology course last year. If you look at this cell, what happened is that this is the chromatin and you have a dividing cell. A dividing cell is supposed to be bilaterally symmetrical b/c its dividing equally. This one theres tree. See it? Up here this one is dividing cell also, and the chromosomes are all lining up in the middle and were going to hope that it divides bilaterally sysmetrical. This one is an example of an aneuploid cell that happens to be something we see in cancer. Well talk about that more when we get to neoplasia in the course.

Slide 118 Numerical abnormalitiesDr. Phelan Most of the chromosomal abnormalities that occur form from something called nondisjunction. Nondisjunction means that the paired chromosomes or chromatids dont separate and move to the opposite poles of the spindle correctly. Most of the abnormalities happen b/c they dont divide the way they are supposed to. Nondisjunction during meiosis is going to occur more common in people that have structurally abnormal chromosomes. Before we looked at all of those potential structural abnormalities. If youre going to have nondisjunction during meiosis its usually in somebody that has gotten abnormal chromosomes. Children born to older women have more frequent chromosomal women than those to younger mothers. Its thought that over time, the chromosomal component of the ova goes through degernation that makes this possible.

Slide 119 Cytogenic TerminologyDr. Phelan There is some terminology and there is a very complex terminology that if you were going to be an expert in cytogenetics youd have to know the whole thing. We dont. You need to just understand at this point how the terminology goes. Youll see it very often when theres any discussion of genetic diseases or chromosomal abnormalities. Normal male is a 46, which refers to the number of chromosomes. There are two sex chromosomes and they are both X. A normal female is defined as 46XX. A normal male is 46XY. Thats the easy part. In trying to identify the location of chromosomal abnormalities, you first start w/ the number of chromosomes. If you go back and look at the karyotypes that I showed you each one of those pairs of chromosomes has a number. Then the short arm if there is one, is designated as p. The long arm is designated as q. From there the regions are numbered from the centromere outward. Youll see a genetic disease and youll see its p-whatever number. Itll be the chromosome 3 and p whatever number that is numbered from the centromere. Thats the way the chromosomes are actually mapped out. Theres something called a Philadelphia chromosome where theres a chromosome where theres a translocation you can actually see on one of the chromosomes. Theres a translocation b/w chromosome 9 & 22. Here were looking at the chromosome and this is the abnormality thats described. Here is the numerical ( you dont have to memorize this) thats associated w/ a CML. Almost all CMLs has this Philadelphia abnormality. All this is, please dont memorize this. You can know that the Philadelphia chromosome is a translocation related problem. Its associated w/ CML. I really dont expect you to learn that designation. I just want you to see how its used.

Slide 120 Examples Dr. Phelan These you do need to know though. These are relatively common. Theyre pretty easy to understand. There is one called Trisomy 21 and the other name for that is Down Syndrome. In a male what would you have would be 47 meaning there is one too many chromosome. This is the male designation. The sex chromosomes are fine, where is a problem? There is a plus 21, theres an extra chromosome 21. In a female, heres the abnormal number. The X chromosomes are fine and theres an addition of chromosome 21. Another one were going to talk about is Klienfelters syndrome. The problem here is that theres an abnormal number of Xs. This illustrates a problem that is hard to describe b/c its hard to believe. Most of us are mosaics. If you looked at every cell in our body they wouldnt look all the same. They have slightly different make-up and yet we come out ok. In Klinefelter syndrome some of the cells would look normal while other cells have too many X chromosomes. As a result of that abnormality in the chromosomal structure a very specific type of abnormality develops. A final one that I will use as an illustration is something called Turners syndrome. Here youre missing the second sex chromosome. Either X or Y but thats missing. That would be designated as one too few chromosome overall but you can see where the problem is when you see the missing chromosome is the X or Y chromosome. Whichever one is missing.

Slide 121 Trisomy 21Dr. Phelan Well start looking at Trisomy 21 or Downs Syndrome. The most common by far of the chromosomal disorders. It appears that maternal age is an important component for Down Syndrome. There are actually two different maternal age categories for Down syndrome. There are young women that bear children w/ Down Syndrome and usually there is a genetic predisposition to that and youll find that theres some family inheritance pattern. The other is trisomy 21 that occurs in older mothers. Thats more common. Whats the abnormality is/ starts it is that theres 3 copies of chromosome 21. By having the extra genetic material in somatic cell, the problem develops.

Slide 122 - Dr. Phelan - It appears that the problem is that there is nondisjunction during the first meiotic division. Early on in gametogenesis and you end up w/ an extra chromosome 21. Mosaicism which is hard to imagine that we dont have all exactly the same cell, we dont have them normally. Mosaicism isnt that are. It does cause a difficulty in understanding genetic diseases b/c its hard to understand that people can have more than one complement of chromosomes in different cells. Mosaicism would occurs when the nondisjunction occurred during meiosis of a somatic cell early on so youll have some cells that has the abnormality and some that dont. If it occurs in the ova or the sperm, it would be passed on through all of the cells. You wouldnt have some with the abnormality and some w/o. You have to get past that to have some cells w/ the abnormality and some cells that dont

Slide 123 - KaryotypeDr. Phelan Heres an example of a karyotype of trisomy 21. They are paired, they are all numbered. Heres chromosome 21. Thats what makes the abnormality. This would be a male w/ trisomy 21.

Slide 124 Picture Dr. Phelan There are a number of very classic features of trisomy 21 or Downs Syndrome. They are illustrated here for you. There is usually some mental/ developmental disorders involved. The front of the forehead is usually flatter than most other people. They have frequent congenital heart disease. They have a large colon leading to gastrointestinal problems. They have a change in the shape of the eyes. Ears are dysplastic. Every often have a fissured tongue, the tongue is large. One of the techniques used in small children w/ this syndrome is to try to get them to keep their tongue in their mouth. Its thought that maybe its enlarged b/c the tongue starts by being held outside the mouth. Outside of Downs Syndrome when youre making dentures for a patient that hasnt had teeth in years, whats happened is that the tongue filled the space. You do your beautiful dentures and the patient come s back and says I cant fit these teeth in my mouth b/c my tongue is too big. The patient has to wait until the tongue muscle b/c the muscle can enlarge and you have to wait until they get back to the place and fit in the mouth. Its thought that perhaps you can prevent some of the enlargement by keeping the tongue in the mouth as much as possible. The fissured tongue is very common. They have short broad hands and theres a crease different from our hand pattern. They are at increased risk at developing a certain kind of leukemia. Theres a change in the space or abnormality of the space b/w the toes.

Slide 125 - PictureDr. Phelan For the face there is a very distinctive facial characteristic. These patient of ours will have a very high palate. They are at a much higher risk of periodontal disease than of people of the same age. Slide 126 Klinefelter SyndromeDr. Phelan Thats Down Syndrome. You need to know that one. I didnt give you very many to learn but you need to know these b/c they each demonstrate something about cytogenetics. Klinefelter Syndrome is the one b/c there are too many Xs. The degree of the abnormality depends on the number of Xs there are. The more Xs the more abnormal. Apparently, the additional X chromosome arise as a result of mitotic disjunction during gametogenesis. Youre gaining it very early.

Slide 127 - Klinefelter SyndromeDr. Phelan If an individual has a Y chromosome that individual has male characteristics no mater how many X chromosomes he has. Sometimes I see some smiles. If there is a Y chromosome, the individual is male. Phenotype means what youre looking at. Phenotype can be everything from the way we look as an individual to a genetic phenotype to a molecular phenotype. Its what you can see in the package put together. Here the phenotype means this is what the person looks like. The more X chromosomes the more abnormal the individual will look.

Slide 128 - Klinefelter SyndromeDr. Phelan In Klinefelter Syndrome, Klinefelter Syndrome illustrates something that is an interesting concept in the area of genetics. That is something called the Barr body. The Barr body is something you see in cells when there is more than one X chromosome. Thats what the Barr body is. Women, in cells of women, you if you have a microscope that is powerful enough, you can find the Barr body. In the nucleus of the cell, the second X chromosome stays condense. In our lab, the cells that are usually easiest to find a Barr body is in smooth muscle cells. The body sits right at the tip of the nucleus. Cells of women normally have a Barr body. This condensation of the nucleus/ extra X chromosome, is an interesting phenomenon in how the process works. It has been thought that the chromatin that is condensed in women doesnt work. Its condense and it doesnt contribute to anything. Its just stuck there. We know now that it isnt true. There is some action of the chromatin and the genetic component of the Barr Body. For you right now, what you need to recognize is that the Barr body is the condensed X chromosome. Men w/ a normal chromosomal makeup will not have a Barr body. Klinefelter Syndrome there will be as many Barr bodies as there are extra X chromosomes. If you notice here, this individual is XXY. Theres only 1 X chromosome thats decided to be condensed but even though the extra X chromosome is condensed, the individual still has the syndrome. The concept that the Barr body is non-functioning chromatin, this is an example that this is not completely true. If that Barr body were noncontributing to the individual, it wouldnt make any difference and the condensed X chromosome wouldnt mean anything. Did I just make sense? Sometimes I get this and Ive been trying each year to make it clearer what that Barr body is. Its an interesting concept and if you want to read about it theres some interesting things. Here is an example of a cell w/ a Barr body. I wanted you to see the condensed chromatin in a cell.

Slide 129 Turner SyndromeDr. Phelan Then we have Turner Syndrome and in Turner Syndrome youre missing something here. What we have in Turner Syndrome, as I showed you before is 45X. What that means is that theres one missing chromosome and here its either an X or a Y but its missing. Theres only one sex chromosome. In Turner Syndrome the one chromosome present is the X chromosome. Do Turner Syndrome individuals have a Barr body? No why? There arent 2X chromosomes. The one has to function but the individual w/ one X chromosome has a set of abnormalities/ phenotype that is well described. of the cases the X chromosome appears to be the maternal chromosome. Most of the time, the problem is on the paternal side of the development of the individual. The chromosomal abnormalities that weve talked about before, are the kind that might lead to these abnormalities where the Y chromosome is missed.

Slide 130 - PictureDr. Phelan These are the characteristics of Turners Syndrome. Turners syndrome women are hard to recognize unless they tell you. Their phenotype is not distinctly abnormal. They are usually shorter and smaller. One abnormality that you might notice is that the neck is abnormal and is webbed. They have problems w/ their heart. They have poor breast development, they have a difference in the way their arms are developed. They only have rudimentary ovaries. They are sterile. They cannot produce children. They dont menstruate normally. On their skin the have multiple nevi. Benign tumors of melanocytes and youll need to know that later in the course.

Slide 131 - PictureDr. Phelan Heres an individual that illustrates the web neck of an individual w/ Turner Syndrome.

Slide 132 - Dr. Phelan Finally we get to this one which is much harder to define.

Slide 133 Multifactorial InheritanceDr. Phelan Thats the issue of multifactorial inheritance, this is the concept that describes why certain conditions run in families. Thats the way we describe it. There really isnt a clear inheritance pattern to the way the problem emerges. It appears that the problem is related to multiple genes and some kind of environmental factors that may enter the picture. Theres probably multiple genes and some of the factors that produce disease. The family aggregation doesnt follow the rules. We looked at autosomal dominant/ recessive and it doesnt follow the rules. Its clustered in families.

Slide 134 - Dr. Phelan Genetics as weve talked about before is the study of a single gene and their phenotypic effects. Genomics is the study of all the genes in the genome and their interactions. The attempts to look at multifactorial inheritance would fall into the area of genomics. Slide 135 Disease AssociatedDr. Phelan These are the classic ones that are seen to be associated w/ multifactorial inheritance. Clef lip and clef palate are part of some well established inherited disorders but we havent talked about those. Most of the time, they are spontaneous but they tend to be. This occurs more in some families and other families have one person w/ cleft lip/ palate while the rest of the family is fine. Type II diabetes mellitus is one of the best examples of this kind of inheritance. High blood pressure is another one that in some situation runs in families. Atherosclerosis is another one and schizophrenia. All of these have family clusters which suggest that there is a multifactorial inheritance involved.

Slide 136 Diabetes mellitusDr. Phelan Talking about diabetes, in monozygotic twins which are identical twins, theres a concordance rate of type II diabetes not type I of 35-60%. Not all identical twins equally develop type II diabetes mellitus. The possibility is quite high so it appears were looking at some kind of inheritance pattern that doesnt follow any of the patters that weve looked at it. In dizygotic twins its much lower. Thats those non-identical twins. The lifetime risk of children of parents w/ Type II diabetes is more than double if both parents have type II diabetes. There are health issues like obesity that are associated w/ type II diabetes. You recognize that there are environmental factors that are ongoing in this same story and how these environmental factors are related to obesity and the genetic factors that may put a person at an increased risk of type II diabetes are working together to make it much more difficult to follow the pattern. Some people who appear to be obese are not going to have a problem w/ diabetes and other people are. Youre going to find one family where its much more common to have diabetes even though theres a problem where you have another problem w/ this problem of obesity and nobody has diabetes. Again, its a multifactorial problem where you have a genetic component and an environmental component working together. There are in type 1 diabetes it works very differently. There are some links to MHC Class 1 and II. In type II theres no MLA/ MHC identified link yet.

Slide 137 - Dr. Phelan Were back to where we started in those conditions that are caused by the factors in the environment and I gave you some examples last time. W/ those environmental assaults on the developing fetus. You can have problems that we see in the phenotypes as that baby is born or as the individual grows up. On the other end, we have those genetic diseases that we know the inheritance pattern. In the middle we have those that are combined and are harder to tease out in terms of what the risk is and how great the risk is. And thats it.