General Pathology Transcriber: Laura Rayne 10/28/2008 54:08 Genetic Disorders I, Part I Slide 1: This should be real simple stuff. I just want you to know – if I am asked to write questions, I’m not going to make them horribly hard questions. So far I haven’t been invited to write questions but I’m not up here to overwhelm you or to make you feel like there’s no way you’re going to learn this stuff. I have talked at length with Dr. Waites about exactly what he wants you to learn and what he kept saying to me was basic principles and understanding processes of disease, understanding the difference between autosomal dominant and recessive disorders and understanding a bit about how these disorders work – the pathology of them. Slide 2: Traditionally defined, around 10% of the population will have some genetic disorders. Roughly around 1% of folks have an autosomal dominant disorder. But now if you look at people with all of the genetics testing that has been done, there are easily half of us, if not more, who have some type of genetic disorder or genetic predisposition to getting a disorder later in life, or to having it be expressed. The incidence will depend on the population you look at. If you look at embryos, fully have of them have a genetic disorder and they are spontaneously aborted. So over half of all pregnancies are spontaneously aborted. The late period is probably in most cases a spontaneous abortion. If you look at stillborns and fetuses, over a third of them will have some structural or genetic abnormality. If you look at newborns and any infant hospitalized, roughly 20% of them will have a genetic disorder. So it really depends upon your population. Slide 3: Basically, genetic disorders are “present at conception”. When you talk about congenital defects, you’re talking about something that is recognized at the time of birth, but that defect was present in the intrauterine life. In fact, it may have been present even as early as the embryonic period, depending on what it is. The other thing that is frustrating about many of these disorders is that the original descriptions were really done on live-born infants and/or children. So some of the features, for example nuchal translucency, which is a feature on ultrasonogram when there is an extra fold or some fluid that looks like it is collecting at the back of the neck – that is something that is now recognized as a feature for Down’s Syndrome and some other genetic disorders. So that would never have entered into the original description of Down’s Syndrome. The challenge you have now is to take these adult and older kid pictures and remember that they had their origins in fetal life. The other is that you will come upon testing now that is going to be available to babies before they are born. There are 3 different types that you probably will need to know about as a background: amniocentesis, chorionic villous sampling, and maternal blood sampling. When a woman is pregnant, at any one time there are little bits of cells from the placenta that are actually floating around in her circulation. They are little bits that have broken off and we would say they embolize. There are ways to capture those rare cells and to analyze them. That is called fetal cell trafficking. Slide 4: Most but not all structural abnormalities are due to genetic abnormalities, and an individual’s susceptibility to infections, allergies, unexpected reactions to drugs, and the risk for development of chronic disease. All of these are genetically determined for a large part. There is also mounting Microbiology: Introduction to DNA viruses pg. 2 Laura Rayne evidence that some of the conditions you get as an adult (some cardiovascular diseases and risk for renal failure for example) are related to unfriendly intrauterine environment, things that happened to you while your mom was pregnant, her blood pressure problems or something like that. So genetic disorders are more or less being blamed on your mom. Slide 5: So what is amniocentesis? I have this picture because I want you to have an idea of where it is you’re starting from. This is an in situ picture in a uterusof a little tiny embryo at about 7 weeks of development. You’ll notice around it is a little layer of tree-like tissue that is going to become the placenta that will support this baby as it grows (middle left picture I think). This is the chorionic villus, what the placenta is made of. It is these little stalks with blood vessels in them and they go out and invade into mom’s tissue and blood space. Basically it becomes a lake of blood that this tree is suspended in over time. But early on, at 7 weeks or so, geneticists can sample this tissue. This is called chorionic villous sampling and this is what it actually looks like (bottom left picture). It is like a little fuzzy tennis ball and as development goes, this is first trimester. So you are all the way into your first trimester. You start out as a little tiny embryo and by the end of the 8th week, you have everything you are going to get, and from that point forward it is going to be more developed. All of your equipment has to be present by the 8th week. As the baby is sitting in this little bag, this is the bag of waters (bottom middle picture), that bag of waters grows and expands as does the baby inside. As that bag expands, by about the 18th week of development, there is enough fluid in there to sample so that is where amniotic fluid sampling comes from. Slide 6: So amniocentesis is a technique in which you can harvest cells. The baby is actually shedding some skin cells and there are some cells that are floating that live on the surface of the placenta that coat the cord that attaches the baby to the placenta. They are floating in this fluid and you can aspirate some of these cells out, centrifuge them down, collect them and put them on a culture plate, culture them, and analyze their genetic makeup. That is a very standard technique. Slide 7: If you look at the importance of intrauterine environment, you will see there is a list of disorders here that are classic multifactorial disorders. In other words, they are a combination of many genes that can bring about these problems, as well as your environment. But if you look at the ones that are starred, these have all now been associated with adverse conditions in intrauterine environment. For example, the susceptibility in individuals to getting hypertension or chronic renal disease are related to the intrauterine environment. We’re going to concentrate on the genetic material that is in the cell nucleus. There is another source of genetic material in our cytoplasm in our mitochondria. The mitochondria has its own little DNA. There are a whole bunch of mitochondrial disorders. Most of them are neurodegenerative disorders. We’re not going to talk about mitochondrial disorders, which are inherited from the mom. Slide 8: First we’re going to talk about some basic concepts. What are structural abnormalities? How are they classified? Then we’ll go through some of the specific disorders. Microbiology: Introduction to DNA viruses pg. 3 Laura Rayne Slide 9: A malformation means that the tissue that made that site or organ is by definition intrinsically abnormal. When it tries to make something like your heart or thumb or nose, it is intrinsically abnormal and it results in a malformation, a structural abnormality. What the word atavistic means is that it is a developmental process that is present throughout development in the embryo. In other words, it is a normal process of development that goes awry. Here is a meningomyelocoel, a big cleft in the baby’s spinal cord, the neural tube defect. Here is cleft palate, a malformation. The tissue that was supposed to close and make that palate fuse either didn’t move correctly or there was insufficient tissue. A deformation is something that started off just fine but then had some kind of extrinsic compression phenomenon going on. The classic example of that is oligohydramnios sequence. I showed you that bag of waters and said that the baby is floating in this amniotic fluid. There is an optimal amount of that fluid. If there is too little fluid, the bag of waters (the bag in particular) comes down and sits on top of the baby and restricts its movements. It is sort of like being wrapped in saran wrap. So, oligo means few, hydramnios means water. Too little amniotic fluid in the sack results in deformations. The baby itself was doing just fine, except when this other thing happened (too little fluid), the baby became deformed and ended up crouched up with a flat face and these big pouches under his eyes. Slide 10: Deformations can exist with malformations. So if you have a malformation, you will have a structural abnormality in an organ and adjacent tissue may be pushed away out of its normal place. This is an example of that. This is a malformation (I think she meant deformation) that is due to a malformation of the lung. The lungs are buds off the esophagus in early ambryogenesis and they take form and bifurcate and you get two lungs. You have a common pharynx and then you’ve got your trachea and your esophagus. That branch point is where those lungs bud from. That is a normal process. However, in some cases the esophagus either buds an extra branch or sometimes it is so far down that it is way at the distal esophagus like is pictured here (picture on the right). Instead of being fed by pulmonary arteries, or arteries coming out of the heart and going to the lungs, this branch of lung has no airway and has its blood supply from the aorta. It is a malformation. It continues to grow and produce lung fluid and makes airspaces. That thing expands and the heart is squished and pushed over, and the other lungs in there developing can’t quite do it. Here is an example. Here is the descending aorta with the blood supply coming straight off the aorta and this huge lung thing. Here is this poor little left lobe of the lung and the heart is shoved over to the side (middle picture). Slide 11: Dysplasia means that you have an abnormality of the tissue that results in its abnormal organization or formation. Usually it is an abnormality that is not confined to a single organ. It is usually a systemic problem because the intrinsic abnormality is something in say the collagen formation. So if you have a dysplasia of collagen you may have osteogenesis imperfecta, you might have Ehlers-Danlos. It is not a single site in your body. Microbiology: Introduction to DNA viruses pg. 4 Laura Rayne Slide 12: Anomaly is just a structural external or internal abnormality. There are minor and major ones. Major ones are usually life-threatening. A minor one might be your little finger is a little malformed. It doesn’t actually interfere with your life. Major abnormalities would be like having a cardiac defect. The minor abnormalities however may be clues to a genetic syndrome and that is why they are worth knowing about. The word agenesis means you didn’t ever have it. It never developed. Whatever part of the primordium was supposed to be there was not there. Sometimes there are developmental areas in the body that act in concert. For example, the midline of your thoracic cavity is a developmental field. It has a heart growing in it, lungs growing in it, a pericardium, a pleural space, it has ribs that have to come around. That is a developmental field. Slide 13: Sequence – I showed you a picture of a baby who was all deformed because of oligohydramnios. The picture of that baby is going to be fairly uniform. An oligohydramnios fetus is going to have arthroglyposis, or contractures. It is going to have kind of a flat face. It may have hip rotation abnormalities. It may have flecture of the extremities. But it won’t tell you why there was too little amniotic fluid. The term sequence means there is a pattern of abnormalities that are common to see and they may or may not have the same cause. For example, if the baby has no kidneys (renal agenesis), the baby is not going to be producing any urine. Urine is a major component of amniotic fluid in the second half of gestation. So in the first half of gestation that water bag is filled because mom is doing her part, but as the baby is supposed to take over with urine output, that bag gets crunched down. So the baby has no kidneys and no urine output so you have oligohydramnios. How about if the baby has kidneys but they are cystic and don’t function correctly. It is not renal agenesis but a malformation and you still have the same outcome. The sequence is sort of a pattern of abnormalities. A syndrome is where there are many abnormalities that are thought to be pathogenetically related, but you can’t look at them and say I think the problem started here and you go this series. They are a predictable constellation of abnormalities, but you can’t necessarily say that is the inciting incident. Down’s Syndrome (having an extra copy of chromosome 21) is a syndrome because individuals with Down’s Syndrome tend to look like each other, tend to have similar abnormalities, but the problem is even though we know it is an extra copy of 21’s material, we don’t know exactly why every kid doesn’t have exactly the same abnormalities. So it is a syndrome because it is a constellation of similar things that we think we can explain, but it is not a series of patterned events. An association. There are some abnormalities that occur more frequently than would be expected just by chance alone, but the cause of them is not necessarily known. They are not necessarily due to an extra copy of a chromosome, but they are believed to be developmentally related as a cluster of abnormalities that occur very early in embryogenesis, known as blastogenesis. Blastogenesis is the first 4 weeks of development. Abnormalities that occur very early on give rise to associations. Slide 14: VACTERL is an acronym for a baby or an individual who has an increased likelihood of having vertebral anomalies, anal atresia, cardiac anomalies, a fistula between the trachea and esophagus, renal abnormalities, limb abnormalities, and only one umbilical artery. Do you have to know what VACTERL Microbiology: Introduction to DNA viruses pg. 5 Laura Rayne is? No. Am I going to ask you a question “What is VACTERL?” No. What I’m trying to do is show you that it is an association of abnormalities that have a tendency to occur together. Every single one of those abnormalities is a midline abnormality Slide 15: Skipped Slide 16: This baby here has oligohydramnios sequence because in this particular case of VACTERL this baby had no kidneys. So what have we said about no kidneys? No urine and no amniotic fluid so this kid has a deformation. He has facial features that make him look like the other kid, except the reason is completely different Slide 17: Now we’re going to talk about chromosomal abnormalities. When genetics people talk about abnormalities, they try to determine if it is a malformation, a deformation, a dysplasia, an association, or a syndrome, and if there is a way to find the cause. Those terms have implications for recurrence risks and they have implications for treatment of the patient. There are chromosomal abnormalities. They occur in live born infants and in still births, but in this case we are all going to talk about live born babies. Trisomies. So there are two types of chromosomes that we have – autosomes (1-22) and gonosomes, or sex chromosomes, which are X and Y. Trisomy is usually an extra copy of one of those chromosomes, either the whole one or at least just most of the functional part. There are 3 of them that occur commonly enough to end up in textbooks. Trisomy 18s and trisomy 13s usually don’t live very long. Translocations mean that there are a normal number of chromosomes, except that a piece of one is stuck onto another one and vice versa, so you have swapped parts. Numerically you may be normal, but you have misalignment of some of your material. If it is balanced, that means that those parts have exchanged places reasonably completely. If it is unbalanced, that means that in the process of swapping parts somebody huge fell off and some of the material is still missing. Also, while balanced translocations look balanced when you do a Giemsa banding pattern, every time you have swapping you lose a tiny bit of material. So even though they look balanced, if we did some analysis we would probably find that there are a few things missing. That is a term that was developed when we were limited to Giemsa banding. Triploidy. I’m not going to show you it because you won’t see it. It is almost always spontaneously aborted. Triploidy means an extra copy of everything. More is not necessarily better. What we’re going to concentrate on is trisomy 21 and monosomy X and I will show you Klinefelter’s which is another sex chromosomal abnormality. Slide 18: I want you to learn the main features of these syndromes, but keep in mind that Dr. Waites doesn’t want you to go crazy learning Edward’s and Patel’s, he wants you to know Down’s and Turner. In prior years, I showed pictures of all these so I condensed this so it’s meaningful to you. Microbiology: Introduction to DNA viruses pg. 6 Laura Rayne Slide 19: Trisomy means there’s an extra copy of genetic material somewhere, Aneuploid means abnormal number so trisomies are an abnormal number; you’ve got an extra copy of material from 1 chromosome or the whole chromosome itself, that’s abnormal. Slide 20: Down’s Syndrome. What are the main features of Down’s syndrome? Down’s syndrome’s main phenotypical appearance are characteristic. You may have a child with Down’s from native American, Asian, from UK etc. , but all with look more like each other than they do their parents. They will all have typical features like up slanting palpebral fissures, these used to be called anti-mongoloid slant, but don’t use that anymore. They will have a single palmar crease that used to be called a Simian crease but also that term is no longer used. Epicampal fold is an additional portion of tissue on the inner aspect of the eye, the inner campus. Clinodactyly, that’s where the little finger turns in because there’s deficiency in the middle phalanx, and so the tip of the finger becomes abnormally positioned on this proximal phalanx. Clinodactyly in itself is not necessarily bad, she has a surgeon friend who has bilateral clinodactyly, but he’s not even a mosaic nor does he have Down’s. Down’s also have wide spaces between their first and second toes. Also have very low set ears, so draw line from lateral campus and should contact at least the top of the ear. Low set ear means it’s below that point. Down’s babies have low set and malformed ears. Slide 21: Here’s Giemsa banding. See extra copy of 21, 22 and 2 gonosomes, so this should be a 46 XX individual because there’s no Y. 22 autosomes and the two sex chromosomes. Slide 22: Around 90% of people with Down’s syndrome have a whole extra chromosome 21; there are times where there is a translocation. 21 doesn’t have much of a short arm, most is long arm (Q arm). 21 is already small to start with, and so it’s not uncommon for this little bit to be translocated to 14 or 22. About 1% of Down’s kids are mosaics, so part of their genetic makeup is normal so 46 XX and part is 47 XX +21. They have dual cell populations. Keep in mind that most of these genetic disorders die in utero, so less than 30% of full trisomies make it to birth. Features: short stature, hypotonia. Hypotonia means that your GI tract doesn’t work well. They can’t swallow very well so keep in mind when drilling. It also means that their tongue hangs out, because they lack the capacity to keep it in their mouth. Mental retardation is fairly commonly known, get central obesity in the back, and tend to have very flat back of heads (occipital flattening). Small heads, epicampal folds and predisposition to getting infections, particularly upper respiratory tract infections. They have a flattened face, nasal bridge. So get upper respiratory tract infections very easily. Slide 23: About 40% of them have a significant cardiac abnormality, a huge hole in their heart. This is how most of them look. You don’t see these because they are aborted, but a trisomy 21 fetus is usually terribly abnormal looking, this one looks like a balloon, from a huge collection of fluid. Slide 24: So the cardiac defect. Why do I bring that up? In dentistry, need to know about cardiac defects because when you are jiggling around in their gingiva, (according to wikipedia this is the most current term the majority of periodontist use instead of scaling and planing) you’re going to seed their mouths and therefore their blood with bacteria, and they do extremely well on abnormal heart valves. They love it there because there is turbulence there because the valves do not function properly. With Microbiology: Introduction to DNA viruses pg. 7 Laura Rayne turbulence comes thrombosis and fibrin deposits, which is fabulous food for bugs. They live there and destroy the valves. This process is called bacterial endocarditis. You want to avoid this complication for your patients, so with Down’s’s patients 40% of them have a huge hole in their heart called a complete atrio-ventricular valve defect. 40% have cardiac defect and 40% of those patients have this. If you look at a normal heart, there are 2 atria and 2 ventricles. The right atrium goes to right ventricle and goes to lungs, then back to the left atrium and left ventricle and goes out the aorta. This keeps your oxygenated and deoxygenated blood separate, this is important. In Down’s you don’t have a nice closure between the 2 atria and 2 ventricles. This part of the heart is open, it’s a developmental arrest. They don’t get the rest of their division, so their atria don’t separate completely and same thing with ventricles, so blood goes everywhere when heart pumps. This is a picture of a heart where you see a huge common valve instead of separate valves. No separation so can go straight from right to left and vice versa and can jump across ventricles to. You re looking at the crest of the septum right here and the valves are incomplete. Slide 25: As I’ve said, valvular defects are associated with fibrin deposition, turbulence, dysfunction, not closing efficiently, gets hypooxygenated, they’re cyanotic. You have mixing of oxygenated and not oxygenated blood between right and left side of heart and because you have this big hole in your heart, the left ventricle is also supplying blood to your lungs at a much higher pressure than lungs are used to, which gives rise to pulmonary hypertension and lungs can’t function. Big problem for us is high endocarditis risk. Slide 26: Other features of babies with Down’s syndrome. We’ve already discussed antibiotic therapy with cardiac defects, they tend to have hypoplastic teeth, periodontal disease, they are hypotonic (GI tract doesn’t work well) cant swallow that well. They have hypoplasia of the frontal sinuses and get infections from that. They have a short hard palate and protruding tongue due to hypotonia, and tend to have frequent middle ear infections. With ocular they have inner campal folds, brushfield spots (on step 1 of boards because easy to make questions on). They are tiny white spots on periphery of patients iris, very characteristic of Down’s. They are tiny foci of incomplete development, so peripheral hypoplasia of the iris, so if the dots totally coalesce you have peripheral hypoplasia of the iris. Lensopathy that you see with slit lamp exams. They are very myopic and need glasses early on. They tend to have disconjugate gaze (failure of the eyes to turn in the same direction together), nastagmus (flickering of the eyes when moving far to the side), stribismus (squints or eye turn), and tend to get blockage of lacrimal ducts. Slide 27: Next we’re going to do Turner’s syndrome. Down’s was an extra copy of 21 in most cases or a translocation. Turner’s in when you’re missing one X, so have monosomy X. Phenotypically look like a female, but with one X. look down here on the genetic map and see nothing in second spot. Phenotypic features: mental retardation, very broad neck (webbed neck), with webbed neck comes a mal position and formation of the ears (large and low set). Have large space between inner campi (wide set eyes) and tend to be truly hyperteloric (large distance between eyes) and tend to have broad chest so nipples are facing sides almost. Slide 28: So monosomy X. The likelihood of a patient being completely monosomy X is remote because Microbiology: Introduction to DNA viruses pg. 8 Laura Rayne the X has a lot of info on it and when you are completely missing one, you have an imbalance in function. 95% of these babies are spontaneously aborted so patient with Turner’s is probably a mosaic somewhere but it just hasn’t been picked up yet. Features: short stature, infertility, the ovaries start out losing egg number, may be mildly retarded and may have abnormalities, particularly webbed neck. Hypertelorism, inner campal folds, acute aclasis (relaxed skin stretchy skin basically at nape of neck). Slide 29: What is it? Here is a spontaneously aborted monosomy X. this has a huge thing called a Nuchal Hygroma, a big bubble on the back of head, fluid filled soft tissue. In development, in a baby that’ll survive with Turner’s that fluid becomes partially reabsorbed, but the overlying skin has been stretched out that leaves webbing when the baby is born. This webbing stays because it’s skin that can’t come back to itself. So fluid is gone but saggy stuff left over. That same fluid interferes with the hairline formation. Babies that are spontaneously aborted and survivors are high risk for a congenital heart defect called, coarctation of the aorta. This means there is a narrowing in the aortic arch. Usually the aorta goes out of heart to the left, gives off three branches that go to head and arms, and continues down to rest of body. This is narrowing in the turn of the aorta Slide 30: A baby with Turner’s syndrome. If we go back and look at this one you can see all the fluid accumulation, not only in the neck but also in the soft tissues, hands and feet. For babes who make it with Turner’s, they have persistence of puffiness of hands and dorsal aspects of feet, and abnormal hairline due to webbing of neck and also persistence of ear abnormalities. Same chest edema keeps nipples from approaching the right place. Slide 31: Basically all of what a Turner’s baby has in some form is explainable by this huge collection of fluid they have during development. Slide 32: Klinefelter’s syndrome. This is an extra copy of an X chromosome in a male. So normal male is 46 XY and Klinefelter’s is 47 XXY. These patients don’t have specific features that we need to know for eyes and teeth, but you may treat one because they have a good lifespan and they tend to be mildly retarded, also have attention deficit kinds of problems. If taking care of Klinefelter’s patient you may have to do different explanations because they won’t have normal social skills. Their risk for germ cell tumors of the mediastinum, basically this means they can get malignant tumors developing in their chest. Slide 33: Skipped. “We’ve gone through that stuff” Slide 34: So now we’re on to the autosomal dominant and recessive and X linked disorders. These are now normal chromosome number, just bad material on it. Everything we’ve done so far in the aneuploidies is abnormal numbers now we’ve got presumably normal numbers just bad info. Slide 35: There are several types but autosomal dominants are most important to understand what’s going on, we’ll see these patients because most of them live to adulthood. Autosomal dominant traits Microbiology: Introduction to DNA viruses pg. 9 Laura Rayne mean that if you have 2 chromosomes, you only need 1 copy of the gene to be expressed. Height, for example, is one of those features, so tall and short person have kid, the kid will be taller than the short person because it’s a dominant gene. So one copy is only needed for expression. Doesn’t matter if you’re male or female, passed on equally. If you have an autosomal dominant disorder, that means each time you have kid, one gene will have bad material, even if person is normal, 50% of combinations will have bad genetic material in kids. Four fingers held up. Two are normal and index finger abnormal, send down egg with only 1 copy of DNA, so have 2 out of 4 chances to be ok and same for sending bad material. Usually effected individuals have an effected parent, makes sense because it’s a dominant disorder. What if you have a dominant disorder and none of your parents have it? You have 5 siblings and you’re the only one that has it, then you had a mutation and none of your siblings did. But if a few of the siblings did have it, then there was a mutation in the germline (in egg or sperm) of one of your parents. Slide 36: Skipped Slide 37: There are many autosomal dominant disorders. Huntington’s disease, a neuro degenerative disease due to nuclear DNA not mitochondrial DNA like most neuro disorders. Miltonic dystrophy is one, tuberous sclerosis we’ll talk about. The starred ones we’ll talk about or is in a lab, like polycystic kidney disease lab. Slide 38: I’m going to talk about a couple of autosomal dominant disorders. There are 2 main ones that the mutation results in a predilection for getting tumor like growths. They are neurofibromatosis and tuberous sclerosis complex. They both have very different phenotypes but what they have in common is a mutation in a gene that normally suppresses cell replication or tumor production. So you’d be at risk for having tumor like growths. Then there are ones with a mutation involving some structure in the extra cellular matrix (basically connective tissue). We’ve talked about dysplasia, intrinsically abnormal tissue that causes thing to be disorganized elsewhere. This happens in many of the collagen disorders. 2 important ones for us, osteogenesis imperfecta and ehlers-danlos. The third one is a malformation of fibrilin, which is involved Marfan’s Slide 39: First we’re going to talk about Neurofibromatosis, but first let’s take a break.