Transcribed by Vandeep Bagga

March 31, 2014

Craniofacial Biology Lecture 13 Principles of Teratology by Dr. Wishe Slide 1 Teratology Dr. Wishe Slide 2 Critical Periods Dr. Wishe *clears throat* Mmmmmmmm. Okay, we might as well continue. The one thing I did mention, Ill reiterate, is that the smooth muscle and cardiac muscle is not derived from your lateral plate mesoderm, the somatic layer, it is derived, however, from the inner visceral or splanchnic layer of the lateral plate mesoderm. And the head musculature really for the most part comes from the paraxial mesoderm. So a lot of the musculature, well actually the musculature has 2 sources, one is the myotome and the other one is the paraxial mesoderm. Now were into teratology, and anything that ends in -ology means study of. Study of teratogens. And teratogens are substances, chemicals, environmental, what have you, that cause anomalies ahhh, good morning! She was buried in her coat, couldnt see her face Anomalies, malformations, birth defects, they all mean the same things. And these could be structural level, behavioral level, functional level. And no matter how you look at it, its an abnormal development. The susceptibility of a child to come down with these malformations depends upon the genotype of the mother, and the child thats forming. If the mother has a very good resistance to medications, drug metabolism, etc, then there's a good chance the child will have it, and will feel less of an effect in terms of malformations. So genetic makeup of mother and child are important. What's also important is the teratogenic agent, the number of doses, the length of exposure to the agent and the resistance. Keep in mind that young embryonic tissues are very susceptible to damage. You look at them the wrong way, something goes wrong. The susceptibility period for the most part, for major malformations, are going to be weeks whoops didnt want to do that weeks 3 through 8, and thats known as the embryonic period. Weeks 1 and 2 as it says here, you're having mitosis occurring, implantation, and in the second week, you get the formation of your bilaminar germ disk. And usually susceptibility to teratogens does not exist or if it does, you have some minor defects occurring but since its young individual is developing, it can overcome these defects. Or the embryo just plain dies. But it is weeks 3 through 8 that are pretty critical. And you just follow across, youll see this is where most of the major morphological abnormalities start. So in the formation of the CNS, thats started in week 3, that was your neural tube formation, and so weeks 3 through 6 are especially critical. The heart starts developing around the same time, somewhere in the mid 3 week and starts off as a pericardial bulge. And then again through week 6 is a problem in terms of malformations. The arms, the eyes, and the legs, start off approximately week 4 development and it goes weeks 4 through roughly week 8, those are critical. The formation of the palate starts off forming much later on, but there's a critical period within this embryonic period as well, and notice that the ears form earlier than the eyes and the formation of the ear extends a little further into literally the beginning of the fetal period. So this just shows you a time table, and its showing you what is forming at that particular time. Now teratogens act in a specific way, on different 1

Transcribed by Vandeep Bagga

March 31, 2014

cells and tissues and if you have abnormal development during this embryonic period, you cant correct it. What youre born with, youre stuck with. In terms of major structural anomalies, and that what we looked at when I gave you examples actually, this occurs in about 3% of live born infants. However, go another 2 years or so, or maybe age 5, youre going to get another 3% of the population showing abnormalities. And that refers really to things like your teeth and your palate, because they start much later on in development. So you can roughly say about 6% of the infants that are born will have some sort of major structural anomaly. There are minor anomalies as well, that occurs in about 15% of the population of newborns. A minor anomaly could be a small ear, a little notch in the ear, a cleft lip, things like this can be corrected. But minor anomalies are also associated with major anomalies. So if you have 1 minor anomaly or abnormality, there's a 3% chance that its going to be associated with a major. If you have 2 minor abnormalities or anomalies the percentage increases, becomes 10% of being associated with a major abnormality. And then if you have 3 or more minor anomaly, there's a 20% of those minor anomalies being associated with a major. Slide 3 Birth Defects Dr. Wishe this is essentially showing you a curve comparing increasing risks with weeks of gestation, and you have the embryonic and fetal period outline. And there's where birth occurs. So initially you are starting off with either death or no major thing occurring. But starting with week 3, it slowly but surely escalates to around week 5, where you have the greatest risk of something wrong happening. And then it starts to gradually decrease, so by the time you get to week 8, this is still a pretty large risk of coming down with something abnormal, but not like in week 5. And then as we enter the fetal period, the risk of birth defects slowly but surely decrease. Now things that happen during the fetal period could be correctable. But things that happen during the embryonic period cannot. And along those lines, we have different categories. So thats what I want to talk about now. First we have the malformations, these are major birth defects, and they occur during the embryonic period. This is when your major body plan is being developed. This is when architecture comes in, youre constructing you're house, where the living room is, where the bedroom is, etc, thats whats being done to you, where the different parts of the body should be located. And so you can have anomalies ranging from complete absence to missing parts of something, this can be caused via genetics, it can be caused by environment agents. And theyre non correctable. Disruptions is another category. And here's where you have an alteration of the structure that is already formed due to something happening internally. You might have a vascular accident, a hemorrhage, a clotting, and that interrupts the normal flow of events, as a result something is going to happen, it can be correctable if the blood clot disappears and you return to a normal state. But if it doesnt, then you have a problem. And these things are not caused by genetics, but rather by exposure to environmental agents, whether its drugs, viruses, etc. And a common example of that is the formation of amniotic rings. And Ill show you pictures of that momentarily. Deformations, this is caused by unusual mechanical forces, placed upon the developing child and this can lead to all sorts of things. Lets say there is a 2

Transcribed by Vandeep Bagga

March 31, 2014

decrease in the amniotic fluid, for instance, and as a result, one limb comes to rest up against another limb, and the positioning of the limbs changes. So thats going to cause some sort of abnormality. If the fluid increases in size and the limbs separate, the condition is reversible. Another common scenario as youll see people with clubbed feet, 1 foot is shorter than the other, and you look at their shoes, the shorter foot has a very thick sole. And that came about by some sort of pressure placed upon that foot during the developmental period. And now everything starts off normal, but then it changes. But again if the pressure is reduces, you can get problems reversed or corrected. Then we have things like dysplasia, which well deal with in pathology, and this is an abnormal organization or formation of cells into tissues. So you get abnormal tissue formation. And this can effect organ development seriously. Then we spoke about syndromes and sequences. And whether someone uses syndrome or sequence depends on how they feel about it, you look at different textbooks, the terms are mixed up. So the first thing we really discussed was Treacher Collins Syndrome. That is definitely a syndrome where you have a homogeneous complex of events all happening at the same time. And the most common example Treacher Collins is not necessarily so bad is Downs Syndrome. And when you look at anybody with Downs syndrome, you recognize it immediately by just looking at the face. And thats not a sequence of events. Treacher Collins is where you have underdevelopment of the mandible, the maxilla, the zyogmatic bone, we spoke about that in a previous lecture, because I said that thats not as complex or bad a defect as these other things. And a person can exist, doesnt necessarily involve mental retardation. The sequences or scenarios where 1 effect occurs first, that leads to a 2nd effect and that leads to a 3rd effect, and thats why I gave you the example of bowling, knocking 1 pin down causing other pins to fall, etc. And I used Robins sequence and I was just informed that Dr. Saint Jeannet used Robins syndrome. Neither 1 of us are going to ask you really are these sequences or syndromes, but be prepared on an example to see Robins Sequence or Robins Syndrome. Depends on who made the question. Realized that theyre being used interchangeably in that case. And that also leads to underdevelopment of your mandible, and once the mandible is underdeveloped, and depending how much underdeveloped, youre tongue doesnt form properly, it forms more posteriorly, and it possible blocks the respiratory passages. Then we spoke about DiGeorge Sequence. I'm sure some people call it a syndrome. For the most part, these are genetic in nature, although they can be caused by environmental agents as well. And DiGeorge is a pretty serious type of abnormality because you are effecting the formation of the thymus gland and the parathyroid gland. The thymus involves immunology of the body, youre protective feature, protecting you against certain germs. Parathyroid gland doesnt have anything to do with immunology, but it does have to do with bone formation. So in an individual who has DiGeorge sequence or syndrome, you're getting 2 major effects, the immune system of the body and the formation of the bone. And you get other defects dealing with the eyes, the ears, and even the palate.

Transcribed by Vandeep Bagga

March 31, 2014

Slide 4 Congenital Malformation Causes Dr. Wishe This is a table which shows you congenital malformation causes. And lets just look at the numbers. Chromosomal aberrations, Mendelian inheritance, this is all genetic. So if you take the 2 high points, this could account for about 25% of malformations based on a genetic basis. And then if you add up, 3, 8, 11, 12, 13 percent, those could be environmental in nature. So 13 and 25 comes out to about 38% and youll notice this multifactorial, which means a combination of genetic and environmental, so when all else is done, if we have 40% accounted for in terms of defects, what about the other 60%? These are unknown causes. So most of the causes of malformations we just dont know what they really are. Slide 5 Amniotic Band Syndrome Dr. Wishe now here's an example of youre amniotic band syndrome, and this is an older edition. You can see the child developing, here's the head, here's you're superior and inferior extremity. But look right over here, there seems to be a string like structure wrapping around the thigh. And here's a string like structure also, these are folds of the amnion forming bands. And it looks like something is happening down here as well. So if you take an area, literally tie it off, you strangulate the area, it doesnt get its full blood supply and eventually the tissues die. So amniotic band syndrome could lead to amputations while the child is actually developing. Slide 6 Amniotic Bands: Limb Dr. Wishe here's another case. Very possible that right over here there was an amniotic band and the rest of the leg just disappeared. It got amputated. Its hard to see what's happening in this leg, but if you look at a side view, you can see right over there, that there's some sort of constriction, probably from an amniotic band. These things can also, by the way, be caused by vascular accidents. Slide 7 Disruptions/Vascular Abnormalities Dr. Wishe and so this picture shows you what we just saw, disruptions, vascular abnormalities, amniotic bands, they're all disruptions in the normal formation. So the limbs started to develop, they were well on there way, and then something unusual happened. Slide 8 Digit Amputations Dr. Wishe Here we have a case of digit amputations, could be an amniotic band wrapped around it, maybe there was a vascular problem. If you look here, these 2 look like normal digits, these 3 dont. and here we seem to have an alternation, normal, abnormal, normal, abnormal. Same thing here. 2 normal, these are abnormal. Its hard to see what's going on in this picture. Slide 9 Amniotic Band Defects Dr. Wishe now as you look at the middle picture, B, there seems to some sort of crease happening in here, probably amniotic band wrapped around it, and then you look at just before the digits, there's an abnormal crease as well, and here the hand 4

Transcribed by Vandeep Bagga

March 31, 2014

is being pinpointed, so there are abnormal creases, not only before the digits, but in the digits as well. So you know these 3 have had some sort of amputation and these probably are not fully developed. And in this particular child were interested in amniotic band defects, but, lets look at a A. What do we have here? This is a complete cleft lip. You can see the tongue in the back. And the nose is deformed. And I dont know is just the picture, but it looks like this eye is clouded over. So there's several things that are playing a role in terms of development in this child. Slide 10 Abnormal Leg Positions Dr. Wishe now here's the other example where pressure was placed upon the individual, whether it was actually loss of amniotic fluid, or whatever have you here, notice the position of the legs, this is not normal. Look at this one. It is completely bent up. And this position is not normal. So as a result, because of the pressure from this leg on this foot, same thing sort of happening down here, but the pressure is being caused by something else in the background, youre not going to get normal development of the feet. So this is your clubfeet development, abnormal leg position. Slide 11 Syndrome Sequences Dr. Wishe And these are what we looked at previously when we spoke about the branchial arches and Ive briefly reviewed them for you. This ones Treacher Collins syndrome, this is Robbins Sequence, they both have similar types of effects, but usually with the Treacher Collins, it may not be as bad as Robbins sequence. And you can notice that malformed ear, down sloping of the palpebral fissures, underdevelopment of the mandibular maxillary processes. But generally does not involve mental retardation, whereas Robbins sequence can. And this is DiGeorge sequence, different shape of the mouth, and you cant see the ears but there's a good chance there will be malformed ears. And the eyes are just too close together, but the real problem is this poor diagnosis because of a lack of, or poorly developed immune system, or problems with the parathyroid, which leads to bone problems. And this of course was your hemifacial scenario, microsomia, everything's underdeveloped in terms of the face, etc. Slide 12 Amelia/Phocomelia Dr. Wishe now we saw this picture before. Thalidomide. Amelia, phocomelia, where the actual hands and feet are attached by a small bone to the body. Slide 13 Limb Defects Dr. Wishe Here's another example, it looks like the child is missing a limb over here, and here we have partial limb formation, so more like meromelia, but look at the digits, I only see 2. So you having a meromelia, plus a syndactyly at the same time. And this one shows you very small hands, and they're attached to the body by a short bone. So you're missing most of your limb.

Transcribed by Vandeep Bagga

March 31, 2014

Slide 14 Phocomelia Dr. Wishe this we just saw, here's another version. And this one even has a smaller bone attaching the hands to the body. Slide 15 Fetal Alcohol Syndrome Dr. Wishe Okay, before we get to this. So there's a whole bunch of drugs and stuff that have different effects. It has been estimated that maybe 40 to 90 percent of pregnant women are taking some sort of medication during pregnancy. And in reality, they really shouldnt. So you might be taking vitamins, which might have a negative effect, too much vitamin A. Taking a folic acid is good, because that tends to prevent, especially neural and gastrointestinal defects. Now they talk about marijuana as having no teratogenic effect, but the number of children born from woman who use marijuana seem to be reduced. So you got to take everything with a grain of salt here. When they say no, this is really no. Infectious agents will cause problems. These are environment agents, like rubella or German measles used to be a big problem, and what really happened was a very high risk of malformation, if occurred during the first 4 weeks of development. You had literally a 50% chance of getting a malformation. Weeks 5 through 8 was still pretty high but reduced, 22%, and then once we got to weeks 9 and up, like 9 through maybe through 16 or so, you were dealing with a 6-7% chance of getting this condition. So again weeks through 8 are the most critical, and the number of children with German measles has been reduced tremendously. So the conditions are not as severe. Anything virus, is going to lead to underdevelopment of the brain and retardation. That's the nature of the virus. Now this type of virus could be in the mother, it could spread to the placenta, and it could even spread into the developing child. So all depends what really happens. And when they had German measles occurring rather frequently, it was transmissible to hospital personnel, and the hospital personnel may come into contact with other children and pass it along. Malformations dealing with German measles include eye malformations like cataracts formations, problem with the internal ear, hearing, heart malformations, malformations in teeth, palates, vascular abnormalities, and the chief malformations dealt with eye were 50% of the individuals had eye malformations. Another 30% had heart malformations, and another 35% had hearing malformations. Those are pretty high percentages. And mental retardation, as I said always occurs because of a virus, and that was 10%. And if you follow this child through age, maybe 5 or so, the percentage could increase, because the malformations dont necessarily appear immediately, but they will occur within the first 5 years. Today, about 85% of the women are autoimmune, there's a vaccine for it, but in your third world countries, where medicine hasnt progressed that far, its a possibility that this condition can still be transmitted. Another virus called cytomegalovirus is really a fatal condition effecting the embryo or fetus and leads to spontaneous abortions. When the developing child is effected early on, embryonic period, you get zero survival. If they get affected later on, they could survive, but theyll have a small head, microcephaly, mental retardation, and usually with those conditions, you get problems in terms of eyes, blindness, deafness, etc. And initially this condition was not detected so readily, but they detected it in an autopsy when they found unusually large cells, large nuclei and 6

Transcribed by Vandeep Bagga

March 31, 2014

giant occlusion bodies. Those that survived for the most part did have mental retardation. And is usually unrecognizable in pregnant women. Something youre more familiar with is the herpes simplex virus. I mean most of us get it when we have a problem with a cold, we get a cold sore, that's the herpes virus, doesnt cause any problems in us, but if youre pregnant, and the virus gets into the placenta and transmitted to the developing child, you could have an increase in abortion rate, spontaneous abortion rate by a percentage of 3. The child can get infected after 20 weeks, so you tend to get an increase in premature births, which means that the child cannot exist on its own, has to be kept in a special incubator and brought up to snuff, that's equivalent to a child being born normally. Chicken pox is a virus called varicella, and if the childs infected during the first trimester, there's a 20% of anomalies, and these anomalies really tend to effect muscle more than anything else, and development of the brain. Every single virus effects the development of the brain. And this leads to mental retardation. HIV, interestingly enough, they do not consider this as a major teratogen, however, children born from woman with HIV, again you get the underdevelopment of the brain, the microcephaly, mental retardation, growth retardation. Everything depends on when the virus is transmitted. Syphilis is a virus, and there's several stages, if its caught early enough, it can be cured and prevent any problems maternal, placental, embryo. But if it isnt, its going to lead to brain, mental retardation, deafness, abnormal bones and teeth. And those are some of the more common types of effects of environmental agents. Radiation is important, there's radiation all over, the sky, the air, the ground, the water. There are different types of radiation, gamma rays, cosmic rays, radioactive elements. A pregnant woman goes for a thyroid scan, or some other scan, there's radiation there. And in your practice, when you take X-rays, you cover the woman as well as the man, with this lead shield, which extends from below the chin covers the neck, all the way down covering the reproductive organs. Although radiation doses have been controlled pretty well, such that these type of effects are avoided, there's still a problem and you cant be blas about it. Different cells respond differently to radiation. 1 type of cell may respond to just a few rads, another cell may be able to withstand 100 rads. So all the cells are different, their responses are different and everything depends on the dose. And if you have children born who have been exposed to radiation, youre going to get again microcephaly, mental retardation, blindness, problems with the formation of the dentition, the palate, etc. There are chemical agents that are problems also. And you cant assume that chemical agents are not harmful. Penicillin, amoxicillin which are given to a lot of people, may be good antibiotics, but in terms of pregnant women, its not necessarily great. There tends to be a greater incidence of abortion, fetal death, and prematurity. I once taught a PG course, and there were some oral surgery residents in it. And 1 of them said that he gave penicillin to all his patients, pregnant or not. That's a stupid attitude, because there's a chance something could happen, and he wasnt very smart about it. Streptomyocin is known for premature birth and hearing defects and equilibrium defects possibly. Tetracycline we already spoke about. You give it to a young child, you give it to a pregnant woman, this is going to effect the dentition, its going to permanently stain their dentition. It will stain the bones, you wont see the bones but you certainly see the dentition. In addition, it weakens the bones. So you 7

Transcribed by Vandeep Bagga

March 31, 2014

stay away from tetracycline under all circumstance. Thalidomide we spoke about, you saw limb defects. Some people take antineoplastic agents to control cancer of some sort. They can cause problems, again relating to brain, mental retardation, cleft lip, hydrocephalus, etc. But giving folic acid helps control that. It reduces neural defects by a factor of good 30-35%. Anticonvulsive drugs produce problems. Major tranquilizers produce problems. Minor tranquilizers, which some of you might be taking, like valium, they're antianxiety agents, will increase by a factor of 4, the amount of children born with cleft lip and or cleft palate. People who have heart problems are giving anticoagulants, Coumadin or Coumarin, in reality by the way is a rodent poison known as Warfarin. And when the rodent eats the Warfarin, it goes off into the wall, it dies in the wall, which is not a good idea, then youre going to smell the carcass. Then you have to break the wall open to find the rodent, but the Coumadin is a blood thinner. However, it crosses the placental barrier, that's not good. Youre smarter off using something like Heparin which is also a blood thinner but it doesnt cross the placenta. Some people take ACE inhibitors in controlling blood pressure, this causes problems. Aspirin, by the way, so many people take, known effects to cause bleeding. People that take aspirin to prevent stroke, they hit their hand on the table, they bruise, that means they're bleeding internally. And some bleeding does occur internally. Cocaine, this is a vasoconstrictor, whether you realize it or not, it causes hypoxia, shortage of oxygen to the brain. What's that mean? That means you're going to effect brain development. Eventually retardation. Cigarette smoking, which has nicotine, has the exact same effect as the cocaine, causing the hypoxia. So cocaine is not good, smoking is not good for pregnant women. And a lot of pregnant women do smoke. And what you're looking at on the board here happens to be fetal alcohol syndrome. There have been reported cases of a child being born drunk, the mother was an alcohol, and the alcohol actually crossed the placenta. And if you look at the picture of the child, it has a certain look to the face, short nose, the eyes may even slant down, and alcohol is the most common cause of mental retardation, that means underdevelopment of the brain. So you really have to be careful what you take into you if you're pregnant. People who are diabetic can give birth as long as they are under appropriate medication, insulin. If they're not taking something like insulin, there is an 80% chance that the children born are going to be malformed. Thyroid problems dont really occur in most of the world because of the presence of iodine. Some water is iodized, but basically the salt is iodized. You can buy salt that doesnt have iodine, and so you're just dealing with a deficiency of iodine that is causing the problem here. Organic mercury, known to cause neurological problems. Fungicides might have that, and you spray the corn seeds and you consume that, that produces a problem. And a few years ago, there was contamination with mercury in the seas off of Japan, eating the fish caused problem. Almost anything can cause problems. Slide 16 Fetal Alcohol Syndrom Dr. Wishe Here's another picture again, notice the face, with the eyes and the nose. And you cant tell of course if the person has mental retardation. And thats our last picture of the day. And dont forget I changed the schedule for you, since were ahead in CFB, Thursday on the CFB timeslot, when people are here and isnt, were 8

Transcribed by Vandeep Bagga

March 31, 2014

going to start organ systems digestive system 1 and 2, and Friday well finish up in separate sections in Nagle.