13: Principles of Teratology

7/14/2019 13: Principles of Teratology

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Transcribed by Vandeep Bagga March 31, 2014

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Craniofacial Biology Lecture 13 Principles of Teratology by Dr. Wishe

Slide 1 Teratology

Dr. Wishe

Slide 2 Critical PeriodsDr. 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 thesecould 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 3through 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 ofmalformations. 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


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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. Wishethis 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 havedifferent 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, asa 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


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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 uponthat 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 DownsSyndrome. 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 2ndeffect and that leads to a 3rdeffect, 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 orRobins 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 doeshave 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.


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Slide 4 Congenital Malformation Causes

Dr. WisheThis 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 about38% 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. Wishenow 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 ishappening 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. Wishehere'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. Wisheand 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. WisheHere 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. Wishenow 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


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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'sseveral things that are playing a role in terms of development in this child.

Slide 10 Abnormal Leg Positions

Dr. Wishenow 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. WisheAnd 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 developedimmune 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. Wishenow 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. WisheHere'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 atthe 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.


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Slide 14 Phocomelia

Dr. Wishethis 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. WisheOkay, before we get to this. So there's a whole bunch of drugs and stuffthat 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 ofgetting 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 Germanmeasles 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


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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 istransmitted. 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'sstill 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 themsaid 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


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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 betaking, 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 hittheir 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 mostcommon 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 causedproblem. Almost anything can cause problems.

Slide 16 Fetal Alcohol Syndrom

Dr. WisheHere'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 thatsour 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


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

separate sections in Nagle.

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13: Principles of Teratology