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Amit Amin October 03

rd
, 2014

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

Slide 68 Dominant vs. Recessive Traits
Dr. 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 Dominant
Dr. 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
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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 - Definitions
Dr. 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 trait
Dr. Phelan I showed you with pedigree for autosomal dominant trait.

Slide 72 Locus vs. Alleles
Dr. 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 trait
Dr. Phelan Did I go backwards?

Slide 74 Autosomal Recessive
Dr. 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
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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 trait
Dr. 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 Disorders
Dr. 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
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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 Traits
Dr. 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 Dominant
Dr. 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
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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 Traits
Dr. 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 pedigree
Dr. 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.
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Slide 82 - Single Gene Disorders
Dr. 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 syndrome
Dr. 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 - Image
Dr. 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 I
Dr. 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
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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 Syndromes
Dr. 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
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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 - Images
Dr. 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 Fibrosis
Dr. 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
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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 Disease
Dr. 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 Diseases
Dr. 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
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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 A
Dr. 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.
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Slide 94 Autosomal Dominant Disorders
Dr. 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 slide
Dr. 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
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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 issues
Dr. 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 - Rickets
Dr. 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 Disorders
Dr. 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
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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 defects
Dr. 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 abnormalities
Dr. 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 Chromosomes
Dr. 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.
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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 karyotype
Dr. Phelan This, we talked about this before. This is a normal female karyotype and
this was a normal male.

Slide 106 No title
Dr. 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 banding
Dr. 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 picture
Dr. 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 abnormalities
Dr. 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 Translocation
Dr. 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
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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 Deletions
Dr. 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 Inversions
Dr. 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 Chromosomes
Dr. 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 - Isochromosomes
Dr. 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.
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Slide 115 Number of chromosomes
Dr. 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 - Picture
Dr. 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 abnormalities
Dr. 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 Terminology
Dr. 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
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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 21
Dr. 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/
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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 - Karyotype
Dr. 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 - Picture
Dr. 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.
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Slide 126 Klinefelter Syndrome
Dr. 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 Syndrome
Dr. 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 Syndrome
Dr. 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 Syndrome
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Dr. 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 - Picture
Dr. 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 - Picture
Dr. 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 Inheritance
Dr. 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.
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Slide 135 Disease Associated
Dr. 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 mellitus
Dr. 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.

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