Transcribed by Jacqueline Heath 9/29/14

General Pathology [26 -27] Developmental & Genetic Disorders I and II by Dr. Phelan

[1] Developmental and Genetic Disorders
[Dr. Phelan] Okay, lets begin. Were going to start a new unit and this unit does get
covered on our exam for, on exam 2. I didnt get a question from somebody about the, um
about the nature of the second exam and yes the second exam is cumulative because um as we
move on in this course, its very hard to separate out what you had before from what you have
now. Clearly, most of the exam has to be on new stuff because we have a 60 question exam
and in order to cover the new stuff, I have to spend most of the 60 questions covering the new
stuff. But you will have questions that inter, that use some of the new stuff and some of the
old stuff. And there will be some of the old stuff, some questions kind of straight from the old
stuff, but not very many. Okay? It really cant be a major part of the exam. When we get to
the final, it will be a little different because by that time, everything is interacting or
interconnected and you already, youre working with, for example youre working with
immunology to do inflammation, so to make, there is no way of making them separate. So its
cumulative but when you look at the exam, most of the questions on the exam will look like
they came from new stuff. I cant make it nay clearer than that. But you really cant forget any
of the old stuff because its going to come up on this exam and its going to come up in this and
the first material will come up on your final. Okay?
So our unit for the next two sessions is developmental and genetic diseases. And the
developmental part of this might be sort of new, its certainly not, I dont think its very difficult.
The genetic diseases is sort of a genetics 0.5 because what we need for genetics in our world of
pathology is a basic knowledge that lets you understand the way the diseases that are genetic
diseases work. So for those of you that studied genetics and spent a lot of time studying
genetics in your undergraduate days, this stuff should be easy, youll just have to add the
diseases portion to it if you havent had that before.
So were going to start with some of the developmental concepts and then work on the
genetics, specific genetic material when we get to the, when we get to the lecture on Friday.
*2+ Diagram (conditions)
Okay, so as we look at developmental and genetic diseases, there is a spectrum of those
diseases. Some of them are conditions that are caused very specifically by factors that are in
the feta l environment. And we will see that as I show you some examples as we move on.
There will be some others that we will talk about on Friday and we will talk about them more in
Systems pathology and then again as you get to oral pathology next year. And those are
conditions that are determined by genetic abnormalities. And then we have some that require
both in order to occur. So there is this spectrum of developmental genetic diseases and it
becomes, for some of them, difficult to separate them into either the right side or the left side.
And you see the interaction between them.
[3] Causes of Birth Defects in Humans
Okay if we look at birth defects in humans, most of them are unknown causes. And
between unknown causes and inherited diseases, that accounts for about 90 percent of the
birth defects that are described in humans. And then there are some others. Cytogenetic
diseases well talk about on Friday. Drugs and chemicals well talk about some of that in todays
lecture. Radiation well talk about a bit more when we get to the end of the course. And well
talk about radiation in pathology. Maternal infection were gonna to talk about today. And
some maternal metabolic factors, theyre really very rare and were not going to speak much
about either those or birth trauma or, uterine factors we are because there is one set of birth
defect sequence that fits into that category. But if you look at this, most of them belong up at
the top and so most of the causes of birth defects are really unknown and with another big,
another big percentage related to those diseases that we can describe as hereditary disease
and we can actually follow the pattern of inheritance that is related to those diseases.
[4] Definitions
There are some definitions that, if you dont know them, please know them. I would
like to not ask you the definitions on your exam, but on the short answer I might. That, I might
not ask you the definition itself but actually give you some examples of these and then have
you work out the, use the word.
Congenital abnormality means that the abnormality was present at birth. It may be that
it is identifiable at birth or it may not be identified til later, but it was there. So a congenital
defect, or a congenital abnormality is an abnormality that is present at birth. And thats when
you use congenital
Developmental disorders is really broad. Its a broad term that can be used for, used in
a number of different contexts and as we looked at a congenital abnormality, a congenital
abnormality can be an environmentally induced abnormality and it would be a developmental
abnormality. It could be a genetically caused abnormality, it would be a developmental
abnormality. So it is just a very very broad term that talks about abnormalities that are related
to fetal development
Hereditary trait or disease is much more specific. And this is a trait thats transmitted
from generation to generation. And not all of these are present at birth. The genetic
component is, but the abnormality or the disease itself may not be present at birth and may
show itself later on in life. And you will see a number of those that have head and neck or oral
manifestations
Lets move here *I think thats what she said?+
*5+ Syndrome:..
Okay. The term syndrome is not just used in relationship to developmental or genetic
conditions. But it is very commonly used here. But there are diseases that are neither
developmental nor genetic that are syndromes. And its a group of signs and symptoms that
occur together. So Sjogren syndrome weve talked about. Its a group of signs and symptoms,
its not genetic as far as we know. There may be a genetic predisposition, but its not one of
those genetic diseases. And its not an environmental, its the developmental abnormality that
you would see congenitally because you dont see Sjogren syndrome until you have adults and
usually adults over 40. So its a set of signs and symptoms. Youll see that term syndrome a lot
as we work through pathology and as you get to systems pathology, youll work on a number of
different symptoms. But here in the developmental and genetic group of diseases, again, its
those things that occur together but its not specific to this section of the course.
A malformation is the, a malformation is a problem in the development of an organ or a
part of an organ or a region, and it results in some kind of abnormality or perturbed if youd
like, messed up morphogenesis. So a malformation has to be occurring during the time of
development of a human
The term anomaly is used also. And this is used in relationship to development al or genetic
anomalies. Its not usually used in terms of other systemic diseases that dont fall into this
category.
And then the term teratogen is an agent that can cause developmental abnormalities
and Im going to show you a couple of those. I wont give you the examples now, Ill give them
to you as we move along in this, in this section of the course.
[6] Developmental and Genetic Disorders
Today were going to talk about developmental disorders and errors of morphogenesis.
Some of these as we talk about them will pop up again when we talk about genetic diseases.
And youll see, I hope, what I mean as we move along and if you dont youll have to raise your
hand and say I dont know what youre talking about. Okay, and then on Friday were going to
talk about genetic disorders and divide them into single gene defects, chromosomal
abnormalities and then those that are polygenic inherited diseases. And well move along with
that on Friday.
[7] Developmental Disorders (Errors of Morphogenesis)
So we have a group of abnormalities that have names, and these different kinds of
abnormalities will emerge as we talk about different kinds of developmental abnormalities.
Some of them will be in the context of genetic, with a genetically uh determined diseases. And
others will be either an environmental cause or a fetal environmental cause. So you need to
know these and they sound awfully similar, some of them, to some of the words we had right in
the beginning of these course. But they are different and they mean something different and
you need to know what they mean. Agenesis, aplasia, hypoplasia, dysraphic anomalies,
involution failures, division failures, atresia, dysplasia, sounds familiar? Ectopia or heterotopia
and dystopia and well go through each one of these and show you what they mean.
[8] Agenesis
So the term agenesis. And I think you could figure it out if you just wrote the word
down. And agenesis it was never, theres an absence of an organ, or even a part of an organ,
but the primordial tissue wasnt there. And so its the absence of the cells or the part of the
organ or the organ, is because there was an absence of the organ primordium..
[9] Pulmonary Agenesis
And we have a couple of examples, in this patient, this person never developed one lung
and there was no primordial tissue for that lung.
[10] Agenesis Anodontia/Partial anodontia
For us, agenesis, we use that term in relationship to teeth. Anodontia usually means
there are no teeth at all. And there are some individuals that do not develop any teeth. And
youve been through the embryogenesis of teeth and the development of teeth. It appears in
this situation that there was no tooth bud, okay? Theres no primordium, theres no tooth bud
and its easier sometimes for us to understand these words if we understand them in the
context of our own world. And so there are individuals who never have teeth. We have some
people who are edentulous because weve extracted all their teeth, but thatd different from
this. This is a situation in which the teeth never developed. Complete anodontia means all of
the teeth are missing and partial anodontia means some of the teeth are missing. And there are
certain teeth that are more common than others to be missing. And um this again is an
illustration of an individual with partial anodontia. But youre the dentist. What do you have to
find out here? What do you need to do here in your evaluation of this patient? Youve never
seen this patient before, its a new patient. What are you going to ask the patient? [student
response+ Did you have any teeth extracted? Okay? Youre really going to want to know
whether or not there were ever teeth there, and its very possible that for whatever reason this
person had multiple teeth extracted, but in your history, this patient never had teeth in those
areas. So this is an example of agenesis
[11] Agenesis picture
Here again is multiple missing teeth. But in addition to the missing teeth, the teeth that
are there are not formed correctly. Okay? Thats not agenesis. Agenesis means that theres
nothing there at all. Okay? Um
[12] Aplasia
Aplasia is, theres an organ missing or somethings present that in the area of the, where
the organ is supposed to be. Or something that never quite developed. Oaky? So we could
consider this an example of aplasia (she flips back to slide 11 of the patient with missing teeth),
especially with those anterior teeth. Okay?
[13] Radiograph of Primordial cyst
You all know what a cyst is now, correct? Whats the definition of a cyst? *quiet+ Okay,
did you have cysts with Dr. Shah? Any cysts? Okay, a cyst is a cavity. Okay? It could be in soft
tissue or it can be in bone. But its a pathologic cavity. And a true cyst is a cavity that is lined by
epithelium, and thats a cyst. So we can have cysts in soft tissue, and one of the cysts that we
work with a lot is around the apex of the tooth, and do you know what we call that? [student:
an abscess+ No, not an abscess, we have a cyst. Thats a periapical cyst. Or a radicular cyst.
Two words that are synonymous. And its a cyst that forms from, at the apex of the tooth and
its related to a tooth that has become necrotic and the development of that cyst is something
that we can talk about in another course.
The maxillary sinus is a space in bone. Its completely lined by epithelium. Is it a cyst?
No! Its not a pathological cavity, its a normal anatomic cavity. Doesnt mean you cant have
abnormalities in a sinus, but a sinus itself is a cavity in bone that is lined by epithelium but its
an anatomical structure. A cyst is a pathologic structure, its not supposed to be there. In some
patients, a cyst develops in the third molar area. Now we have lots of cysts that develop in the
maxilla and them mandible. And as you get to oral pathology net year youll have to know the
names of all of them, where they are and how they form, and some of them are formed from
teeth and some of them are not formed from teeth. And in the world of oral pathology, or the
world of pathology, there are no other cysts in bone in the rest of the body. All of the cysts in
bone are in the maxilla and mandible, so we own all of the bone cysts when it comes to
pathology. Soft tissue cysts, thats different. There are soft tissue cysts that occur in skin and in
multiple other organs but the bone cysts belong to us and many of them are related to teeth.
This cyst, and um I think you can see it a bit better on your own laptops than is
projected. Notice that there is a very well circumcised radiolucency, its coming over there
some place, okay? And when we talk to this patient, notice theres supposed to be a third molar
there. There was never any third molar in the area. Okay? The patient never had it extracted,
were looking at the x-ray, theres no remnant of the third molar, but what were looking at
here, and from our experience looking at odontogenic cysts, were looking at a cyst that looks
like its formed from odontogenic epithelium. Whats it doing there? Well in order for it to be
there, there has to be some remnant of odontogenic apparatus in order for that epithelium to
form a cysts. So we call this a primordial cyst and it would be an example of a rudiment of the
epithelia remnant somehow of odontogenesis that were able to form a cyst.
[14] Hypoplasia
This one is a word that I would have like at the beginning of the course, because it
sounds like a word that should be the opposite of hyperplasia. But we dont have any word.
What was the word that I told you that was the opposite, or we could use as an opposite of
hyperplasia? Hyperplasia among our, in the beginning of the course was described as? An
increase. In the number of cells and the size of the organ. So hyperplasia was an increase in
number of cells. We might have a developmental problem that was hyperplasia, but we talked
about hyperplasia when it was a response to injury. So its an increase in the number of cells
and the size of the tissue organ. We had it as a reactive response in the beginning of the course
where, if you remove the irritant, the hyperplasia would resolve. In a developmental context, if
you have a hyperplastic mandible, you have a mandible thats larger than its supposed to be.
More cells, more tissue and we can use the term hyperplasia. What, we have a development
that we didnt have with the cells in the beginning of the year, was hypoplasia, which is a word
that describes the reduced size of an organ, and its due to a problem in development, not
anywhere related to the, to an irritant. Its related to development. Does anyone remember
what the word I gave you in tissue responses as the opposite of hyperplasia? What makes it
smaller? Atrophy. And in that context, we used atrophy two different ways. One was when the
cells got smaller and the other is when you had a decreased number of cells, and if you
remember the pernicious anemia patient who had lost all of the papilla on her tongue due to
that nutritional deficiency. So within that context of reactive lesions, or reactive cellular
responses, atrophy is the term that we use when we have fewer cells and, or smaller cells.
Here, in development, we use the term hypoplasia. So well have individuals with a hypoplastic
mandible. Hypoplastic organs, and youll see that as certain abnormalities are described.
[15] Hypoplasia - Micrognathia
This is a baby with a hypoplastic mandible. And its called Micrognathia. You could also
have a hypoplastic maxilla. You could have a hypoplastic ears, you could have hypoplastic arms
or hypoplastic legs. So you have a number of different ways you could use this term. But its a
developmental term, its not a term that is a cellular reaction to injury that we had in the
beginning of the course.
[16] Turner Hypoplasia picture
There is a phenomenon in our dental world thats called a Turners tooth, or Turner
hypoplasia and in this situation, what happened, this is a permanent tooth. And what
happened is there was a problem with the primary tooth sitting right on top of this tooth while
this tooth was trying to develop. So this tooth didnt develop, a lot of the tooth itself didnt
develop. Thats hypoplasia. And youll see as we get to dental abnormalities there are a
number of different examples of dental, of dentinal hypoplasia, but this one is rather dramatic,
and so Ill use this one now and well use other enamel hypoplasias and dentinal hypoplasias
later on.
[17] Dysraphic Anomaly
Okay, another one of these developmental abnormalities is something known as a
dysraphic abnormality. And this is an abnormality that is caused when structures that are
supposed to fuse dont fuse. And so if youve looked ahead in your PowerPoint handout, we
have a really good example of this in dentistry. *+ The palate. Okay? The palate is supposed
to lift and fuse. So cleft palate is a dysraphic anomaly. Also, cleft lip is a dysraphic anomaly.
Can you think of what the most, um, minor type of cleft might be in the oral cavity? This one
youll see more than cleft palate. If youre working in a cleft palate clinic, youll see lots of cleft
palate. But a bifid uvula. And you remember the palate that closes like a zipper? Well,
sometimes it doesnt get all the way to the uvula and youll see a uvula that actually seems like
it has two halves rather than the one structure that hangs from the soft palate.
[18] Spina Bifida
Uh, spina bifida is an example of a birth defect that is considered probably the most
common of the disabling birth defects in the US. And when we get to nutritional deficiencies,
were gonna talk about folic acid deficiency in pregnancy because there is a dramatically
increased requirement for folic acid in pregnancy so it appears that this may be one of the
causes for spina bifida. Theres also some association with agent orange that was an exposure
to the veterans during the Vietnam war. So again this, the neural tube doesnt close. This is a
dysraphic defect.
[19] Pictures of clefts
And heres a cleft palate and a bifid uvula. And cleft lip. These are all dysraphic
abnormalities and there are many of them, but I think this would help you to remember what
the, what the word means.
[20] Involution Failure
Okay and involution failure is a developmental anomaly that occurs because certain
fetal structures are supposed to disappear. They are supposed to involute. At some stage of
development. The best example we have in our head and neck area is the thyroglossal duct.
The thyroglossal duct goes from where to where? Where does it start in the oral cavity? How
about the back row, where does it start in the oral cavity? [back of the tongue] On the back of
the tongue, and whats the marker? *foramen cecum+. Foramen cecum, okay, thats the oral
comp, the oral site, and so the thyroglossal duct or tract is the tract that the thyroid follows
from its initial development on the base of the tongue down to its final resting place in the
lower part of the neck below the cricoid cartilage. Thats how the thyroid gets from where it
starts to where it goes. Okay. And it probably very often leaves remnants. But we only know
about it when we have some pathologic entity that tells us that those remnants were left
behind. And there is a cyst called thyroglossal duct cysts, or thyroglossal tract cyst, which is a
cyst in soft tissue, so its a pathologic cavity, and its lied by epithelium and the epithelium is
derived from that thyroglossal tract that the thyroid followed. And to make our lives a little bit
easier, when these cysts are identified, usually there is some residual thyroid thats in the soft
tissue around the cyst. Its an interesting cyst and for those people that get one, if the entire
tract isnt removed, theyll get another one. And the tract goes right through the middle of the
hyoid bone, so usually to remove the tract, they remove the tract plus the middle section of the
thyroid [hyoid] bone. And apparently people get along fine without the middle section of their
thyroid [hyoid] bone. Not thyroid, hyoid bone.
[21] Involution Failure: Thyroglossal Duct (Tract) Cyst
And so this is an example of involution failure, and there are other examples but Im
trying to give you examples so that you have something to hang the definition on as we move
further on into pathology in this course and then in our systems pathology, oral pathology and
even when you get to pediatric dentistry, some of these are going to come back and have more
examples for you.
[22] Division Failure
Okay so a division failure. Division failure happens when something is supposed to
cleave and it doesnt. In development there are certain structures that form because the
program is for an apoptotic process to actually, to actually um cause certain cells to die by
apoptosis and then allow the division to occur.
[23] Division Failure - Syndatyly
And probably the best example of this is syndactyly where fingers or toes dont
separate. And that separation or division of fingers and toes occurs because theres an
apoptotic process that allows those cells to die and the fingers to be separated.
[24] Atresia
Okay atresia. There are a couple of different examples of atresia, but in atresia theres
supposed to be a lumen and the lumen doesnt develop. So there are individuals that dont
develop a patent esophagus or there is a tricuspid area in the heart. Atresia where that uh the
hole doesnt develop where the valve is supposed to be. There is a description of atresia in a
dental environment where there is a dentin abnormality where you dont form a pulp. And in
order to maintain our vital teeth, you need pulp in the center part of the tooth. Theres also
atresia of the colon. And so that in those individuals. And those are congenital abnormalities
that would be present from very early on. Dentinal dysplasia though, if its in permanent teeth,
the dentinal dysplasia wouldnt necessarily be congenial but youd see it a little bit later.
[25] Esophageal Atresia diagram
Here youre looking at a diagram. Heres the trachea, and heres what should be the
esophagus and theres no patent esophagus and theres no lumen.
[26] Tricuspid atresia diagram
And in tricuspid atresia, here what happens is instead of a tricuspid valve being fictional,
it is not functional and it doesnt function as a valve and it causes some severe problems.
[27] Radicular Dentin Dysplasia
And here is an example of dentinal dysplasia and by now, you know what teeth are
supposed to look like and you know theres supposed to be a pulp chamber and pulp canals in
teeth and when theyre not there, somethings missing. So these are examples of atresia.
[28] Dysplasia
And this one is, I think is less confusion because I spend more time talking about it, but if
you remember back at the beginning of the course, we talked about epithelial dysplasia. And
epithelial dysplasia is defined as an abnormality in the epithelium, in the basal layers, in the
maturation of the epithelium, but it is an abnormality that occurs long after the development of
the individual and its usually due to some kind of environmental factor. Smoking is a big one.
It appears that HPV can do this kind of change in epithelium. At the beginning of the course we
talked about this as far as we know that this point, it is usually a premalignant change or its
considered a premalignant change. Thats epithelial dysplasia and that term only goes to
epithelium. That whole definition of dysplasia. But dysplasia is used a lot I n developmental
abnormalities, and also in a number of diseases which its hard to know whether or not its
development, but they do occur and the tissue is abnormal. And so the term dysplasia is an
effect that is describing the abnormal organizational structure of the cells and the tissue.
[29] Dysplasia Fibrous Dysplasia
So we have a couple of those that are easy to talk about because theyre so different
from epithelium. There is a disease called fibrous dysplasia that youre going to talk about
systems pathology and talk about it in oral pathology where the bone is abnormal. And instead
of having normal trabeculae and normal marrow, there is combination of irregular trabeculae
and a lot of very cellular and very vascular fibrous connective tissue and it doesnt develop in
relationship to function. So you have abnormal bone, its abnormally arranged, it doesnt
develop in relationship to function, and so we call that fibrous dysplasia but its a dysplasia of
bone. Its not pre-malignant. Its a benign condition. It is, it can be a problem for patients
because the bone is involved and it doesnt just affect jaws, it can affect any bone in the body,
and some patients get one bone involved, some get multiple bones involved but it is an
abnormal development of the trabeculae and the marrow and it just is kind of, there is a
generalized abnormality. Here is a tra *shes struggling to say the word..+ these are
trabeculae, I can do it better plural than singular, and then this is what would be marrow and is
very cellular connective tissue. And again its an abnormal development of the bone but its not
pre-malignant.
[30] Dentinal Dysplasia
A few minutes ago I talked about dentinal dysplasia Here, whats abnormal is the
dentin. The development of the dentin or the development of the dentin never develops
normally. It doesnt develop normally in change, it never develops normally. And so we have
an abnormal dentinal development, we call that dentinal dysplasia. It has nothing to do with a
premalignant lesion. The premalignant lesion with dysplasia is only used for epithelium and its
not a developmental abnormality, it is a reactive abnormality in epithelium.
[31] Ectopic or Heterotopic Abnormality
And then there are abnormalities that are are called ectopic or heterotopic. And Im not
going to ask you to learn the different between these two words because the medical literature
mixes them up all the time. And uses one for the other and the other for the other. And so I
would like you, you could lump them together for now, if you get a course where someone
wants you to separate them its fine, but for this course you do not have to separate these. And
so its a developmental anomaly where an organ is outside its normal anatomic site.
[32] Ectopia radiograph
And so Ill give you an example here. Okay. This is radiolucency in the bone is a very well
circumscribed radiolucency and if the surgeon is concerned about that radiolucency and wants
to go in and find out what it is, what is going to be identified in there is just salivary gland tissue
and its normal salivary gland tissue. And so this, the right name for this, or probably the
clearest name for this is a developmental salivary gland inclusion. Now, you will see this called
a stafne bone cyst. Okay its one of the pseudocysts were going to bother you with in the jaws
where, what do you think makes something a pseudocyst? [response] I wish I could hear you a
little better because I bet some of you are getting the right answer. Its not lined by epithelium
but by x-ray it looks like a cyst. So we have a couple of them that you work on, and this is one.
You know the term cyst here really is confusing because there is nothing about it in any way,
shape or form that is a cys.t it just got that name because of it s radiographic appearance.
[33] CT scan
And what happened here, you can see on this CT scan, as the, as the submandibular
gland developed, somehow the gland actually became incorporated in the mandible. And so
this is the mandible and this is salivary gland. And its an extension from salivary gland from the
floor of the mouth.
[34] Skull picture
This is somebody found a, a skull that exemplified the kind of thing thats happening
here. If you take an x-ray of this skull, because there is less bone in this area, its going to look
like a very, very well circumscribed radiolucency. Its going to look like a cyst. But it isnt a cyst
at all, its just this salivary gland material that isnt where it belongs. Its supposed to be on the
floor of the mouth, its not supposed to be in bone.
[35] Dystopia
Okay dystopia is the retention of an organ in the site where its located during
development. The interesting thing is something called an ectopic kidney is actually dystopic
kidney. So these w0ords get used and I really have trouble making you guys go really fussing
over ectopia and dystopia because theyre mixed up on a regular basis. So if you see ectopic or
dystopic, recognize that something isnt in the right place. So um dystopia is something that
is, if you do this in ectopic means its where it doesnt belong. Dystopic means that it is
developing in an area where it belongs but its not the right thing. And Ill give you the best
example of a couple of them.
One of them is the thyroid develops in the posterior part of the tongue. And if it doesnt
descend and it stays there, thats dystopic thyroid, except it will be called ectopic thyroid if you
look in a number of different textbooks. So again, this is an example of dystopia, but dont be
surprised if its called ectopic. Also, Fordyce granules, you all know about Fordyce spots and
Fordyce granules. Very often they are called ectopic sebaceous glands because sebaceous
glands are supposed to be on the skin. Okay, but these are in the oral mucosa. The problem is
that 90% of adults have Fordyce granules, so how can they be ectopic when most people have
them? But anyway, they arent on skin, so they get the term ectopic sebaceous glands.
[36] Dystopia Lingual Thyroid
And here again, we did the thyroid before. I hear a somebody ask a questions? No,
okay. Okay.
Uh. From here, Im just taking a breath whether or not. Lets take a break. 5
minutes. I was asked to not go without giving a break. Stand up, its 3:44, by that, I dont want
to go quite til 4 because then you wont get a break in the middle. So stand up and get a
stretch and Ill start talking again in 5 minutes.

[37] Polytopic developmental effect: .
Okay lets go again. When we talk about developmental abnormalities, there are,
several categories were going to be talking about. Were going to talk about something called a
polytopic developmental effect, something called a monotopic developmental effect, single
gene defects, chromosomal abnormalities and as I said before some polygenic inherited
diseases. And these are different categories but within those categories we can find the
developmental abnormalities that we were just talking about. And those developmental
abnormalities just tell you what it is that happened, it doesnt tell you how it got there. Okay?
A polytopic effect, and if this isnt clear, Ill do it again a couple of times until we get the
difference between a polytopic and monotopic effect clear. As you know, a fetus, an embryo
fetus is developing and different organs develop and different structures develop at different
times. But also, many of them are developing at the same time. Right? Okay. In a polytopic
effect, the problem or the injury, the environmental agent, the drug, the maternal infection,
any one of those, okay, happened and everything that was developing at the time of that, that
assault, gets, can get affected. And so its polytopic because you can have different organs that
were developing when this event occurred. Thats a polytopic effect. A monotopic effect is
described as a sequence which is, you can have multiple abnormalities that happened with a
monotopic effect, but there is one thing that starts it, and the rest follows. So there is
something called potter complex and well talk about it, where there is a problem with
amniotic fluid, and because of the amniotic fluid, the baby is kind of squished into the uterus.
And so abnormalities occur because of that event, not because of everything that was forming
at that time. And so its called a developmental sequence anomaly when its a monotopic
effect because something happens, and because that happens, the next thing happens and the
next thing happens and the next thing happens. So the difference between polytopic and
monotopic is that in monotopic, one thing starts it and then the sequence follows through.
[38] Polytopic effect: a noxious...
So, this would illustrate what would happen in a polytopic effect. Okay. So if something,
an event that is going to affect the developing fetus occurred here in what, in this area here
*pointing at number 7+, okay, and heres the developing fetus, what might be developing, or
what might be abnormal here, is whatever in the central nervous system is developing,
something with the heart. Now probably not the arms because they havent started yet, and
eyes would probably be okay, and legs, and so on. And so you have to, again, see what was
developing at the time that the noxious event or injury occurred. And so there are some classic
examples of polytopic effects in development.
[39] Examples of Malformations due to Chemical/Infectious Agents
One of them is due to a drug called thalidomide, and there are some other drugs that
have teratogenic effects, again, remember in the beginning we talked about what a teratogenic
effect is. And so thalidomide is one drug, there are others. And, and you need to be very
careful if you prescribe drugs that you have, that you know whether any of them that you
prescribe have teratogenic effects if youre pregnant or planning to become pregnant, you need
to be very careful that the drugs you take, to make sure that they dont have, as much as you
can determine, teratogenic effects. Something called fetal alcohol syndrome, the effects are
much less specific than thalidomide, okay. Torch complex were going to talk about, and
congenital syphilis, all as examples of polytopic effects.
[40] Thalidomide Induced Malformations (Polytopic Effect)
Okay. Thalidomide was a drug that was tested in mice and rats. And it was not found to
be teratogenic in mice and rats and it was given to pregnant women, more particularly in
Europe more than the United States, for whats called morning sickness or nausea. Apparently
there was a, one of the directors of the FDA here in the US that felt that the testing of
thalidomide was not sufficient to be passed by the FDA here, so if there was anybody In the
country that got it, they got it by going out of the country to get it. Its teratogenic between the
28
th
and 50
th
days of pregnancy, so if the woman took it before the 28
th
days or later than the
50
th
days, it probably didnt have any effect. But it caused some major skeletal deformities, and
later with more work that was done, it was found to be teratogenic in rabbits and monkeys.
[41] Diagram
And looking at our, back at our, uh, developmental uh, sequence, again between the
28
th
and the 50
th
days, these are the structures that are developing.
[42] Thalidomide induced deformity of the arms
And one of the very dramatic effects of thalidomide was the effect on the limbs. And so
children born with this defect have very very short arms. Sometimes there were fingers at the
end of their very short arms. And then multiple other abnormalities as well. And this is an
example of a polytopic effect. Now its very interesting because thalidomide has come to be
recognized a very important drug in a number of different settings. Its used in some
malignancies, there are number of different ways thalidomide is used, but it is used with great
caution, and if ever given in this country, its given with all kinds of protections involved in using
the drug because of this teratogenic effect. Its also used in treating leprosy, it seems to be an
agent used in that context as well. So it isnt that its a useless drug, but its a drug that has a
traumatic teratogenic effect and it needs to be used very carefully.
[43] Fetal Alcohol Syndrome/Fetal Alcohol Effect
Okay, there is another complex called fetal alcohol syndrome or fetal alcohol effect. And
as you can imagine, this is not something that is going to be taken, the mothers alcohol intake
is not something that is going to be one week. Its going to be something that is given over,
usually quite a long time because the mother is drinking alcohol, and that alcohol intake is
going to be continuous. So the effects of alcohol are not nearly dramatic as the effects of
thalidomide, but theyre affecting structures that are going to be developed during fetal
development. Its also important for remember that injuries to the embryo early on in
development very often, in spontaneous abortions because the problem is too great for the
baby to develop. Its those injuries or those problems that hit the fetus as the fetus is
developing, and is more developed than very early on in development that re going to cause
developmental effects. Its not clear how alcohol does what it does but when the mother is a
heavy alcohol user, the effects are rather dramatic. Its not clear whether one or two drinks is a
problem so its, at this point its recommended that pregnant women dont drink any alcohol
because you dont know where the level is that alcohol may affect the developing fetus, but
there is a syndrome that is well recognized but its not nearly as specific as the illustration that I
just gave you with thalidomide.
*44+ Discriminating Features
So there are some discriminating features. There is a change in the eyes. Theres a
change in the nose, the upper lip is slightly different. There is a smaller mouth, usually a
smaller hypoplastic mandible. There are some certainly some developmental abnormalities in
terms of mental development, so its much more diffuse than the problem that I just described
for you with thalidomide.
*45+ TORCH Complex (1)
And then theres something called torch complex. The torch complex, many years the TORCH
complex pops up on the boards so you really do need to know. I dont know what comes up on
boards anymore because we dont have the feedback quite the way we used to, but torch
complex seems to be a popular one.
*46+ TORCH Complex (2)
Torch complex, or this whole concept of TORCH complex was developed because three
are many infectious diseases that infect the mother that have effects on the developing fetus.
And the effect on the developing fetus is very similar from one of these infectious diseases to
the other. So the concept of TORCH complex was developed so the neonatologist or the
individual who is assessing the newborn has a complex or a spectrum to work in that might
suggest that abnormalities in the baby are related to some maternal infection. The one we
know best is Rubella. Okay, and rubella has had dramatic, or has a dramatic teratogenic effect,
however because of vaccination, rubella is rather rare so we dont see the effects of Rubella
anymore. But the infectious diseases that form TORCH complex are toxoplasma or
toxoplasmosis. Rubella, um cytomegalovirus and Herpes simplex virus. And the O to make our
lives a little bit more complex is other there are other infectious diseases that can do it but they
are not quite as specific and not as well identified. But the complex is. And you could call
TORCH complex a syndrome, but its usually just called Torch complex. Ive seen it called torch
syndrome though. But most of the time its torch complex.
Its complex of similar signs and symptoms produced by fetal or neonatal infection with
a variety of microorganisms. Keep in mind that the baby is still developing after the baby is
born and if the mothers infection has infected the newborn, then those developmental effects
can continue unless the baby is treated for the infection. And Ill show you probably the classic
example of that in a minute.
[47] Torch complex picture
But if you look at this diagram from your textbook for TORCH complex, there are eye
problems that include some problems with the retina and with the conjunctiva, there is a
smaller head that occurs, there is some problem with the brain, there is smaller eyes, there is
some skin lesions, there is a larger spleen, some heart disease, some liver abnormalities and
some problems with lungs. So these are a complex that if one of them is present its not so easy
to identify the infectious disease but they dont usually work that way. The infectious disease is
still, like alcohol, kind of a longer term effect so while the mother is infected, the baby is
infected and these specific infections will cause teratogenic effects. Every maternal infection
doesnt do that. Okay. Upper respiratory infections in mothers dont usually cause teratogenic
effects and multiple other infections dont, but these infections are well known to do this.
[48] Chart
This is again from the =, I think I picked this up from your oral pathology book but Im
not going to tell you exactly where it came from because I dont want you to memorize it. I put
it in here for one reason, and that is to show you how many different abnormalities could be
part of this complex of TORCH complex. So what I want you to know about torch complex: I
want you to know what the initials stand for and if you know the components that are on this
diagram, thats enough. If you want to go memorize all these, go for it. Except that it isnt
necessary for this course. What I want to know is that here is a complex of effects and these
are polytopic effects because theyre occurring as the baby is developing but some of them, like
the skin rashes are probably the disease, the infection that is continuing after the baby is born.
[49] Congenital Syphilis
One of these is congenital syphilis. And youre going to spend some time probably in
pediatrics or probably oral pathology, talking about congenital syphilis. The organism that
causes syphilis, Treponema pallidum is transmitted to the fetus by a mother who has
developed, who has syphilis during pregnancy. The mother could develop before the
pregnancy, syphilis does not always clear, there are multiple stages of syphilis, well talk about
that when we get to infectious disease. Syphilis is a condition that does not, in some people,
doesnt resolve unless its treated. There are some people with syphilis that it does resolve, so I
dont want to make that too adamant. But any time that the organism can invade the fetus
during any time during the pregnancy, however, when it does, it is going to cause polytopic
effects. But it can be from any time very early on, right through the birth of the baby that this
organism is causing damage to the baby. I f the infection occurs very early on in the pregnancy,
its very likely that it induces spontaneous abortion and the fetus doesnt develop. After the
16
th
week of the pregnancy, then some of the dramatic effects develop.
[50] Diagram
And here is where, in syphilis, some of the most dramatic effects development.
[51] Congenital Syphilis
So the development, the effects that, some of them are in our area, there is a nose
change where the bridge of the nose becomes flattened. And in, even after birth, that area,
that bone in that area or that cartilage in that area will become destroyed and there will be
whats called a saddle notes because the bridge is flat. And the baby that is born with syphilis
will have very often a maculopapular rash, which is a flat rash with some papules in it. There
can be cracks and fissures in the mouth and in the mucosal area around the anus and vulva in
baby girls. There is a lung infection, or a lung inflammation that occurs. There is enlargement
of the spleen and liver that can occur. There is anemia that can occur because of the infection.
The effect of the infection on the bone marrow. There is also what happens in response to
inflammation and infection is lymphadenopathy. There are some very specific effects on teeth.
And there are classic teeth that are described in syphilis. And one of them is Hutchinsons
incisors and the other one is mulberry molars and Ill show you a picture in a minute.
[52] Congenital Syphilis
Uh bones. Is that a question? Okay. Bones are involved and there is a change in the
configuration of the legs. A saber is a curved sword and so the legs take on a curved
appearance. There is a progressive change in the cornea that can lead to blindness. There is
change in the brain, infection of the brain and then something called Hutchinsons triad, which
includes the teeth, deafness and changes in keratin.
[53] pictures
And so here are some of the changes on the skin, you can see here, and this is the saver
configuration of the bones of the legs.
[54] another picture
Uh this is an example of the saddle nose.
[55] Hutchingsons Incisors
And these changes do not disappear as the individual ages. Those developmental
effects and destructive effects will persist. This is an example of Hutchinsons incisors. They
are sometimes called screwdriver shaped incisors and you can see by the notch here. Mulberry
molars- you may find an abnormal shaped molar that is mulberry-ish that has nothing
whatsoever to do with syphilis. But these teeth combined... and keep in mind that you know
now when these teeth are developing, so if the syphilis infection is ongoing at the time when
the incisors, the incisors and the molars, first molars are begin developed then we might see
this kind of change but if we look back at the premolars, the premolars arent changed so its
the teeth that are developing at just about the time of birth, because when this is identified,
then usually the baby is treated very rapidly to try to stop the damage that would continue if
the infection continued.
[56] Neville, 2
nd
and 3
rd
ed.
Okay and this comes from your oral pathology textbook that you havent seen yet but it
just goes through the multiple, multiple changes that can occur in congenital syphilis. And
youre going to get this later. What Id like you to stick to now is the ones Ive given you on the
ppts. So you really dont have to go memorize these. I just want you to know that there are
more than Ive given you that can be abnormal in congenital syphilis.
[57] Monotopic Developmental Defect
So thats a polytopic effect. Does that make sense to everybody? Okay. That usually
easy. Where I really have trouble is when I try to explain to you what a monotopic effect is.
And partly because its hard to find examples of a monotopic effect that really make it as clear
as the polytopic effect. But here, think of it descried as a sequence. And when you think about a
sequence it means, one thing happens and because that happened, the next thing happened,
and because that happened, the next thing happened, and its not because things were
developing at the same time, its that one thing caused another caused another cause another.
So its a tumble down sequence if you will. So the pattern isnt just one abnormality. You still
have a pattern of abnormalities but the way they develop occurs differently in a monotopic
effect than a polytopic effect.t okay.
[58] Potter Complex
Potters complex is something that occurs because there is a decrease in the amount of
amniotic fluid. And thats what starts the problem .and because of that, the feet are shaped
abnormally. There is a change in the kidneys. There is an abnormality in thaw ay the hands
develop and are positioned there are smaller lungs and there is another, you dont have to
worry about the amnion nodosum but what Im really concerned about is that you understand
these abnormalities in the fetus are occurring not because of something that was damaging the
fetus at a single time or even an extended time in its development but one thing started the
sequence and the other things emerged from there.
[59] Pierre Robin Sequence
Um, the one that is in our area is something called Pierre Robin Sequence. Ad youre
not likely to find, unless you really are in very early pediatric dentistry, and dealing with
syndromes and abnormalities in children, to deal with Pierre Robin Sequence. But again, this is
something that happens because one thing started the process and what apparently starts the
process is the tongue doesnt descend and because the tongue doesnt descend and its not
clear why, the palatal shelves dont fuse. And as a result there is a cleft palate. And as a result
there is a retrognathic retruded mandible. And Ive already shown you a child with Pierre Robin
syndrome earlier on in the lecture. And the tongue obstructs the airway. So there is a change in
the way the tongue fits in the mouth. And all of this is because the tongue didnt descend and
the other pieces of development didnt fall into sequence and thats a monotopic effect.t so
monotopic effect involves a sequence where the polytopic effect involves an injury where all of
the things developing at the time of the injury get affected. And thats monotopic and
polytopic effect. Its though, there is a hypothesis that what happens in Pierre Robin Syndrome
is somehow in the growth of the fetus that something constrained the mandible, so the
mandible, the micrognathic mandible was first and then all of these other things happened
because the mandible was micrognathic. It wasnt really clear, but right now thats the theory
of pathogenesis.
[60] Neville et al. Oral & Maxillofacial Pathology
Okay and heres a baby with Pierre Robin Syndrome.
[61] Causes of Birth Defects in Humans
Okay, so we have some time to move on and so well get into some of the information
that we have on hereditary disease and start that a little early. So see where weve been.
Unknown causes, were not going to be able to do that. Those birth defects that involve, that
are due to unknown causes can have any one of those or multiple of the developmental
abnormalities that weve already described. We just dont know exactly why they happen so
they fall in this large category of unknown causes. Weve talked about drugs, weve talked
about drugs and chemicals, well put those together. Weve talked about maternal infection,
and notice where they are in terms of the percentages.
[62] Mutations = A permanent change in the DNA
Okay. So when we get to genetics and we talk about mutations, were talking about a
permanent change in DNA. So germ cell mutations are transmitted to offspring. Somatic cell
mutations may cause developmental or congenital effects or cancers, but somatic cell
mutations are not transmitted to offspring. Some of you that have studied genetics have this
clear, and some of you that havent studied as much might have to think it through a little bit,
but again its not really a difficult concept to understand. In order to get an inherited defect or
an inherited disease or any inherited trait, it has to be a mutation or it has to be a genetic
component of germ cells. There is a term thats called a point mutation. And that point
mutation is when a single nucleotide base is substituted for another one. Then there is another
kind of abnormality where you can get a DNA change, we can get a couple of base pairs that are
either deleted or inserted in a place where they dont belong. And then there is something that
almost acts like a stutter where you get multiple trinucleotide repeat mutations, and any one of
these possibilities can end up causing either a developmental abnormality or an inherited
disease depending on what can be sorted out.
[63] Developmental and Genetic Disorders
Okay so we are going to talk first about single gene defects, and for these I think that
most of you have been through this before, if you didnt do it in college you did it in HS biology.
And that is those traits that are transmitted using the Mendelian inheritance pattern, and well
talk about those first.
[64] Single Gene defects Mendelian Disorders
And the idea or the hypothesis behind this type of disorder is that single genes encode
identifiable traits. And again, Im sure most of you did this in HS biology. If you have two copies
of the same gene, then its called homologous. And it means, well talk a little bit about alleles
and loci in a little bit for those of you that didnt have this in college. Autosomal genes are
those that are on the autosomal chromosomes. And the sex-linked genes are the ones that are
on the X chromosome. There are some Y chromosomal abnormalities but they are
extraordinarily rare. We will mention them when we get to the end.
[65] Human Karyotype
This I think you should all recognize as the pattern that is called a human karyotype. And
what were looking at here, is a normal, or at least under karyotype, a normal karyotype, and
can you figure out if its male or female? Its male. Okay, and so heres the X chromosome and
heres the Y chromosome. Did any of you get to do this? Did any of you get to make karyotypes
when you were in college? Okay. In the olden days, the way this was done, and I cant even tell
you how old, but I know that when I was in college, and even in dental school, it was still being
done this way. The way karyotypes were developed was to uh, capture cells that uh, and
stimulate them into division. And usually its done with buccal mucosal cells and some lymphoid
cells. And you stimulate those cells to divide and the you capture the cells that are dividing and
you blow them up into a, I mean you magnify them is what I meant by blowing them up, and
then you capture the chromosomes and you pull the chromosomes out and match them up,
and Ill show you up in a little while how you match them up, and you actually paste them onto
a grid that was the way a karyotype was developed. Now, you can imagine how its done now.
Its not done with a scissors like with a paper doll. Its obviously done with a computer and you
can move these things around and find the place where they go. So, but at one point, this was
all done by cutting and pasting and getting all the pairs of chromosome s together. There are
some disorders where you can pick up the disorder by actually examining the chromosomes but
others you cant do that way. And I figure you have all found the X and Y chromosomes, so this
is normal male chromosome.
[66] Locus vs. Allele
Two words that are helpful to know, is the term locus and alleles. The locus is the term
used for the place on the chromosome where the gene resides. The term allele, or alleles, is
the term thats used for the two genes that are coding for the same thing on the two
chromosomes. One chromosome comes from the mother, one chromosome comes from the
father and you have two loci for alleles for genes that are coding the same thing.
[67] Classification of Mendelian Traits
Okay, um there are patterns of Mendelial traits or disorders that are well understood at
this point, where, and these are the same patterns that are used for traits that are normal.
Same kind of pattern that are used for eye color. A number of different normal traits follow
this pattern, but at this point were in pathology so were going to talk about these patterns of
inheritance as we look at them toward the way diseases are transmitted from one generation
to another.
One pattern is called autosomal dominant, and in autosomal dominant it means that
one gene of the pair will control the trait or the presence of the disease. So in an autosomal
dominant, the gene that were talking about, and here, the gene that is responsible for the
disease in pathology is on only one chromosome. So, either the mother or the father, we really
dont know at this point until we talk about the disease, is on an autosome, not on one of the
sex chromosomes, and the individual only has to inherit one. And so this means that either the
mother or the father can have the trait or the gene for the disease, and if the child gets that
chromosome with the gene, the abnormal gene, the disease will be evident most of the time.
In biology nothing is all the time, I think, but you only need the one gene, and that is called
autosomal dominant. There is one gene that controls the presence of the disease. You only
need one. Now, its possible that the parents went to some support group and you have two
people that both have the same disease and both have the same gene and you might even have
a child thats born with a, that happens to have two of the affected genes, and usually the
abnormality would be more severe. But it only requires one gene for the disease to emerge, or
for the trait to emerge when its normal.
Autosomal recessive means that the disease is only going to show when both parents
have the abnormal gene and the baby gets both of them. So that the parents were very often
have one normal gene and one diseased gene. Its possible, well, well do that in a minute. So
the parent has one normal and one abnormal. The other parent would have one abnormal and
one normal and the baby would get both. But not all the kids in that family are going to get
both genes, some of them are going to get one, and some of them are going to get none. The
ones that are going to get one, their children will never see that disease, those that get one, if
they find a mate that has that abnormal chromosome, they have the risk of having the
abnormal, the disease emerge. And then, if you ha eth child that has two, that child is going to
show the disease. Thats autosomal recessive.
Sex linked, for the most part, the genes for the trait or the disease reside on the X
chromosome. And there are, again, there are a couple of rally pretty rare diseases where the
problem is on the Y chromosome, but almost all sex-linked inherited diseases are related to the
X chromosome so we spend most of our time talking about those because the others are so
rare and usually for us in dentistry, the children usually do not survive so that they become part
of even our pediatric dentistry word. So in X=linked dominant, the same rules are true, sort of.
Ok. So you remember that in the autosomal patterns, you had two identical chromosomes, or
two chromosomes coding, and two genes coding for the same thing. In sex-linked, thats true
of women, but its not true of men. Men dont have two x chromosomes, its women that do.
So we have a different setting in a male who develops the, who gets an abnormal gene. And so
theres X linked dominant and X linked recessive and well go at that in a little bit.
[68] Dominant vs. Recessive Traits
So, a dominant trait, this is what I mentioned already, requires only one allele of a
homologous pair. Ok. And the trait is present whether the allelic genes are homozygous or
heterozygous. So if the person happened to get two, you will still see the trait, you may see it
in a disease more severe, but youll see the trait if they get two. But you only need one. Okay?
Recessive trait, you have to have both, and thats called homozygous when you have
both traits the same. Sex linked traits again are on the X chromosome.
[69] Autosomal Dominant
So we have time to talk about autosomal dominant a little bit. Autosomal dominant,
obviously were on the autosomes so it has nothing to do with the X chromosomes. So males
and females are equally affected. And remember when the chromosomes and the genes are
passed from the mother and the father, okay, you have sort of a mix and match so you cant say
that, if you look at the risk youll get some description of risk, but each baby is a 50-50 chance.
Okay, but if you look at all of them, you might be able to change the risk in multiple children in
a family. But again, its males and females because theyre on the autosomal chromosomes.
Um the trait again, when were talking about it being on the the trait that is the mutant gene
can be transmitted from one generation to the next because even though they are autosomes,
they are being passed through the through the. Back here where we were well I want to
go back here (shes switching slides all over finding) Where do I want to go, just a minute.
*still flipping+ Well, Im going to skip what I was going to say because its going to come out
funny and I dont want to mix you up. So anyway, the trait is passed from one generation to
another, unaffected members of a family usually dont have the affected gene. Okay. There
are sometimes, and well talk about it a little bit later, where the affected gene seems to be
there, but silent, and it shows up in another generation. It would be nice if all of this was
perfect, but it doesnt always work perfectly, but for the basic rules for now, unaffected
members of the family dont transmit the trait to their offspring. Im going to try to hold that a
little bit in advance because its a not completely and totally true, so you can put a little star by
it for when we get a little bit further on in the lecture on Friday.
The proportions of normal and diseased offspring of patients with the disorder are on
average, equal. Yeah but you have to have a100 people, the family would have to have 100
offspring to be 50- 50 because each one is going to be 50-50 and so you could have a family
where you didnt have affected people and that would be the end in that line and youd have a
family where everybody gets affected. So again, each person has a 50-50 chance.
[70] Definitions
Okay here are our problems. Something called variable expressivity and something
called incomplete penetrance. Variable expressivity is a term used in those inherited diseases
where not all the individuals that have that given genetic disease are affected to the same
degree. One of them that is in our area that you will learn about is a syndrome called... ahh.
Jawbone cyst bifid rib syndrome, it has a number of different names and there are multiple
different abnormalities that occur in that syndrome. 50-60 of them, and not everybody gets
the same ones, even though they have that syndrome. So for us, one of the characteristic
features is a certain kind of odontogenic cyst in the jaws that those individuals get. But not
everybody in the family gets the cysts and not everybody in the family gets the bifid rib, and not
everybody in the family gets the calcified falx cerebri, so there are multiple different ways that
that condition can express itself. Thats called variable expressivity. And there are autosomal
dominant inheritance patterns that give you a condition with variable expressivity. And then
there is something called incomplete penetrance which really can be confusing because what
you have here is an autosomal dominant trait and it skips a generation. So how do you figure
that out and how do you explain that? Well, it gets explained by this term called incomplete
penetrance that sometimes the autosomal dominant trait just doesnt penetrate and show, so
there is a generation where the gene is there, and over time you know that that is a disease or
disorder that is transmitted as an autosomal dominant trait, and you use it in the grandparents
and you see it in the parents and it skips a generation then you pick it up and you see it again.
How do you explain that? Well explaining that is more complex than giving it a name. The
name for it is incomplete penetrance and its the term thats used when a trait does not emerge
in every generation even when its supposed to. The term pedigree doesnt mean the same
thing here as it does in our pets. It is, and Ill show you one, there is a number of different ways
of constructing a pedigree, and its the genetic history of an affected individual and its done by
making a map. Proband is a term for the individual for which where the map was started.
[71] Pedigree pattern for an autosomal dominant trait
And this is a pedigree pattern. There are a number of different ways of constructing a
pedigree. And if youve ever worked in genetics, depending on the group you worked with, use
their own system for developing a pedigree. Its done by genetic counselors to try to sort out an
abnormality that seems to be passing through a family in order to try to figure out whos
affected and figure out whether or not youre looking at an autosomal dominant trait, an
autosomal recessive trait or even a sex-linked dominant or recessive trait. And so the genetic,
the person dealing with the family will develop a map like this to look at the family history. So
the proband is indicated here by the arrow. Okay, so and you always have to have a key to be
able to figure out a pedigree. And if the key isnt there, forget about it because you cant do it.
You have to know what it is that the developer of the pedigree was using and what the symbols
mean to make sure that you can read the pedigree or you can understand the pedigree.
So here, in this pedigree, a square with, that is filled in, is an affected male, a circle is an
affected female, a square that, on this one, is an unaffected male and a circle, a white circle is
an unaffected female. So we start with the proband, and its this affected female. We dont
know what the condition is, but at this point it doesnt matter, we can make it into one of the
autosomal dominant ones that were going to do later, but this young woman has the problem.
And so what then gets asked is, um, do either of your parents have the problem. And if we back
up here, we find that her mother has the problem. Okay. We can ask, do any of your brothers
and sisters, well, if we started with brothers and sisters, we dont get very far because none of
her sisters have the problem and she doesnt have any brothers. So if you go over and ask
about her cousins, you find out that here is a male cousin that has the problem and hes the
only one, but there is a male cousin that has the problem. So again were looking at both male
and female that tare affected. So if we go back up to her parents, you find that one of her
parents, her mother, has the condition, and then we go back up to her cousin and find out that
she has, it looks like an uncle, that has the problem. And then we go back up here, and find as
far back as we can go, that there is a grandmother who has the problem and a great
grandfather. Well its nice to be able to go that far. So this disease in this family is something,
lets call it Marfans syndrome. WE know Marfans syndrome, we know about Marfans
syndrome, dont take notes right now because Im going to show you that in a minute and then
you can take the notes then. So Marfans syndrome, lets say for example this is Marfans
syndrome. Well, we know this disease, we know its an autosomal dominantly transmitted
disease, and suddenly, we come up with a family where there is one individual with Marfans
syndrome and you cant find it anywhere else in the family and you go back and back and back,
its assumed in this situation that you had a new mutation and you started the process and
since it happens to be Marfans syndrome, and we know its an autosomal dominantly
transmitted disease, that you can expect that the offspring of this individual with Marfans
syndrome are going to have the same risk as the offspring over here, even though you didnt
see it before, but you know at this point that that disease, and thats the way the disease or
that disorder is transmitted. It looks like you have a question. [Student: I think this is what he
said: could this be caused by decreased penetrance by any chance?] Well, it could be but its a
long standing problem with penetrance if its never shown before. So again, if you dont have
it, you dont have it. And you cant study what you dont have. Studying the negative becomes
very difficult.
[72] Locus vs. Allele
Okay, were back to our locus versus our alleles, heres our locus and heres our alleles.
[73] Pedigree pattern for an autosomal dominant trait (repeat slide)
And oh I went the wrong way. Thats where I went.
[74] Autosomal Recessive
Okay autosomal recessive. Okay, again, you need two affected genes, two affected
alleles on the loci, on each of those chromosomes. And the more infrequent the mutant gene
is in the general population, the less the probability that unrelated parents are heterozygous for
the trait. Does this make sense? Because Ill spend a couple minutes on it in case it doesnt. If
this gene that can cause this problem is really rare, it is much, its unlikely that you get two
people together. Its not impossible, but its unlikely that you get two people together so the
disease itself becomes very rare. However, in cultures where there is, there are more people
with that trait, or that abnormal gene, then its more likely that you will get two people
together with the same gene. And thats why youre certain inherited disorders that are more
common in one ethnic croup that another. When theres more people, even if you dont have
cousins marrying. I mean, any boyfriend that I every brought home, the first thing my
grandfather asked was, Is he Norwegian? because I wasnt supposed to find anyone that
wasnt Norwegian, well, I did, and so the rest is history. But I think some of you have the same
kind of issue, that your parents, or most likely your grandparents would like you to find
someone that is more like them. And so we have cultures where certain genetic problems are
more common than others and then those diseases become more common in that group of
people. So as long as we have a really rare abnormal trait that is really rare and you keep
people kind of mixing and matching, then that autosomal recessive disease stays nice and rare.
And autosomal recessive diseases tend to be pretty rare. Both parents are usually, not always,
but usually heterozygous for the trait, and both parents are usually clinically normal. It is
possible in certain circumstances for the parents to be homozygous, and Ill give you a situation,
and that is in cystic fibrosis.
Cystic fibrosis is probably the most common autosomal recessive disease in the US. And
it used to be that kids with cystic fibrosis didnt live past their teens. Well now people with
cystic fibrosis are living into their 30s and 40s and so there is the possibility that a
homozygous, which a person with cystic fibrosis is going to be homozygous is going to be able
to be old enough to be able to have children. And those children of the person who is
homozygous would be heterozygous and not homozygous, but again, so both parents are
usually heterozygous, is true if its true. Okay. But it is possible that you might have particularly
now, as certain diseases are managed better, you might have parents who are not clinically
normal. So again if we go to statistics, symptoms in the offspring appear on an average of a
fourth of the offspring, well thats again if you have 100. Okay, if you have a family with 100
kids, you might be able to, to do this. But it doesnt work that way in a family, so a family will
have one affected child and three unaffected or all affected and none non-affected because
again, each child is getting one of the parents genes and you dont know what it is until you get
there. Okay. And so... those children that get the gene and only get one of them, are not going
to be affected and the parents usually will only have one gene.
*75+ Autosomal recessive traits are transmitted.
Okay, autosomal recessive traits are transmitted evenly to males and females. Um.
Compared to autosomal dominant traits, autosomal recessive disorders are usually much less
variable. People with autosomally recessive diseases almost always have the same complex of
disease. They are very very similar and most of the time, autosomal recessive disorders are
seen very early in childhood so either it is in newborns or very early in childhood that its clear
that this disease emerges. Thats not true in autosomal dominant traits. Autosomally dominant
diseases or particularly diseases can emerge in much older individuals.
[76] Pedigree pattern for an autosomal recessive trait
So here we look for a pedigree pattern for an autosomal recessive trait. We dont have
on this one a proband so we dont know where this one started but we do have a key. Same key
as before because I dug it from the same book, and one thing thats different here is this is a
related, the mother and father are related and thats the consanguineous mating here and
thats indicated here by the double line. And so here what happened is you have two related
individuals mating, they both had the abnormal gene and they had multiple kids and they were
transmitted, the autosomal recessive disorder to their, to two of their kids. To one girl and one
boy. We dont know from this whether or not these received the abnormal gene because we
just dont know. We do know that these received two. And there are possibilities now of
identifying the abnormal genes and predicting ahead of time who has them and working from
there.
I think from this point well stop right here. Its 4:50 and well continue with this on
Friday.