26/27: developmental & genetic disorders

8/11/2019 26/27: Developmental & Genetic Disorders

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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, umabout the nature of the second exam and yes the second exam is cumulative because um as wemove on in this course, its very hard to separate out what you had before from what you havenow. Clearly, most of the exam has to be on new stuff because we have a 60 question examand in order to cover the new stuff, I have to spend most of the 60 questions covering the newstuff. But you will have questions that inter, that use some of the new stuff and some of theold stuff. And there will be some of the old stuff, some questions kind of straight from the oldstuff, but not very many. Okay? It real ly cant be a major part of the exam. When we get tothe final, it will be a little different because by that time, everything is interacting orinterconnected and you already, youre working with, for example youre working withimmunology to do inflamma tion, so to make, there is no way of making them separate. So itscumulative but when you look at the exam, most of the questions on the exam will look likethey came from new stuff. I cant make it nay clearer than that. But you really cant forget anyof the old stuff because its going to come up on this exam and its going to come up in this andthe first material will come up on your final. Okay?

So our unit for the next two sessions is developmental and genetic diseases. And thedevelopmental 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 ofpathology is a basic knowledge that lets you understand the way the diseases that are geneticdiseases work. So for those of you that studied genetics and spent a lot of time studyinggenetics in your undergraduat e days, this stuff should be easy, youll just have to add thediseases portion to it if you havent had that before.

So were going to start with some of the developmental concepts and then work on thegenetics, 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 thosediseases. Some of them are conditions that are caused very specifically by factors that are inthe 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 inSystems pathology and then again as you get to oral pathology next year. And those areconditions that are determined by genetic abnormalities. And then we have some that requireboth in order to occur. So there is this spectrum of developmental genetic diseases and it


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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. Andbetween unknown causes and inherited diseases, that accounts for about 90 percent of thebirth defects that are described in humans. And then there are some others. Cytogeneticdiseases well talk about on Friday. Drugs and chemicals well talk about some of that in todayslecture. Radiation well talk about a bit more when we get to the end of the course. And welltalk about radiation in pathology. Mater nal infection we re gonna to talk about today. Andsome maternal metabolic factors , theyre really very rare and were not going to speak muchabout either those or birth trauma or, uterine factors we are because there is one set of birthdefect sequence that fits into that category. But if you look at this, most of them belong up atthe 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 diseaseand 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 wouldlike to not ask you the definitions on your exam, but on the short answer I might. That, I mightnot ask you the definition itself but actually give you some examples of these and then haveyou work out the, use the word.

Congenital abnormality means that the abnormality was present at birth. It may be thatit is identifiable at birth or it may not be identified til later, but it was there. So a congenitaldefect, or a congenital abnormality is an abnorm ality that is present at birth. And thats whenyou use congenital

Developmental disorders is really broad. Its a broad term that can be used for, used ina number of different contexts and as we looked at a congenital abnormality, a congenitalabnormality can be an environmentally induced abnormality and it would be a developmentalabnormality. It could be a genetically caused abnormality, it would be a developmentalabnormality. So it is just a very very broad term that talks about abnormalities that are relatedto fetal development

Hereditary trait or disease is much more specific. And this is a trait thats transmittedfrom generation to generation. And not all of these are present at birth. The geneticcomponent is, but the abnormality or the disease itself may not be present at birth and mayshow itself later on in life. And you will see a number of those that have head and neck or oralmanifestations

Lets move here *I think thats what she said?+


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*5+ Syndrome:..

Okay. The term syndrome is not just used in relationship to developmental or geneticconditions. But it is very commonly used here. But there are diseases that are neitherdevelopmental 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 ofthose genetic diseases. And its not an environmental , its the developmental abnormality thatyou would see congenitally because you dont see Sjogren syndrome until you have adults andusually adults over 40. So its a set of signs and symptoms. Youll see that term syndr ome a lotas we work through pathology and as you get to systems pathology, youll work on a number ofdifferent symptoms. But here in the developmental and genetic group of diseases, again, itsthose things that occur together but its not specific to t his 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 youdlike, messed up morphogenesis. So a malformation has to be occurring during the time ofdevelopment of a human

The term anomaly is used also. And this is used in relationship to development al or geneticanomalies. Its not usually used in terms of other systemic diseases that dont fall into thiscategory.

And then the term teratogen is an agent that can cause developmental abnormalitiesand Im going to show you a couple of those. I wont give you the examples now, Ill give themto 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 yourhand and say I dont know what youre talking about. Okay, and then on Friday were going totalk about genetic disorders and divide them into single gene defects, chromosomalabnormalities and then those that are polygenic inherited diseases. And well move along withthat on Friday.

[7] Developmental Disorders (Errors of Morphogenesis)

So we have a group of abnormalities that have names, and these different kinds ofabnormalities 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. Andothers will be either an environmental cause or a fetal environmental cause. So you need toknow these and they sound awfully similar, some of them, to some of the words we had right inthe beginning of these course. But they are different and they mean something different and


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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 softtissue or it can be in bone. But its a pathologic cavity. And a true cyst is a cavity that is lined byepithelium, and thats a cyst. So we can have cysts in soft tissue, and one of the cysts that wework 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 andits related to a tooth that has become necrotic and the development of that cyst is somethingthat we can talk about in another course.

The maxillary sinus is a space in b one. Its completely lined by epithelium. Is it a cyst?No! Its not a pathological cavity, its a normal anatomic cavity. Doesnt mean you cant haveabnormalities in a sinus, but a sinus itself is a cavity in bone tha t is lined by epithelium but itsan anatomical structure. A cyst is a pathologic structure, its not supposed to be there. In somepatients, a cyst develops in the third molar area. Now we have lots of cysts that develop in themaxilla and them mandible . And as you get to oral pathology net year youll have to know thenames of all of them, where they are and how they form, and some of them are formed fromteeth and some of them are not formed from teeth. And in the world of oral pathology, or theworld of pathology, there are no other cysts in bone in the rest of the body. All of the cysts inbone are in the maxilla and mandible, so we own all of the bone cysts when it comes topathology. Soft tissue cysts, thats different. There are soft tissue cys ts that occur in skin and inmultiple 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 isprojected. Notice that there is a very well circu mcised radiolucency, its coming over theresome place, okay? And when we talk to this patient, notice theres supposed to be a third molarthere. 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 athere, and from our experience looking at odontogenic cysts, were looking at a cyst that lookslike its formed from odontogenic epithelium. Whats it doing there? Well in order for i t to bethere, there has to be some remnant of odontogenic apparatus in order for that epithelium toform a cysts. So we call this a primordial cyst and it would be an example of a rudiment of theepithelia 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 itsounds 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


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hyperplasia? Hyperplasia among our, in the beginning of the course was described as? Anincrease. In the number of cells and the size of the organ. So hyperplasia was an increase innumber of cells. We might have a developmental problem that was hyperplasia, but we talkedabout hyperplasia when it was a response to injury. So its an increase in the number of cellsand the size of the tissue organ. We had it as a reactive response in the beginning of the coursewhere, if you remove the irritant, the hyperplasia would resolve. In a developmental context, ifyou 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 developmentthat we didnt have with the ce lls in the beginning of the year, was hypoplasia, which is a wordthat describes the reduced size of an organ, and its due to a problem in development, notanywhere related to the, to an irrita nt. Its related to development. Does anyone rememberwhat the word I gave you in tissue responses as the opposite of hyperplasia? What makes itsmaller? Atrophy. And in that context, we used atrophy two different ways. One was when thecells 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 tothat nutritional deficiency. So within that context of reactive lesions, or reactive cellularresponses, 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 hypoplasticmandible. Hypoplastic organs, and youll see that as certain abno rmalities are described.

[15] Hypoplasia - Micrognathia

This is a baby with a hypoplastic mandible. And its called Micrognathia. You could alsohave a hypoplastic maxilla. You could have a hypoplastic ears, you could have hypoplastic armsor 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 thebeginning of the course.

[16] Turner Hypoplasia picture

There is a phenomenon i n our dental world thats called a Turners tooth, or Turnerhypoplasia and in this situation, what happened, this is a permanent tooth. And whathappened is there was a problem with the primary tooth sitting right on top of this tooth whilethis tooth wa s trying to develop. So this tooth didnt develop, a lot of the tooth itself didntdevelop. Thats hypoplasia. And youll see as we get to dental abnormalities there are anumber 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 hypoplasiaslater on.

[17] Dysraphic Anomaly

Okay, another one of these developmental abnormalities is something known as adysraphic abnormality. And this is an abnormality that is caused when structures that aresupposed to fuse dont fuse. And so if youve looked ahead in your PowerPoint handout, we


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have a really good example of this in dentistry. *+ The palate. Okay? The palate is supposedto 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 oneyoull see more than cleft palate. If youre working in a cleft palate clinic, youll see lots of cleftpalate. 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 likeit 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 mostcommon 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 dramaticallyincreased requirement for folic acid in pregnancy so it appears that this may be one of thecauses 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 doesn t close. This is adysraphic defect.

[19] Pictures of clefts

And heres a cleft palate and a bifid uvula. And cleft lip. These are all dysraphicabnormalities and there are many of them, but I think this would help you to remember whatthe, 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 ofdevelopment. 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? Howabout the back row, where does it start in the oral cavity? [back of the tongue] On the back ofthe tongue, and whats the marker? *foramen cecum+. Foramen cecum, okay, thats the oralcomp, the oral site, and so the thyroglossal duct or tract is the tract that the thyroid followsfrom its initial development on the base of the tongue down to its final resting place in thelower part of the neck below the cricoid cartilage. Thats how the thyroid gets from where itstarts to where it goes. Okay. And it probably very often leaves remnants. But we only knowabout it when we have some pathologic entity that tells us that those remnants were leftbehind. And there is a cyst called thyroglossal duct cysts, or thyroglossal tract cyst, which is acyst in soft tissue, so its a pathologic cavity, and its lied by epithelium and the epithelium isderived from that thyroglossal tract that the thyroid followed. And to make our lives a little biteasier, when these cysts are identified, usually there is some residual thyroid thats in the softtissue around the cyst. Its an interesting cyst and for those peop le that get one, if the entiretract isnt removed, theyll get another one. And the tract goes right through the middle of thehyoid bone, so usually to remove the tract, they remove the tract plus the middle section of the


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thyroid [hyoid] bone. And apparently people get along fine without the middle section of theirthyroid [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 I mtrying to give you examples so that you have something to hang the definition on as we movefurther on into pathology in this course and then in our systems pathology, oral pathology andeven when you get to pediatric dentistry, some of these are going to come back and have moreexamples for you.

[22] Division Failure

Okay so a division failure. Division failure happens when something is supposed tocleave and it doesnt. In development there are certain structures that form because theprogram 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 dontseparate. And that separation or division of fingers and toes occurs because theres anapoptotic 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 theressupposed 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 thehole doesnt develop where the valve is supp osed to be. There is a description of atresia in adental environment where there is a dentin abnormality where you dont form a pulp. And inorder to maintain our vital teeth, you need pulp in the center part of the tooth. Theres alsoatresia of the colon. And so that in those individuals. And those are congenital abnormalitiesthat 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 littl e bit later.

[25] Esophageal Atresia diagram

Here youre looking at a diagram. Heres the trachea, and heres what should be theesophagus 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


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And here is an example of dentinal dysplasia and by now, you know what teeth aresupposed to look like and you know theres supposed to be a pulp chamber and pulp canals inteeth 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 ifyou remember back at the beginning of the course, we talked about epithelial dysplasia. Andepithelial dysplasia is defined as an abnormality in the epithelium, in the basal layers, in thematuration of the epithelium, but it is an abnormality that occurs long after the development ofthe 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 wetalked about this as far as we know that this point, it is usually a premalignant change or itsconsidered a premalignant change. Thats epithelial dysplasia and that term only goes toepithelium. 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 itsdevelopment, but they do occur and the tissue is abnormal. And so the term dysplasia is aneffect 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 differentfrom epithelium. There is a disease called fibrous dysplasia that youre going to talk aboutsystems pathology and talk about it in oral pathology where the bone is abnormal. And insteadof having normal trabeculae and normal marrow, there is combination of irregular trabeculaeand a lot o f 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 doesntdevelop in relationship to function, and so we call that fibrous dysplasia but its a dysplasia ofbone. Its not pre -malignant. Its a benign condition. It is, it can be a problem for patientsbecause 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 anabnormal development of the trabeculae and the marrow and it just is kind of, there is ageneralized abnormality . Here is a tra *shes struggling to say the word..+ these aretrabeculae, I can do it better plural than singular, and then this is what would be marrow and isvery cellular connective tissue. And again its an abnormal development of the bone but its notpre-malignant.

[30] Dentinal Dysplasia

A few minutes ago I talked about dentinal dysplasia Here, w hats abnormal is thedentin. The development of the dentin or the development of the dentin never developsnormally. It doesnt develop normally in change, it never develops normally. And s o we havean abnormal dentinal development, we call that dentinal dysplasia. It has nothing to do with a


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premalignant lesion. The premalignant lesion with dysplasia is only used for epithelium and itsnot 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 notgoing to ask you to learn the different between these two words because the medical literaturemixes them up all the time. And uses one for the other and the other for the other. And so Iwould like you, you could lump them together for now, if you get a course where someonewants you to separate them its fine, but for this course you do not have to separate these. Andso its a dev elopmental 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 wellcircumscribed 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 tissueand its normal salivary gland tissue. And so this, the right name for this, or probably theclearest name for this is a developmental salivary gland inclusion. Now, you will see this calleda stafne bone cyst. Okay its one of the pseudocysts were goin g to bother you with in the jawswhere, what do you think makes something a pseudocyst? [response] I wish I could hear you alittle better because I bet some of you are getting the right answer. Its not lined by epitheliumbut 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 submandibulargland developed, somehow the gland actually became incorporated in the mandible. And sothis is the mandible and this is salivary gland. And its an extension from salivary gland from thefloor of the mouth.

[34] Skull picture

This is somebody found a, a skull that exemplified the kind of thing thats happeninghere. If you take an x-ray of this skull, because there is less bone in this area, its going to looklike a very, very well circumscribed radiolucency. Its going to look like a cyst. But it isnt a cystat all, its just this salivary gland material that isnt where it belongs. Its supposed to be on thefloor 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 duringdevelopment. The interesting thing is something called an ectopic kidney is actually dystopickidney. So these w0ords get used and I really have trouble making you guys go really fussing


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over ectopia and dysto pia because theyre mixed up on a regular basis. So if you se e ectopic ordystopic , recognize that something isnt in the right place. So um dystopia is something thatis, if you do this in ectopic means its where it doesnt belong. Dystopic means that it isdeveloping in an area where it belongs but its not the right thing. And Ill give you the bestexample of a couple of them.

One of them is the thyroid develops in the posterior part of the tongue. And if it doesntdescend and it stays there, thats dystopic thyroid, except it will be called ectopic thyroid if youlook in a number of different textbooks. So again, this is an example of dystopia, but dont besurprised if its called ectopic. Also, Fordyce granules, you all know about Fordyce spots andFordyce granules. Very often they are called ectopic sebaceous glands because sebaceousglands are supposed to be on the skin. Okay, but these are in the oral mucosa. The problem isthat 90% of adults have Fordyce granules, so how can they be ectopic when most people havethem? But anyway, they arent on s kin, so they get the term ectopic sebaceous glands.

[36] Dystopia Lingual ThyroidAnd 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 bre ak. 5minutes. I was asked to not go without giving a break. Stand up, its 3:44, by that, I dont wantto go quite til 4 because then you wont get a break in the middle. So stand up and get astretch and Ill start talking again in 5 minutes.


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[37] Po lytopic developmental effect: .


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Okay lets go again. When we talk about developmental abnormalities, there are,several categories we re going to be talking about. Were going to talk about something called apolytopic developmental effect, something called a monotopic developmental effect, singlegene defects, chromosomal abnormalities and as I said before some polygenic inheriteddiseases. And these are different categories but within those categories we can find thedevelopmental abnormalities that we were just talking about. And those developmentalabnormalities 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 thedifference between a polytopic and monotopic effect clear. As you know, a fetus, an embryofetus is developing and different organs develop and different structures develop at differenttimes. But also, many of them are developing at the same time. Right? Okay. In a polytopiceffect, 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, thatassault, gets, can get affected. And so its polyto pic because you can have different organs thatwere developing when this event occurred. Thats a polytopic effect . A monotopic effect isdescribed as a sequence which is, you can have multiple abnormalities that happened with amonotopic effect, but there is one thing that starts it, and the rest follows. So there issomething called potter complex and well talk abo ut it, where there is a problem withamniotic 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 formingat that time. And so its called a developmental sequence anomaly when its a monotopiceffect because something happens, and because that happens, the next thing happens and thenext thing happens and the next thing happens. So the difference between polytopic andmonotopic 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, orwhat might be abnormal here, is whatever in the central nervous system is developing,something with the heart. Now pro bably not the arms because they havent started yet, andeyes would probably be okay, and legs, and so on. And so you have to, again, see what wasdeveloping 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 thathave teratogenic effects, again, remember in the beginning we talked about what a teratogeniceffect is. And so thalidomide is one drug, there are others. And, and you need to be verycareful if you prescribe drugs that you have, that you know whether any of them that you


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born and if the mothers infection has infected the newborn, then those developmental effectscan continue unless the baby is treated for the infection. And Ill show you probably the classicexample of that in a minute.

[47] Torch complex picture

But if you look at this diagram from your textbook for TORCH complex, there are eyeproblems that include some problems with the retina and with the conjunctiva, there is asmaller head that occurs, there is some problem with the brain, there is smaller eyes, there issome skin lesions, there is a larger spleen, some heart disease, some liver abnormalities andsome problems with lungs. So these are a complex that if one of them is present its not so easyto identify the infe ctious disease but they dont usually work that way. The infectious disease isstill, like alcohol, kind of a longer term effect so while the mother is infected, the baby isinfected and these specific infections will cause teratogenic effects. Every maternal infectiondoesnt 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 p icked this up from your oral pathology book but Imnot going to tell you exactly where it came from because I dont want you to memorize it. I putit in here for one reason, and that is to show you how many different abnormalities could bepart of this complex of TORCH complex. So what I want you to know about torch complex: Iwant you to know what the initials stand for and if you know the components that are on thisdiagram, thats enough. If you want to go memorize all these, go for it. Except that it isntnecessary 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, likethe 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 inpediatrics or probably oral pathology, talking about congenital syphilis. The organism thatcauses syphilis, Treponema pallidum is transmitted to the fetus by a mother who hasdeveloped, who has syphilis during pregnancy. The mother could develop before thepregnancy, syphilis does not always clear, there are multiple stages of syphilis, well talk aboutthat when we get to infectious disease. Syphilis is a condition that does not, in some people,doesnt resolve unless its treated. There are some p eople with syphilis that it does resolve, so Idont want to make that too adamant. But any time that the organism can invade the fetusduring any time during the pregnancy, however, when it does, it is going to cause polytopiceffects. But it can be from any time very early on, right through the birth of the baby that thisorganism 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. A fter the16 th week of the pregnancy, then some of the dramatic effects develop.


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[50] Diagram

And here is where, in syphilis, some of the most dramatic effects development.


So the development, the effects that, some of them are in our area, there is a nosechange 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 bewhats called a saddle notes because the bridge is flat. And the baby that is born with syphiliswill have very often a maculopapular rash, which is a flat rash with some papules in it. Therecan be cracks and fissures in the mouth and in the mucosal area around the anus and vulva inbaby girls. There is a lung infection, or a lung inflammation that occurs. There is enlargementof 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 toinflammation 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.


Uh bones. Is that a question? Okay. Bones are involved and there is a change in theconfiguration of the legs. A saber is a curved sword and so the legs take on a curvedappearance. There is a progressive change in the cornea that can lead to blindness. There ischange in the brain, infection of the brain and then something called Hutchinsons triad, whichincludes 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 saverconfiguration 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 Hutchinson s incisors. Theyare sometimes called screwdriver shaped incisors and you can see by the notch here. Mulberrymolars- you may find an abnormal shaped molar that is mulberry-ish that has nothingwhatsoever to do with syphilis. But these teeth combined... and keep in mind that you knownow when these teeth are developing, so if the syphilis infection is ongoing at the time whenthe incisors, the incisors and the molars, first molars are begin developed then we might seethis kind of change but if we look back at the premolars, the premolars arent changed so its


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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 ifthe 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. Andyoure going to get this later. What Id like you to stick to now is the ones Ive given you on theppts. So you really dont have to go memorize these. I just want you to know that there aremore 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 usuallyeasy. Where I really have trouble is when I try to explain to you what a monotopic effect is.

And partly beca use its hard to find examples of a monotopic effect that really make it as clearas the polytopic effect. But here, think of it descried as a sequence. And when you think about asequence 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 weredeveloping 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 isn t just one abnormality. You stillhave a pattern of abnormalities but the way they develop occurs differently in a monotopiceffect than a polytopic effect.t okay.

[58] Potter Complex

Potters complex is something that occurs because there is a decrease in the amount ofamniotic fluid. And thats what starts the problem .and because of that, the feet are shapedabnormally. There is a change in the kidneys. There is an abnormality in thaw ay the handsdevelop and are positioned there are smaller lungs and there is another , you dont have toworry about the amnion nodosum but what Im really concerned about is that you understandthese abnormalities in the fetus are occurring not because of something that was damaging thefetus at a single time or even an extended time in its development but one thing started thesequence 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 yourenot likely to find, unless you really are in very early pediatric dentistry, and dealing withsyndromes and abnormalities in children, to deal with Pierre Robin Sequence. But again, this issomething that happens because one thing started the process and what apparently starts theproc ess is the tongue doesnt descend and because the tongue doesnt descend and its notclear why, the palatal shelves dont fuse. And as a result there is a cleft palate. And as a resultthere is a retrognathic retruded mandible . And Ive already shown you a child with Pierre Robin


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syndrome earlier on in the lecture. And the tongue obstructs the airway. So there is a change inthe way the tongue fits in the mouth. And all of this is because the tongue didnt descend andthe other pieces of development didn t fall into sequence and thats a monotopic effect.t somonotopic effect involves a sequence where the polytopic effect involves an injury where all ofthe things developing at the time of the injury get affected. And thats monotopic andpolytopic effec t. Its though, there is a hypothesis that what happens in Pierre Robin Syndromeis somehow in the growth of the fetus that something constrained the mandible, so themandible, the micrognathic mandible was first and then all of these other things happenedbecause the mandible was micrognathic. It wasnt really clear, but right now thats the theoryof 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 informationthat 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 t hat involve, thatare due to unknown causes can have any one of those or multiple of the developmentalabnormalities that weve already described. We just dont know exactly why they happen sothey fall in this large category of unknown causes. Weve talked about drugs, weve talkedabout 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 geneti cs and we talk about mutations, were talking about apermanent change in DNA. So germ cell mutations are transmitted to offspring. Somatic cellmutations may cause developmental or congenital effects or cancers, but somatic cellmutations are not transmitted to offspring. Some of you that have studied genetics have thisclear, 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 oran inherited disease or any inherited trait, it has to be a mutation or it has to be a geneticcomponent of germ cells. There is a term thats called a point mutation. And that pointmutation is when a single nucleotide base is substituted for another one. Then there is anotherkind of abnormality where you can get a DNA change, we can get a couple of base pairs that areeither deleted or inserted in a place where they dont belong. And then there is something thatalmost acts like a stutter where you get multiple trinucleotide repeat mutations, and any one ofthese possibilities can end up causing either a developmental abnormality or an inheriteddisease depending on what can be sorted out.

[63] Developmental and Genetic Disorders


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Okay so we are going to talk first about single gene defects, and for these I think thatmost 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 welltalk about those first.

[64] Single Gene defects Mendelian DisordersAnd 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 copiesof the same gene, then its called homologous. And it means, well talk a little bit about allelesand loci in a little bit for those of you that didnt have this in college. Autosomal genes arethose that are on the autosomal chromosomes. And the sex-linked genes are the ones that areon the X chromosome. There are some Y chromosomal abnormalities but they areextraordinarily 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. Andwhat were looking at here, is a normal, or at least under karyotype, a norm al karyotype, andcan you figure out if its male or female? Its male. Okay, and so heres the X chromosome andheres the Y chromosome. Did any of you get to do this? Did any of you get to make karyotypeswhen you were in college? Okay. In the olden days, the way this was done, and I cant even tellyou how old, but I know that when I was in college, and even in dental school, it was still beingdone this way. The way karyotypes were developed was to uh, capture cells that uh, andstimulate them into division. And usually its done with buccal mucosal cells and some lymphoidcells. 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, andthen 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 ontoa grid that was the way a karyotype was developed. Now, you can im agine how its done now.Its not done with a scissors like with a paper doll. Its obviously done with a computer and youcan move these things around and find the place where they go. So, but at one point, this wasall done by cutting and pasting and getting all the pairs of chromosome s together. There aresome disorders where you can pick up the disorder by actually examining the chromosomes butothers you cant do that way. And I figure you have all found the X and Y chromosomes, so thisis normal male chromosome.

[66] Locus vs. Allele

Two words that are helpful to know, is the term locus and alleles. The locus is the termused for the place on the chromosome where the gene resides. The term allele, or alleles, isthe term thats used for the two genes that are coding for the same thing on the twochromosomes. One chromosome comes from the mother, one chromosome comes from thefather and you have two loci for alleles for genes that are coding the same thing.


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[67] Classification of Mendelian Traits

Okay, um there are patterns of Mendelial traits or disorders that are well understood atthis 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 ofinheritance as we look at them toward the way diseases are transmitted from one generationto another.

One pattern is called autosomal dominant, and in autosomal dominant it means thatone gene of the pair will control the trait or the presence of the disease. So in an autosomaldominant, the gene that were talking about, and here, the gene that is responsible for thedisease in pathology is on only one chromosome. So, either the mother or the father, we reallydont know at this point until we talk about the disease, is on an autosome, not on one of thesex 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 thatchromosome 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 calledautosomal dominant. There is one gene that controls the presence of the disease. You onlyneed one. Now, its possible that the parents went to some support group and you have twopeople that both have the same disease and both have the same gene and you might even havea child thats born with a, that happens to have two of the affected genes, and usually theabnormality would be more severe. But it only requires one gene for the disease to emerge, orfor the tra it to emerge when its normal.

Autosomal recessive means that the disease is only going to show when both parentshave the abnormal gene and the baby gets both of them. So that the parents were very oftenhave one normal gene and one diseased gene. Its possible, well, well do that in a minute. Sothe parent has one normal and one abnormal. The other parent would have one abnormal andone normal and the baby would get both. But not all the kids in that family are going to getboth genes, some of them are going to get one, and some of them are going to get none. Theones that are going to get one, their children will never see that disease, those that get one, ifthey find a mate that has that abnormal chromosome, they have the risk of having theabnormal, the disease emerge. And then, if you ha eth child that has two, that child is going toshow the disease. Thats autosomal recessive.

Sex linked, for the most part, the genes for the trait or the disease reside on the Xchromosome. And there are, again, there are a couple of rally pretty rare diseases where theproblem is on the Y chromosome, but almost all sex-linked inherited diseases are related to theX chromosome so we spend most of our time talking about those because the others are sorare and usually for us in dentistry, the children usually do not survive so that they become partof 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


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two chromosomes coding, and two genes coding for the same thing. In sex- linked, thats trueof 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 sotheres X linked dominant and X linked recessive and well go at that in a little bit.

[68] Dominant vs. Recessive TraitsSo, 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 orheterozygous. So if the person happened to get two, you will still see the trait, you may see itin a dise ase 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 haveboth 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 malesand females are equally affected. And remember when the chromosomes and the genes arepassed from the mother and the father, okay, you have sort of a mix and match so you cant saythat, 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 ina 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 genecan 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 togo 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 outfunny and I dont want to mix you up. So anyway, the trait is passed from one generation toanother, unaffected members of a family usually dont hav e the affected gene. Okay. Thereare sometimes, and well talk about it a little bit later, where the affected gene seems to bethere, but silent, and it shows up in another generation. It would be nice if all of this wasperfect, but it doesnt always work perfectly, but for the basic rules for now, unaffectedmembers of the family dont transmit the trait to their offspring. Im going to try to hold that alittle 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 100offspring to be 50- 50 because each one is going to be 50-50 and so you could have a familywhere you didnt have affected people and that would be the end in that line and youd have afamily where everybody gets affected. So again, each person has a 50-50 chance.


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[70] Definitions

Okay here are our problems. Something called variable expressivity and somethingcalled incomplete penetrance. Variable expressivity is a term used in those inherited diseaseswhere 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 multipledifferent abnormalities that occur in that syndrome. 50-60 of them, and not everybody getsthe same ones, even though they have that syndrome. So for us, one of the characteristicfeatures is a certain kind of odontogenic cyst in the jaws that those individuals get. But noteverybody in the family gets the cysts and not everybody in the family gets the bifid rib, and noteverybody in the family gets the calcified falx cerebri, so there are multiple different ways thatthat condition can express itself. Thats called variable expressivity. And there are autosomaldominant inheritance patterns that give you a condition with variable expressivity. And thenthere 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 figurethat out and how do you explain that? Well, it gets explained by this term called incompletepenetrance that sometimes the autosomal dominant trait just doesnt penetrate and show, sothere is a generation where the gene is there, and over time you know that that is a disease ordisorder that is transmitted as an autosomal dominant trait, and you use it in the grandparentsand 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. Thename for it is incomplete penetrance and its the term thats used when a trait does not emergein every generation even when its supposed to. The term pedig ree doesnt mean the samething here as it does in our pets. It is, and Ill show you one, there is a number of different waysof constructing a pedigree, and its the genetic history of an affected individual and its done bymaking 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 apedigree. And if youve ever worked in genetics, de pending on the group you worked with, usetheir own system for developing a pedigree. Its done by genetic counselors to try to sort out anabnormality that seems to be passing through a family in order to try to figure out whosaffected 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. Sothe proband is indicated here by the arrow. Okay, so and you always have to have a key to beable 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 symbolsmean to make sure that you can read the pedigree or you can understand the pedigree.


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So here, in this pedigree, a square with, that is filled in, is an affected male, a circle is anaffected female, a square that, on this one, is an unaffected male and a circle, a white circle isan unaffected female. So we start with the proband, and its this affected female. We dontknow what the condition is, but at this point it doesnt matter, we can make it into one of theautosoma l 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 backup here, we find that her mother has the problem. Okay. We can ask, do any of your brothersand sisters, well, if we started with brothers and sisters, we dont get very far because none ofher sisters have the problem and she doesnt have any brothers. So if you go over and askabout her cousins, you find out that here is a ma le cousin that has the problem and hes theonly one, but there is a male cousin that has the problem. So again were looking at both maleand female that tare affected. So if we go back up to her parents, you find that one of herparents, her mother, has the condition, and then we go back up to her cousin and find out thatshe 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 greatgrandfather. Well its nice to be able to go that far. So this disease in this family is something,let s call it Marfans syndrome. WE know Marfans syndrome, we know about Marfanssyndrome, dont take notes right now because Im going to show you that i n a minute and thenyou can take the notes then. So Marfans syndrome, lets say for example this is Marfanssyndrome. Well, we know this disease , we know its an autosomal dominantly transmitteddisease, and suddenly, we come up with a family where there is one individual with Marfanssyndrome 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 andsince 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 Marfanssyndrome are going to have the same risk as the offspring over here, even though you didntsee it before, but you know at this point that that disease, and thats the way the disease orthat disorder is transmitted. It looks like you have a question. [Student: I think this is what hesaid: could this be caused by decreased penetrance by any chance?] Well, it could be bu t its along standing problem with penetrance if its never shown before. So again, if you dont haveit, you dont have it. And you cant study what you dont have. Studying the negative becomesvery 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


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Okay autosomal recessive. Okay, again, you need two affected genes, two affectedalleles on the loci, on each of those chromosomes. And the more infrequent the mutant geneis in the general population, the less the probability that unrelated parents are heterozygous forthe trait. Does this m ake sense? Because Ill spend a couple minutes on it in case it doesnt. Ifthis gene that can cause this problem is really rare, it is much, its unlikely that you get twopeople together. Its not impossible, but its unlikely that you get two people together so thedisease itself becomes very rare. However, in cultures where there is, there are more peoplewith that trait, or that abnormal gene, then its more likely that you will get two peopletogether with the same gene. And thats why your e certain inherited disorders that are morecommon in one ethnic croup that another. When theres more people, even if you dont havecousins marrying. I mean, any boyfriend that I every brought home, the first thing mygran dfather asked was, Is he Norwegian? because I wasnt supposed to find anyone thatwasnt Norwegian, well, I did, and so the rest is history. But I think some of you have the samekind 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 aremore common than others and then those diseases become more common in that group ofpeople. So as long as we have a really rare abnormal trait that is really rare and you keeppeople 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 ispossible 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. Andit used to be that kids with cystic fibrosis didnt live past their teens. Well now people withcystic fibrosis are living into their 30s and 40s and so there is the possibility that ahomozygous, which a person with cystic fibrosis is going to be homozygous is going to be ableto be old enough to be able to have children. And those children of the person who ishomozygous would be heterozygous and not homozygous, but again, so both parents areusually heterozygous, is true if it s true. Okay. But it is possible that you might have particularlynow, as certain diseases are managed better, you might have parents who are not clinicallynormal. So again if we go to statistics, symptoms in the offspring appear on an average of afou rth of the offspring, well thats again if you have 100. Okay, if you have a family with 100kids, 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 becauseagain, each child is getting one of the parents genes and you dont know what it is until you getthere. Okay. And so... those children that get the gene and only get one of them, are not goingto be affected and the parents usually will only have one gene.

*75+ Autosomal recessive traits are transmitted.


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Okay, autosomal recessive traits are transmitted evenly to males and females. Um.Compared to autosomal dominant traits, autosomal recessive disorders are usually much lessvariable. People with autosomally recessive diseases almost always have the same complex ofdisease. They are very very similar and most of the time, autosomal recessive disorders areseen very early in childhood so either it is in newborns or very early in childhood that its clearthat this disease emerges. Thats not true in autosomal dominant traits. Autosomally dominantdiseases 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 haveon this one a proband so we dont know where this one started but we do have a key. Same keyas before because I dug it from the same book, and one thing thats different he re is this is arelated, the mother and father are related and thats the cons anguineous mating here andthats 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 weretransmitted, the autosomal recessive disorder to their, to two of their kids. To one girl and oneboy. 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 ofidentifying the abnormal genes and predicting ahead of time who has them and working fromthere.

I think from this point well stop right here. Its 4:50 and well continue with this onFriday.

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