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Genetics in Clinical Practice

Etiology of genetic disorders. 46 chromosomes, 6 billion base pairs of DNA, 100 thousand genes. They Human Genome Project is charging along, estimated by the year 2005 every gene will be mapped. Right now we are sitting, not quite halfway through the project and about 50 thousand genes have been mapped.

Weíll talk specifically about chromosome abnormalities first. You can again see children or adults who have developmental disorders either due to a change in the number of chromosomes or certain structural rearrangements. Again, remember your karyotypes: 46 chromosomes, 22 sets of autosomes that occur in pairs, the last pair are the sex chromosomes. Males have an X and a Y. Females have

In humans we can see whole chromosome changes. Polyploidy is very unusual. More of an obstetrical sort of a problem - by polyploidy we mean that you have a whole extra set of chromosomes. So an individual with 69 chromosomes and those sort of things. Because of phenomena like imprinting thereís a difference between if that whole extra set came from the sperm or the egg, but by and large it presents either with pregnancy loss, or with a molar pregnancy. Again, a whole extra set of chromosomes is not typically going to direct development in the way that youíd expect it to. So from a practical standpoint medically, at least in humans with birth defects or developmental anomalies, trisomyís and monosomyís are the major chromosome abnormalities. An important fact to remember is that chromosome abnormalities in and of themselves are actually very common. In fact, if you screen women very carefully with something lik

Again, I wonít take you clear back to your first year of medical school, but again non- disjunctional events are the cause of whole chromosome aneuploidyís. The vast majority of these are maternal. And most of these are miosis too. So these are the last stage of miotic development and mostly oocytes that are responsible for this. Again, something that I donít need to remind you, that thereís an association between these whole chromosome aneuploidyís and in advancing maternal age. That as the mothers get older the risk of not just Down syndrome but other whole chromosome aneuploidyís go up with an advancing maternal age, and again Iíve grouped them - over 42 is about 1:40. But in fact if you break it down and take it year by year, once you hit about 48 the risks are incredible like 1:8. So the risks clearly go up as maternal age goes up.

These are the major whole chromosome aneuploidyís in humans. Not very many to recognize because again most of these are lost as miscarriages and most are not compatible with postnatal life. So you donít see - other than Turnerís syndrome, other than an XO because of the unique nature of the sex chromosomes - you donít see chromosome monosomyís in humans. In other words, you donít see an individual born with 45 chromosomes, missing one of their chromosome 1ís. It just doesnít happen. The developmental sequelae of that are so severe that itís just incompatible with a successful pregnancy. So the only human

So real quickly Iíll go over the major human chromosome aneuploidyís and again, more from the standpoint of pointing out healthcare issues with them and the things that probably the general practitioner should know, as you follow these kids in your practice. Most importantly, because you are here and you paid your money, hopefully put in such a way that you can answer your board questions.

So weíll talk about Turnerís syndrome first. Again, this is the only human chromosome monosomy. Little girls born with the missing x chromosome, the phenotype should be familiar to you. This is just showing you the more classic features. The girl on the right showing the very marked webbing of the neck, that broad

A couple of things to remember. This is also a fetus with Turnerís syndrome. Remember most of these conceptions are lost as miscarriage. Most of the time itís a very severe phenotype and again, what you can see in this baby is one of the most striking features is this marked lymphedema. Thereís something about an XO karyotype that these individuals just donít have the proper lymphatic flow. The reason I show you this slide again is to kind of put into your minds as you think about your test questions, that sort of stuff, is this explains a lot of the things that you ought to know. Number one: you can see why these individuals have a webbing of the neck. You can see that marked accumulation, that cystic hygroma on the back of the neck there. You can see why that when that fluid resolves

The other important aspect, at the other end of the spectrum is out of that very long list of features that you know about with Turnerís, like everything else in genetics the more striking cases got described first. But in fact that a full 50% of girls with Turnerís syndrome have nothing more than short stature and ovarian failure. So all those other features that you look for arenít going to be there. So again, idiopathic short stature outside of the genetic potential in a girl is an

Klinefelterís syndrome. Now we are into the extra chromosomes. Klinefelterís syndrome, 47 chromosomes now. The extra chromosome is an x. Hereís a textbook case presentation. A male with very small mushy-feeling testicles. You can see the gynecomastia due to the sequelae of having primary testicular failure. This so-called described eunuchoid habitus. This very tall individual in which the excess height is in the limbs. It comes from the term of the eunuchs. Basically, if you castrate an individual early in life they donít go through their pubertal growth spurt, their epiphyses donít fuse under sex steroid influence, they continue to grow for a longer period of time, and so they tend to be taller than average and again that excess growth occurs distally in the epiphyses that donít have the sex

XYY syndrome. Again, extra chromosome. Now this is the extra y. This is the karyotype. You can see 47 chromosomes and down on the far right there you see the extra y chromosome. This is an important one to remember just from the fact of some misconception. A lot of you look like you are my age or older. You may remember back in the 70ís there was an interesting study that came out where somebody went out and did karyotypes on all the guys in prison and they found out

The bottom line is, a positive family history of mental retardation, particularly in males, should be evaluated and fragile X is going to be by far the most common diagnosis. Just a karyotype showing you where it got its name. Back in the mid-70ís when this condition was described, some little tricks in the laboratory with the culture media can then produce the finding. It just looks like the end of the x chromosome is broken off. The next thing is that when this condition was described, the second thing that people discovered was that it had an inheritance pattern that was very unusual. It showed two things. It showed 

Down syndrome: again, diagnosis isnít the issue. Most people on the street will pick up this phenotype. The major issue is both for your clinical practice and for things to know about on the test are some of the unique healthcare issues for children with Down syndrome. Again, 1:700 to 1:800 live births. Actually in

Two or three other health issues to keep in mind. These kids have a much higher incidence of leukemia, so again if you get a case history of a kid with Down syndrome with a lot of petechia or bruising or something like that, they should be evaluated for leukemia. And of then of course hypothyroidism is a very common

Trisomy 13 and 18, again just recognize that they are there. I doubt if youíll get many questions on it. Probably the only real issue for the general practitioner in this situation is that recognizing a child with multiple anomalies probably should be evaluated relatively early. This is a child with trisomy 13. Very recognizable

Trisomy 18 has a very similar phenotype and in fact I know that it would be unfair to ask anybody to distinguish those on a board question. The most important issue again is to evaluate these kids because the long term outlook is very poor. About 50% of these children die in the first two months of life, 98% don't make it

Just a brief mention, that besides whole chromosome changes, the list is catalogs long of partial changes. You can see duplications, deletions, translocations, things we bored you about early in medical school. The important part is simply to remember that in children, or individuals who have chromosome rearrangements, is family studies are further indicated. Hereís an example of what Iíve been talking about. Does this child look like anything Iíve just shown you? Looks like trisomy

For instance, this was a clear cut clinical diagnosis of trisomy 13. Sometimes we are asked by practitioners, "Why should I waste the $750 to do the karyotype?" You can say the same sort of thing in Down syndrome. I donít think I brought that slide, but Iíve got a family that has eight children with Down syndrome. So again, to look at the child and say, "Heís got Down syndrome, chromosome aneuploidy, go home and donít worry about it. Low recurrence risk" is not giving the

Chromosome abnormalities. Those are the more common ones. Those are the more critical healthcare issues. Any questions before I get out of chromosomes and get into single gene disorders? Okay, so real quick. Single gene disorders. Again, just remember your copies of your pedigree. It wonít read definitions to you but again you need to be familiar with homozygous, heterozygous. This is just a reminder. Again, the question, as I started off talking about the Human Genome Project, the question that a lot of people ask when the thing was first proposed, was "Okay, whose chromosomes are you going to study?" because we are all

So probably the best example of co-dominance in humans is the ABO blood type, so again if you receive an A allele from your mom and B allele from your dad, you have AB blood type. Thatís what we mean by co-dominance. The A or the B donít mask each other. Because what you are looking for phenotypically is the presence of the antigen or not.

Autosomal dominant conditions: again, autosomal means not on the sex chromosome. Dominant means it only takes one copy of the abnormal gene to produce features. So the typical inheritance pattern, or what you see in a family with dominant inheritance - because itís on the autosome - males and females are affected with equal frequency, and again because itís dominant means that if you have the condition you can pass it on. If you donít have the condition you canít pass it on.

Two or three things important to remember about dominant conditions: one is that they have notoriously variable expression. Hereís a boy who has neurofibromatosis and came into the clinic because heís got lots of birthmarks and these little benign tumors on his skin. So in fact we know that neurofibromatosis is an autosomal dominant condition and you would sit down and counsel this kid that thereís a 50-50 chance that any of his children could have NF as well. And the answer might be, "Hey, no sweat. My kids have a few spots and bumps." But again you know that NF has a marked range of expression. This is also neurofibromatosis. This girl has, as you can see, these marked chest deformities due to this huge peri-spinal tumor that eventually took her life. This is also neurofibromatosis. So again, when you talk about dominant conditions, not only do you have to talk about the 50-50 chance of transmission, but the patients need Recessive conditions: again, means that both the copies, both the alleles have to be mutated and so, as you would expect, two or three different things. Number one, as we already talked about, recessive conditions are very much less variable expressed than dominant conditions. Because you are talking about total insufficiency of the gene product. If itís gone, itís gone. Second thing, they are much rarer because both parents have to be carrying the condition. The third thing is that there is one situation where recessive conditions are more common and what would that be? Incest. Thatís right. Consanguinity, as this pedigree would 

So again, just to throw in an example here. This is a condition called Smith Lemli-Opitz syndrome. Itís a rare condition. Itís autosomal recessive. A multiple anomaly syndrome with genital and facial malformations as well. A known autosomal recessive condition. Again, the most important part is simply that the

X-linked inheritance now because the gene we are talking about happens to be on the x chromosome, the inheritance pattern is different. The classic pattern of an x-linked inheritance then is - because females have two x chromosomes - that they have milder expression. In the recessive conditions, they donít have any

Hereís a little boy, 11-years-old, having problems making it up the stairs. Put a reflex hammer on the floor, ask him to pick it up, he canít straighten back up without pushing off of his knees with his hands. This is a sign called a Gowerís maneuver. Itís a sign of proximal muscle weakness and of course he has Duchenneís muscular dystrophy. A well-known x-linked recessive disorder. Actually dominant conditions, as we described in fragile x syndrome means that the females have partial expression. Because there are two x chromosomes, they are not as severely affected but in fact they can have partial expression. A rare multiple anomaly syndrome is called Asperger syndrome. Short stature, unusual facies, limb abnormalities, genital abnormalities, x-linked semi

Lastly then, teratogens: just remember that some non-genetic causes of birth defects in children, major potential teratogens the list in the handout. You might just look that over. Those are things to avoid in pregnancy. Well, anything you can avoid is important. These are the ones that are the most critical. Alcohol still is by far the most abused teratogen. I hope everybody in this room recognizes that the only reasonable recommendation is complete abstinence of alcohol throughout pregnancy. The other thing too is to remember, particularly in the area of teratogenesis is that the Ö whatís the average age of identification of pregnancy? Gestational age in this country? Eight weeks, actually. About eight weeks. So by the time the woman has missed her second period she realizes sheís pregnant. Remember back to your freshman medical school days, your embryology days. All of morphogenesis is done by ten-and-a-half weeks of pregnancy. If a woman 

Infections: of course, you know the classic torsion infections, hyperthermia even without infections - like raising your core body temperature, too much time in the sauna, too much time in the Jacuzzi. If you raise your core body temperature enzymes are temperature specific. Enzymes are involved in critical developmental pathways so hyperthermia can be a teratogen. Cigarettes clearly are. Not just low birth weight but at least associated with cleft lip and cleft palate, with an increased incidence. You know about radiation exposure. Donít irradiate a woman until youíve documented that she is not pregnant. Seizure disorder and anticonvulsants are very common. Sometimes canít be avoided. Itís much worse for the woman to seize than to be on the medications but recognize that if a woman is on anticonvulsants and thinking about getting pregnant, consult with your teratogen hotline and those sorts of things. Sometimes a change in medications can greatly reduce the risk of birth defects in the baby without changing her seizure control. Accutane, red flag. Very few category X drugs. This is one of those. 

Vitamin E is a developmental stimulus and it has its own receptors. It plays a critical role in early embryogenesis and itís like anything else in nature. Thereís a balance. So too much of an antagonist causes problems, too much of the real thing causes problems. So it just disrupts pathways. The other thing thatís important about both of those is remember that these are fat-soluble compounds. Vitamin A is a fat-soluble vitamin, isotretinoin acid is a fat-soluble compound. This stuff hangs around for a long time and thereís been documented cases of birth defects in women who have been off of this for several months. The best

The last one, Iíll just finish up with, the last category. This is a little baby born to a 22-year-old couple, dual professionals. Took immaculate care of themselves, read the books, did everything they are supposed to, and yet had this child born with a severe set of birth defects. This is called otocephaly. Basically the entire second, third and fourth branchial arch derivatives didnít develop. There is also total situs inversus. Like I said, young couple. Took good care of themselves. No exposures. Chromosome analysis on this baby was normal and what this kid has is, "I donít know." Just remember too, be gentle to your geneticist if you have