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Dr. Ona Faye-Petersen
I.
Genetic Disorders
Scribe: Teresa Kilborn
Proof: Ashley Holladay
Page 1 of 6
Genetic Disorders [S1]: Focus will be on babies and adults. Will not be asked to identify a lesion (microscopic
photograph) by histology. She wants us to be able to take what we learn here and think through to a reasonable
answer. No a and b or all of the above answers from her at least.
II. Genetic Disorders: The Basics [S2]
a. Traditionally, defined genetic disorders affect 10% of the population
b. But in reality they really affect about 50% or higher if you take into account the fact that we all have DNA and
within our DNA is stored material that makes it possible for us to contract a particular disorder or develop a
diseased state
c. 1-2% of the population has an autosomal dominant disorder.
d. Keep in mind that you may never see one of these, but you probably will.
e. You won’t be diagnosing people with these disorders but you will be treating them.
f. 1% doesn’t reflect the number of people seeking medical attention, just how many there are.
g. Also depends on how far back you go. Any inherited disorder starts in the zygote. All of the risk factors are
there from the start, although environmental factors do play a role as to whether you develop the disease.
h. Over half (60%) of all conceptions result in spontaneous abortion- late period.
i. There is a natural sorting process that starts very early. If you look at previable fetus, those that if they were
born could not sustain life themselves, it is already 35%. If you look at all hospitalized newborns and infants
about 20% have a genetic disorder.
j. [ S3] Descriptions of disorders have been made on infants that are viable, toddlers, adolescents, and young
adults.
k. On a side note: She went through everything that she is presenting to us with Dr. Waites, and he selected the
topics. Her goal is to teach us everything for us to know to become an informed practicing optometrist or dentist
and for us to be able to take new information and to process it and to continue to learn and educate ourselves
throughout our careers.
l. Prenatal testing
i. Amniocentisis- Take cells from the amniotic fluid, done at around 18 weeks.
ii. Chorionic villi sampling- can be done early around 6 or 8 weeks. Taking a tiny bit of the placental tissue
from around the developing baby
iii. Maternal blood sampling- any time during pregnancy there are little cells of the fetus in the mother’s
circulation, not a lot, they obtain access to the maternal blood circulation. You can isolate them and test
them. That aspect of fetus cells being in the maternal blood is “fetal trafficking”.
iv. Of the three tests, the first two are done here, fetal trafficking is not done at UAB.
m. [S4] Most, but not all of structural abnormalities are due to genetic abnormalities.
i. Most of the time you see something missing or something malformed, it is due to a genetic disorder.
ii. This does not include abnormalities of missing fingers or toes, those are processes called disruptions, they
happen very early in development due to the breakage of the bag of water so the little limbs go outside of
the bag and the bag remnants are floating around and actually strangulate and cause amputations.
iii. With the exceptions of those and things that happen to you in your environment the majority of structural
anomalies are mainly due to genetic abnormalities.
iv. Individual susceptibility to infections, allergies, unexpected reactions to drugs are all genetically determined
n. There is evidence that adverse connections during intrauterine life have a major role in determining one’s long
term and immediate risks for developing disorders as in chronic cardiovascular disease, kidney disease,
hyertension and diabetes.
III. Picture of uterus with embryo inside, developmental bag, and placenta [S5]
a. Chorionic villi sampling takes little bits of tissue from placenta and analyses them.
b. Somewhere before term rupture of bag of water can happen and the amnion which is the bag can actually can
get loose ends and that can cause disruptions-disruption abnormalities.
c. On right is term baby, uterus, and placenta. This gives idea of relative idea of size of you, the house you are
living in, and the placenta that has to support you later.
d. Amniocentesis [S6]- performed at 18 weeks, that means there is enough fluid in this bag, it is separate from the
surface of the placenta itself. It literally has to expand and apply itself like a transparent balloon so it is applied
to the surface of the placenta where the blood vessels. There is a time in which you are too small and your bag
is too small for anyone to go needling anything. But by 18-20 weeks, you have expanded your bag so that the
other side is to the uterine wall. You are now floating in enough fluid and it is safe to try to suck some of it out.
Amniotic cells are taken out, grown on a plate, and analyzed for various things such as chromosomal
abnormalities, functional abnormalities of enzymes, and many others.
e. Intrauterine environment [S7]-
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Thursday, November 20, 2008
Proof: Ashley Holladay
Dr. Ona Faye-Petersen
Genetic Disorders
Page 2 of 6
i. All of these diseases with asterisks are disorders that you have an unfavorable intrauterine life (placenta
doesn’t grow big enough to support you etc.) these can make you vulnerable for chronic disorders later on.
ii. There is a big source of DNA in you, the nucleus, but the mitochondria also has DNA (circular DNA). There
is a family of disorders that may be brought about due to defects in that mitochondrial DNA, but we are not
to discuss them. Mitochondrial DNA disorders are degenerative disorders. They affect the CNS and your
ability to walk, talk, etc. in particular the loss of neuronal (brain) function.
IV. Objectives [S8]
a. Having too much DNA or having abnormal DNA- neither are good
b. Basic premises of inheritance: dominant, recessive, x-linked recessive
c. Major disorders with high frequencies
d. Less common disorders that have either ocular or dental findings that may turn up on boards.
V. Anueploidy [S9]
a. Means abnormal number of chromosomes
b. Trisomies have to do with chromosomes 1-22. We have 23 chromosomes, but the last is our XX and XY, sex
chromosomes or gonadal chromosomes. In general, trisomies are having an extra one of those 22 first
chromosomes.
c. Down syndrome [S10]i. Most important trisomy
ii. Full extra copy of chromosome 21
iii. The features of the syndromes are important because you know someone has the syndrome because of
these characteristic phenotypic features. The features make someone with the syndrome look more like
other people with the syndrome than their own parents.
iv. Features:
1. Upslanting palpebral fissures-sometimes referred to as anti-mongoloid slants but politically incorrect
2. Epicanthal fold- extra fold on the inner campus of their eye
3. Single palmar crease instead of two creases- used to be referred to as semian creases, usually
bilateral, but sometimes just one
4. Clinodactyly- in turning of the little, 5th finger, because there is missing portion of the middle bone, so
distal fornix is stuck on the strut of the first on and it curves in. if you have clinodactyly does that
mean that you have down syndrome? No. Does every person with Down Syndrome have
clinodactyly? No, but a good percentage, 75% do.
5. Sandal toe abnormality- big space between the hallux, or big toe and the second one. Looks like
they’ve been wearing thongs during development.
6. Abnormal posterior hair line
7. Abnormally shaped and positioned ears- low set- lower than a line drawn from your lateral campus
and back, usually posteriorly positioned as well
v. [S11] If you look at their karyotype, there is a whole extra chromosome on number 21.
vi. [S12] 95% of patients with Down Syndrome are mentally retarded and that is one of the major
characteristics. Most of them have a full extra copy of chromosome 21, however some have a portion of
chromosome 21 stuck on another chromosome, that would be called a translocation.
vii. Less than 30 % of all conceptions that have Down syndrome actually make it to be born. It is not good to
have extra stuff
viii. Babies tend to be short and small and are hypotonic.
ix. If you see a patient that has a midfacial hyperplasia, upslanting palpebral fissures, and a tongue that hangs
out that is because they have a tongue that is hypotonic. They have generalized low muscle tone. They
cannot keep their tongue in their mouth. It is not because their tongue is too big (macroglossia). They have
a normal sized tongue.
x. They are not able to pass things normally with their GI tract so they have to thicken their feds to give them
something to grab on to push through their GI tract. They tend to have continued low weigh. They don’t
thrive.
xi. They are also predisposed to infections particularly because their mid-face is underdeveloped so they get a
lot upper respiratory tract infections and inner ear infections.
xii. They have a predisposition to getting Alzheimer’s. They have small heads, a nuchal hygroma (a swelling
at the back of their necks from fluid accumulation during development), and a flat occipital (back of their
head).
xiii. [S13] Picture with things crossed out that aren’t true.
xiv. Still born fetus with trisomy 21- huge neck, edema, its called hydrops, as in extra fluid in the fetus. Having
this disorder is generally lethal- remember less than 30% even get to become your patients. If they
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Thursday, November 20, 2008
Proof: Ashley Holladay
Dr. Ona Faye-Petersen
Genetic Disorders
Page 3 of 6
manage to make it to birth they still tend to have some residual fluid in the back of their neck that gives
them abnormal hair line.
xv. They tend to have megacolon. They can’t push things through that well so they don’t have good
peristalsis.
xvi. They are also at risk for having atresia or closing off of their duodenum.
xvii. [S14] The most important thing for us to remember is that 40% of Down syndrome babies have congenital
heart disease and 40% of those have this particular abnormalities called complete atrioventricular canal
defect.
1. Normally you have a 4 chambered heart- 2 atria and 2 ventricles are separated from each other and
a very well developed connection our right atrium and ventricle and between our left atrium and
ventricle. In complete atrioventricular canal defect, the atrioventricular valves, the tricuspid and
mitral, are not separate, they are one big hole because they do not develop appropriately. Instead
of having a normal situation with separation and conduction system between atria and ventricles,
blood goes from ventricle to ventricle, both directions and to the atria. This is not good because this
means that your heart is inefficient and you are mixing oxygenated blood and deoxygenated blood.
You are unable to get enough oxygen to your tissues, you are unable to grow.
2. Picture on left is looking down with the two atria removed. It is a big ovoid and you can see in to the
right ventricle and in to the left ventricle. The leaflets of the valve are crossing over.
3. If you are treating a patient with this disorder, particularly if treating in the mouth, you need to make
sure that they get antibiotics before they come to your office because these valves that are very
abnormal are flopping around very uncontrollable and causing turbulence. Turbulence causes fibrin
disposition. Fibrin is lots of protein that bacteria make homes on and they are called vegetations.
Vegetations will flip off, travel through body particularly to head, spleen, kidneys, anywhere. Bacteria
is showered throughout your system and clots are thrown into vessels which everything distal to the
clot to become ischemic. When you have a patient with this make sure they are on antibiotics.
Thromboembolic- means thrombus as in coagulation in the blood space and embolic means thrown
somewhere else.
xviii. [S16] They can also have very hypoplastic teeth. They tend to have a lot of periodontal disease. They
have swallowing difficulties, so we have to suck their mouths more (they have a hypotonic problem).
Hypoplasia of the frontal sinuses. Many have middle ear fluid because of their malplacement. From an
ocular standpoint, brushfield spots (watch from this on boards) are little small white spots on the periphery
of the iris. White spots are milder forms of true hypoplasia of the iris. They can have lens opacities. They
myopic and tend to need glasses very early on. Nystagmus, strabismus, and lacrimal duct blockage.
xix. Down Syndrome is one of 3 or 4 different syndromes, one of the most important because it is not lethal.
There is a lot more babies born with trisomy 21 than 13 or 18 which are lethal.
VI. Turner’s Syndrome [S17,18]
a. Gonosomal abnormality, missing a sex chromosome
b. Female, 45 X
c. Broad webbed neck, low set ears, big large posteriorly positioned ears, large space between eyes, tend to have
shield chest (broad and flat with nibbles laterally positioned)
d. Over 95% of 45 X are spontaneously aborted, If you see something with this then it is more than likely that she
is not a pure 45 X, she is probably a mosaic with a complement somewhere.
e. If she is sterile will depend on if her ovaries and eggs are 46 XX even though parts of her are 45 X, parts of her
will have a normal complement. It is not uniform that these women are mentally retarded and/or sterile.
However, if you have to pick one of these answers that would be the answer that you pick. What is on a test is
not necessary what you see in life. This is not new information, but it is probably not going to be in your text
books in that way.
f. Characteristics:
i. They tend to not grow very well.
ii. Infertile
iii. Mildly mentally retarded
iv. Craniofacial hypertelorism- too wide of a space
v. Inner canthal folds
vi. Cutis laxa- extra skin on the back of the neck (as in the trisomy 21 baby) has to do with poor connection of
the lymphatic sack to the central venous system. The lymph fluid needs to be returned to the intravascular
volume and failure of that connection to happen results in what is referred to as a nuchal hygroma, it will
look like the kid has a bubble on the back on their head. If that fluid somehow reabsorbed, then they will
still end up with that loose skin, wide neck, and abnormal hair line (like trisomy 21).
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Proof: Ashley Holladay
Dr. Ona Faye-Petersen
Genetic Disorders
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vii. [S19]One of the problems when you are developing if you have all of this extra fluid (hydrops) you can’t
move very well. That gives rise to odd carrying angle. They are not able to move their arms as freely as
fetuses and it stiffens them and causes huge swelling on the dorsum of their hands and fingers so their
nails get an embedded look to them- hypoplastic or embedded nails.
viii. High risk for a particular type of cardiovascular defect called coarctation of the aorta. Coarctation means
narrowing, like stenosis, but they never call it a stenosis. It is essentially a narrowing of the distal aorta that
interferes with blood reaching the lower part of your body. The typical baby with Turner’s will have big
pulses in the arms but very little in the legs.
ix. These patients need to be on antibiotic therapy.
g. [S20] Here is a baby that did not get aborted. Shows characteristic phenotype- lymphodema.
i. [S21] Here is that lymphatic sac that does connect to the central venous system near the internal jugular
like it is suppose to and so fluid backs up everywhere and it also interferes with cardiovascular
development and the migration and development of the chest. Virtually everything is due to this so called
jugulolymphatic obstruction.
VII. Klinefelter’s syndrome [S22]
a. Gonozomal abnormality
b. Extra copy of a chromosome, 47 XXY
c. Phenotypic male, but not normal
d. Long and thin
e. Under development of secondary sex characteristics
f. Mildly retarded with limited social skills
g. 1 in 500 males
h. Lesser % of these is going to have mosacism. They will have normal complement of 46 XY. The amount of this
extra stuff may have something to do with how severely retarded, tall, or underdevelopment of secondary sex
characteristics.
VIII. Basic premises of autosomal dominant, recessive, and x- linked disorders [S23]
IX. Autosomal dominant disorders [S24]
a. Means you only have to have one copy of the gene to have the disorder
b. Doesn’t matter what your sex is
c. If you carry the gene you have a 50% chance of passing it on
d. Usually one of your parents is affected.
e. The only way for you to have it if neither of your parents do is for you to be a mutation or for one of your parents
to have a mutation in their germ-line meaning that some of their ova or sperm would have that mutation and
some of them would not. If you have an autosomal disorder and have a sibling with it as well, but neither parent
has it, then that means that one of your parents have an affected germ-line.
f. Clinical characteristics [S25]:
i. Penetrance and expressivity:
1. penetrance, in genetics, means the ability to look at someone and tell what disorder they have, there
is a phenotypic expression of the disorder. Some disorders have 100% penetrance. The ones that
don’t are still dominant disorders, just your ability to detect them by phenotypic reason is either 100%
or not.
2. Expressivity means that there are a collection of abnormalities that are associated with that
autosomal dominant disorder and you may have all of them or just a couple. Expressivity is a
severity factor.
ii. [S26] Generally autosomal dominant disorders have a delayed onset which is both good and bad. It
means by the time you figure out someone has an autosomal disorder, they have already had their kids
before they actually show features themselves. Not something you can see at birth. Some of these
autosomal dominant disorders have features detectable at birth and some do not. Usually autosomal
dominant disorders affect regulators or tweekers of pathways. It is not going to usually be an enzyme per
se. Enzymopothies are autosomal recessive disorders. Autosomal dominant disorders are usually you
make a product and then you have to modify it and there is a problem with the modification process.
g. Most of the autosomal dominant disorders affect some sort of regulator. Neurofibromatosis is like having a
tumor diagnosis, but the tumors in type I are generally limited to peripheral nerves (in skin and mesentery of GI
tract in particular). Neurofibromin is a regulator or a tumor suppressor gene. If you have a mutation in
something that should normally tell you to stop proliferating, then you end up with abnormal growths. There are
others that cause abnormalities in the extracellular matrix and the extracellular matrix is important that is your
connective tissue that holds you together. If you have defects in it then your bones, joints, and skin attachment
will not function well. That is what is wrong with Osteogenesis imperfecta, Ehlers-Danlos, and Marfans [S27].
h. Neurofibromatosis (NF) [S28]
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Dr. Ona Faye-Petersen
Genetic Disorders
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i. Many types of Neurofibromatosis, but she will mainly talk about type 1.
ii. We are not responsible for where the locus of the gene is that is effected
iii. Also called von Recklinghausen Disease
iv. Effects a tumor suppressor gene
v. Characteristics:
1. Café au lait (coffee with milk or cream) spots- light colored, flat lesion, ovoid shape, tan/brown
colored
2. Painful neurofibromas of the nerve trunks of the skin
vi. Half of the cases represent new mutations
vii. [S29] Diagnosis is based on how many café au lait spots you have and how big they are
1. 6 or more (1 cm or more in diameter)- neurofibromatosis type I
2. Another feature is auxillary freckles
3. Lesions are also called plexiform, what they look like is bag of worms kind of configuration. The
reason they are important is because each one of them has a 3% chance of becoming malignant or
cancerous.
4. Optic gliomas- tumors in nerve trunks, particularly the optic nerve
5. Meningiomas- tumors of the brain covering
6. 8th nerve acoustic neuroma- having a tumor in the 8th nerve on one side
7. From our standpoint, a Lisch nodule is important. They are little neurofibromas of the iris.
8. Hamartoma- cells that are normally in that position, only they are all gumbled up, they are not
making a certain structure. These are neurites that have piled up and gone crazy and made a
nodular configuration. They are normally present in that site but they are not normally mixed up.
viii. [S30], [S31] This is two patients with severe neurofibromatosis. Each nodule is a neurofibroma. Not all
look this dramatic. It is a disease that has multiple sites and if you cut into one you see this firm, swollen
pile of neurites and fibroblasts in a very confused fashion.
ix. [S32], [S33] Picture of café au lait spots and axial freckles. Sometimes they can be so massive that they
can go down nerve trunks and cause asymmetry in limbs.
x. [S34] Gross picture of neurofibroma taken from nerve trunk. Tend to follow nerve trunk and look like a pile
of worms.
xi. [S35] Histologically what they look like. Little nerve trunks and pressure pacinian corpuscle that are
normally present in the skin but they are not forming a normal pattern.
xii. [S36] From a retinal exam, one of these will be an optic nerve glioma. Optic nerve comes out of the brain
and goes to the back of the eye ball. When you have something growinig in that nerve it puts pressure on
the back of the retina so there is a blanching of the blood going to the retina, it can’t get there. So it looks
like this big white patch. Notice the blanching from the pressure of the optic nerve glioma that is sitting
behind the eyeball.
xiii. [S37] This is what it looks like histologically. Football shaped mass. Swelling and proliferation. Optic
gliomas are very characteristic of NF-1.
i. NF-2 [S38-40]
i. Very unusual for it to have peripheral neural fibromas
ii. Normally they have nerve trunk tumors of both 8th nerves
iii. Referred to as central neurofibroma
iv. Have more characteristic tumors of the meninges
v. NF-1 is more common than NF-2 so she prefers that we know about NF-1
j. Tuberous Sclerosis Complex (TSC) [S41]
i. Autosomal dominant disorder
ii. Many types of it
iii. Effects tumor suppressor gene, mutation in a gene that normally controls proliferation and organization
iv. Process of TSC- tumor suppressor gene that is effected in a cell line, most are new mutations (50-75%), 1
in 2 or 3 in 4 times where a child has the disorder and neither parent does
v. Mutation in the germ line (ova or sperm) and it effects neural precursors (things that are going to become
nerve cells). These nerve precursors disperse to the heart, kidneys, GI tract, etc. Then something happens
in the second site- second hit (no one really knows what it is) and you have potentially lost control of your
proliferation in multiple sites and you get tumorogenesis
vi. TSC has a triad of features- mental retardation, epilepsy, and ademoma sebaceum
vii. Penetrance seems to be there, but expressivity does not- only 1/3 of them have these features
viii. Some features are more classic than others. They have to do with subependymal calcifications.
Ependymal cells are cells that line the ventricle of the brain. The brain has CSF inside the hemisphere that
also tracks down a canal back to where the cerebellum is. The fluid circulates through the brain comes up
FUN2: 10:00-11:00
Scribe: Teresa Kilborn
Thursday, November 20, 2008
Proof: Ashley Holladay
Dr. Ona Faye-Petersen
Genetic Disorders
Page 6 of 6
over the top and get internally circulated up and down the spinal cord. The ependymal cells are the cells
that line those cavities. To say subependymal cells means that the tumor like processes don’t develop in
the ependymal cells, but just on the other side of it. When tumor like things proliferate, they become
calcified, hence the origin of the seizures. It is not good to have calcium in the brain. Mental retardation
and olfactory hamartomas.
ix. They typically have an Ashleaf spot which you can’t typically see unless you put them under a UV light.
Think of these as neural precursors, they are involved in telling the skin to make pigment. If they “run-amuck”, the skin is not able to orient its pigment properly. It takes a special light for that to be revealed.
x. Adenoma sebaceum- adenoma means like a little tumor, sebaceum means sweat gland. Initially these
were thought to be plugged up sweat glands, but they are actually hamartomas- normal jumbled stuff of the
face. They are fibroblasts, blood vessels, connective tissues, and epithelium. If you took one of these and
cut across it this is what it would look like [S43]. This is not acne because acne does occur symmetrical
and does not usually effect 5 year olds.
xi. The neurofibromas continue to grow throughout adolescents until they slow done in adults and are not as
apparent. Neurofibromas are actually Angiofibromas.
xii. [S44] Example of Ashleaf spot visible under UV light
xiii. [S45,46,47] Girl with multiple calcifications in her brain and multiple seizures.
xiv. They are subependymal.
xv. She doesn’t expect us to be able to read the CT scan, but she does want us to know that if someone has
these lesions growing in their CSF tract then they would be an explanation for seizures.
xvi. The way they are shaped is called “candle gutterings”.
xvii. [S48] TSC is called that because the lesions look like potatoes when cut into.
xviii. [S49] The lesions are just very confused proliferations of neural cells, astrocytes, CT in the brain, and
calcification.
xix. [S50] Neural precursors that have been hit have been spread out throughout the body, so you have the
potential to have these hamartomas anywhere in your body in your organs.
1. In particular, they tend to go to the kidneys. You tend to have bilateral angiomyolipoma- angio for
blood vessel, myo for muscle, and lipo for fat. They are usually bilateral and they are multiple.
2. They can also have a very confused tumor growing in their heart particularly in intrauterine life and
they are called cardiac rhabdomyomas which are basically very confused cardiac muscle. Having a
huge lump of cardiac muscle in your heart when you are trying to circulate blood is not a good thing
as a fetus.
3. They will also have along their gum line some of these growths. They tend to have enamel
hypoplasia because there is interference with the formation of dental enamel. Because there is
interference with that formation they have pits in their teeth.
xx. Picture of a cardiac rhabdomyoma [S51]- heart is opened up with big tumor that makes it hard for any
blood to get into that cardiac chamber. It is usually not that compatible in life to have one of these. The big
mass acts as a ball valve and every time blood goes from the atria to the ventricle, this ball thing goes with
it.
xxi. [S52] The idea is that if a baby is born with a cardiac rhabdomyoma it is considered to be TSC until proven
otherwise. You can have them by themselves but in general they are associated with TSC.
xxii. [S53] Example of angiomyolipoma of the kidney. These tend to bleed and people tend to die from
hemorrhage of these things.
xxiii. [S54] Picture of the dental pits
xxiv. [S55] They can also have hamartomas of the supportive cells around nerves, astrocytes. As astrocytic
hamartoma can show up as a retina lesion during ophthalmic examination.
xxv. [S56] If you have this, this girl is 13. She has had 7 surgeries. Over 5,000 seizures and over 11,000
dosages of antileptics. One thing to learn about this and another to understand the effects of these
diseases on people’s lives.
[End 58:24]