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Microbiology
Genetic Disorders 2
10-28-08
Brian Bolerjack
50 minutos
Half the slides are missing from the handout, so I will try to keep it straight as best I can.
We talked about Neurofibromatosis being an autosomal dominant (AD) disorder, being a defect
in a suppressor gene so these people end up with tumor like growths. There are several types of
neurofibromatosis, but most types are referred to as Type 1 or Type 2. Type 1 refers to more peripheral
things and Type 2 refers to more central things like in your brain. That’s a very loose consolidation of
information. Neurofibromin, if someone said that it would make me think of neurofibromatosis (NF).
39(?): There are a couple different chromosomes that have an abnormality and with NF-1 it’s on the
long arm of 17 and is a neurofibromin thing. This disorder is also called Van Recklinghausen’s disease,
and he was the person that described it. It’s is characterized by café au lait spots. Coffee with cream
flat lesions on the skin (though lait is French for milk). It is also characterized by these nodular growths
that are quite sensitive. They are pain and temperature sensitive because they are a mixture of nerves
and connective tissues and fibroblasts, so they can make little nobs and bumps everywhere and be quite
painful. It is an AD disorder with at least half being new mutations.
40:
Café au lait spots are flat, macular lesions, no raises on the surface, that are areas of
pigmentation that look like coffee with cream. They must be 1.5cm in diameter and there must be six of
them, so that’s a criteria for diagnosis. If you are examining a patient and happen to notice little brown
spots, you might ask if they have the condition. You might be the one to make the diagnosis because
more people go to the eye doctor and dentist than the regular doctor. They get neurofibromas,
plexiform lesions, it looks like a bag of worms. Each lesion has the risk to undergo malignant change.
There are some central lesions in type 1 NF, and they are optic nerve gliomas. Optic nerve can get a
tumor like growth in it called a glioma. You can get a tumor like growth in the cavities of the brain. The
ependymal cells that line the ventricles can get ependemomas. The meningiomas are tumor like
conditions of the meninges and dura. You can get a unilateral acoustic neuroma, they can’t hear you on
one side because of a tumor of the eighth nerve. They can also have a hamartoma, a tumor like lesion.
Hamartomas are groups of cells normally found in that place but they are all jumbled up. A hamartoma
in the skin would have fibroblasts, nerves, connective tissue, skin cells, but with nobs macroscopically.
Iris hamartomas are tumor like lesions in the iris, and are pathognomonic, meaning they are a dead on
diagnostic for the disease, 95% of NF-1 have them.
41:
Extreme cases. Each person has nodules all over their body and nodule has the capacity to
undergo malignant transformation. Doesn’t mean they are going to, but 3-5% of patients with NF1 end
up with malignant tumors.
42:
This is a neurofibroma and this is what makes a nob. It is a proliferation with connective tissue,
fibroblasts, nerve tissue.
43:
Café au lait spot. It’s a flat lesion, sometimes oval, sometimes circular. For little kids, having
freckles under your armpits is not normal.
44:
Neurofibromas can track nerves that are already there. Deformations in the leg. It’s a tumor
like condition that causes a secondary deformation in the leg.
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Plexiform neurofibroma. It looks like a nodule of lumpy noodles. They can be nodular or track
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Microbiology: Genetic Disorders 2
along the nerve.
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Here’s the histology. CT, fibroblasts, everything is jumbled up.
47:
Optic nerve glyoma. It’s a tumor in the optic nerve. In the retina exam you have a central pale
area because the tumor is compressing the branching vessels of the ophthalmic artery.
48:
Looks like a big onion. Here’s the nerve and the swelling. It looks like a football. They can be
seen in children. That’s an NF-1 finding. Café au lait spots are the big things, plexiform neurofibromas.
49:
NF-2 on 22q, the long arm. There is a locus on #22, and it’s a tumor suppressor gene, codes for
merlin. It is referred to as central because it affects central things more frequently. You won’t have
Lisch nodules. They have a later age of onset, young adulthood at 22. Lisch nodules show up at 6. They
have bilateral acoustic neuromas, eighth nerve tumors, many more meningiomas, and schwannomas of
dorsal roots of spinal cord, nerve sheath tumors. They can have blindness, cataracts, and retinal
hamartomas- stuff normally there but jumbled up.
50:
Bilateral acoustic neuromas. (The white puffy cottonballs).
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Patients will have tumors of the meninges, meningiomas, the big white areas.
52:
Tuberous sclerosis complex, TSC, a different autosomal dominant disorder, with type 1 and type
2. TSC is grossly underdiagnosed. 1/5800 is what is actually diagnosed. It is much more common than
realized. This could cause real problems with eyes. Most are new mutations, half to three quarters. It’s
a tumor suppressor gene. It’s probably a mutation that in and of itself is not sufficient to cause tumors,
but the cell line gets distributed throughout the body and there is a second hit. There is a predilection
that is inherited in the germline, it is hit, and it’s dispersed throughout the body and there are multiple
foci throughout the body for tumor formation.
53:
There is a triad of MR, epilepsy, and adenoma sebaceum, only 30% have all three. Sebaceum
makes you look like you have oil glands on your cheeks, little pimples. They aren’t sebaceous glands.
They are tiny proliferation of connective tissue and vessels called angiofibromas. They show up in little
kids, 4 year olds. Bilateral, symmetrical over the cheeks in little kids. They may have olfactory
hamartomas. They can have abnormal skin pigmentation, areas of depigmentation in the skin, and can
be detected by UV light Wood’s lamp. Not too many people have those, so you will look for adenoma
sebaceum. Or lots of nobs under the fingernails is ungwald fibromas.
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Adenoma sebaceum in this is a five year old boy, and histology of the adenoma. Lots of
capillaries makes it redish. Don’t scratch it or it will bleed.
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They can become more numerous with age. Seen in adults and children.
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Example of an Ashleve(sp?) spot or area of depigmentation of the skin, don’t see anything
normally but put it under Wood’s lamp and you can see it.
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Subependymal lesions. Fairly classic. Tumor like proliferations that live under the inner coating
of the ventricles of the brain. They are also hamartomas, they have neurons, astrocytes, helper cells.
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Microbiology: Genetic Disorders 2
58:
They show up along the cavities, and because they are lumpy they look like candle drippings,
and are called candle guttering. They are called tuberous sclerosis because they reminded someone of
potatoes.
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Patient with a seizure. CT with more lesions at multiple sites. They live beneath the ventricular
system.
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This is jumbled histologically.
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Features of TSC. It was a hit in the germ cell, a second hit, and then it dispersed throughout the
body. There is a tumor in the heart, rhabdomyoma, one in the kidneys. They are a combination of
lipoma- meaning fat, myo- meaning muscle, and angio- meaning blood vessel in them and they make
tumor like nodules in the tissues. Particularly if they are bilateral and multiple. Those can kill you by
spontaneously bleeding. They can have cysts, blockage of blood vessels, gingival fibromas,
abnormalities in enamel formation resulting in pitted teeth, and retinal hamartomas.
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Cardiac hamartoma. Heart of an infant sectioned in half. The right ventricle is filled with the
tumor like thing. Dysplasia is something intrinsicly wrong with the tissue and usually multiple sites are
affected. TSC is an AD disorder but it is a kind of dysplasia.
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Dysplasia, intrinsically abnormal tissue with multiple sites effected. This growth grows in the
baby’s heart in utero, things don’t circulate well, and the baby dies in utero. Cardiac rhabdomyoma
doesn’t have to kill you in utero, but it will cause trouble. The histology is for fun.
64:
These disorders can show up early. Here’s a kidney, it’s an angiomyolipoma of the kidney.
Multiple sites and usually bilateral. Bleeding into these is a problem.
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Dental pits. Defects in enamel. Many pits.
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Astrocytic hamartoma, astrocytes are the helper cells of the CNS. They can proliferate and
become an –oma, or a tumor (Ahnuld says IT’S NOT A TOOMUH!!!, sorry I had to). They are not
malignant cells, just terribly confused and proliferative, become mixed up, and can cause a tumor like
growth themselves. They are supportive glial cells with processes that direct the growth of neurons and
nurture them after that.
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Bring it home because it is easy to learn and not have it affect you. She has had 7 surgeries,
5000 seizures, and 11000 doses of anticonvulsants. So people with TSC are people too. Not just a bag
of symptoms. She is 13. Look at her skin, it looks like acne but its not. They can have a normal lifespan.
Or a short one due to death during a seizure or complication of the disease.
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Osteogenisis imperfecta. It’s making bone imperfectly. It is a bone dysplasia. There are many
kinds. It’s quite common. 1 in 30,000 isn’t big until it happens to you. Type 1 and 2. What happens?
They have osteopenia, insufficient bone, that’s what old ladies get. Osteoporosis is a tendency to
fracture. Skeletal deformity, so the bones themselves might look ok but aren’t ossified enough, and
because they are so fragile they break and deform. In AD form, there is a 50% reduction in collagen type
1 production. There is a decreased amount or stability of the collagen made. The bones do not ossify
because the calcium must sit on collagen.
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Microbiology: Genetic Disorders 2
69-70: Features of Type 1. Bone fragility, multiple fractures. The vertical column and particularly
tubular bones, arms, legs, ribs, clavicles. Different bones will break at different times. Penetrance
means you have the disorder and you have an abnormality that allows it to be detected. OI has a 90%
penetrance. That means 90% of people with OI have something wrong you can pick up (bone fragility).
So you have the disorder, and whether or not you know you have the disorder is through penetrance.
The multiple things you may have with that, like with TSC you might have MR and epilepsy, the other
person with TSC may have adenoma sebaceum and subependymal tumors, that is called expressivity.
Expressivity has to do with the constellation and severity of findings. Penetrance is your ability to
diagnose it.
Other things with abnormal collagen, they bruise easily, tend not to grow well, bone and
posture problems, kyphoscoliosis. They may have bowing at the femurs. The bones of the middle ear
can be affected. There are bones up there believe it or not, the little ossicles. So they may have
deafness. Particularly early onset deafness.
What do you need to know for the test? Guaranteed question on some test in your life, the
ocular presentation of someone with OI is blue sclerae (the whites of the eyes are blue). 100%
penetrance. That means if you look at someone’s eyes and they are not white but bluish, think of OI.
The underlying choroid has blood going to it, and the sclerae are made of collagen. If you have
abnormal collagen you have abnormal passage of light to where you see the blood filled choroid, and it
makes it bluish. They can have oral problems, and there are subtypes. They can have dental problems.
They can have opalescent teeth, they can break more easily, and can also be kind of blue.
71:
This is OI. Here’s the mom and the kid, both with blue sclerae. Mom has OI, every child she has
will have a 50% chance of getting OI because it is an AD disorder. This child got it. This (the bottom
right picture) is OI Type 2 in a newborn. This baby has blue sclera already at a few hours old.
72:
OI-2 has such extreme bone fragility that they break in utero, everytime they move. Most are
due to new mutations.
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The babies look like the Michelin tire man because the skin continues to grow but the bones are
breaking underneath and not keeping up with the skin. The radiograph shows multiple fractures
everywhere, its like an accordion in the ribs. There’s no skull formation.
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Skip. So how would you know someone has OI? First blue sclera. Second is history of bone
fractures. First thing that is thought of when children have repeated broken bones is child abuse. But
could be OI.
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Ehlers-Danlos, the people with really stretchy skin. She can’t do it because she doesn’t have any
skin (she really said that). It is hyperelasticity of skin and joints. When they stand the backs of their
knees will bow out backward like a bow (she said that too). Ehlers-Danlos is a disorder of fibrillar
collagen, another type of collagen disorder. AD disorders affect a process of a component that is made
such that it is a tweaking, the molecule may be too long or tangled up. You make the product but there
is a final processing/modification that doesn’t happen correctly. Most AD disorders and disorders of
structural proteins. Most autosomal recessive disorders are with enzymes, where you don’t make it at
all. There are like 13 Ehlers-Danlos variants. Most have marked skin hyperextensibilty and joint
hyperlaxity. That’s what they all share in common. Here’s a picture I got off the interwebs so you all can
see.
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Microbiology: Genetic Disorders 2
76:
There are multiple ways to inherit the disorders. There’s AD. Some are recessive, and one is xlinked. You need to know number 6, because they have ocular fragility. The collagen that makes the
globe of the eye is not very good and you can have ocular rupture (spontaneous exploding eyeballs!).
77:
Most have skin hyperextensibility and joint hyperlaxity. They may or may not have easy
bruising. So when you examine patients keep that in mind. Most of the AD disorders affect proteins.
Most recessive disorders are ineffective or absence of enzymes. So Kyphoscoliosis is a recessive ED
disorder, though most are AD. It affects a gene that encodes for lysyl hydroxylase, which causes
crosslinking of the collagen. You can also get ocular fragility, corneal rupture and retinal detachment.
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Most of them are disorders of collagen, and again, easy bruising, joint laxity, poor scarring. She
can’t go to Cirque de Soleil because all she sees is (mutant) people with Ehlers-Danlos.
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Marfan’s Syndrome, another important AD disorder. It has a broad spectrum of manifestations,
but is a defect in the fibrillan 1 gene for the most part. Fibrillan is the molecule that provides the
scaffolding for the formation of elastin. It is decreased quality and number of the fibrillan, you can’t
make the aggregates, so you can’t make elastin. So what are the elastic fibers in? They are in your heart
and vessels, little things that hold the lens in your eye (zonula) which changes the lens shape. Most
defects result in a decrease in the elastin strength. Most are familial, in contrast to the other things we
have seen thus far.
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Microbiology: Genetic Disorders 2
80:
Features. Dolicocephaly, means you have abnormal head growth and it looks like you put your
head in a shoe box. Frontal bossing, superorbital prominence where your eyebrows are. These are
consequences of a type of elastin formation. There are places where elastin is in the dura, and you get
ectasia or distension at the end of the dura, the dural sac. These patients, at least half have ADHD. Why
that’s true is not clear. They have a typical body habitus. People think she has Marfan’s, but she
doesn’t. Why do people think that? Because she has long fingers and can touch them around her wrist
and when she bends her thumb over across her palm it sticks out like four inches past her pinky and she
is tall and has long arms and long legs and a short torso and a heart murmur, all clinical manifestations
of Marfan’s. But she doesn’t have Marfan’s. People with Marfan’s have excessively long arms and legs
for their body habitus. People with Marfan’s also have a caved in chest, called pectis excavatum. She
doesn’t have flat feet. She does have some joint laxity. The question is does she have Marfan’s. She
doesn’t think so. She has been to a geneticist, she doesn’t have Marfan’s. You could look at her and
suspect she has Marfan’s because she can do those things, but just because she can DOESN’T MEAN SHE
HAS MARFAN’S PEOPLE! These are features that are found more commonly in these patients but they
are not diagnostic. (she was really adamant on getting it across to us that she doesn’t have marfans, so
that might be a test question. I kid.)
81:
This is an eight year old boy who is way tall for his age. His arms and legs are long, has pectis
excavatum. The girl has frontal bossing and a high forehead. They have kyphoscoliosis and tend to have
teeth crowding. These are all signs for Marfan’s and things that tend to end up on exams like what’s
wrong with this patient.
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Someone with really long fingers. The nobs on the ends are due to smoking, but the length is
because of Marfan’s.
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What do they have other than the external signs? Visceral and cardiovascular findings. Mitral
valve prolapsed (between the left atria and ventricle). The valve should be shut during systole, so the
blood goes out the aorta, but the valve is floppy and some blood goes back into the left atria. The leafs
herniated into the left atrium and go “wulah”. Many women have mitral valve prolapsed, half the
people you meet do. It doesn’t mean they have Marfan’s.
One thing really dramatic about Marfan’s patients is their tendency to have rupture of the
ascending aorta. That’s because there is elastin in your aorta, and their’s is deficient in some way so it
tends to enlarge and become ectatic. It can cause death. It can also cause aortic dissection which is
where the muscle fibers of the aorta start to split and blood starts to tract in between the planes
causing an aneurysm. Between 1/3 and ½ of Marfan’s have acute death due to aortic rupture.
Lens subluxation. You have elastin in the zonula of your eye. If those are defective, your lens
can dislocate. Particularly if they are bilateral, that’s characteristic. The dislocation tends to be up and
out, supratemporal. They tend to have ocular globe abnormalities, the globe increases and the retina
pops off. They have poorly formed mouths, small mandibles, tooth crowding and malocclusion because
of a recessed chin, retrognathia.
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This is a ectatic aorta. Here’s the left ventricle, here’s the aorta coming out. Here’s the arch, its
not normal caliber, its massive. If you look at the CT, it’s big. You can see how it would bleed or dissect.
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Lens, eye problems. The lens is up here. Here’s the pupil and here’s the lens up here. It is
bilateral,symmetric and supratemporal.