Pathology - Genetic Diseases

Down's Syndrome
Edward's Syndrome
Turner's Syndrome

Neurofibromatosis
Tuberus Sclerosis Complex
Osteogenesis Imperfecta
Ehlers-Danlos
Marfans
AD polycystic kidney disease
Familial Hypercholesterolemia

Lysosomal storage disease
Glycogen storage

Chorionic villus - 6 to 7 weeks
Amniocentesis - 18 weeks

1) mid-facial hypoplasia
2) atrio-ventricular canal (40% of down's babies with heart problems have this)
3) Epicanthal folds in front of eye
4) single palmer crease
5) sandal toe deformity
6) clinodactyly - in-turning of little finger
7) low-set, malformed ears
8) hypotonia - esp in tongue
9) nuchal hygroma (due to stretched neck, abnormal lymph drainage in-utero
10) brushfield's spots - hypopigemented spots on iris

Chr 18

- first and fourth finger overlap middle two
- severe mental retardation
- missing radius bone, thus missing thumb
- rocker bottom feet
- dorsiflexion of big toe
- omphalocoel of gut
- 95% die in utero

- coarctation of aorta, so you don't have good blood perfusion to lower extremeties
- nuchal hygroma - swelling in back on neck
- short stature, wide nipples, shield chest
- enlarged ears, recessed hairline
- edema in hands/feet - due to lymphatic drainage problems

- reduced penetrance: genotype present, but phenotype normal
- expressivity: severity and constellation differ
- delayed age of onset often
- affect regulators of complex pathways (usually not enzymes)

defect in tumor supressor gene neurofibromin

Cafe au lait spots - >6
Axillary freckles - diagnosed as child
Neurofibromas - peripheral nerve tumors, subcutaneous, "bag of worms"
CNS: optic nerve gliomas, acoustic nerve neuromas (1 side), meningiomas (tumor of dura)

Bag of worms appearance, has pascinian corpuscles (mechanoreceptors) and spindle cells (bad!)

Blanched (white) look due to blocking of opthalmic artery

Type 1 and Type 2 are most common. And 50-75% of these cases are due to new mutation.

TSC-1: hamartin
TSC-2: tuberin
(these are the first hit?)

mental retardation - not all have this
epilepsy - most of this
adenoma sebaceum - all of this

1) CNS - seizures due to subependymal calcification of tumors. Olfactory hamartomas in infants.
2) skin - adenoma sebaceum: acne like skin, bilateral, symmetrical. AND "ashleaf spots" seen by Wood's lamp examination, hypopigmented area that you need UV light to see

1) cardiac rhabdomyoma - hamartoma in the heart, benign tumor, can lead to ball valve that obstructs blood flow
2) renal angiomyolipoma - hamartomas that include vessels, muscle, fat in the kidney. Develop renal cysts. Risk of rupture
3) astrocytic hamartomas in back of eye "mulberry like".


extra: pulmonary cysts, lymphatic abnormaliteis, gingival fibromas

50% decrease in collagen type I, osteopenia (decrease bone), osteoporosis, skeletal malformation,

type 1 - most common
type 2 - lethal

- excessive bone fragility (90% penetrance)
- easy bruising, short stature, kyphosis, joint hypermobility,
- hearing loss (ear bones)
- blue sclera (100% penetrant), most common in type 1/4

Autosomal Dominant

Aortic cysts

Defect in the Fibrillin gene on the 15th chromosome, decrease in fibrillin, so improper elastin array in blood vessels .

Tall, slender, with long arms, arachnodactyly (long fingers), thumb sign, wrist sign, Pectus excavatum - pigeon, caved chest
Kyphoscoliosis

- aortic dissection
- aortic regurgitation
- lens displacement, optic glob elongation, flat corneas, retinal detachment, increased risk for glaucoma and cateracts
- tooth crowding
-

100%

cilia dysfunction, kidneys can't excrete fluid

- berry anyeurism in circile of willis
- mitral valve prolapse
- liver cysts

- premature atherosclerosis
- pancreatitis (elevated chylomicrons)
- retinal/neurological disease - vit E deficiency due to low VDL/LDL)

Type IIa - LDL receptor deficiency
Type IIb - LDL receptor problems

LDL released from fats cannot get into liver due to no receptor, so the accumulate in arteries

Homo - more severe, childhood onset
Heterzygous, milder
- tendon xanthomas, extra ear folds
Other risks: aortic stenosis murmur, MI

In patients with hypercholesterolemia. (ring around eyes)

acid hydrolase

- 3-6 months age of onset
-2-5 yrs death occurs
- retinal cherry red spot
- easily startled
- seizures, blindness, deafness, hypotonia, paralysis

Hexoaminidase A, leads to accumulation of ganglioside G2, a complex lipid, in neurons and macrophages

Chr 15

true. don't know why she emphasized this.

defect in sphingomyelinase, seen in neurons, causes psychomotor retardation
- Cells have bubbly appearance in ganglion, cells missing sphingomyelinase, zebra bodies in lysosomes
- also has cherry red spot on macula
- increase size in spleen and liver

Type I - Von Gierke: defect in 1st enzyme needed for breakdown (glucose-6-phosphatase). Big problem, can't get sugar to brain. Causes hypoglycemia, seizures, hepatomegaly, death early age. BUT you can treat with enzymes
Type V - MacArdle's. Glycogen can't be broken down in muscles. Increase in cramps, no lactate used, myoglobinuria
Type II - Pompe's. Acid maltase deficiency, involves heart. Glycogen just floating in cytoplasm. Death w/o enzyme replacement

Hurler MPS Type I - MR, progressive CT Increase with coarse facies, face stiffness, small stature, large heads, CORNEAL CLOUDINGdeath due to cardiac failure
Hurlers Type II - everything above, but with no corneal clouding

- causes panacinar emphysema
- decrease protection from proteases, destruction of alveoli
- cirhosis in liver due to accumulation

1) asymptomatic hyperuricemia, no symptoms before age 30
2) sudden, painful acute arthritis

primary - overproduction of uric acid
secondary - like chemo that destroys DNA, causes purine breakdown

- hydration
- cholchicine
- NSAIDS
- allopurinol