Path Exam 2 Spring

alpha-1 antitrypsin
sickle cell anemia
Factor V Leiden

beta-thalassemia

Prothrombin mutation: hypercoagulability
Hereditary spherocytosis: mutation results in decreased production of ankyrin, failure to assemble spectrin

Blood Type O
Tay-Sachs (gene HEXA)

CF-mutated CFTR

Huntington's Disease
Myotonic dystrophy
Friendrich ataxia
Fraxile X syndrome

Single mutation that has multiple effects.
Ex: Sickle cell, Marfan's Syndrome

Same defect is produced by many different mutations.
Ex: deafness

AR

AD

AD

AD

AR

AR

AD

AD

AR

AD

AD

AD

AD

AD

AD

AD and AR

AD

AD

AD

AR

AR

AR

AR

AD

AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

AR

XLR

XLR

XLR

XLR

XLR

XLR

XLR

XLR

XLR

XLD

a lysosomal storage disease (AR)

Hexosaminidase-a subunit deficiency

GM2 ganglioside accumulates predominantly in the nervous system.

Neurons ballooned with cytoplamsic vacuoles containing fat = Lamellar bodies

Sphingomyelinase deficiency

Sphingomyelin accumulates in phagocytic cells and neurons

Type A

Type B

Cherry red spot on retina
Severe deterioration evident at 6 months

Tay-Sachs = no hepatosplenomegaly
Niemann-Pick = massive HSmegaly

NPC-1 gene: involved in cholesterol trafficking

Cholesterol accumulates; terminal axons and dendrites deteriorate, organomegaly

a lysosomal storage disease (AR)

Deficiency of glucocerebrosidase

accumulation of glucocerebroside/glycosylceramide from break down of cell membrane glycolipids

Gaucher Cells: swollen phagocytic cells w/ PAS positive cytoplasm

massive splenomegaly (up to 10kg)
Since membranes of senescent RBCs and WBCs are the greatest source of the glucocerebroside/glycosylceramide you see pancytopenia, thrombocytopenia, leukopenia, etc (and also the huge spleen!).
Also see pathological fractures and bone pain because the bone marrow is being replaced by Gaucher cells. Erlenmeyer flask deformity of long bones, due to packing of bone marrow - risk for bone infarction/aseptic necrosis

deficiency of alpha-galactosidase

accumulation of globosides: ceramide trihexoside

Angiokeratomas - telangiectasias of the skin = red-purple rash in childhood on trunk, legs

deficiency of alpha-L-iduronidase

deficiency of alpha-L-iduronidase (different mutation than Hurler Syndrome)

Gargoyles

vascular disease: MI, heart failure

Scheie syndrome has a different mutation in the Alpha-L-iduronidase and even though the accumulation is the same (dermatan sulfate and heparan sulfate) the people have stiff joints and corneal clouding (like Hurler's) but intelligence and life expectancy are normal

Dermatan sulfate and Heparan Sulfate

X-linked

L-iduronate sulfatase

Dermatan sulfate and Heparan sulfate

No corneal clouding!
Males only --> x-linked
Milder course

deficiency of phosphorylating enzymes essential to formation of mannose-6-phoshate recognition marker.
Looks like Hurler's

Glucose-6 phosphatase deficiency in cytosol

Deficiency of debranching enzyme

glycogen in the heart, liver, and muscle

deficiency of muscle phosphorlyase

glycogen in muscle

Muscle cramps, weakness with exercise
Serum lactate does NOT rise with exercise (serum ammonia, muscle enzymes increase from myoctyolysis/rhabdomyolysis)

Lysosomal alpha-1,4-glucosidase (acid maltase) defiency

glycogen in the liver, heart, skeletal muscle

Pediatric form = massive cardiomegaly and death from CV/CR arrest
Adult form = skeletal muscle only involved

alkaptonuria (ochondrosis)

deficiency of homogentisic oxidase

accumulation of homogentisic acid in collagen and cartilage (homogentisic acid --> methylacetylacetate blocked)

Blue-black pigementation in cartilage in ears/nose.
Seen in Alkaptonuria

Ochondrosis
Severe, crippling arthritis at an early age - starts in vertebral column, intervertebral discs and progresses to knees, shoulders, hips. Hands and feet usually spared*
Urine turns black on exposure to light.

Mutation of tumor suppressor NF-1 on chromosome 17.
Codes for neurofibromin --> down-regulates p21 ras oncogene protein product

Multiple neural tumors (neurofibromas) anywhere in or on the body.
Cafe-au-lait spots
Lisch nodules - pigmented iris hamartomas

Sarcoma arising in neurofibromas ~3% (most likely to occur in large, deep, plexiform lesions)
Increased risk or other tumors (Myeloid leukemia:200-500x risk)

NF-2 gene: merlin gene product
(cytoskeletal protein, interactions between actin, membrane)
(Regulates contact inhibition and proliferation of Schwann cells)

Bilateral acoustic neuromas
Multiple meningiomas
NO LISCH NODULES!

additive effect of 2 or more genes of small effect conditioned by environmental nongenetic influences

Day 35 of gestation - fusion of maxillary process to frontal prominence

21q22.2

AFP decreased
hCG increased
inhibin A increased
PAPP-A decreased

keratoconus
Brushfield's spots of irises
Risk for cataracts increased

Defects of endocardial cushions
- venous inflow
AV septal defect
VSD
ASD - ostium primum

mean age of 40

TBX1 - found in deleted region
Expressed in pharyngeal mesenchym
Target gene of PAX9 which controls the development of palate, parathyroids, thymus.
Embryologic derivatives of the 3rd and 4th pharyngeal pouches

5p-: deletion of short arm of chromosome 5

androgen receptor, located on X is inactivated --> CAG trinucleotide repeat polymorphism

FSH elevated
Estradiol elevated
variably reduced testosterone

extragonadal germ cell tumors
breast cancer (risk 20x increased)

severe acne due to increased testosterone

SHOX gene haploinsufficiency

coarctation of the aorta
preducta and bicuspid aortic valve

hypothyroidism - thyroid autoantibodies
celiac disease

FMR-1 gene

Fragile X associated tremor/ataxia syndrome
coccurs in 30% of carrier men between 50-60 years

CGG

excess androgens during embryogenesis. CAH - 21 hydroxylase deficiency -> fetal adrenal glands produce excess androgen (leads to a genetic female with ovaries but male external genitalia)

SRY gene translocation from Y to autosome.

AR

XLR

Testicular feminization (most common)
Androgen insensitivity syndrome (X-Linked Recessive)
Defective androgen receptor
Defects involving WT gene on chromosome 11
Defects in testicular hormones

CAG

the trait worsens with each generation

Long, large mandible
Large, everted ears
Macro-orchidism post puberty in 90%+
Hyperextensible joints, high arched palate*, mitral valve prolapse

primary ovarian insuficiency

defective mitochondrial oxidative phosphorylation (mitochondrial inheritance)

Progressive B/L loss of central vision
Onset 15-35 years
Cardiac conduction defects;minor neurologic manifestations occur in some

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
(Mitochondrial inheritance)

may be normal for first few yrs of life
motor and cognitive developmental delays
Stroke-like episodes with CT/MRI abnormalities leading to dementia.
Other associations: exercise intolerance, visual abnormalities, cardiomyopathies, etc

interstitial deletion chromosome 15 inherited from father

interstitial deletion chromosome 15 inherited from mother
Inactivated (imprinted) UVE3A gene normal chromosome inherited from father

mental retardation
short stature
obesity due to compulsive eating disorder (Peptide YY decreased)
Small hands/feet, hypotonia
Hypogonadism

"Happy puppet syndrome"
Mental retardation and seizures
Ataxia
Inappropriate laughing

function to silence gene expression: miRNA pairs with posttranscriptional target mRNA

lacrimal gland lesions: sarcoid, neoplasms
Optic nerve tumors: glioma, meningioma
Thyroid ophthalmopathy: Graves disease
Other orbital inflammatory conditions

idiopathic orbital inflammation/psuedotumor = chronic inflammation, fibrosis of lacrimal gland, orbital muscle and/or fascia-sclera

acute purulent (staph) inflammation of superficial gland or hair follicle of eyelid. Involve meiboman or glands of Zeis

painLESS nodule or papule of the eyelid. Chronic granulomatous inflammation of the meiboman glands.
Gross DDx: sebaceous adenocarcinoma

epidermal inclusion and dermoid cysts

syringoma

basal cell carcinoma (most common)
Sebaceous carcinoma
Squamous cell carcinoma

paget-like growth that thickens the eyelid - resembles blepharitis

1st to parotid and submandibular glands

Marfan syndrome
Down Syndrome

eye inflammation that involves the vitreous

eye inflammation that involves retina, choroid, and sclera. Extends into orbit to cause orbital cellulitis, proptosis

painful, often red, eye
Photophobia
blurred vision
mild miosis

granulomatous uveitis (noncaseating: asteroid bodies)
calcific band keratopathy
Mutton fat keratotic precipitates
Retina: candle wax drippings (perivascular inflammation)
Sarcoidosis may also involve lacrimal glands and lead to dry eyes

mets to the choroid

liver (late)

hereditary defect of pigmentation by intact melanocytes, absent/reduced melanin synthesis

no melanin pigment in eyes, skin, hair
Predisposes to actinic keratoses, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma.
Ophthalmic problems

Tyrosinase positive OCA
- most common type of albinism
- tyrosine transport mutation (P gene)
- small amount of pigment accumulate over time
Tyrosinase Negative OCA
- total absence of pigment, white hair, red pupil.
- Severe ophthalmic problems
- least frequent type

ephelis

pigmented macule formed of hyperplastic melanocytes within the epidermis or mucosa. Cause is unknown and they don't fade in the offseason (like freckles do)

nevus cells confined to epidermal-dermal junction

nevus cells both at the epidermal-dermal junction and in the dermis

cell clusters in dermis, matures with depth into neural like cells

increases risk of melanoma if large

dendritic (spindle cells) highly pigmented cells within the dermis.
Blue/black color secondary to dermal location

spindle and epithelioid nevus.
Reddish nodule - may resemble hemangioma, melanoma

depigmentation of skin around a nevus associated with lymphatic infiltration (malignant melanoma may "halo" -- bad sign!)

precursor lesion of malignant melanoma

CDKN2A gene complex (p16INK4a) or CDK4 germline mutation
AD inheritance

in situ melanoma
Nonfamilial
AKA: Hutchinson's Freckle
Occurs in sun-exposed areas: face
Remains in situ for years
Precursor to lentigo maligna melanoma.

Assymetry in shape
Borders are irregular
Color is mottled
Diameter is usually >6mm
Elevation above surrounding tissue

Nodular melanoma

on the face

trunk and extremities

superficial spreading melanoma

on hands and feet - including plantar aspect and subungual
Can affect dark-skinned people

Lentigo maligna melanoma: long radial growth phase
Superficial spreading melanoma: radial growth phase
Nodular melanoma: vertical growth phase
Acral-lentigenous melanoma: none listed

mutations in p16INK4a and BRAF
also aberrant increases in PI-3K/AKT signaling
PTEN silencing
c-KIT activation

Dermatosis papulosa nigra

pregancy
DM
intestinal polyposis

Acrocordon

epithelial cysts formerly sebaceous cysts - dome-shaped moveable nodule

down growth and cystic expansion of epidermis

expansion of the epithelium of the hair follicle

skin appendages in wall

may rupture and produce a painful foreign body granuloma in the dermis

sporadic or inherited (AD) tumor of the forehead and scalp
"Turban tumor of the scalp"
apocrine derivation

Sporadic or inherited (AD) tumor of the face, scalp, neck, upper trunk.
Basaloid cells resmebling those of hair follicles

internal malignancy - MSH-MLH mutations

found on palms and soles!!!!

Beta-catenin mutation (regulates early hair development)

Angiofibromas - acne-like lesions of the face
Hypopigmented lesions: ash-leaf macules
Peirungual fibromas
Shagreen patches - connective tissue hamartoma

basal cell carcinoma

Gorlin Syndrome/Nevoid basal cell syndrome (AD)

unrepaired mutations, UV induced, of PTCH and p53

tumor suppressor gene - 2 hits produce basal cell carcinoma in NBCCS.
Common mutation in sporadic basal cell ca.
Receptor protein for SHH gene (SHH determines polarity during embyrogenesis)

dermatofibroma - tan to brown papules <1 cm that may enlarge rapidly to a few cm in diameter.
**Dimple on compression = collar button sign!!!!

Dermatofibrosarcoma protuberans

well differentiated, spindle cell tumor in a storiform pattern of proliferating nuclei

urticaria pigmntosum

due to eosinophilic granulomas/Langerhans cell infiltrates.
Triad: Skull defects, exophthalmos, and diabetes insipidus
May have HSmegaly, lymphadenopathy, fever, skin rash

Post-partum panhypopituitarism
Necrosis of the pituitary secondary to complication of labor: hemorrhage, shock. Posterior spared because of the separate blood supply. Onset of hypopituitarism may be late. Hypogonadism is first symptom

sudden hemorrhage into gland.
Often occurs in an adenoma.
Clinical: sudden onset of excruciating HA, diplopia, hypopituitarism.
Neurosurgical emergency: may cause CV collapse (due to adrenal insufficiency)

Subacute granulomatous thyroiditis. Painful.
Seasonal: peak in summer
Pathogenesis: HLA predisposition. Viral antigen/tissue damage results in formation of cytotoxic T cells. Follicle cells damaged/content released --> transient thyrotoxicosis. Onset sudden or grandual following URI w/ coxsackie, adenovirus or other. Pain in teh neck: worse on swallowing, radiates to jaw, throat, ears.
Transient thyrotoxicosis then hypothyroidism. Multinucleate giant cells

middle aged adults - females. May occur postpartum.
Pathogenesis: HLA-related autoimmunity. Clinically presents with thyrotoxicosis.
Self-limited in 70% ~2 months
Thyroid diffusely enlarged non-tender/painless

fibrosis of thyroid extending into tissues surrounding the thyroid.
Associated with idiopathic fibrosis elsewhere: retroperitoneal, mediastinal

hyperfunctioning nodule produces clinical hyperthyroidism - hot nodule on radioiodine scan. May occur from a non-toxic goiter

1. overwhelming septicemic infection - N. meningitidis
2. rapidly progressive HoTN with shock
3. DIC with purpura
4. Massive B/L adrenal hemorrhage with rapid adrenocortical insufficiency

1. solitary nodules are more likely to be neoplastic than multiple
2. nodules in younger pts more likely to be neoplastic
3. nodules in males more likely to be cancer than in females
4. history of radiation tx to head/neck associated with cancer.
5. "cold" nodules more likely to be malignant

follicular epithelium

Somatic mutations in some component of signaling system (TSH receptor) cause chronic stimulation of cAMP pathway, generates cells with growth advantage

parafollicular/c-cells
secrete calcitonin

thyroglossal cyst/duct

1. branching papillae w/ fibrovascular stalk covered by single/multiple layers of cuboidal epithelium
2. orphan annie, ground glass nuclei
3. psammoma bodies

ionizing radiation

Papillary carcinoma
Follicular carcinoma
Medullary carcinoma
Anaplastic carcinoma

10% arise in association with MEN syndrome
10% are extra-adrenal
10% are biologically malignant
10% arise in childhood, usually familial, males
10% of non-familial are B/L

Pituitary
Parathyroids
Pancreas

Pheochromocytoma
Medullary carcinoma
Parathyroid hyperplasias

suprabasal acantholytic blister

flaccid bullae

Fishnet-like staining of IgG

life threatening fluid loss; infection

subepidermal vesicles and bullae

tense bullae

continuous linear basement membrane immunoglobulin and complement - lamina lucida

complement fixing antibody to basal cell basement membrane.
BPAG = bollous pemphigoid antigen

heals without scar

IgG antibody to intercellular cement - desmoglein 1,23