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Medical Pathology and Genetics
PPT 18: Musculoskeletal
121
Pathology
Graduate
03/21/2012

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Term
What are dysostoses? Describe the lesions. They are components of what types of syndromes?
Definition
localized disorders in the ossification of fetal cartilages
-isolated, sporadic lesions
-components of complex syndromes
Term
What are dysplasias? describe the lesions.
Definition
abnormalities in the growth and maintenance of cartilage and bone
-more diffuse effects
-hundreds of different disorders
Term
What is another name for osteogenesis imperfect (OI)?
Definition
"brittle bone disease"
Term
OI is a group of __________ disorders of _________ tissue
Definition
genetic
connective
Term
What are 6 signs and symptoms of OI? What type of inheritance pattern does it show?
Definition
-bone fractures with minimal or no trauma
-short stature, based on stature of unaffected family members, often with bone deformity
-blue sclerae
-dentinogenesis imperfecta (DI)
-progressive, post-pubertal hearing loss
-family history of OI, usually consistent with autosomal dominant inheritance
Term
How many recognized forms of OI exist? How many genes are associated? What are the two most common types?
Definition
9
mutations on 4 different genes
1 and IV
Term
More than 90% of individuals with OI have dominant mutations in which two genes? What do they encode for?
Definition
COL1A1 (collagen, type 1, alpha 1)
COL1A2 (collagen, type 1, alpha 2)
they encode the chains of type 1 pro collagen
Term
Achondroplasia is a disorder of what type of inheritance?
Definition
autosomal semidominant
Term
Achondroplasia is often due to why type of mutation in what gene? It can be due to advanced age in what parent? What percentage of pt's are due to de novo mutations?
Definition
gain of function in the FGFR3 gene
advanced paternal age
80%
Term
What are 4 major phenotypic features of achondroplasia-- what is the age at onset? stature? size of head in relation to body? spinal cord issues?
Definition
-prenatal
-rhizomelic short stature
-megalencephaly
-spinal cord compression
Term
achondroplasia is the most common cause of what?
Definition
human dwarfism
Term
What is the duty of FGFR3? What happens when there is a dominant mutation, like in achondroplasia?
Definition
-activation of FGFR3 inhibits proliferation of chondrocytes within the growth plate, which help coordinate the growth and differentiation of chondrocytes with the growth and differentiation of bone progenitor cells
-mutations cause premature inhibition of chondrocyte proliferation within the growth plate, leading to shortening long bones and abnormal differentiation of other bones
Term
Achondroplastic dwarfs sometime exhibit (lordosis/kyphosis). Is intelligence normal? Respiratory function? Why does hydrocephalus sometimes occur?
Definition
-lordosis
-normal intelligence
-respiratory function may be compromised by obstructive apnea and brainstem compression
-hydrocephalus due to obstruction of the sigmoid sinus
Term
How is achondroplasia diagnosed? What is the management?
Definition
-clinical features and usually confirmed by radiographic findings
-supportive management (monitor for chronic otitis media, hydrocephalus, brainstem compression, and obstructive apnea)
Term
If one parent is affected with achondroplasia, what is the risk of recurrence in each child?
Definition
50% because achondroplasia is an autosomal dominant disorder with full penetrance
Term
What are the odds of a child having achondroplasia if both parents are affected?
Definition
50% of having it
25% of having lethal homozygous achondroplasia
25% being normal stature
Term
What are two other disorders caused by mutations in FGFR3 besides achondroplasia?
Definition
-hypochondroplasia
-thanatophoric dysplasia
-achondroplasia
Term
What is osteopetrosis? what is it caused by?
Definition
-abnormal thickening and hardening of the bone
-abnormal fragility of the bones with partial or complete obliteration of the marrow cavities
-caused by reduced osteoclast-mediated bone resorption, leading to defective bone remodeling
Term
What is the most common form of osteopetrosis?
Definition
autosomal dominant osteopetrosis (ADO)
Term
ADO may be asymptomatic or include what other 4 problems?
Definition
multiple bone fxs
scoliosis
arthritis
osteomyelitis
Term
Mutations in what gene are responsible for 75% of cases of ADO and 10-15% of cases of ARO? What is the function of this gene?
Definition
chloride channel 7 (CLCN7)
helps to balance the acidic environment that osteoclasts use to dissolve bone
Term
What is reduction of bone mass without alteration in the composition of bone, leading to fractures?
Definition
osteoporosis
Term
Disuse osteoporosis is __________. Metabolic bone disease affects the __________ skeleton. Senile osteoporosis affects all __________ people.
Definition
localized
entire
aging
Term
In osteoporosis, bone resorption by osteoclasts __________ bone deposition by osteoblasts
Definition
outpaces
Term
What parts of the skeleton are affected most in osteoporosis?
Definition
those with abundant trabecular bone (vertebral bodies, femoral necks, and other weight bearing bones)
Term
Osteoporosis due to age related changes is mostly due to decreased activity of __________.
Definition
osteoblasts
Term
Osteoporosis due to hormal influences is do to decreased levels of __________ following __________. Elevated IL-1 and TNF leads to elevated __________, __________
Definition
estrogen
menopause
RANK
RANKL
Term
Osteoporosis due to physical activity is usually associated with (increased/reduced) PA
Definition
reduced PA increases bone loss
Term
Osteoporosis due to genetic factors: vitamin __/__________ polymorphisms account for 75% of the maximal peak bone mass achieved in any given individual.
Definition
D receptor
Term
Most adolescent __________ have insufficient dietary intake of calcium which can lead to osteoporosis due to decreased calcium intake
Definition
girls
Term
What type of fxs are extremely common in pt's with osteoporosis? What are some complications of fractures of the femoral neck, pelvis, or spine?
Definition
-thoracic and lumbar vertebral
-PE and pneumonia
Term
Is osteoporosis difficult to diagnose? WHen can radiographs detect it?
Definition
Yes, usually asymptomatic until fractures; radiographs cannot detect until after 30-40% of bone mass is lost
Term
What is another name of osteitis deformans?
Definition
paget disease
Term
what is paget disease? when does it occur?
Definition
abnormal osteoblast-osteoclast bone remodeling leads to a gain in bone mass, but newly formed bone is distorted and fragile. occurs in mid adulthood, increasing with age
Term
What is a possible cause of paget disease?
Definition
paramyxovirus infection leading to increased expression of IL-1 and M-CSF leading to activation of osteoclasts
Term
Does paget disease usually affect just one site or multiple?
Definition
can be either monostotic or polyostotic
Term
the __________ skeleton and proximal __________ are involved in as many as 80% of paget disease cases
Definition
axial
femur
Term
Patients with extensive polyostotic paget disease have hypervascularity which can lead to what? what type of fxs are common in their long bones?
Definition
high output congestive heart failure
chalk stick fractures
Term
what is softening of the bones caused by vitamin D deficiency or abnormal metabolism of vitamin d?
Definition
rickets and osteomalacia
(defective bone mineralization resulting in overabundant non-mineralized osteoid)
Term
Who does rickets affect? Osteomalacia?
Definition
-growing children (derange bone growth and skeletal deformities)
-adults (remodeled bone is under mineralized; osteopenia- predisposition to fractures)
Term
Hyperparathyroidism is high __________ and __________
Definition
PTH and calcium
Term
What is the catchy phrase to remember hyperparathyroidism? explain it
Definition
"painful bones, renal stones, abdominal groans, psychic moans"
-osteoporosis, osteitis fibrosa cystica, "brown tumor"
-renal stones
-GI: constipation, peptic ulcer, pancreatitis, gallstones
-CNS: lethargy, depression
-Muscle weakness and hypotonia
Term
What is a compound fracture?
Definition
bone penetrates the skin
Term
comminuted fracture?
Definition
bone is splintered
Term
displaced fx?
Definition
fractured bone not aligned
Term
pathological fracture?
Definition
at site of previous disease
Term
stress fracture?
Definition
develops over time from collection of micro-fractures
Term
young people often have __________ fractures with almost perfect reconstitution of the bone
Definition
uncomplicated
Term
What is the name for ischemic necrosis with resultant bone infarction?
Definition
osteonecrosis (avascular necrosis)
Term
most cases of osteonecrosis occur after a __________ or __________ use
Definition
fx
corticosteroid
Term
WHat are the two types of infarcts? describe them.
Definition
-subchondral infarct: pain during PA; often collapse and can lead to osteoarthritis
-medullary infarct: usually clinically silent unless large; usually stable
Term
Osteomyelitis is an acute or chronic bone infection, what type of infection is pyogenic osteomyelitis? what is the usual causative agent? how does it usually spread within the body?
Definition
bacterial
staph aureus
hematogenous dissemination
Term
What bones are usually affected in children with osteomyelitis? adults? how does it present?
Definition
-long bones
-vertebrae, pelvis, feet
-presents as acute systemic illness with fever, malaise, leukocytosis, throbbing pain
Term
what is the usual tx for osteomyelitis?
Definition
surgical drainage and abx
Term
Tuberculous osteomyelitis is due to a __________ infxn of the bone. how does it usually spread to the bone? what bones are most often affected? what is pott disease?
Definition
-mycobacterial
-in 1-3% of pulmonary TB cases, the bacilli spread to the bone through the blood
-long bones and vertebrae are affected most often
-pott disease: a form of osteomyelitis with TB of the vertebral bodies; causes deformity and collapse
Term
What are the most common malignant tumors of the bone?
Definition
metastatic malignant tumors arising mainly in the prostate, breast, kidney, and lung
Term
most primary bone tumors are __________ and occur before the age of __________
Definition
benign
40
Term
bone tumors in the elderly are more likely to be malignant
Definition
Term
__________ imaging is critical in the evaluation of bone tumors, but __________ and __________ analysis are required for the final diagnosis
Definition
radiologic
biopsy
histologic
Term
What is the most common benign tumor of the bone?
Definition
osteochondromas
Term
What does an osteochondroma look like?
Definition
cartilage capped bony outgrowth from metaphysis of long tubular bones (exostoses)
Term
Osteochondromas can be sporadic or hereditary, what gene is inactivated in hereditary osteochondromas?
Definition
EXT1 or EXT2 (both copies)
Term
What is a malignant mesenchymal tumor that produces a cartilage matrix?
Definition
chondrosarcoma
Term
what areas if the body do chondrosarcomas typically arise in?
Definition
pelvis, shoulder, and ribs
Term
most chondrosarcomas are low grade and do not metastasize, the high grade metastasize to the __________ and __________
Definition
lungs and skeleton
Term
what is the tx for chondrosarcomas?
Definition
wide surgical excision
Term
What is a bone producing malignant mesenchymal tumor?
Definition
osteosarcoma
Term
where are osteosarcomas found most commonly?
Definition
the long bones of teenagers and young adults, m>f
Term
What mutation is present in 60-70% of sporadic cases of osteosarcomas?
Definition
RB gene mutation
Term
Patients with hereditary __________ have a 1000 times greater risk of osteosarcoma
Definition
retinoblastoma
Term
how does osteosarcoma usually present?
Definition
a painful enlarging mass near a joint
Term
What is a codman triangle associated with osteosarcoma?
Definition
the tumor breaks through the cortex and lifts the periosteum and forms a triangle on x ray
Term
what is a highly malignant small round-cell tumor of bone and soft tissue?
Definition
ewing sarcoma
Term
what region of what chromosome is associated with ewing sarcoma?
Definition
a translocation in the ewing sarcoma breakpoint region 1 (EWSR1) gene on chr 22 and genes in several other chromosomes
Term
who does ewing sarcoma most often affect?
Definition
most children or young adults, often in puberty when bones are growing rapidly
Term
how does a ewing sarcoma present?
Definition
presents as painful enlarging masses in the diaphyses of long tubular bones of the arms and legs (esp femur) and the pelvis
Term
Where do ewing sarcomas metastasize? how often?
Definition
lungs and other bones
metastasis at the time of dx present in approx 1/3 of children
Term
what is the tx for ewing sarcoma?
Definition
surgical excision +/- radiation
Term
What is the most common joint disorder?
Definition
osteoarthritis
Term
osteoarthritis is __________ of the articular cartilage
Definition
degeneration (not inflammation!)
Term
What are the most common sites of osteoarthritis in men and women/
Definition
women: knees and hands are more common, with Heberden nodes in the fingers
men: hips are more common
Term
What are 3 rf.'s for osteoarthritis?
Definition
increasing bone density
high estrogen levels
being overweight
Term
does joint fusion occur in osteoarthritis?
Definition
no, but it does in RA
Term
what is gout?
Definition
the excessive biosynthesis or reduced elimination of uric acid in the body, formation of uric acid crystals in joints
Term
what joints are most frequently affected with gout?
Definition
big toe, ankle, wrists
Term
describe how gout presents?
Definition
pain frequently starts during the night; throbbing, crushing, or excruciating. attack may go away in several days but may return from time to time. additional attacks usually last longer
Term
what is pseudo gout?
Definition
accumulation of salt called calcium pyrophosphate forms crystals in the joints
Term
describe a pseudo gout attack?
Definition
attacks of joint swelling and pain in the knees, wrists, elbows, shoulders, and ankles are the most commonly affected. first occurs in people over 50; increases with age
Term
what is the tx for gout?
Definition
supportive
Term
what is suppurative arthritis? how many joints are usually affected?
Definition
direct infection of a joint space by bacteria with sudden pain, redness, swelling, fever
-usually a single joint: knee, hip, shoulder, wrist, elbow
Term
What is lyme arthritis? what is the vector? what joints affected?
Definition
cross-reactive immune response to systemic infection
-borrelia burgdorferi transmitted by deer ticks
-develops in 60-80% of untreated pt's late in dz
-large joints: knees, shoulders, elbows, ankles
Term
What is muscular dystrophy? What age group?
Definition
a group of genetic diseases associated with progressive degeneration of muscles usually manifesting in childhood
Term
Duchenne and Becker muscular dystrophy (DMD and BMD) are inherited as what type of mutations in what gene?
Definition
x-linked recessive mutations in the DMD gene
DMD complete loss of function mutations and BMD by partial loss of function mutations
Term
DMD encodes what protein?
Definition
dystrophin (expressed predominantly in smooth, skeletal, and cardiac muscle as well as in some brain neurons) . it is a part of a large complex of sarcolemma-associated proteins that confers stability to the sarcolemma
Term
DMD is a progressive myopathy resulting in muscle _________ and _________
Definition
degeneration and weakness
Term
pt's usually present between 3 and 5 years of age with _________/_________
Definition
gait abnormalities
Term
what muscles does DMD usually begin with?
Definition
hip girdles and neck flexors and progressively involves the shoulder girdle and the distal limb and trunk muscles
Term
Most boy patients with DMD have what two very characteristic signs of the dz by 5 yoa?
Definition
gowers maneuver
calf pseudohypertrophy (replacement of muscle by fat and CT)
Term
In DMD since the dystrophin proteins that normally stabilize the muscle cells during contraction are defective, what happens?
Definition
plasma membranes are torn apart by muscle contraction, causing death of the muscle tissue
Term
what do most male patients with DMD usually die of?
Definition
impaired pulmonary function by age 18
Term
what is the intelligence of pt's with DMD?
Definition
IQ 1 standard deviation below the mean and nearly a third have some degree of mental retardation
Term
what does the age at onset and the severity of DMD in females depend on?
Definition
the degree of skewing of x inactivation
Term
regardless of whether they have clinical symptoms of skeletal muscle weakness, most carrier females of DMD have what?
Definition
cardiac abnormalities such as dilated cardiomyopathy, left V dilatation, and ECG changes
Term
how is the diagnosis of DMD made? what is the tx?
Definition
-family hx and either DNA analysis or muscle biopsy to test for immunoreactivity for dystrophin
-currently there are no curative tx for DMD. objective of therapy are slowing the disease progression, maintenance of mobility, prevention, and correction of contractures and scoliosis, weight control, and optimization of pulmonary and cardiac function
Term
what type of therapy has shown can slow the progression of DMD for several years/
Definition
glucocorticoid therapy
Term
in 2/3 of cases an affected male inherits the mutation from a _________ who carries an altered copy of the DMD gene. how do the other third get it?
Definition
mother
new mutations
Term
if a mother is a carrier each son has a _________ risk of DMD and each daughter has a _________ risk of inheriting the dmd mutation
Definition
50%
50%
Term
Becker MD (BMD) results from mutations in the DMD gene that lead to _________ or _________ dystrophin, not a complete loss as seen in DMD pts
Definition
deficient
defective
Term
patients are said to have BMD rather than DMD if they are still _________ at the age of 16
Definition
walking
Term
Since BMD is not a _________/_________ in males like it is in DMD it can be passed from fathers to their daughters
Definition
genetic lethal
Term
in both DMD and BMD female carriers may develop _________/_________ in the absence of apparent weakness
Definition
dilated cardiomyopathy
Term
Limb-girlde muscular dystrophies are autsomal _________ usually and _________ rarely MD's
Definition
recessive
dominant
Term
in limb girdle MD weakness and wasting is usually in what muscles?
Definition
arms and legs, mainly proximal muscles; shoulders upper arms, pelvic area and thighs
Term
what is the intelligence with limb girdle MD?
Definition
unaffected usually
Term
What is the most common form of muscular dystrophy that begins in adulthood?
Definition
myotonic dystrophy
Term
myotonic dystrophy is characterized by progressive muscle _________ and _________ with _________
Definition
wasting
weakness
myotonia (failure of muscle to relax immediately after contraction has stopped)
Term
What is an eye and heart disorder common with myotonic dystrophy?
Definition
cataracts
cardiac conduction abnormalities
Term
what type of mutation is myotonic dystrophy?
Definition
autosomal dominant
Term
TYPE 1 myotonic dystrophy is common in what part of the body? what gene is effected?
Definition
lower legs, hands, neck and face
-CTG trinucleotide repeat expansion in the DMPK gene (genetic anticipation: usually maternal repeat size larger in next generation -- can be paternal too)
Term
What part of the body does myotonic dystrophy type 2 affect? what gene is affected?
Definition
neck, shoulders, elbows, hips
CCTG tetra nucleotide repeat expansion in the CNBP gene, somatic instability-- repeat size gets larger in an individual as they age.. there is no correlation between CCTG repeat size and age of onset or severity of disease
Term
in type 1 myotonic dystrophy, as repeat sizes get larger, what happens?
Definition
onset occurs at a younger age and the phenotype is more severe
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