CH18 - Musculoskeletal Pathology Flashcards
What is achondroplasia?
Impaired cartilage proliferation in the growth plate
What is achondroplasia a common cause of?
dwarfism
What is achondroplasia due to?
an activating mutation in fibroblast growth factor receptor 3 (FGFR3) Autosomal dominant
What does the overexpression of FGFA3 do?
It inhibits growth
What are most mutations for achondroplasia?
they are sporadic and related to increased paternal age.
What are the clinical features for achondroplasia?
Short extremities with normal-sized head and chest?
In achondroplasia, why is there short extremities with normal-sized head and chest?
its due to poor endochondral bone formation; intramembranous bone formation is not affected.
How is endochondral bone formation characterized?
by formation of a cartilage matrix, which is then replaced by bone; it is the mechanism by which long bones grow.
How is intramembranous bone formation characterized?
by formation of bone without a preexisting cartilage matrix; it is the mechanism by which fiat bones (e.g., skull and rib cage) develop.
In achondroplasia, what aspects are not affected?
Mental function, life span, and fertility are not affected
What is osteogenesis imperfecta?
It?s a congenital defect of bone resorption resulting in structurally weak bone
What is osteogenesis imperfecta most commonly due to?
an autosomal dominant defect in collagen type 1 synthesis
What is blue sclera?
thinning of scleral collagen reveals underlying choroidal veins.
What are the clinical features for osteogenesis imperfecta?
1) Multiple fractures of bone (can mimic child abuse, but bruising is absent) 2) blue sclera?3) Hearing loss
Why is there hearing loss in osteogenesis imperfecta?
Bones of the middle ear easily fracture
What is osteoporosis?
inherited defect of bone resorption resulting in abnormally thick, heavy bone that fractures easily
What is osteoporosis due to?
Its due to poor osteoclast function
What is an example for the multiple genetic variants that exist for osteoporosis?
carbonic anhydrase II mutation leads to loss of the acidic microenvironment required for bone resorption
In osteoporosis, why is there anemia in osteoporosis?
It is due to bony replacement of the marrow (myelophthisic process)
What are the clinical features for osteoporosis?
1) Bone fractures 2) Anemia, thrombocytopenia, and leukopenia with extramedullar hematopoiesis 3) Vision and hearing impairment 4) hydrocephalus 5) renal tubular acidosis
In osteoporosis, why is there vision and hearing impairment?
due to impingement on cranial nerves
In osteoporosis, why is there renal tubular acidosis?
Its seen with carbonic anhydrase II mutation, a lack of carbonic anhydrase results in decreased tubular reabsorption of HCO3 leading to metabolic acidosis.
What is the treatment for osteoporosis?
It is bone marrow transplant; osteoclasts are derived from monocytes.
What do Ricketts and osteomalacia result in?
Defective mineralization of osteoid
What do osteoblasts normally produce?
Osteoid which is then mineralized with calcium and phosphate to form bone
What are Rickets and osteomalacia due to?
low levels of vitamin D, which results in low serum calcium and phosphate
What is vitamin D normally derived from?
the skin upon exposure to sunlight (85%) and from the diet (15%).
What does activation of Vitamin D require?
25-hydroxylation by the liver followed by 1-alphahydroxylatton by the proximal tubule cells of the kidney
What does active vitamin D do?
it raises serum calcium and phosphate
How does active Vitamin D raise serum calcium and phosphate?
by acting on the intestines, kidney and bone
What is the effect of active Vitamin D on the intestine?
It increases absorption of calcium and phosphate
What is the effect of active vitamin D on the kidney?
it increases reabsorption of calcium and phosphate
What is the effect of active vitamin D on bone?
It increases resorption of calcium and phosphate
In whom is vitamin D deficiency seen?
with decreased sun exposure (e.g.. northern latitudes), poor diet, malabsorption, liver failure, and renal failure.
What is Rickets due to?
due to low vitamin D in children, resulting in abnormal bone mineralization.
In whom does Rickets most commonly arise?
in children < 1 year of age
How do Rickets present?
1) Pigeon-breast deformity 2) Frontal bossing (enlarged lorehead) 3) Rachitic rosary 4) bowing of the legs may be seen in ambulating children
What is pigeon-breast deformity in Rickets?
It?s inward bending of the ribs with anterior protrusion of the sternum
What is the frontal bossing in Rickets due to?
The enlarged forehead is due to osteoid deposition on the skull
What is Rachitic rosary due to?
osteoid deposition at the costochondral junction
What is osteomalacia due to?
low vitamin D in adults.
What is seen in ostomalacia?
Inadequate mineralization which results in weak bone with an increased risk for fracture.
What are the laboratory findings for osteomalacia?
decreased serum calcium, decreased serum phosphate, increased PTH, and increased alkaline phosphatase
What is osteoporosis?
It?s a reduction in trabecular bone mass
What does osteoporosis result in?
porous bone with an increased risk for fracture
What is the risk of osteoporosis based on?
peak bone mass (attained in early adulthood) and rate of bone loss that follows thereafter
When is peak bone mass achieved?
by 30 years of age
What is peak bone mass based on?
it is based on (1) genetics (eg vitamin D receptor variants), (2) diet, and (3) exercise.
What happens to bone mass after age 30?
slightly less than 1% of bone mass is lost each year
What might cause bone mass to be lost more quickly (after age 30)?
with lack of weight-bearing exercise (eg space travel), poor diet, or decreased estrogen (e.g., menopause).
What are the most common forms of osteoporosis?
They are senile and postmenopausal.
What are the clinical features for osteoporosis?
Bone pain and fractures in weight-bearing areas such as the vertebrae (leads to loss of height and kyphosis), hip, and distal radius, Serum calcium, phosphate, PTH, and alkaline phosphatase are normal; labs help to exclude osteomalacia (which has a similar clinical presentation).
What must be excluded when osteoporosis is suspected? How is this done?
Osteomalacia and the labs help to exclude it
How is bone density measured?
using a DEXA scan
What is the treatment for osteoporosis?
- Exercise, vitamin D, and calcium?limit bone loss 2. Bisphosphonates?induce apoptosis of osteoclasts 3. Estrogen replacement therapy is debated (currently not recommended). 4. Glucocorticoids are contraindicated (worsen osteoporosis).
What is paget disease of bone due to?
Imbalance between osteoclast and osteoblast function
When is paget disease of bone usually seen?
in late adulthood (average age > 60 years)
What is the etiology for Paget disease of bone?
It is unknown; possibly viral
Is Paget disease of bone localized or systemic?
It?s a localized process involving one or more bones; does not involve the entire skeleton
What are the three distinct stages of Paget disease of bone?
(1) osteoclastic, (2) mixed osteoblastic-osteoclastic, and (3) osteoblastic.
What is the end result for paget disease of bone?
it is thick, sclerotic bone that fractures easily
What does biopsy for Paget disease of bone reveal?
a mosaic pattern of lamellar bone
What are the clinical features for Paget disease of bone?
1) bone pain 2) increasing hat size 3) hearing loss 4) lion like faces 5) isolated elevated alkaline phophatase
In Paget disease of bone, why is there bone pain?
Its due to microfractures
In Paget disease of bone why is there increasing hat size?
Skull is commonly affected.
In Paget disease of bone, why is there hearing loss?
impingement on cranial nerve
In Paget disease of bone, why is there lion-like facies?
involvement of craniofacial bones
In Paget disease of bone, why is there isolated elevated alkaline phosphatase?
most common cause of isolated elevated alkaline phosphatase in patients > 40 years old
What is the treatment for Paget disease of bone?
1) calcitonin 2) bisphosphonates
Why does calcitonin help in Paget disease of bone?
It inhibits osteoclast function
Why does bisphosphonates help in Paget disease of bone?
It induces apoptosis of osteoclasts
What are the complications for Paget disease of bone?
1) High-output cardiac failure?due to formation of AV shunts in bone 2) Osteosarcoma
Why is there high-output cardiac failure as a complication for Paget disease of bone?
Its due to formation of AV shunts in bone
What is osteomyelitis?
Infection of marrow and bone
In whom does osteomyelitis usually occur?
in children
What type of infection is most commonly involved in osteomyelitis?
bacterial
In osteomyelitis, why would it most commonly arise?
It arises via hematogenous spread
What happens in osteomyelitis in children?
Transient bacteremia (children) seeds metaphysis.
What happens in osteomyelitis in adults?
Open-wound bacteremia (adults) seeds epiphysis.
What are the causes for osteomyelitis?
1) Staphylococcus 2) Gonorrhoeae 3) Salmonella 4) Pseudomonas 5) Pasteurella 6) Mycobacterium tuberculosis
What bacteria is the most common cause of osteomyelitis?
Staphylococcus aureus (90% of cases)
What is the cause of osteomyelitis in sexually active young adults?
gonorrhoeae
What is the cause of osteomyelitis in sickle cell disease patients?
Salmonella
What is the cause of osteomyelitis in diabetics or IV drug abusers?
Pseudomonas
What is the cause of ostoemyelitis in associated with cat or dog bite/scratches
pasteurella
What is the cause of ostoemyelitis in that usually involves vertebrae (Pott disease)?
mycobacterium tuberculosis
What are the clinical features for osteomyelitis?
1) Bone pain with systemic signs of infection (e.g., fever and leukocytosis) 2) Lytic focus (abscess) surrounded by sclerosis of bone on x-ray
What is the lytic focus in osteomyelitis called?
Sequestrum
What is the sclerosis in osteomyelitis called?
involucrum
How is the diagnosis for osteomyelitis made?
by blood culture.
What is avascular (aseptic) necrosis?
Ischemic necrosis of bone and bone marrow
What are the causes for avascular (aseptic) necrosis?
trauma or fracture (most common), steroids, sickle cell anemia, and caisson disease.
What are major complications for avascular (aseptic) necrosis?
osteoarthritis and fracture are major complications.
What are the bone tumors?
Osteoma, osteoid osteoma, osteochondroma, osteosarcoma, giant cell tumor, ewing sarcoma, chondroma, chondrosarcoma, metastatic tumors
What is osteoma?
Benign tumor of bone
Where does osteoma most commonly arise?
arises on the surface of facial bones
What is osteoma associated with?
Gardner syndrome
What is osteoid osteoma?
Benign tumor of osteoblasts (that produce osteoid) surrounded by a rim of reactive bone
In whom does osteoid osteoma occur?
in young adults < 25 years of age (more common in males)
Where does osteoid osteoma arise?
in cortex of long bones (e.g., femur)
How does osteoid osteoma present?
as bone pain that resolves with aspirin
In osteoid osteoma, what does imaging reveal?
a bony mass (< 2 cm) with a radiolucent core (osteoid)
How does osteoblastoma compare to osteoid osteoma?
it is similar to osteoid osteoma but is larger (> 2 cm), arises in vertebrae, and presents as bone pain that does not respond to aspirin
What is osteochondroma?
It is a tumor of bone with an overlying cartilage cap
What is the most common benign tumor of bone?
osteochondroma
How does osteochondroma arise?
from a lateral projection of the growth plate (metaphysis); bone is continuous with the marrow space.
Is there a connection between osteochondroma and cancer?
Overlying cartilage can transform (rarely) to chondrosarcoma.
What is osteosarcoma?
Malignant proliferation of osteoblasts
In whom is the Peak incidence for osteosarcoma seen?
in teenagers; less commonly seen in the elderly
What are the risk factors for osteosarcoma?
include familial retinoblastoma, Paget disease, and radiation exposure.
When does osteosarcoma arise?
in the metaphysis of long bones, usually the distal femur or proximal tibia (region of the knee)
How does osteosarcoma present?
as a pathologic fracture or bone pain with swelling
What does imaging for osteosarcoma reveal?
a destructive mass with a sunburst appearance and lifting of the periosteum
What does biopsy for osteosarcoma reveal?
pleomorphic cells that produce osteoid
What is giant cell tumor?
Tumor comprised of multinucleated giant cells and stromal cells
In whom does giant cell tumors occur?
in young adults
Where do giant cell tumors arise?
in the epiphysis of long bones, usually the distal femur or proximal tibia (region of the knee)
In giant cell tumors, what is seen on x-ray?
Soap-bubble appearance on x-ray
Are giant cell tumors aggressive or benign?
its locally aggressive tumor; may recur
What is ewing sarcoma?
Malignant proliferation of poorly-differentiated cells derived from neuroectoderm
Where does ewing sarcoma arise?
in the diaphysis of long bones; usually in male children (< 15 years of age)
For ewing sarcoma, what is the appearance on x-ray?
Onion-skin appearance on x-ray
What does biopsy for ewing sarcoma reveal?
small, round blue cells that resemble lymphocytes
What might ewing sarcoma be confused with?
lymphoma or chronic osteomyelitis
What translocation is characteristic of ewing sarcoma?
T(11;22)
How does ewing sarcoma often present?
with metastasis
Does ewing sarcoma respond to chemotherapy?
yes
What is chondroma?
Benign tumor of cartilage
Where does chondroma usually arise?
in the medulla of small bones of the hands and feet
What is chondrosarcoma?
Malignant cartilage-forming tumor
Where does chondrosarcoma arise?
in medulla of the pelvis or central skeleton
Which are more common, primary or metastatic tumors of the bone?
Metastatic tumors are more common than primary tumors
What do metastatic tumors usually result in?
osteolytic (punched-out) lesions
What classically produces osteoblastic lesions?
Prostatic carcinoma.
What is a joint?
Connection between two bones
How do joints provide structural strength?
Solid joints are tightly connected (eg cranial sutures)
What are synovial joints?
They have a joint space to allow for motion
What is the articular surface of adjoining bones in a synovial joint made of?
hyaline cartilage (type II collagen) that is surrounded by a joint capsule
What facilitates smooth motion of the synovial joint?
Synovium lining the joint capsule secretes fluid rich in hyaluronic acid to lubricate the joint and facilitate smooth motion.
What is osteoarthritis?
Progressive degeneration of articular cartilage; most common type of arthritis
What is the most common type of arthritis?
osteoarthritis
What is osteoarthritis most often due to?
wear and tear
What is the major risk factor for osteoarthritis?
Age
In whom is osteoarthritis common?
after 60 years
In addition to age, what are some additional risk factors for osteoarthritis?
obesity and trauma.
What joints are affected by osteoarthritis?
a limited number of joints (oligoarticular); hips, lower lumbar spine, knees, and the distal interphalangeal joints (DIP) and proximal interphalangeal joints (PIP) of fingers are common sites
What is the classic presentation for osteoarthritis?
joint stiffness in the morning that worsens during the day
What are the pathologic features for osteoarthritis?
1) Disruption of the cartilage that lines the articular surface; fragments of cartilage floating in the joint space are called joint mice 2) Eburnation of the subchondral bone 3) Osteophyte formation (reactive bony outgrowths); classically arises in the DIP (Heberden nodes) and PIP (Bouchard nodes) joints of the lingers
What are Heherden nodes?
Osteophyte formation in distal interphalangeal joints
What are Bouchard nodes?
Osteophyte formation in proximal interphalangeal joints
What is rheumatoid arthritis?
Chronic, systemic autoimmune disease
In whom does rheumatoid arthritis classically arise?
in women of late childbearing age
What is rheumatoid arthritis associated with?
HLA-DR4
What is rheumatoid arthritis characterized by?
involvement of joints
What is the hallmark for rheumatoid arthritis?
synovitis leading to formation of a pannus (inflamed granulation tissue).
What does rheumatoid arthritis lead to?
destruction of cartilage and ankylosis (fusion) of the joint
What are the clinical features for rheumatoid arthritis?
1) Arthritis with morning stiffness that improves with activity 2) Fever, malaise, weight loss, and myalgias 3) Rheumatoid nodules 4) Vasculitis 5) Baker cyst 6) Pleural effusions, lymphadenopathy, and interstitial lung fibrosis
For rheumatoid arthritis, describe the arthritis that is seen clinically?
Symmetric involvement of PIP (proximal interphalangeal joints) joints of the fingers (swan-neck deformity), wrists (ulnar deviation), elbows, ankles, and knees is characteristic; DIP (distal interphalangeal joints) is usually spared (unlike osteoarthritis)
What is a difference between the arthritis seen in rheumatoid arthritis and osteoarthritis?
In rheumatoid arthritis the DIP is usually spared unlike osteoarthritis
For rheumatoid arthritis, what is seen on x-ray?
Joint-space narrowing, loss of cartilage, and osteopenia
What are rheumatoid nodules?
They are a central zone of necrosis surrounded by epithelioid histiocytes; arise in skin and visceral organs
What is vasculitis?
Multiple organs may be involved.
What is Baker cyst?
swelling of bursa behind the knee
What are the laboratory findings for rheumatoid arthritis?
1) IgM autoantibody against Fc portion of IgG (rheumatoid factor); marker of tissue damage and disease activity 2) Neutrophils and high protein in synovial fluid
What are the complications for rheumatoid arthritis?
anemia of chronic disease and secondary amyloidosis
What are the seronegative spondyloarthropathies?
1) Ankylosing spondylarthritis 2) Reiter syndrome 3) Psoriatic arthritis
What characterizes seronegative spondyloarthropathies?
It?s a group of joint disorders characterized by 1) Lack of rheumatoid factor 2) Axial skeleton involvement 3) HLA-B27 association
What does ankylosing spondylarthritis involve?
the sacroiliac joints and spine.
In whom does ankylosing spondylarthritis arise?
in young adults, most often male
How does ankylosing spondyloarthritis present?
with low back pain; involvement of vertebral bodies eventually arise leading to fusion of the vertebrae - bamboo spine
What are the extra-articular manifestations for ankylosing spondylarthritis?
They include uveitis and aortitis (leading to aortic regurgitation)
What is reiter syndrome characterized by?
the triad of arthritis, urethritis, and conjunctivitis.
In whom does Reiter syndrome arise?
in young adults (usually males) weeks after a GI or Chlamydia trachomatis infection
Psoriatic arthritis is seen in whom?
10% of cases of psoriasis.
What does psoriatic arthritis involve?
axial and peripheral joints; DIP joints of the hands and feet are most commonly affected, leading to sausage fingers or toes
What is infectious arthritis?
Arthritis due to an infectious agent, usually bacterial
What are the causes for infectious arthritis?
1) N. gonorrhoeae 2) S. aureus
What is the most common cause for infectious arthritis overall?
N. gonorrhoeae (its seen in young adults)
What is the 2nd most common cause of infectious arthritis overall?
S. aureus, and is seen in older children and adults
What does infectious arthritis classically involve?
It classically involves a single joint, usually the knee
What does infectious arthritis present as?
a warm joint with limited range of motion; fever, increased white count, and elevated ESR are often present
What is gout?
Deposition of monosodium urate (MSU) crystals in tissues, especially the joints
What is gout due to?
hyperuricemia; related to overproduction or decreased excretion of uric acid
Where is uric acid derived from?
purine metabolism
What excretes uric acid?
It is excreted by the kidney
What is the most common cause of gout?
Primary gout is the most common form;
What is the etiology of hyperuricemia?
it is unknown
What is secondary gout seen with?
1) Leukemia and myeloproliferative disorders 2) Lesch-Nyhan syndrome 3) Renal insufficiency
How does leukemia and myeloproliferative disorders lead to gout?
Increased cell turnover leads to hyperuricemia
How does Lesch-Nyhan syndrome lead to gout?
X-linked deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (which is the salvage pathway); presents with mental retardation and self-mutilation
How does renal insufficiency lead to gout?
decreased renal excretion of uric acid
How does gout present?
as exquisitely painful arthritis of the great toe (podagra)
Why does gout present as podagra?
- MSU crystals deposit in the joint, triggering an acute inflammatory reaction.
What may precipitate gout?
Alcohol or consumption of meat may precipitate arthritis.
What does chronic gout lead to?
1) development of tophi 2) renal failure
In gout, what happens in the development of tophi?
white, chalky aggregates of uric acid crystals with fibrosis and giant cell reaction in the soft tissue and joints
In gout, why is there renal failure?
Urate crystals may deposit in kidney tubules (urate nephropathy).
What are the laboratory findings for gout?
include hyperuricemia; synovial fluid shows needle-shaped crystals with negative birefringence under polarized light
What is pseudogout?
It resembles gout clinically, but is due to deposition of calcium pyrophosphate dihydrate (CPPD); synovial fluid shows rhomboid-shaped crystals with weakly positive birefringence under polarized light
What is dermatomyositis?
Inflammatory disorder of the skin and skeletal muscle
What is the etiology for dermatomyositis?
some cases are associated with carcinoma (e.g., gastric carcinoma)
What are the clinical features for dermatomyositis?
1) Bilateral proximal muscle weakness; distal involvement can develop late in disease. 2) Rash of the upper eyelids (heliotrope rash); malar rash may also be seen. 3) Red papules on the elbows, knuckles, and knees (Grotton lesion)
What are the laboratory findings for dermatomyositis?
1) Increased creatinine kinase 2) Positive ANA and anti-Jo-l antibody 3. Perimysial inflammation (CD4+ T cells) with peritascicular atrophy on biopsy
For dermatomyositis, what is seen on biopsy?
Peritascicular atrophy
What is the treatment for dermatomyositis?
corticosteroids.
What is polymyositis?
Inflammatory disorder of skeletal muscle
What does polymositis resemble?
dermatomyositis clinically, but skin is not involved
For polymositis, what is seen on biopsy?
endomysial inflammation (CD8+ T cells) with necrotic muscle fibers is seen on biopsy
What is x-linked muscular dystrophy?
Degenerative disorder characterized by muscle wasting and replacement of skeletal muscle by adipose tissue
What is x-linked muscular dystrophy due to?
mutations of dystrophin
What is dystrophin?
it is important for anchoring the muscle cytoskeleton to the extracellular matrix.
Describe the mutations for x-linked muscular dystrophy?
They are often spontaneous; large gene size predisposes to high rate of mutation.
What is Duchenne muscular dystrophy?
it is due to deletion of dystrophin
How does Duchenne muscular dystrophy present?
as proximal muscle weakness at 1 year of age; progresses to involve distal muscles
What is a characteristic of Duchenne muscular dystrophy?
Calf pseudohypertrophy
What enzyme is elevated in Duchenne muscular dystrophy?
Serum creatinine kinase
In Duchenne muscular dystrophy what does death result from?
cardiac or respiratory failure; myocardium is commonly involved.
What is Becker muscular dystrophy due to?
mutated dystrophin
What does Becker muscular dystrophy clinically result in?
milder disease than Duchenne muscular dystrophy
What is myasthenia gravis?
Autoantibodies against the postsynaptic acetylcholine receptor at the neuromuscular junction
In whom is myasthenia gravis more commonly seen?
in women
What are the clinical features for myasthenia gravis?
1) Muscle weakness that worsens with use and improves with rest; classically involves the eyes, leading to ptosis and diplopia 2) Symptoms improve with anticholinesterase agents. 3) Associated with thymic hyperplasia or thymoma; thymectomy improves symptoms.
In myasthenia gravis, what does the muscle weakness lead to?
Ptosis and diplopia
What does the symptoms of myasthenia gravis improve with?
Anticholinesterase agents
What is myasthenia gravis associated with?
Thymic hyperplasia or thymoma; thymectomy improves symptoms
What is Lambert-eaton syndrome?
Antibodies against presynaptic calcium channels of the neuromuscular junction
What does Lambert-eaton syndrome arise as?
a paraneoplastic syndrome,
What is Lambert-eaton syndrome most commonly due to?
small cell carcinoma of the lung
What does Lambert-eaton syndrome leads to?
impaired acetylcholine release
In Lambert-eaton syndrome the impaired acetylcholine release causes what in the neuromuscular junction?
The firing of presynaptic calcium channels is required for acetylcholine release
What are the clinical features for Lambert-eaton syndrome?
- Proximal muscle weakness that improves with use; eyes 3re usually spared. 2. Anticholinesterase agents do not improve symptoms. 3. Resolves with resection of the cancer
What is a lipoma?
Benign tumor of adipose tissue
What is the most common benign soft tissue tumor in adults?
lipoma
What is a liposarcoma?
Malignant tumor of adipose tissue
What is the most common malignant soft tissue tumor in adults?
liposarcoma
What is the characteristic cell for liposarcoma?
Lipoblast
What is rhabdomyoma?
Benign tumor of skeletal muscle
What is cardiac rhabdomyoma associated with?
tuberous sclerosis
What is rhabdomyosarcoma?
Malignant tumor of skeletal muscle
What is the most common malignant soft tissue tumor in children?
rhabdomyosarcoma
What is the characteristic cell for rhabdomyosarcoma?
Rhabdomyoblast
Rhabdomyosarcoma is positive for what?
desmin positive
What is the most common site for rhabdomyosarcoma?
it is the head and neck
What is the classic site for rhabdomyosarcoma for young girls?
vagina
