Robbins Flashcards
extracellular component of bone, the matrix, is composed of osteoid (__%) and minerals (__%)
35%, 65%
Mineral in bone is primarily
calcium hydroxyapatite [Ca10(PO4)6(OH)2]
hydroxyapatite in bone serves as a repository for (2)
99% of the calcium and 85% of the phosphorus in the body
Osteoid is what type of collagen?
Type 1
This is produced by osteoblasts and is used as a specific marker of osteoblast activity
Osteopontin (osteocalcin)
This type of bone is always abnormal in adults
Woven bone
most bones form via
endochondral ossification
flat bones form via
intramembranous ossification
The balance between bone formation and resorption is modulated by ___ and ___ signaling
RANK, WNT
When stimulated by RANKL, RANK signaling activates NF-κB, which is essential for the generation and survival of
osteoclasts
a secreted decoy receptor made by osteoblasts and several other types of cells that binds RANKL and thus prevents its interaction with RANK
osteoprotegerin (OPG)
developmental disorder characterized by shortening of the terminal phalanges of the thumb and big toe, respectively
Brachydactyly types D and E
Brachydactyly types D and E are caused by mutations in
homeobox HOXD13 gene
developmental disorder characterized by patent fontanelles, delayed closure of cranial sutures, Wormian bones (extra bones that occur within a cranial suture), delayed eruption of secondary teeth, primitive clavicles, and short stature.
cleidocranial dysplasia
mutation in cleidocranial dysplasia
Loss-of-function mutations in RUNX2
most common skeletal dysplasia and a major cause of dwarfism
achondroplasia
achondroplasia is an autosomal dominant disorder caused by gain-of-function mutations in
FGF receptor 3 (FGFR3)
Normal FGF-mediated FGFR3 activation function and how does mutation in this cause dwrafism
inhibits endochondral growth, this effect is exaggerated by FGFR3 gain-of-function mutations causing shorter proximal extremities
most common lethal form of dwarfism
Thanatophoric dysplasia
mutation in thanatophoric dysplasia
FGFR3 gain of function mutation distinct from what causes achondroplasia
T/F FGFR3 gain-of-function mutations in thanatophoric dysplasia cause less FGFR3 signaling thus show a less severe phenotype
False, more severe phenotype, which cause underdeveloped thoracic cavity, leads to respiratory insufficiency, and these individuals frequently die at birth or soon after.
most common inherited disorder of connective tissue
Osteogenesis imperfecta (OI)
Osteogenesis imperfecta (OI) is a phenotypically heterogenous disorder caused by deficiencies in
type I collagen synthesis
The fundamental abnormality in OI is
too little bone
OI variant, which is uniformly fatal in utero or during the perinatal period, is characterized by extraordinary bone fragility and multiple intrauterine fractures
Type 2
comprises a group of rare genetic diseases characterized by reduced bone resorption due to deficient osteoclast development or function, which leads to diffuse, symmetric skeletal sclerosis
osteopetrosis
Most of the mutations underlying osteopetrosis interfere with
acidification of the osteoclast resorption pit
Albers-Schönberg disease, a mild autosomal dominant form of osteopetrosis, is caused by mutation of
CLCN7
mutation in autosomal recessive osteopetrosis accompanied by renal tubular acidosis
carbonic anhydrase (CA2)
developmental disorder that presents with lack of a medullary canal, and the ends of long bones are bulbous (Erlenmeyer flask deformity) and misshapen
osteopetrosis
lysosomal storage disease where mucopolysaccharides accumulate within chondrocytes and induce apoptosis and leads to structural defects in articular cartilage
mucopolysaccharidoses
Developmental abnormalities caused by defects in nuclear proteins and transcription factors (2)
Brachydactyly types D and E
cleidocranial dysplasia
Developmental abnormalities caused by defects in hormones and signal transduction proteins (2)
achondroplasia
thanatophoric dysplasia
Developmental bone abnormalities caused by defects in extracellular structural proteins (1)
Type 1 collagen diseases - osteogenesis imperfecta
Developmental bone abnormalities caused by defects in metabolic pathways (1)
osteopetrosis
Developmental bone abnormalities caused by defects in degradation of macromolecules (1)
mucopolysaccharidoses
_____ refers to decreased bone mass; _____ is defined as osteopenia that is severe enough to significantly increase the risk of fracture
osteopenia, osteoporosis
most common forms of osteoporosis (2)
senile and postmenopausal
This form of ostepososis includes a reduced proliferative and
biosynthetic capacity, and attenuated response to growth factors of osteoblasts, resulting in a diminished ability to make bone.
senile
form of osteoporosis that affects mainly bones or portions of bones that have increased surface area, such as the cancellous compartment of vertebral bodies
Postmenopausal osteoporosis
(2) manifestations of impaired mineralization of bone matrix
Osteomalacia and rickets
disorder in children, in whom it interferes with the deposition of bone in the growth plates
rickets
disease where bone formed during remodeling is undermineralized and predisposed to fractures
osteomalacia
parathyroid hormone (PTH) has a central role in calcium homeostasis through the following effects: (4)
Activation of osteoclasts, Increasing calcium resorption by the renal tubules, Increasing urinary phosphate excretion, and Increasing synthesis of active vitamin D, 1,25(OH)2-D, by
the kidneys, thereby enhancing intestinal calcium absorption
untreated primary hyperparathyroidism manifests with three interrelated skeletal abnormalities (3)
osteoporosis, brown tumors, and osteitis fibrosa cystica
describes the collective skeletal changes that occur in chronic renal disease, including those associated with dialysis
renal osteodystrophy
disorder marked by increased, but disordered and structurally unsound, bone mass.
Paget Disease (Osteitis Deformans)
three sequential phases of Paget Disease (Osteitis Deformans)
(1) osteolytic stage; (2) a mixed osteoclastic-osteoblastic stage; and (3) osteosclerotic stage
Approximately 50% of cases of familial Paget disease and 10% of sporadic cases are associated with mutations in the
SQSTM1 gene
histologic hallmark of paget disease
jigsaw puzzle–like appearance produced by prominent cement lines
The most dreaded complication of Paget disease is
sarcoma
defined as loss of bone integrity
fractures
marks the completion of the healing process of fractures
restoration of the medullary cavity
characterized by empty lacunae surrounded by necrotic adipocytes
dead bone
responsible for 80% to 90% of culture-positive pyogenic osteomyelitis
Staphylococcus aureus
characteristic saber shin is produced by reactive periosteal bone deposition on the medial and anterior surfaces of the tibia and is seen in this infection
congenital syphilis
benign bone- producing tumors with similar histologic features but different sizes, sites of origin, and symptoms
Osteoid Osteoma and Osteoblastoma
Osteoid osteoma size
<2 cm
osteoblastoma size
> 2cm
Osteoid osteoma or osteoblastoma
has a predilection for the appendicular skeleton
osteoid osteoma
Osteoid osteoma or osteoblastoma
has a predilection for the posterior spine
osteoblastoma
Osteoid osteoma or osteoblastoma
induces a thick rim of reactive cortical bone
osteoid osteoma
Osteoid osteoma or osteoblastoma
nocturnal pain not relieved by aspirin
osteoblastoma
Osteoid osteoma or osteoblastoma
treatment requires curettage
osteoblastoma
2 somewhat similar bony lesions which demonstrate randomly interconnected trabeculae of woven bone rimmed by a single layer of prominent osteoblasts and surrounded by loose connective tissue with many dilated and congested capillaries Both have a relatively small size, well- defined margins, and benign cytologic features of the neoplastic osteoblasts
Osteoid osteoma and osteoblastoma
most common primary malignant tumor of bone
Osteosarcoma
region of the long bone where osteosarcomas usually arise in
metaphysis of long bones, 50% near the knee
Osteosarcoma frequently breaks through the cortex and lifts the periosteum, inducing reactive periosteal bone formation. The triangular shadow between the cortex and raised periosteal ends, known radiographically as
Codman triangle
Usual mutations in osteosarcoma (4)
RB, TP53, CDKN2A, and MDM2
Diagnosis of osteosarcoma requires the presence of malignant tumor cells producing (2)
unmineralized osteoid or mineralized bone
Bone forming tumors (3)
osteoid osteoma
osteoblastoma
osteosarcoma
the most common benign bone tumor
Osteochondroma, or exostosis
attached to the skeleton by a bony stalk capped by cartilage
osteochondroma
About 85% of osteochondromas are solitary and sporadic, with the remainder occurring as part of this autosomal dominant syndrome
multiple hereditary exostosis syndrome
region of the long bone where osteochondroma most commonly arise in
metaphysis near the growth plate of long tubular bones, especially near the knee
Hereditary ostechondromas/exostoses are associated with germline loss-of- function mutations in
either the EXT1 or the EXT2 gene
In osteochondroma, a thick and irregular cap measuring _____ may be indicative of progression.
> 2 cm
benign tumor of hyaline cartilage that occurs in bones of endochondral origin
chondroma
chondroma that arise within the medullary cavity are termed
enchondroma
chondroma that arise on the bone surface are termed
juxtacortical chondromas
most common intraosseous cartilage tumor
enchondroma
nonhereditary disorders characterized by multiple enchondromas (2)
Ollier disease and Maffucci syndrome
Heterozygous mutations present within enchondromas (2)
IDH1 and IDH2 genes
a phenomenon where in an entity causes oncogenic epigenetic changes in genetically normal neighbors
transformation by association
Individuals with _______ syndrome develop multiple enchondromas and spindle cell hemangio- mas and are also at risk of developing other malignancies, including brain gliomas, another type of cancer associated with IDH gene mutations
Maffucci
second most common malignant matrix-producing tumor of bone
Chondrosarcomas
Chondrosarcomas commonly arise in this location
axial skeleton
The clear cell variant of chondrosarcoma is unique in that it originates in the
epiphyses of long tubular bones
Chondrosarcomas arising in multiple osteochondroma syndrome exhibit mutations in the
EXT genes
chondromatosis-related and sporadic chondrosarcomas may have mutations in
IDH1 or IDH2
malignant bone tumor characterized by primitive round cells without obvious differentiation
Ewing sarcoma
second most common group of bone sarcomas in children after osteosarcoma
Ewing Sarcoma
Bone region Ewing sarcoma usually arises in
diaphysis
Greater than 90% of Ewing sarcomas contain a balanced translocation involving the
EWSR1 gene on chromosome 22
majority of Ewing sarcomas have a fusion gene namely
EWS/FLI1
Age of approximately 80% of patients with Ewing sarcoma
< 20 years old
Ewing sarcoma usually arises in what bone layer?
medullary cavity
bone lesion characterized by the presence of numerouus multinucleated osteoclast-type giant cells
giant cell tumor of bone / osteoclastoma
T/F Giant cell tumor of the bone is composed of neoplastic osteoclasts and their precursors.
False. The neoplastic cells are primitive osteoblast precursors that express high levels of RANKL, which in turn promotes the proliferation of osteoclast precursors and their differentiation into mature osteoclasts.
The neoplastic cells in GCT of bone have acquired mutations in the gene encoding
histone 3.3
GCT of bone usually develop in this region of the bone
within the epiphysis and may extend into the metaphysis
large bony lesion with red-brown masses that frequently undergo cystic degeneration. Histologically, the tumors consist of uniform oval mononuclear tumor cells and abundant osteoclast-type giant cells with 100 or more nuclei
GCT of bone
bone lesion characterized by multiloculated blood-filled spaces
aneurysmal bone cyst
chromosomal 17p13 rearrangements in aneurysmal bone cysts results in fusion of the
USP6 coding region with the promoters of genes that are highly expressed in osteoblasts
developmental abnormalities in which fibrous connective tissue replaces bone. sharply demarcated radiolucent masses surrounded by a thin rim of sclerosis.They are grossly yellow-brown and consist histologically of bland fibroblasts that are frequently arranged in a storiform (pinwheel) pattern and macrophages that can take the form of clustered cells with foamy cytoplasm or multinucleated giant cells
fibrous cortical defect is <5cm
nonossifying fibroma is >5 cm
a benign tumor that has been likened to localized developmental arrest; all of the components of normal bone are present, but they do not differentiate into mature structures
fibrous dysplasia
All forms of fibrous dysplasia result from somatic gain-of- function mutations in
GNAS1
a polyostotic fibrous dysplasia disease, associated
with café-au-lait skin pigmentations and endocrine abnormalities, especially precocious puberty
McCune-Albright syndrome
GNAS1 mutation occuring during early embryogenesis produces
McCune-Albright syndrome
syndrome with fibrous dysplasia(usually polyostotic) and soft tissue myxomas
Mazabraud syndrome
composed of curvilinear trabeculae of woven bone that lack conspicuous osteoblastic rimming and arise in a background of fibrous tissue.
fibrous dysplasia
most common form of skeletal malignancy
Metastatic tumors
radiographic appearance of metastases of prostatic adenocarcinoma to bone is usually blastic or lytic?
blastic
specialized macrophages lining the synovial membrane with phagocytic activity
Type A synoviocytes
Cells similar to fibroblasts lining the synovial membrane which synthesize hyaluronic acid and various proteins
Type B synoviocytes
T/F The synovial lining lacks a basement membrane, which allows for efficient exchange of nutrients, waste, and gases between blood and synovial fluid
true
is characterized by cartilage degeneration that results in structural and functional failure of synovial joints. It is the most common type of joint disease it is considered to be primarily a degenerative disease of cartilage
osteoarthritis
chronic autoimmune disorder that principally attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis
Rheumatoid arthritis (RA)
The autoimmune response in RA is initiated by
CD4+ T cells
It is estimated that 50% of the risk of developing RA is related to inherited genetic susceptibility namely having the
class 2 HLA-DR4 allele
RA typically affects
small joints of hands and feet
characteristic histologic features of RA (5)
- synovial cell hyperplasia
- dense inflammatory infiltrates forming lymphoid follicles
- increased vascularity
- fibrinopurulent exudate
- osteoclastic activity in subchondral bone
a mass of edematous synovium, inflammatory cells, granulation tissue, and fibroblasts that grows over and causes erosion of articular cartilage in RA
pannus
In RA, after the cartilage has been destroyed, the pannus bridges the apposing bones to form a
fibrous ankylosis
composed of central necrosis rimmed by palisaded macropahges and is seen in RA
Rheumatoid nodule
is a heterogeneous group of disorders of unknown cause that present with arthritis before 16 years of age and persist for at least 6 weeks
Juvenile idiopathic arthritis (JIA)
marked by transient attacks of acute arthritis initiated by monosodium urate crystals deposited within and around joints
Gout
Repeated attacks of acute arthritis lead eventually to the formation of _____, aggregates of urate crystals and inflammatory tissue in the inflamed synovial membrane and periarticular tissue as well as severe cartilage damage that compromises joint function.
gouty tophi
partial deficiency of _______ interrupts the salvage pathway, so purine metabolites cannot be salvaged and are, instead, degraded into uric acid causing an increase in uric acid production
hypoxanthine guanine phosphoribosyl transferase (HGPRT)
distinctive patterns of gout (4)
- Acute arthritis
- chronic tophaceous arthritis
- tophi
- urate nephropathy
Crystals associated with gout vs pseudogout
uric acid crystal - gout
calcium pyrophosphate - pseudogout
An autosomal dominant variant of pseudogout is caused by germline gain-of-function mutations in ___ an inorganic pyrophosphate transporter
ANKH
small cysts, up to 1.5 cm, and nearly always located near a joint capsule or tendon sheath, develop due to cystic or myxoid connective tissue degeneration; hence the cyst wall lacks a cell lining
Ganglion cysts
Herniation of synovium through a joint capsule or massive enlargement of a bursa may produce ______. It is associated with rheumatoid arthritis. The cyst lining resembles the synovium, and both cyst and synovium may be hyperplastic. Cyst fluid often contains inflammatory cells and fibrin.
synovial cyst / baker cyst
benign giant cell rich neoplasm that develops in the synovial lining of joints, tendon sheaths, and bursae
Tenosynovial giant cell tumor
diffuse tenosynovial gct most commonly involves
large joints, most common in knee, followed by hip and ankle
localized tenosynovial gct most commonly involves
the tendon sheathes along the hands
what feature must ALWAYS be present to make a diagnosis of tenosynovial GCT
epithelioid mononuclear cells
Both diffuse and localized tenosynovial giant cell tumors harbor this reciprocal somatic chromosomal translocation (1;2) (p13;q37) causing the tumor cells to overexpress ____
M-CSF
components of tenoysunovial GCT (4)
- epithelioid mononuclear cells
- foamy macropahges
- osteoclast-like giant cells
- hemosiderin-laden macrophages
the most common soft tissue tumor in adults
lipoma
most common sarcomas of adulthood
liposarcoma
three distinct subtypes of liposarcoma
well-differentiated
myxoid
pleomorphic
Well-differentiated liposarcomas harbor amplifications of chromosome region 12q13–q15, which includes the p53 inhibitor ____
MDM2
myxoid liposarcoma, a fusion gene generated by a ______ arrests adipocyte differentiation, leading to unregulated proliferation of primitive cells
t(12;16) translocation
self-limited fibroblastic and myofibroblastic proliferation that occurs in young adults and arises in the deep dermis, subcutis, fascia, or muscle. It is composed of plump, immature-appearing fibroblasts and myofibroblasts containing elongated nuclei with punctate nucleoli. Mitoses are frequent, but atypical forms are notably absent
Nodular fascitis
nodular fascitis was previously considered a reactive lesion but is actually clonal and harbors a t(17;22) translocation that produces this fusion
MYH9-USP6
benign growth that can cause local deformity but has an innocuous clinical course, and is composed of plump spindle cells arranged in poorly defined broad bundles or long, sweeping fascicles surrounded by abundant dense collagen
superficial fibromatosis
subtypes of superficial fibromatosis (3)
Dupuytren contracture, Ledderhose disease, and Peyronie disease
is an irregular or nodular thickening of the palmar fascia that can be unilateral or bilateral. Incidence increases with age. Attachment to overlying skin can cause puckering or dimpling and a slowly progressive flexion contracture
Dupuytren contracture, or palmar fibromatosis
occurs in boys from under 10 years of age into adolescence. It is unilateral and does not cause contractures but can be associated with palmar and penile fibromatosis.
Ledderhose disease, or plantar fibromatosis
is a palpable induration or mass on the dorsolateral aspect of the penis. Eventually, it may cause abnormal curvature of the shaft and constriction of the urethra.
Peyronie disease, or penile fibromatosis
large, infiltrative masses that frequently recur but do not metastasize. They are rubbery and tough and infiltrate surrounding muscle, nerve, and fat. Bland fibroblasts arranged in long parallel fascicles amid dense collagen are characteristic
Deep fibromatoses (desmoid tumors)
Deep fibromatoses (desmoid tumors) contain mutations in
APC or CTNNB1 (β-catenin) genes
In contrast to tumors of other cell types, skeletal muscle neoplasms are almost all (benign or malignant?).
malignant
a malignant mesenchymal tumor with skeletal muscle differentiation
rhabdomyosarcoma
4 subtypes of rhabdomyosarcoma in order of most common
embryonal
alveolar
pleomorphic
spindle/sclerosing
Alveolar rhabdomyosarcoma frequently contains fusions of the _____ gene with ____ or ____
FOXO1 gene, PAX3 or PAX7
rhabdomyosarcoma subtype that is traversed by a network of fibrous septae that divide the cells into clusters or aggregates, creating a crude resemblance to pulmonary alveoli.
alveolar
T/F synovial sarcoma can not present in locations that lack synovium
False
A characteristic chromosomal translocation t(x;18) (p11;q11) that produces fusions of the_____ gene is present in most synovial sarcomas
SS18
