Genetic Diseases of Bone Flashcards
Disorder of bone development: Cleidocranial dysplasia
- Absent / underdeveloped _____
- Delayed closing of _____
- _____ (reduced bone density)
- _____ (weak bones)
_____ normal
allows them to fit into very small spaces
bigger _____ > fontanelles close slowly
_____ models don’t recapitulate the disease; RunX2 is the TF involved > no _____ development, no skeleton only cartilage is formed; this phenotype is not seen in humans
don’t know why clavicles are specifically impacted
clavicles
fontanelles
osteopenia
osteoporosis
psychologically
skulls
mouse
bone
Cleidocranial dysplasia • RUNX2 – \_\_\_\_\_ – \_\_\_\_\_ stages of bone development – \_\_\_\_\_ stages of tooth development • Commits \_\_\_\_\_ cells to osteoblastic lineage
RUNX2 = protein important in tooth and bone development
formation of _____ teeth that don’t usually erupt
in mice: lose this protein > no teeth, start development but then tooth bud _____
in humans: protein prevents from developing a _____ set of teeth (sharks); mutations in this protein, several teeth, but they usually don’t erupt
transcription factor all later mesenchymal supernumerary arrests third
Cleidocranial Dysplasia
important in differentiation of pre-osteoblast to immature osteoblasts;
in mice, RunX2 involved in converting _____ stage to _____ stage; unsure of whether it plays this role in human development
unless there’s reason to extract teeth, you usually don’t; patients are usually _____
bud
cap
asymptomatic
Disorder of ossification: Achondroplasia
- Most common cause of _____
- Limbs disproportionately _____
- _____ head
- _____ trunk size
you see the differences as you grow older > the change in stature > short limbs (heads are normal bc they ossify differently) > defect in _____ ossification (how long bones ossify, axial and appendicular skeleton) (FGFR-3)
large head not actually, head looks normal, but _____ it looks off compared to rest of body
dwarfism short large normal endochondral proportionally
Achondroplasia
• Defect in _____ ossification – Impairs growth of _____ bones
• Fibroblast growth factor receptor-3 (FGFR3)
– Normally stops chondrocyte _____ and promotes
differentiation into _____
• Normal _____ and _____ ossification
with this mutation > chondrocytes actively proliferate > never begins _____
pelvis, craniofacial bones are all normal ossification
endochondral long proliferation bone periosteal intramembranous ossification
Disorder of stem cell differentiation: Fibrous dysplasia
- Somatic mutation in _____ gene – _____ protein coupled receptor
- Results in overproduction of _____ with activation of _____
- Prevents transition of bone-forming progenitor cells to mature _____ cells
FD > _____ > not loss of bone, but _____ of ossification/bone growth > defect in morphology
not a _____ disease, not inherited; this disease is caused by a somatic mutation in GNAS (GPCR) > membrane protein subunit > constituitively activated > so an overproduction of cAMP > activates a proto-oncogene: c-Fos > now c-Fos becomes _____ > increases risk of _____ (benign and malignant)
if mutation occurs later in dev: _____ disease; if occurs early in development: _____ disease, multifocal, diffuse > not just bone pathology but _____ pathology
GNAS
Gstimalpha
c-AMP
c-FOS
osteogenic
SC differentiation
enhancement
genetic
oncogenic
tumors
limited
severe
endocrine
Fibrous Dysplasia
not common; well recognized oral and maxillofacial disease
these patients in context of jaw disease > a _____-growing, _____ (expanding) bone lesion, that affects _____ side only
slow
expansile
one
Disorder of stem cell differentiation: Fibrous dysplasia
• Monostotic or polyostotic
• Polyostotic FD with endocrinopathies
– _____ syndrome
• Maxillary or mandibular involvement
– _____% of all FD
– _____% of patients with MAS
later in development > one bone > _____
early in dev > can be several bones > _____
bones and endocrine organs (panc, pituitary, thyroid, parathy) > _____ syndrome (not a genetic disease) > pit tumors, parathy tumors, panc tumors, _____ puberty (girls menstruating 7-8, boys with pubic hair 4-5, voice change 9-10) related to the _____
mccune-albright 25 35 monostotic polyostotic
mccune-albright
precocious
endocrinopathy
Clinical manifestations of FD
- _____-growing, _____ expansion
- _____ deformity of leg
- Risk for _____ transformation to cancer
radiographically: unique appearance > show an _____ or _____ appearance to lesion (looks different from normal trabeculation of bone); not pathoneumonic but characteristic
can get of long bones, other parts of cranium, and fingers and legs > hockey-stick defect, not because of disease but because of weight-bearing and cannot hold weight properly
not considered a tumor, FD has a risk of progressing to cancer > rare bone cancers, cancers of cartilage, or other soft tissue types (BV, fat); more lesions, the more the risk is _____ (mccune has _____ risk than those with single lesions (mono)); bc of c-Fos overexpression
typically do not treat patient with phenotype in mouth, surgeons will wait for patient to mature skeletally; if there is still an overt mass > will shave the bone down, will not excise the bone
disease of _____ people (up to 18/20 as first diagnosis); mutation occurs early in life, will not sit dormantly for decades; these lesions do not continue growing, will not regress
slow
painless
hockey-stick
spontaneous
orange peel thumbprint additive higher younger
Disorder of bone integrity: Osteogenesis imperfecta
• Genetically _____
• Skeletal fragility
• Variable phenotypes
going through birth canal; all bones fracture during birth
variants caused in collagen synthesis, defect in sufficient produciton of type I collagene, or defect in protein that regualttes collagen type I synthesis; all implicated in regulating collagen
heterogenous
Osteogenesis imperfecta
• 90% of patients with mutations in type I collagen genes – _____ and _____
• Other implicated genes also regulate type I collagen biosynthesis
mutations in one or the other; both proteins once express make up collagen, if one strand is defective you won’t get _____ formation
insufficiency of collagen becoming mineralized
COL1A1
COL1A2
triple helix
Classification of osteogenesis imperfecta
four main types, all mutations in COL1A1 or COL1A2
I: defect in _____, collagen is normal but not enough produced; _____ phenotype (fractures increased, but a mild phenotype)
2, 3, 4: strucutal defect (_____ lethal, progressively deforming, moderately deforming)
quantity
mild
perinatal
Osteogenesis Imperfecta
• Fractures • Reduced – Bone \_\_\_\_\_ – Bone \_\_\_\_\_ – Bone \_\_\_\_\_ • Deformation
apply weight to bones > cause the bones to deform > bones may become _____
children with this disease either have pins or plates embedded within their bodies
size
mass
strength
deformed
Type I collagen also found in... • Joints – \_\_\_\_\_ / arthritis • Eyes – \_\_\_\_\_ sclera • Ears – \_\_\_\_\_ loss • Skin – More \_\_\_\_\_/ less elastic • Teeth – \_\_\_\_\_
dentinogenesis imperfecta (yellow/orange/gray teeth) -_____ > always associated with the bone phenotype; _____ is strictly DENTAL DISEASE; looks just like type I, but type I is always associated with _____ phenotype
lax joints blue-gray hearing stiff dentinogenesis imperfecta
type I
type II
bone
Disorder of bone mineralization: Hypophosphatasia
• Disorder of bone and mineral \_\_\_\_\_ • Mutations in \_\_\_\_\_ gene – Reduced activity of tissue non-specific form of \_\_\_\_\_ • \_\_\_\_\_ defect • \_\_\_\_\_ defect
• Highly _____ clinical presentation – Mild to lethal
• Six clinical subtypes – Perinatal lethal – Perinatal benign – Infantile – Childhood – Adult – Odonto HPP  genetically \_\_\_\_\_ disease; both bone and \_\_\_\_\_ are affected
common mutatations in ALPL; most commonly implicated: TNSALP > this gene, mutations results in structural defect or quantitative defect; structural: more _____ disease, more than quantitive
6 clinical subtypes (only dental phenotype = odonto HPP); _____ the onset, the less severe the disease; the _____ the onset, worse prognosis
metabolism ALPL alkaline phosphatase (TNSALP) quantitative qualitative
variable
heterogenous
cementum
severe
older
earlier
Alkaline phosphatase
• Membrane-bound _____ – Catalyzes _____ reactions
• At least four _____
– TNSALP abundant in _____, _____ and _____
– TNSALP contributes _____ of all serum ALP activity
• Essential for catabolism of inorganic _____
membrane bound protein > converts pyrophosphate to phosphate, which binds to calcium to produce _____ (used by hydroxy to mineralize)
phosphomonoesterase
dephosphorylation
isozymes liver kidney bone 95% pyrophosphate calcium phospahte
(Hypophosphatasia) Alkaline phosphatase
• Ratio of phosphate to pyrophosphate is critical
– Phosphate needed for _____ crystals
– Pyrophosphate inhibits _____ formation
• Hydroxyapatite
– Deposited along _____ fibrils
– Contained within matrix vesicles
not converting pyrophoshate to phosphate > no _____; bones are weak bc they’re not mineralized properly, collagen and matrix are present
hydroxyapatite
hydroxyapatite
collagen
mineralization
Pathogenesis of HPP
• Accumulation of _____
• Inhibits _____ of calcium/phosphate crystals
– Limits hydroxyapatite crystals within matrix vesicles
• Absence limits matrix mineralization
– Bone remains soft
– _____ fractures
– _____ tooth loss
tooth structure that is affected is _____ (hydroxy also used by dentin and enamel, but they are _____)
disease is “good”; only a _____ gene defect > you can exploit to replace that single protein by an _____ protein (introduce from outside); patient undergone replacement therapy for enzyme loss, one disease where there is a push for novel therapy where you artifically introduce enzyme early in life to help form bones properly
pyrophosphate nucleation spontanoeus premature cementum normal
single
exogenous
HPP manisfestations
_____ pulp chambers and canals
Inadequate cementum production – teeth spontaneously exfoliate
All clinical forms of HPP associated with premature loss of deciduous teeth
enlarged
Disorder of bone homeostasis: Osteopetrosis
• Bone requires equilibrium of
– Osteoclasts for bone resorption
– Osteoblasts for bone formation
– Osteocytes for
• Reception and transduction of _____ stimuli
• Regulation of osteoblast / osteoclast _____
defects in osteoclastic _____; tight equilbirum bt bone growth and resorption
ortho: teeth aren’t physically moving, what’s moving is the actual bone
mechanical
differentiation
resorption
Osteopetrosis
• Caused by _____ failure
• Osteoclasts responsible for degradation of bone matrix
failure of osteoclasts to cause resorption of bone > uncontrolled bone _____
osteoclast
density
Osteopetrosis
• Genetically _____
• Adult form (_____ disease)
• Younger onset, more _____ disease
bone becomes increasingly _____ over time; bone is more likely for fracture becasue of how brittle it is
radiographically, becomes more _____
heterogenous
albert-schonberg
severe
dense
radioopaque
Osteopetrosis • Bone becomes thick, dense, \_\_\_\_\_ – Brittle – Prone to \_\_\_\_\_ – Poor healing • “\_\_\_\_\_” vertebrae • Cranial nerve \_\_\_\_\_
as bone becomes thicker, _____ bones are affected > cranium becomes dense > structures within _____ become more narrow > paralysis of diff nerves > lose _____; facial _____
sandiwch vertebrae > _____ (almost); one or two other diseases in which this manifests
genetic disease that is untreatable; can only treat the _____
sclerotic
fracture
sandwich
entrapment
all
foramina
hearing
paralysis
pathoneumonic
symptom
Disorder of bone homeostasis: Paget disease
• Multifactorial disease
– _____ mutations
– _____ factors
- _____ defect in bone remodeling
- _____ or polyostotic
- Slow _____ bone expansion
multifactorial > genetic forms, but most forms are acquired (environmentally, we do not know, maybe a _____, or some other factor)
some have genetic disease in SQTSM1 protein > regulates osteoclastic activity; osteoclasts _____ resorption
diff bt PD and osteopetrosis > more of a focal phenotype > _____ bones that are affect (as opposed to the entire skeleton); can have several bones in PD but they’re not _____ affected
first sign: could be a complaint that teeth is spreading _____, can’t wear hat properly anymore (heads getting _____); slow-growing disease, they may not realize until it does happen
SQTSM1 environmental focal monostotic symmetric
virus
increase
individualized
uniformly
apart
bigger
