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
