14. Genetics/Osteogenica Imperfecta Flashcards Preview

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Flashcards in 14. Genetics/Osteogenica Imperfecta Deck (30):

Osteogenesis Imperfecta: definition?

"Brittle Bone disease"

•Heterogeneous heritable disorder of bone matrix formation and homeostasis

Type I Collagen disorder


Osteogenesis Imperfecta: cardinal features?

–Low bone mass

–Reduced bone mineral strength

–Increased bone fragility

–Increase bone deformity



What is the #1 cause of fracture in children?

Non accidental trauma: ie child abuse


Define genetic pleotropy. Example?

A single gene product/mutation yields many different effects (different signs and symptoms).

Example: Osteogenesis Imperfecta, since it can cause a number of findings including blue sclera, joint hypermobility, scoliosis, dentinogenesis imperfecta, learing loss, extremity deformities, short stature


Define Genetic Heterogeneity. Example?

Different gene mutations that cause identical disease states.

Example: Osteogenesis Imperfecta. --> Type II OI can be caused by mutation of Pro-alpha 1 OR Pro-alpha 2 genes.

Type I, Type III, Type IV: each can also be caused by mutations of various genes that lead to the same phenotype.


Define variable expression. Example?

Same disease, different symptoms are present.

Example = OI: within each type, patients have slightly different presentations (some will have blue sclera, some will not. some have dentinogenesis, some do not) 


OI: Tarda vs Congenita?

Congenita = forms diagnosed either in utero or shortly post birth. More severe forms.

Tarda = diagnosed later on, generally less severe.


Type I OI: severity?


systemic symptoms?


Q image thumb

Tarda form, Mildest.

Normal stature, little or no deformity.

Possibly: blue sclerae, hearing loss, dentinogenesis imperfecta, joint hypermobility, incr bruising, aortic root dilatation, mitral valve prolapse.

etiology: low quantity, normal quality, normal assembly of collagen


Type I OI: age onset of bone fractures?

Fracture prognosis over the lifespan?

Rarely: prenatally or during infancy.

Occasionally during diaper changes but usually with onset of walking

Frequency is constant through childhood, decr after puberty, increases in 60s/70s


Type II OI:




Universally Lethal. Most severe type.

May be detected by fetal US. 

Extremities are obviously deformed, small thorax -> lung hypoplasia, platyspondyly (shortened vertebrae), hypomineralization of calvaria

etiology: low quantity, low quality, normal assembly of collagen

A image thumb

Type III OI:




Severe but not lethal.

Progressively deforming bones.

Some deformity at birth. Dentinogenesis is common, hearling loss common, very short stature. Otherwise healthy.

etiology: normal quantity, normal quality, mal-assembly of collagen


A image thumb

OI Type III: how do the bones look on imaging?

Short and curved bones, "washed out" appearance on imaging


Accordion effect of long bones (thorax ok so no lung issues)

A image thumb

Type IV OI: severity?



Mild to Moderate

Normal sclerae,

moderate bone deformity.

possible: short stature, dentinogenesis, hearing loss

etiology: normal quantity, low quality, normal assembly of collagen

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Type I vs Type IV OI: difference in disease presentation?

-Type IV has more fractures, more deformity, shorter stature than Type I

-Both have been mistaken for child abuse

-Type IV sometimes presents in adult women as "osteoporosis"


Type IV OI: bone features?


Bone curvature

short bones

If fixes are attempted via rod placement, rods may extrude

A image thumb

Recap: For each type of OI, name severity and predicted stature

Type I: Mild. Normal Stature

Type II: Universally Lethal

Type III: Severe. Short Stature

Type IV: Mild to Moderate. Variable Stature


Type I collagen: Purpose?

where is it found? 

what is its structure? (what monomers is it composed of)?

Type I collagen is the major structural protein in bone, tendon and ligament. 

Most abundant collagen type: found in skin, tendon, bones, arteries.

Trimer structure: 2 monomers of alpha-1(I) & 1 monomer of alpha-2(I)
extremely regular, predictable pattern (pic)

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Type I collagen: what genes are involved?

alpha-1(I) monomer from COL1A1 gene

alpha-2(I) monomer from COL1A2 gene

(you have 2 COL1A1 genes and 2 COL 1A2 genes: a mutation of any of these 4 yields OI)


Collagen Type I biosynthesis: historically we thought that the COL-1A1 gene and COL1A2 genes were the only ones invovled. What have we learned recently?

There are post-translational gene modifications (enzymes, etc) that can also cause disease if mutated.

However, the main causes of OI is mutation of one of the genes that codes for a monomer in the triple helix.


OI: what is the structure of the bone compared to normal? what processes lead to this?

Normal bone on L, OI on R.

OI: decreased bone size & thickness due to slow periosteal bone formation. 

Trabeculae are reduced in number and are abnormally thin. 

Increased activity of both osteoblasts and osteoclasts.

A image thumb

OI types V, VI, VII: how are they different from Types I thru IV?

These types result from mutations in different genes (NOT COL1A1 or Col 1A2). 

Instead, it is a combination of post-translational modification genes that is involved.

Clinical presentation can be just as severe.


OI: treatment options? Efficacy?

Options include PT, orthoses for weight bearing, wheelchairs, surgery....

Not terribly effective.

Experimental tx = bisphosphanates.


Bisphosphonates for treatment of OI?



for which OI will it definitely NOT help?

Bisphosphonates seem to improve bone density.

anti-resorptive agent that adheres to bone and inhibits osteoclast function and promotes their apoptosis (thereby increasing bone mineral density by way of unapposed osteoblast activity)

Imaging: pre and post, note that bone density has increased in R picture.

Won't help in Type IV because there is a defect in mineralization, so even if you provide it, it won't help! 

A image thumb

If we were going to treat with bisphosphonates, which one should we choose?

have we seen clinical improvements with this?

Pamidronate treatment has yielded improvements on both Dexa and biopsy.

The Fracture rate has improved in treated patients but is still not normal.

Photo: note thicker bone cortex on R pic (after 2 yrs of tx).

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What clinical history should cause us to consider OI?

•Recurrent fractures after minor trauma

•Fracture site consistent with history, but mode of injury too minor

•Radiographs consistent with O.I.

•Unexplained osteoporosis, childhood-juvenile osteoporosis

•hearing loss, short stature, dentogenesis imperfecta


comment on the quantity, quality, and assembly of collagen in each type of the OI

Type I: low quantity, normal quality, normal assembly

Type II: low quantity, low quality, normal assembly

Type III: normal quantity, normal quality, bad assembly

Type IV: normal quantity, low quality, normal assembly


why do you see blue sclera in OI?

Which types of OI do you see it in? 

color change is due to hte underlying choroidal veins that show through since the sclera is thinner than normal (since there's less collagen)

See it in Type I (low collagen formation), and Type III (improperly formed collagen)


what gene is mutated in type I collagen? 


forms collagen type I


Typical lab tests for OI? (2)

Alkaline phosphatase (HIGH)

Calcium (HIGH)


pathophysiology behind OI?

bone is THINNER due to sluggish periosteal bone formation
trabeculae are reduced in # and are abnormally thin


Paradoxically, there are INCREASED numbers of osteoblasts, but each OB produces less bone than normal and because bone resorption is also enhanced, there is no NET gain of trabecular bone mass.