Module 6: Bone: Pagets, Achondroplasia, Osteogenesis Imperfecta Flashcards
Moving on to Paget’s Disease, what are the causes?
- -Associated with Paramyxoviruses (measles, RSV and mumps) in childhood
- -common in older French and British men
- -genetic predisposition with p62 mutation – increased RANK-RANKL mutation — increased osteoclasts
What is the pathogenesis for Paget’s Disease?
Virus stimulates IL-6 — IL-6 and M-CSF activate osteoclasts — osteoclasts hyper responsive to RANKL and Vit D — abnormal bone remolding
(Excessive osteoclastic activity with compensatory osteoblastic activity)
What bones are affected in Paget’s disease?
Mainly axial skeleton and long bones
- –femur (most common), humerus, tibia, ulnar, radius, skull and spine
- -affects multiple bones (polyostotic)
What are the three phases of Paget’s Disease?
Osteolytic phase: excess osteoclast activity
Mixed phase: both osteolytic and osteoblastic activity (more osteoblastic) and angiogenesis
Osteosclerotic phase: burn out stage so just osteoblasts (increased bone mass)
–all three co-exist - temporal heterogeneity
What is the presentation for patients with Paget’s Disease?
Asymptomatic but can have pathological fractures in femur
–can also have bowing in tibia
CHF is the most common cause of death in patients with Paget’s Disease, what is the mechanism for the heart failure?
In order for osteoblasts to lay down bone they need angiogenesis and its so much that it leads to increased AV shunting which leads to more blood flow to the heart and this leads to CHF (Called high output CHF)
Explain the bone biopsy in 5b for patients with Paget’s disease?
Mosaic Pattern of lamellar bone with cement lines and resorption pits (Howships lacunae) due to haphazard laying of bone osteoid
- -cement lines
- -pink is osteoid (half hazard)
- -resorption pits (Howship’s Lacunae)
Explain the skull bone in 5b for patients with Paget’s diesase
Gross: thick and hypervascular (b.c of angiogenesis) —phase II and III
Also see holes at the front indicates osteolytic activity – phase I
–example of temporal heterogeneity
Explain the x-ray seen in 5a for patients with Paget’s disease?
Features the radius
- -black arrow: osteosclerotic: phase II and III (radiopaque)
- -white arrow: osteolytic: phase I (radiolucent)
What is seen in blood and urine in patient with Paget’s Disease?
Normal Ca, PO4 and PTH High ALP (marker of osteoblastic activity) Elevated hydroxyproline in urine (marker of osteoclastic activity) -- product of collagen breakdown
Finally what are the complications in patients with Paget’s Disease?
- Pathological fractures — DVTs — PE
- Secondary osteoarthritis of hip and knee
- High output congestive cardiac failure (again excess osteoblastic activity in mixed phase and the increased need for angiogenesis)
- Bowing of the tibia — pathological chalk stick fractures
- Thick bones – press on cranial nerves in skull (CN VIII — hearing loss) or spinal nerves in the spine (paralysis)
Paget’s disease can have malignant transformation, explain
Secondary osteosarcoma of the femur --osteosarcoma in old person think Pagets --more common than osteoclastoma Osteoclastoma --giant cell tumor of bone
Moving on to Achondroplasia, what is the etiology?
FGFR3: gain of function AD mutation which inhibits chondrocyte proliferation at growth plate (normally FGFR3 is inhibited because it does down regulate cartilage proliferation)
- -majority are new, sporadic mutations
- -thanatotropic type: homozygous form is not compatible with life b.c chest cavity is too small
What bones are affected in Achondroplasia?
Affects bones formed from endochondrial ossification (From cartilage)
- long bones: femur and humerus
- -does not affect bones formed from intramembranous ossification (No cartilage)
What is the presentation for patients with Achondroplasia?
Disproportionate short stature : short femur and humerus
–GH deficiency (dwarfism) is proportionate
Normal Intelligence
Normal Head Circumference
Normal life expectancy
(cretinism: short life expectancy and mental retardation due to iron deficiency and therefore hypothyroidism)
What would a biopsy of the growth plate show for a patient with achondroplasia?
Hypoplastic
- -no chondrocyte proliferation (Shorter)
- -more bone formers than should be so your growth plate closes with lack of cartilage proliferation
Moving on to the next topic of Osteogenesis Imperfecta (Brittle bone disease). What is the etiology for type I and type II?
For both types: mutation in Type I collagen (organic component)
—type I: AD mutation
–type II: AR mutation (Worse than type I)
Essentially opposite of osteomalacia
(less than 40% of organic bone)
What is the presentation for type I Osteogenesis Imperfecta?
Type I AD
- -blue sclera: it is thin so reveals the veins (Choroidal veins)(ehler’s danlos also gives blue sclera)
- -deafness (Conductive)
- -Misshapen teeth
- -pathological fractures in long bones
What is the presentation for type II Osteogenesis Imperfecta?
Type II AR (usually die in utero)
- -multiple fractures in utero (defect in type I and II collagen)
- -small thoracic cavity (underdeveloped lungs) – most common COD at birth is respiratory failure
- -Intraparenchymal fractures from multiple skull fractures they are weak
Briefly on Ehler-Danlos Syndrome, what is the pathogenesis?
Inappropriate cleavage of collagen fibers
What is the presentation for Ehler-Danlos Syndrome?
Hyperextensibility of skin and joints
Easy bruising
Blue Sclera
What are the complications in Ehler-Danlos syndrome?
Aortic Dissection
Osteopenic Bone: kyphoscoliosis and spondolisthesis
Briefly on Marfan’s syndrome, what is the etiology?
Mutation of fibrillin gene on chromosome 15
What is the presentation in patients with Marfan’s syndrome?
Tall with long extremities Hyperflexible Joints Kyphosis Scoliosis Pectus Excavatum
What is seen in the eyes and CVS in patients with Marfan’s syndrome?
Eyes: subluxation of lens (ectopic lentis) and blue sclera
CVS: MVP, aortic dilatation due to cystic medionecrosis and aortic regurgitation
Briefly what is the reason for Scurvy?
Abnormality of collagen synthesis
–decreased vitamin C – failed hydroxylation of proline and lysine – defective cross linking of collagen
What is the presentation for patients with scurvy?
Bleed gums
Angulations of the costo-chondral junction
Failure to thrive
What are the complications in patients with scurvy?
Fragile capillaries and venules – subperiosteal hemorrhages
Defective osteoid synthesis – microfractures
Bony deformities
Last topic of this card deck is Osteopetrosis also called marble bone disease, what is the etiology?
Genetic mutation in carbonic anhydrase II gene, chloride channel gene or RANKL gene
–all these affect the ability of osteoclast to demineralize bone aka making an acidic environment
What is the pathogenesis for osteopetrosis aka marble bone disease?
Without acidic environment — osteoclastic activity is impaired – primary spongiosa layer which is normally broken down by osteoclasts is retained – narrowed medullary cavity – no hematopoeisis – pancytopenia
–bone is forming but not breaking down (blast over clast)
–therefore osteoblastic activity is happening so progressive deposition of bone on pre-existing matrix due to the lack of osteoclastic activity
This is opposite from osteoporosis
If you have all this increased osteoblastic activity and thick bones, why are bones not stronger in osteopetrosis?
Because you need a balance of osteoblastic and osteoclastic activity
Osteopetrosis is common in what population?
Common in children — BM failure – EM hematopoiesis in liver and spleen =
hepatosplenomegaly
What is the presentation for patients with osteopetrosis?
- Pancytopenia with EM hematopoiesis: recurrent infections (most common COD), bleeding and fatigue
- Erlenmeyer Flask Deformity: thick bones that can bend quickly (seen on x-ray as metaphyseal flaring)
- Pathological fractures
- Deafness and facial nerve paralysis: affects skull bones and CN 7 and 8 –called lion bone faces (Seen in leprosy)
- Carpel tunnel syndrome: affects ulnar and median nerves
- Compression of spinal nerves
What investigations are done for patients with osteopetrosis?
PCR looking for deficiency
X-ray: deformities
–bone is very white and bright (marble appearance) from excess mineralization (radiopaque)
–Erlenmeyer flask deformity: metaphyseal flaring that is more prominent around the kne and hips
What is seen on bone marrow biopsy, slide 3, for patients with Osteopetrosis?
Cortex (1)
Suppose to be medullary cavity (2) however the primary spongiosa layer is present because there is no osteoclastic activity so therefore retention of this layer — no hematopoiesis and therefore pancytopenia
What is seen in the blood for patients with osteopetrosis?
Low Ca, PO4
High PTH and ALP (Super high)
Finally what are complications of osteopetrosis?
COD= recurrent infections
Heart failure
Deafness
