Bone

Question 2

Achondroplasia:

Answer 2

• Autosomal dominant, causing retarded cartilage growth; most common skeletal dysplasia and major cause of dwarfism
• Results in shortened proximal extremities, with relatively normal trunk, and enlarged head with bulging forehead, depression of the root of the nose
• Cause by gain of function mutations in FGFR3 (FGFR3 usually inhibits endochondral growth, gain of function results in accentuation of FGFR3 effects)
• Approximately 90% of cases stem from new mutations, almost all of which occur in the paternal allele
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Question 3

Thanatophoric dysplasia

Answer 3

• Most common lethal form of dwarfism
• Amongst other changes, results in small underdeveloped chest cavity which leads to respiratory insufficiency, and death frequently at birth or soon after
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Question 4

Osteogenesis imperfecta:

Answer 4

• type 1 collagen disease → deficiencies in the synthesis of alpha1 and alpha2 chains in type 1 collagen
• Results in TOO LITTLE BONE → extreme skeletal fragility
• Most common inherited disorder of connective tissues
• Affects bone, and other tissues rich in type 1 collaged (joints, eyes, ears, skin teeth)
• Blue sclerae due to decreased collagen content making sclera translucent, mixed hearing loss due to abnormalities in the bones of the middle and inner ear, dental imperfections (small misshapen blue/yellow teeth) due to dentin deficiency

4 major clinical subtypes depending on location of the mutation within the protein
* Type 1 Mutations resulting in decreased synthesis of normalcollagen
— Mild skeletal abnormalities
—Normal life span, childhood fractures which decrease following puberty
* Type 2 Mutations resulting in abnormal collagen formation
— Extreme bone fragility → multiple intrauterine fractures → Fatal inutero or in perinatal period

Question 5

Osteopetrosis:

Answer 5

• Aka marble bone disease, Albers-Schonberg disease
• Mutations in CA2 result in osteopetrosis
• Group of rare genetic disease that care characterised by reduced bone resorptions and diffuse symmetrical sclerosis due to impaired formation or function of osteoclasts
• Due to deficiecnt osteoclast activity, bones do not have a medullary canal, and the ends of long bones are bulbous and misshapen; the primary spongiosa which is normally removed during growth persists and fills the medullary cavity, leaving no room for hematopoietic marrow
• Deposited bone is not remodelled and tents to be woven in architecture (as opposed to lamellar)
• Depending on the underlying defect, the number of osteoclasts may be normal, increased or decreased
• The neural foramina are small and compress nerves
• Bone are brittle and fracture easily despite sclerosis, like chalk
• Autosomal recessive severe infantile osteopetrosis usually diagnosed inutero or soon after birth
• Fracture, anaemia, hydrocephalus seen → perinatal mortality
• Those who survive infancy have cranial nerve defects and repeated infections due to leukopaenia despite extramedullary haematopoiesis that can lead to prominent hepatosplenomegaly
• The mild autosomal dominant form may not be detected until adolescence or adulthood, when it is suspected based on repeated fractures
• These pts may also have mild cranial nerve deficits and anaemia
• Osteopetrosis was the first genetic disease treated with hematopoietic stem cell transplantation, which is effective because osteoclasts are derived from hematopoietic pre-cursors. The normal osteoclasts produced from donor stem cells reverse many of the skeletal abnormalities.
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Question 6

Mucopolysaccharidosis

Answer 6

• Accumulation of mucopolysaccharides in chrondrocytes cause apoptosis of the cells, leading to structural defects in articular cartilage
• Therefore, skeletal manifestations result from abnormalities in hyaline cartilage including car the growth plates, costal cartilage and articular surfaces
• Affected pts usually have short stature, chest wall abnormalities, malformed bones
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Question 7

Osteopenia and osteoporosis:

Answer 7

• Osteopenia = decreased bone mass, osteoporosis = severe enough to significantly increase risk of fracture
• Histologically normal bone, but decreased in quantity
• Radiographically, osteoporosis 2.5SD below mean peak bone mass in young adults
• Presence of atrauamtic or vertebral compression fracture signifies osteoporosis
• May be localised to a certain bone or region, such as disuse osteoporosis, or involve the entire skeleton
• Most common forms are senile and postemenopausal types
• Peak bone mass achieved in young adulthood, and is determined largely by hereditary factors. Physical activity, muscle strength, diet and hormonal state contribute.
• Once peak mass is reached, there there a small deficit in bone formation which accrues with every resorption and formation cycle of bone
• age-related bone loss, which may average 0.7% per year, is a normal and predictable biologic phenomenon
• Decreased estrogen levels after menopause actually increase both bone resorption and formation but the latter does not keep up with the former, leading to high-turnover osteoporosis
• In postmenopausal osteoporosis the increase in osteoclast activity affects mainly bones or portions of bones that have increased surface area, such as the cancellous compartment of vertebral bodies
• There is typical loss of horizontal trabeculation, and thickening of vertical trabeculation
• Tx options aside from exercise, vit D and calcium, include bisphosphonates which reduce osteoclast activity and induce apoptosis.
• Denosumab, an anti-RANKL antibody is also used as tx
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Question 8

Pagets disease (Osteitis Deformans)

Answer 8

Disorder of increased but disordered and structurally unsound bone mass

3 sequential phases:
1. Initial osteolytic stage
Active disease has a wedge-shaped lytic leading edge that may progress along the length of the bone at a rate of 1 cm per year.
2. Mixed osteoclastic-osteoblastic stage
3. Burnt out osteosclerotic stage
In the end, the bone is composed of coarsely thickened trabeculae and cortices that are soft and porous and lack structural stability. These aspects make the bone vulnerable to deformation under stress; consequently, it fractures easily

• Usually begins in late adulthood, Typically white people
• Associated with elevated serum alkaline phosphatase levels but normal serum calcium and phosphorus.
• 40-50% familial cases and 10% of sporadic cases have mutations in SQSTM1 gene → increased activity of NF-kB which increases osteoclastic activity
• Paget disease is monostotic in about 15% of cases and polyostotic in the remainder
• The axial skeleton or proximal femur is involved in up to 80% of cases.
• May be asymptomatic or have pain localized to the affected bone is common, secondary to microfractures or bony overgrowth compressing nerves
• Other sites include craniofacial (lion face), femurs which have secondary bowing due to axial force, and distortion of femoral heads causing secondary severe OA,
• Chalk-stick type fractures are common complications, usually in long bones
• Pagetic bone is hyeprvascular and warms the overlying skin. In severe polyostotic disease, increased blood flow can act like AV shunt resulting in high output heart failure or exacerbate underlying heart disease

Variety of tumours/tumour like conditions arise in pagetic bone
* Giant cell tumour
* Giant cell reparatice granuloma
* Extramedullary haematopoiesis
* Sarcome - less than 1% of all pts with pagets, and 5-10% of those in severe polyostotic disease
* Sarcomas are usually osteosarcoma or fibrosarcomas

If no malignant transformation, usually indolent course
readily suppressed by treatment with calcitonin and bisphosphonates

Question 9

Rickets/osteomalacia

Answer 9

• Manifestation of vitamin D deficiency or abnormal metabolism of same
• Rickets = childhood, impaired deposition of bone at the growth plates
• osteomalacia = adult version, bone formed during remodelling is undermineralised predisposing to fractures
• Leads to impaired mineralisation of the matrix
• This is in contrast with osteoporosis, where there is normal mineral content of the bone, but total bone mass is decreased

Question 10

Hyperparathyroidism

Answer 10

• Increased PTH → increased RANKL expression on osteoblasts → stimulates osteoclast activation → decreased bone mass and bony deformities, joint issues
• Associated increased serum calcium due to bone resorption, which would usually then via negative feedback reduce PTH in normal physiology
• Symptomatic, untreated primary hyperparathyroidism manifests with three interrelated skeletal abnormalities:
  Osteoporosis: generalised but most severe in the phalanges, vertebrae and proximal femur, and most prominent in the cortical bone
• brown tumor
• Brown tumour = soft tissue (in the bone) formed by reactive fibrosis secondary to haemorrhages from microfractures due to osteoporosis
• The brown colour is the result of the vascularity, haemorrhage/haemosiderin
• Can undergo cystic degeneration
  Generalised osteitis fibrosa cystica aka von Recklinghausen disease of the bone
• Combination of increased bone cell activity, peritrabecular fibrosis and cystic brown tumours
• Hallmark of severe hyperparathyroidism
• Secondary hyperparathyroidism is usually not as severe or as prolonged as primary hyperparathyroidism, hence the skeletal abnormalities tend to be milder.
• Control of hyperparathyroidism allows bony changes to regress and may completely disappear
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Question 11

Renal osteodystrophy

Question 12

Osteomyelitis

Question 13

Caplan syndrome

Question 14

Rheumatoid arthritis

Question 15

Felty syndrome

Question 16

Liposarcoma

Question 17

Gout

Question 18

Osteoarthritis