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What are the requirements for proper bone formation?
- 1. recipe
- 2. ingredients
- 3. an oven
- 4. the ability to clean up
- (cake analogy)
- defects in any of these 4 areas may cause pathologic formation
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Achondroplasia
- most common form of hereditary short-limbed dwarfism (autosomal dominant)
- disease in which there is a defect in the assembly of bone (“recipe”)
- incidence: 1:30,000
- gene: FGFR3 (chrom 4)
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FGFR3 protein
- functions as a brake to slow bone growth by inhibiting proliferation of chondrocytes (cell that secretes cartilage matrix & becomes embedded in it)
- in fetus: highest FGFR3 mRNA are found in the CNS & pre-bone cartilage rudiments of all bones
- during endochondral ossification: FGFR3 is detected in resting cartilage
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What do FGFR3 gene knockout mice look like?
they're very long (not dwarfs)
- with Achondroplasia, abnormal FGFR3 is more active than the WT gene
- it's a gain of function mutation, therefore bone growth is severely suppressed
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What bone areas are primarily affected in achondroplasia?
- physis of long bones
- foramen magnum (large oval opening in occipital bone)
- vertebral lamina + pedicles
- clinical manifestations of achondroplasia stem from these areas (eg. achondroplastic changes in vertebrae & foramen magnum → spinal & foramen magnum stenosis)
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Rhizomelia
- disproportionate shortening of the proximal portion of the limb
- caused by suppression of bone growth in the physis of long bones
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What are some characteristic features of achondroplasia?
- frontal bossing
- mid-face hypoplasia
- trident hand
- normal intelligence
- normal torso with shortened limbs
- typical lower limb posture is genu varum (“bow-legged”)
- infants & young children may exhibit kyphosis & delayed walking due to hypotonia
- foramen magnum stenosis may compress the lower brain → occult hydrocephalus
- Patients may also experience respiratory problems (apnea, snoring)
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How can achondroplasia be diagnosed prenatally?
- by the discovery of long bone foreshortening (eg. of femur) on ultrasound
- however this finding may be seen in multiple forms of skeletal dysplasia, confirmatory genetic testing with CVS or amnio may be required
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What do the majority of achondroplasia cases result from?
- spontaneous mutation in the father
- may be related to advanced paternal age
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How is achondroplasia clinically managed?
- monitoring for neurologic sequelae
- cranial ultrasounds for hydrocephalus (in infants)
- weight management (obesity risk)
- spinal & foramen magnum stenosis surgery
- Osteotomies (limb realignment to mechanical axes)
- occasional skeletal elongation surgery
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What form of therapy is generally not used after the 1st year of life to increase the stature of patients with achondroplasia?
- growth hormone
- may be effective in the first year of life, but effectiveness declines afterwards
- controversial
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Osteogenesis imperfecta ("brittle bone disease”)
- characterized by bone fragility
- 8 types present with broad spectrum of severity & age of onset
- a disease in which bone “ingredients” are of bad quality or are not available in the correct amounts
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How might someone get OI?
- It can be inherited autosomal dominantly
- in rare cases autosomal recessively
- may be caused by spontaneous mutations
- can be caused by different mutations
- 85-90% of cases involve a defect in type I collagen formation (AD pattern)
- other types are due to mutations of other genes that control collagen production (AR pattern)
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Type 1 Collagen
- located primarily in skin & bone
- is composed of 2 alpha1 chains & 1 alpha2 chain
- alpha1 precursor is the proalpha1 chain, derived from the COL1A1 gene on long arm of chrom 17
- alpha2 precursor is proalpha2, encoded by the COL1A2 gene on the long arm of chromosome 7
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Regardless of the phenotype, OI always involves mutations in what genes?
- COL1A1 or COL1A2
- severity of OI depends on where mutation falls relative to the amino terminus (the closer the milder)
- severity also depends on affected chain & AA substitution from mutation
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Type I OI
- results in a quantitative defect in available collagen
- in this form there's complete absence of Type I collagen genes on one allele → 50% reduction in its quantitylikely due to a premature stop codon (nonsense mutation)
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What is the result of reduced quality and quantity of type 1 collagen?
- bone fragility
- blue sclera
- abnormal dentition
- hearing loss
- lax skin & ligaments
- ↓ BMD (bone mineral density)
- broad forehead with a triangular face, short stature, progressive scoliosis, acetabular protrusion, muscle hypotonia, deafness & sweating
- no intellectual impairments are associated with OI
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X-ray Findings in OI Patients
- Wormian bone (immature bone with no lamellar bone formation)
- fractures at various stages of healing
- osteopenia
- thin cortices
- deformity
- scoliosis
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What drug often used in the treatment of osteoporosis is used to treat OI?
- Bisphosphonates
- they inhibit osteoclast resorption → ↓ bone loss
- they may be combined with GH
- children receiving these treatments are enrolled in clinical trials as neither is approved for use in children by the FDA
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Experimental OI Treatments
- gene therapy to stimulate normal type 1 collagen
- bone marrow transplant
- (these are reserved for the most severe forms of OI)
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Ambulation with OI
- prognosis for ambulation in patients with OI is related to the age of onset of fractures
- neonatal fractures → pts are usually non-ambulatory
- rate of fractures ↓ at puberty
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How might fractures in pts with OI begin?
- as micro-fractures on the tension side of the bone
- this may lead to marked deformity (eg. producing bowed tibia "saber tibia")
- with enough micro-fractures the bone breaks completely
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How are fractures in pts with OI managed?
- Realignment Osteotomies: performed to maintain functional alignment of the bone & prevent re-fracturing
- Telescoping Rod: may be placed in the bone to maintain its mechanical axis during growth
- Bracing: may also be used to help stabilize the bone close to its mechanical axis
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Why is a goal in management of OI helping patients stay active?
because bone resorption is minimized in stressed bones
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How are most diagnoses of OI made?
- postnatally based on clinical exam, growth rate, fracture rate, & radiographic appearance of bone
- if OI is suspected, diagnosis is confirmed by collagen assay using fibroblast cultures from a skin biopsy
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Blount’s disease
- disorder of ossification of the medial aspect of the proximal tibial physis, epiphysis & metaphysis (contains the growth plate)
- results in the medial aspect of the proximal tibia growing less than the lateral aspect
- is manifested by varus angulation & internal rotation of the tibia in the proximal metaphyseal region immediately below the knee
- a disorder in which the environment (“oven”) of bone formation is suboptimal
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How does one get Blount's disease?
- is the result of abnormal compression of bone
- this causes growth retardation
- (it's not genetic)
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Who does Blount's disease typically affect?
- early walkers
- obese children
- males & African Americans are disproportionately affected
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What must occur for the disease to manifest?
- weight-bearing
- one year of ambulation is required for expression
- may have onset in infancy or late adolescence
- age of onset determines treatment
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Where histologically are the changes occurring during Blount’s disease located?
- in the resting cartilage in the medial part of the proximal tibial physis
- islands of densely packed cells in this region hypertrophy
- also visible: islands of nearly acellular fibrous cartilage + abnormal groups of capillaries
- (if left untreated Blount’s Disease → irreversible pathologic changes)
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How is Blount's disease treated?
- it's usually diagnosed after 2 y/o
- if treated with a corrective osteotomy early in life, when bone is still growing, may be curative
- infantile form may not require surgery (is amenable to brace correction)
- non-surgical options, such as bracing, are ineffective for the adolescent form
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Morquio’s syndrome
- inability to degrade keratin sulfate, a GAG found primarily in cornea & cartilagea
- mucopolysaccharidoses (MPS) type of LSD (lysosomal storage disorder)
- inherited in an AR fashion
- incidence: 1 in 100,000
- is one of a number of storage (“cleanup”) disorders
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Glycosaminoglycans (GAGs)
- the oligosaccharide component of proteoglycans (macromolecules that provide structured integrity & function to connective tissues)
- 4 main GAGs: dermatin sulfate, heparin sulfate, keratin sulfate, chondroitin sulfate
- defective ability to degrade GAGs → tissue thickening & compromise in cell & organ function
- they accumulate in lysosomes & extracellular tissue & are excreted in urine
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Mucopolysaccharidoses (MPS)
characterized by a deficiency of lysosomal enzymes required for degradation of GAGS, also known as mucopolysaccharide
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What is the specific mechanism by which excess keratin sulfate results in skeletal dysplasia?
- unknown
- however, there are 2 known enzyme deficiencies associated with this syndrome:
- 1. IVA galactosamine-6-sulfatase (associated with more severe disease)
- 2. IVB beta-galactosidase
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Characteristics of Morquio’s syndrome
- a progressive course of multi-system involvement
- hepatomegaly
- urinary excretion of keratin sulfate fragments
- leukocyte inclusion bodies
- patients may live to the 7th decade in mild cases
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Are course facial features & intellectual disability found in Morquio syndrome?
- No
- while patients with some MPS have these symptoms, they're not found in Morquio’s syndrome
- children with this disorder are healthy at birth & present at 2-3 with spinal deformity, growth retardation or genu valgum (knock kneed)
- patients also have unique spondyloepiphyseal dysplasia & ligamentous laxity
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What are some other musculoskeletal manifestations of Morquio syndrome?
- 1. odontoid hypoplasia: hypoplasia of the second cervical vertebrae (can lead to atlantoaxial instability → cervical myelopathy; is a major cause of death)
- 2. short trunk dwarfism
- 3. scoliosis or kyphosis
- pts are also at risk for pulmonary infections due to trunk deformities
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Characteristic X-ray findings of Morquio
- platyspondyly (flattened vertebrae)
- precocious arthritis
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