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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
- 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)
- 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
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
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)
- disproportionate shortening of the proximal portion of the limb
- caused by suppression of bone growth in the physis of long bones
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)
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
What do the majority of achondroplasia cases result from?
- spontaneous mutation in the father
- may be related to advanced paternal age
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
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
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
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)
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
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
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)
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
X-ray Findings in OI Patients
- Wormian bone (immature bone with no lamellar bone formation)
- fractures at various stages of healing
- thin cortices
What drug often used in the treatment of osteoporosis is used to treat OI?
- 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
Experimental OI Treatments
- gene therapy to stimulate normal type 1 collagen
- bone marrow transplant
- (these are reserved for the most severe forms of OI)
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
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
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
Why is a goal in management of OI helping patients stay active?
because bone resorption is minimized in stressed bones
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
- 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
How does one get Blount's disease?
- is the result of abnormal compression of bone
- this causes growth retardation
- (it's not genetic)
Who does Blount's disease typically affect?
- early walkers
- obese children
- males & African Americans are disproportionately affected
What must occur for the disease to manifest?
- one year of ambulation is required for expression
- may have onset in infancy or late adolescence
- age of onset determines treatment
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)
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
- 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
- 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
characterized by a deficiency of lysosomal enzymes required for degradation of GAGS, also known as mucopolysaccharide
What is the specific mechanism by which excess keratin sulfate results in skeletal dysplasia?
- 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
Characteristics of Morquio’s syndrome
- a progressive course of multi-system involvement
- urinary excretion of keratin sulfate fragments
- leukocyte inclusion bodies
- patients may live to the 7th decade in mild cases
Are course facial features & intellectual disability found in Morquio syndrome?
- 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
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
Characteristic X-ray findings of Morquio
- platyspondyly (flattened vertebrae)
- precocious arthritis