Achondroplasia

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Achondroplasia
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• Achondroplasia is due to changes in the FGFR3
  gene on the short arm of chromosome 4
  
• Autosomal dominant- if you have one copy of the
  mutated gene, you have the condition

FISH photo of chromosome 4
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FGFR3 Gene

• Fibroblast Growth Factor Receptor 3
• The gene makes a protein that is part of the
  family of fibroblast growth factor receptors.
  

Model of FGFR3
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Functions of FGFR3 Protein

• Interacts with specific growth factors and
  enables cells to undergo maturation and take on
  specialized functions
  
• Development and maintenance of bone and brain
  tissue
  
• Limits ossification so that too much bone is not
  created.

Confocal laser scanning microscope image of FGFR3
protein (green)
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Mutations in FGFR3

• Two mutations cause more than 99 of cases
• Both change one amino acid in the FGFR3 protein
  and substitutes arginine for glycine at position
  380.
  
• These substitutions cause the receptor to be
  overly active and cause bone growth disturbances.

Gel electrophoresis of DNA from FGFR3 gene
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Cartilage and Bones

• Achondroplasia literally means without
  cartilage
  
• However, because FGFR3 limits bone development,
  when there is a mutation on the gene, it causes
  malfunctions in bone growth
  
• Cartilage is not properly converted to bone, so
  there is a shortage of bone

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Genetic Possibilities of Achondroplasia

• Occurs in every 1/15,000 to 1/40,000 births.
• 80 of cases from a spontaneous de novo mutation
  (in spermatogenesis of father)
  
• 20 inherited from one or two affected parents

A a a a Affected parent and non-affected
parent
50 chance of having affected child
A a A a Both parents affected 75 chance
of having affected child
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Prenatal Diagnosis

• Recommended if one or both parents affected
• Not recommended in majority of pregnancies to
  detect spontaneous mutation
  
• DNA testing through amniocentesis at 15-18 weeks
  of gestation or chorionic villus sampling at
  10-12 weeks
  
• Limb shortening can be seen in ultrasound after
  22 weeks
  
• DNA sequencing of entire coded region, sequencing
  of select exons, or targeted mutation analysis

Diagram of location of FGFR3 gene on chromosome 4
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Diagnosis in Newborns and Children

• Bone measurement during physicals or x-rays
• Increased front-to-back head size
• Signs of fluid pressure in the brain associated
  with enlargement of chambers
  
• Radiological testing compression of spine,
  notch near hip, short bones
  
• Symptoms such as bowlegs, large head, and limited
  elbow extension
  

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Differences in Dwarfism
Achondroplasia accounts for 70 of diagnosed
cases of dwarfism Other types of dwarfism inclu
de

• Diastrophic dysplasia (1/110,000)-cleft palate,
  respiratory problems, clubfeet, hitchhiker's
  thumb, and ears with a cauliflower appearance

• Pseudoachondroplasia
• (4/1 million)-head size is the same as that of
  average-size people, and they lack the facial
  features characteristic of achondroplasia
  

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Symptoms of Achondroplasia
Abnormal body proportions -Short arms and legs,
normal torso size -Reduced height -Upper arms/
thighs more shortened than forearms/lower legs
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Facial Features

• Large head
• Indicates hydrocephalus
• Flat nose at bridge

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Other Features

• Shortened, stubby fingers
• Trident Hand
• Separation between middle and ring fingers

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Childhood Problems

• Hump on back
• Usually disappears after child begins walking
• Delayed Walking and Bowed Legs
• Markedly Curved Spine
• After walking

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Life Expectancy

• People who inherit FGFR3 mutations from both
  parents have a severely decreased life expectancy
  than those who inherit the mutation from one
  parent
• Homozygous infants usually die a few weeks to
  just months after birth, while heterozygous
  newborns are expected to live out normal life
  spans.

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Prevention of Complications

• Respiratory infections
• Hydrocephalus, the buildup of fluid pressure in
  the brain, during the early years of childhood.
  
  
• Bowed legs, knock-knee, which has the opposite
  appearance of bowed legs, and kyphosis
  (hunch-back).
  
• Jaw abnormalities
• Ear infections must be treated immediately with
  antibiotics in order to avoid hearing loss

Hydrocephalus
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Treatment Options

• Currently, there are no treatments that can cure
  or reverse the effects of achondroplasia.
  
• There are, however, treatment options available
  to those affected that can improve quality of
  life.
  
• Growth hormones and/or surgery may be an option
  for lengthening limbs to a limited extent.

Schematic representation of the mechanism by
which C-type natriuretic peptide compensates for
FGFR3-mediated shortening of bones, a treatment
being tested in mice with achondroplasia
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CNP and FGFR3

• FGFR3 proteins interact with growth factors and
  activate downstream signaling pathways (STAT-1
  and MAPK)
  

CNP prevented the shortening of bones by
correcting the decreased connective tissue
synthesis in the growth plate through inhibition
of the MAPK pathway of FGFR3 signaling
CNP does not effect STAT-1 pathway
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The Growth Hormone

• Growth hormones are especially effective during
  the first year of life, having the potential to
  increase limb length up to 30 cm. However, the
  therapy can cost 10,000-25,000 a year.
• Growth hormone is a messenger protein made by the
  pituitary gland.
  
• It regulates cell growth by binding to a protein
  called a growth hormone receptor.
  
• Recombinant growth hormone is injected under the
  skin.

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Limb-lengthening Surgery

• Painful, long (up to 2 years), expensive (as much
  as 100,000), and hazardous procedure
  
• Surgery can increase height up to 14 inches, and
  better aligns the back.
  
• Risks include bending or twisting of the bone,
  infections, nerve damage, limb paralysis, the
  release of fat into the bloodstream, the
  inability to control the limb

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The Surgical Procedure

• The bone is cut.
• Metal frames around the limbs are constructed,
  and pins are inserted into the cut, which expand
  the gap between the two now separate portions of
  bone.
• Bone tissue eventually grows in this area to fill
  the gap, and the bone is thus lengthened.