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Achondroplasia

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Autosomal dominant- if you have one copy of the mutated gene, ... respiratory problems, clubfeet, hitchhiker's thumb, and ears with a cauliflower appearance ... – PowerPoint PPT presentation

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Title: Achondroplasia


1
Achondroplasia
2
  • 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
3
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
4
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)
5
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
6
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

7
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
8
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
9
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

10
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

11
Symptoms of Achondroplasia
Abnormal body proportions -Short arms and legs,
normal torso size -Reduced height -Upper arms/
thighs more shortened than forearms/lower legs
12
Facial Features
  • Large head
  • Indicates hydrocephalus
  • Flat nose at bridge

13
Other Features
  • Shortened, stubby fingers
  • Trident Hand
  • Separation between middle and ring fingers

14
Childhood Problems
  • Hump on back
  • Usually disappears after child begins walking
  • Delayed Walking and Bowed Legs
  • Markedly Curved Spine
  • After walking

15
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.

16
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
17
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
18
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
19
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.

20
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

21
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.
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