Title: Achondroplasia
1Achondroplasia
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
3FGFR3 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
4Functions 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)
5Mutations 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
6Cartilage 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
7Genetic 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
8Prenatal 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
9Diagnosis 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
10Differences 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
11Symptoms of Achondroplasia
Abnormal body proportions -Short arms and legs,
normal torso size -Reduced height -Upper arms/
thighs more shortened than forearms/lower legs
12Facial Features
- Large head
- Indicates hydrocephalus
- Flat nose at bridge
13Other Features
- Shortened, stubby fingers
- Trident Hand
- Separation between middle and ring fingers
14Childhood Problems
- Hump on back
- Usually disappears after child begins walking
- Delayed Walking and Bowed Legs
- Markedly Curved Spine
- After walking
15Life 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.
16Prevention 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
17Treatment 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
18CNP 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
19The 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.
20Limb-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
21The 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.