Achondroplasia management and treatment.ppt

achondroplacia

2. Obvious phenotype – documented throughout
history
- Ancient Egyptian artwork

- Diego Velazquez – series
of dwarf paintings in the 1600s

3. Exhibited in circus shows, especially in the late
1800s – mid 1900s
Came to be known
as “circus freaks”

4. FISH photo of chromosome 4
•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

5. 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

6. 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)

7. 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

8. 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

9. 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
Aa aa
Aa aa
A a
a
a

Affected parent and non-affected parent
50% chance of having affected child
AA Aa
Aa aa
A a
A
a
Both parents affected
75% chance of having affected child

10. ◦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

11. ◦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

12. 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
Achondroplasia accounts for 70% of diagnosed cases of dwarfism
Other types of dwarfism include:

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

14. Facial Features
•Large head
–Indicates hydrocephalus
•Flat nose at bridge

15. Other Features
•Shortened, stubby
fingers
•Trident Hand
–Separation between
middle and ring fingers

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

17. 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.

18. 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

19. 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

20. FGFR3 proteins interact with growth factors and activate
downstream signaling pathways (STAT-1 and MAPK)
CNP does not
effect STAT-1
pathway
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

21. 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.

22. 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

23. 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.

24. Genetic counseling may be helpful for
prospective parents when 1 or both have
achondroplasia. However, because
achondroplasia most often develops
spontaneously to average-sized parents,
prevention is not always possible.

25. Achondroplasia is a rare disease that
includes bad infections and unusual
shortness. It is genetic and begins in the
mother’s womb. You can never be sure if a
child will have achondroplasia or not. To
lengthen limbs, hormones or surgery can
help, but can be expensive. Achondroplasia
is hard to live with because of breathing and
walking difficulties.