Achondroplasia

Disease most
associated with human
dwarfism

Occurs in 1 / 15,000
17,000 people

Caused by a
missense mutation

History
Obvious phenotype documented throughout history

- Ancient Egyptian artwork





- Diego Velazquez series
of dwarf paintings in the 1600s

History Cont.

Exhibited in circus shows, especially in
the late 1800s mid 1900s

Came to be known
as circus freaks




The Cause Missense Mutation
Achondroplasia (ACH) is caused by a missense
mutation in FGFR3 (fibroblast growth factor receptor
3) on chromosome 4p in humans

This nucleotide, # 1138 in exon 10 on chromosome 4,
has the highest mutation rate known

In 97% of patients, an adenine replaces the normal
guanine at this position (observed in cDNA)

3% have a cytosine instead

Consequence
Both mutations result in the production of the
amino acid arginine instead of glycine

This production of arginine enhances gene
function and # of FGFR3 signals released

Mitosis is promoted, but cell differentiation is
depressed due to enhancement of gene
function

Inhibits proliferation and terminal differentiation,
resulting in reduced bone growth
Cause of Mutation
Studies show correlation with paternal age

Appears that the vast majority of FGFR3
mutations arise as new mutations during
spermatogenesis before Meiosis I

All mutations studied so far occur on the
paternal chromosome

More Genetics
ACH is an autosomal dominant trait, meaning
that a diseased parent has a 50% chance of
passing it on (pedigree next slide)

Despite these odds, almost 90% of patients
have de novo, or spontaneous, ACH

Probably due to either of two missense muta-
tions or difficulty of the diseased to reproduce


Pedigree Analysis
Used to classify the disease as autosomal
dominant

Does not skip a generation, prevalent in
females and males

Lethal gene
homozygous
dominant
individuals usually
die before birth
Phenotype & Symptoms
ACH has 100% penetrance and consistent
expressivity

Height of ~ 4 ft., short extremities, slight to
moderate obesity, and large head

Children have delayed motor milestones,
bowing of lower legs, frequent ear infections
(due to short Eustachian tube), and trouble
breathing (due to airway restriction)

2 5% of infants die due to symptoms
Phenotype & Symptoms Cont.
Statistics show mortality rate more than
doubles the general population

Does not effect intelligence

Biggest challenge is overcoming social
ineptitude and low self-esteem
(Television show Little People, Big
World on TLC)
- Depression is common



Reproduction Restrictions
Difficulty in reproduction due to:
- Restriction of ovarian stimulation and
puncture
- Small pelvic size
- Anesthesia risks
- Assortive mating
- Gene lethality

Similar Dwarfing Diseases
ACH is the most common of ~200 kinds

Thanatophoric dysplasia (TD)

Hypochondroplasia

FGFR3 regulation is linked to all kinds

Other Species
ACH and other dwarfism diseases occur in
other mammals, as well

Same characteristics as in humans



Diagnosis in Humans
Easier since the phenotype is apparent at birth

Expected if a parent is diseased

At least X-ray analysis, at most RFLP
restriction enzyme SfcI

May diagnose prenatal embryos
Treatment
New method of adding height, called distraction
osteogenesis, is being researched
- Lengthen tibia bone with very few risks
- Increase of 4.0 +/- 1.98 centimeters

Growth hormone therapy is still under study

Gene Therapy possibility

Altered clothing, car-pedal extensions, respect from
average-sized individuals, and even a support group
(see next slide) all help the low self-esteem and
depression that is common


Support Group Therapy
Research shows 5,000 10,000
achondroplasts in the U.S.A. and 65,000 on
Earth

Support groups allow for sharing of
experiences and more social interaction

Little People of America, founded by actor
Billy Barty, has more than 5,000 members

Help to lead a normal life
References
1) Aldegheri, Roberto. Distraction osteogenesis for
lengthening of the tibia in patients who have limb-length
discrepancy or short stature. Journal of Bone and Joint
Surgery. Boston: May 1999. Vol.81, Iss. 5; pg 624.
2) Bankowski, Leanne, and Carrie St Michel. They couldnt
see past my size. Good Housekeeping. New York: Nov
1999. Vol.229, Iss. 5; pg. 98.
3) Henderson, Shirley, David Sillence, and John Loughlin.
Germline and somatic mosaicism in achondroplasia.
Journal of Medical Genetics. London: Dec 2000. Vol.37, Iss.
12; pg. 956.
4) Horton, William A., and Gregory P. Lunstrum. Fibroblast
Growth Factor Receptor 3 Mutations in Achondroplasia and
Related Forms of Dwarfism. Reviews in Endocrine &
Metabolic Disorders. Dec. 2002; pg. 381.
References cont.
5) Lanning, Robert W., and Charlotte A. Brown. An Improved
Methodology for the Detection of the Common Mutation in the
FGFR3 Gene Responsible for Achondroplasia. Department of
Pediatrics, Carolinas Medical Center, Charlotte, NC. Aug. 3, 1997.
6) Moutou, Celine, Catherine Rongieres, Karima Bettahar-Lebugle
Nathalie Gardes, Christophe Philippe, and Stephane Viville.
Preimplantation genetic diagnosis for achondroplasia: genetics
and gynaecological limits and difficulties. Human Reproduction.
Mar. 200. Health Module, pg. 509.
7) Sobetzko, Diana, Suzanne Braga, Anna Rudeberg, Andrea
Superti-Fura. Achondroplasia with the FGFR3 1138 a (G380R)
mutation in two sibs sharing a 4p haplotype derived from their
unaffected father. Journal of Medical Genetics. London: Dec.
2000. Vol.37, Iss. 12; pg 958.

References cont.
8) Trotter, Tracy L., Judith G. Hall, G. Bradley Schaefer, Marlyn J.
bull, et al. Health Supervision for Children with Achondroplasia.
Pediatrics. Sep. 2005. Vol116, Iss. 3; pg 771.
9) Winkelman, Willem, and Rachel Buchholz. Keep Staring: I
might do a Trick! National Geographic Kids. Washington: Nov
2004. pg. 46.
10) Young, Ian D. Achondroplasia: A case of neglect? The
Lancet. London: Dec. 19 26, 1998. Vol.352, Iss. 9145; pg. 1950.
11) Pasternak, Jack J. Human Molecular Genetics, 2
nd
ed. 2005
12) http://teratology.org/jfs/History.html Feb. 27, 2006.
13) http://ibis-birthdefects.org/start/achondro.htm). Feb. 27, 2006.
Pictures/Diagrams
1) http://ibis-birthdefects.org/start/achondro.htm
2) http://bob.usuf2.usuhs.mil/biochem/images/ped-1.gif
3) http://www.pathguy.com/lectures/achondroplasia.jpg
4) http://www.mun.ca/biology/scarr/Achondroplasia.gif
5) http://www.mun.ca/biology/scarr/Human_Achondroplasia.gif
6) http://phpbb-
host.com/phpbb/viewtopic.php?p=5395&mforum=thenile&