By: Brittany Beckette

1. Achondroplasia By: Brittany Beckette

2. Achondroplasia • It is a bone disorder that affects the long bones of the extremities and the base of the skull. -characteristics: short extremities, large head, and trident-shaped hands • It is an autosomal dominant disorder (dominant mutant gene) • It is the most common compared to other small stature processes. It is found in about 70% of dwarfs.

3. Achondroplasia • The mutated gene slows down the formation of bone by • inhibiting the production of chrondrocytes, which are the • cells responsible for the • produce of cartilage. • Nonlethal form of chrondoysplasia.

4. History Of • Dr. John Wasmuth led a group of scientists in the discovery of achondroplasia in 1994. • They found that this type of dwarfism resulted from the mutation of the fibroblast growth factor receptor-3 gene, which is only a part of the human chromosome 4. When a mutation occurs on the receptor-3 gene, it severely shortens bones and it’s growth. • Luckily, about 80% of parents are unaffected by this.

5. History Of • The term “achondroplasia” was proposed by Jules Parrott in 1878 to describe a condition with individuals who had disproportionate short stature. It translates as “without cartilage formation”. But this name is misleading because the mutation does not occur in the formation of cartilage but rather in the conversion of cartilage to bone. • In 1909, Pierre Marie introduced clinical terminology to describe the physical and intellectual features of these individuals. Example: trident-shaped hands (the fingers of the hand are nearly all equal in length and are deflected at the first interphalangeal joint, which gives it a forklike shape).

6. Symptoms • Trident-shaped hands with space between the long and ring finger • Bowed legs • Decreased muscle tone and loose joints • Larger sized head (abnormal size to body) • Prominent forehead size called frontal bossing • Shortened arms and legs • Spinal stenosis • Spine curvatures: kyPhosis and lordosis • Crowded or misaligned teeth • Flat feet that are short and broad • Frequent middle ear infections that may lead to hearing loss • Delayed developmental milestones (such as walking)

7. Inheritance • Inherited in an autosomal dominant pattern-one copy of the altered gene in each cell is sufficient enough to cause the disorder • About 80% of people with achondroplasia have average-size parents. These mutations occur in the FRFG3 gene. • In the other cases , the individual has inherited an altered FRFG3 gene from either one or two of the affected parents. (50% chance of passing the gene on if one parent has it)

8. Inheritance • Those who inherit the genes from both of the parents, have a severe case of achondroplasia and have severe shortening of the bones and an underdevelopment of the rib cage. (75% chance of passing the gene if both parents have it) • -Unfortunately, children with two dominant alleles have almost no chance of survival after the first year of life. These individuals are often stillborn or die quickly after birth because of Respiratory failure.

9. Locus • Studies showed that the gene was on the short (p) arm of chromosome 4 in the chromosome band 4p16.3.

10. Linkage • Found on the human chromosome 4 with the marker D4S43. • It was found when researchers were searching for the Huntington’s Disease gene. • Receptor-3 gene.

11. Frequency • Different sources claim different frequencies within the human population. It is varied between 1:10,000 people to 1:40,000 people. • Most common form of short-limbed dwarfism. EFFECTED GROUPS: • The disease affects both sexes and people of all racial and national groups. • The ratio between each sex is about equal.

12. Onset… Amplification Age of Onset: • People are born with achondroplasia. Amplification, Penetracne: • Adult achondroplastics live normal lives and can perform many of the same activities as those without the disease. • Adults may develop arthritis. • Children with achondroplasia grow at a slower rate to a slower height.

13. Outlook (Prognosis) • Estimated to reach less than 5 feet in height • Intelligence remains in the normal range • Should live a normal lifespan • Children who inherit it from both parents often only live for a few months • FGFR3-directed therapies are seen in the future

14. Health Problems Associated with the Disease • Breathing problems • Reduced muscle tone • Obesity • Recurring ear infections • Crowded teeth

15. Treatment THERE IS NO CURE. But scientists are researching ways of trying to create alternate growth factors that have the ability to bypass the missing gene receptor that will lead to normal bone growth. • The human growth hormone can be given as a medication, but there haven’t been many studies on whether or not it helps in greater adult heights.

16. Treatment (cont’d) • When it comes to skeletal deformities, surgery maybe needed. Spinal fusion, laminectomy, and osteotomy are among the most common. -Spinal fusion- permenantly connects separate vertebrae. -Laminectomy- opens the spinal canal to relieve pressure off the spinal cord, helps with spinal stenosis which is the most serious complication of achondroplasia. -Osteotomy- for those with bowed legs, the bones of the leg are cut and allowed to heal in the correct anatomical position.

17. Recent Progress • Three strategies for therapeutic approaches are in the early stage of development: • The first includes chemical inhibitors that are selective for FGFR3 tyrosine kinase. It has been used successfully to treat certain types of cancers. • The second relies on blocking antibodies to interfere with the binding of the FGF ligands to the FGFR3 gene. This particular approach has been successful in treating breast cancer. • The third involves the C-type natriuretic peptide (CNP) that is being considered as a therapeutic agent for cardiovascular dieases. CNP has effects on the fluid and electrolyte balance and on the vascular tone.

18. Progress (cont’d) • These strategies are being explored because the molecular • mechanism that is responsible for the disease is the same as • those of many cancers. It is the gain of function of a tyrosine • kinase-coupled receptor of the signaling molecule. • Research Center, Shriners Hospital for Children, Department of • Molecular & Medical Genetics, • Oregon Health & Science University, Portland, Oregon

19. Famous/ Interesting Cases • Matthew Knox- the longest living dwarf who died at age 105 years old. • Nicole “Snooki” Polizzi- American reality television personality, widely known as the cast member of MTV’s Jersey Shore. • Jason Acuna- “Wee-man! “. He is an American skateboarder and one of the stars on Jackass. • Tony Cox- Very successful actor, most known for “Bad Santa” and “Me, Myself, and Irene”. • Verne J. Troyer- Another successful actor of two feet eight inches. Most known for “Doctor Evil’s”, “Mini Me”, and the second and third “Austin Powers” movies.

20. Famous Examples http://megeve0.tripod.com/id9.html

21. Other Names for Achondroplasia • ACH • Achondroplastic dwarfism • Dwarf, achondroplastic

22. Sources: https://www.medlink.com/medlinkcontent.asp http://www.whodiscoveredit.com/who-discovered-achondroplasia.html http://www.ncbi.nlm.nih.gov/books/NBK1152/ http://ghr.nlm.nih.gov/condition/achondroplasia http://www.knoahsarc.org/2008/11/20/dwarfism-awareness-week/ http://health.nytimes.com/health/guides/disease/achondroplasia/overview.html

23. Sources: http://megeve0.tripod.com/id7.html http://www.nlm.nih.gov/medlineplus/ency/article/001577.htm http://www.thirdage.com/hc/c/achondroplasia-treatment

24. Sources: http://www.childrenshospital.org/az/Site558/mainpageS558P1.html http://staff.jccc.edu/pdecell/heverman/genetics.htm http://alexandra179.tripod.com/achondroplasia101/id2.html • Primary Sources: • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1012739/ • http://emedicine.medscape.com/article/941280-overview • http://www.crecimiento.org/biblio/milestones.pdf