This page was produced as an assignment for Genetics 677 at UW-Madison, Spring 2010

Background on Achondroplasia

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A young girl with Achondroplasia
A condition affecting bone growth, achondroplasia is a Greek word meaning "without cartilage formation." However, it is actually caused a by genetic mutation resulting in the inability to convert cartilage to bone, especially in the arms and legs, causing shortened stature. It is also the most common genetic form of dwarfism, affecting about 1 in every 26,000 births. [1] The characteristic appearance of individuals with the disorder includes an average-sized torso but shortened limbs, especially in the upper portions. They are macrocephalic with an enlarged forehead and a flattened nose bridge. [2]
While achondroplasia does not affect intelligence, it can cause several other health concerns. Due to cranial deformities, people with the condition may suffer from apnea or frequent ear infections. In addition, adults usually develop lordosis, which is a sway in the lower back. [3]  This can result in pain and difficulty in walking.

Gene
Achondoplasia is caused by a mutation in the fibroblast growth receptor 3 (FGFR3) gene. The gene encodes for a cell membrane spanning protein, fibroblast growth receptor 3, that interacts with growth factors outside of the cell and regulates the formation of bone from cartilage, also known as ossification, by limiting it.  There are two mutations in the gene that cause about 99 percent of all cases of achondroplasia, both involving a change of the amine acid glycine at position 380 to arginine. [4]  Recent research indicates that this mutation results in a "gain of function" in which the FGFR3's activity is increased, and therefore less ossification occurs. [2] The reduction in ossification results in a reduction in bone size, particularly in the long bones of the arms and legs, causing the overall short stature and distinct proportions of a person with achondroplasia.
Mutations in other amino acids of the FGFR3 gene result in phenotypes different than that of achondroplasia, they include other bone growth issues as well as certain types of cancers. [4]
The FGFR3 gene is located on chromosome 4:

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Chromosome 4. The position of the FGFR3 gene is indicated by the yellow arrow.
Inheritance
While the inheritance pattern of achondroplasia is autosomal dominant, 80 percent of all cases are caused by de novo mutations in which a child is born with the condition from two parents without it. Since only one copy of the mutated gene is required to produce the condition, children born with two copies, usually because both parents are affected, have severe disabilities. They may either be still born, or they die shortly after birth because they have respiratory difficulties. [3]

Living with Achondroplasia
People with achondroplasia have been the stars of several recent television programs, the most well known of which may be "Little People, Big World" on TLC featuring the Roloff family. Shows featuring little people are a window into the challenges that they face living in a world that is not designed for people of their stature and abilities.
In the video below, Jacob Roloff, the average sized son of two parents with dwarfism (his mother, Amy, has achondroplasia) talks about what life is like in his family and what difficulties a little person can face.
References
[1] Bocian, M., Church, D.M., Fielder T.J., Shiang, R., Thompson, L.M., Wasmuth, J.J., Winokur, S.T., and Zhu, Y. (1994) Mutations in the Transmembrane Domain of FGFR3 Cause the Most Common Genetic Form of Dwarfism, Achondroplasia. Cell, Vol. 78, 335-342. doi:10.1016/0092-8674(94)90302-6 
[2] Achondroplasia. Genes and Disease. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gnd&part=achondroplasia
[3] Achondroplasia. Genetics Home Reference. A service of the U.S. National Library of Medicine. http://ghr.nlm.nih.gov/condition=achondroplasia
[4] FGFR3. Genetics Home Reference. A service of the U.S. National Library of Medicine. http://ghr.nlm.nih.gov/gene=fgfr3

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Created by Alex Joyce
ajoyce@wisc.edu
Last updated: Feb. 7, 2010
Genetics 677 Homepage