Achondroplasia is a common nonlethal form of chondrodysplasia. It is transmitted as an autosomal dominant trait with complete penetrance. De novo mutations cause 75-80% of cases. The mutation rate is estimated to be 0.000014 per gamete per generation. Cardinal features include short stature, rhizomelic shortening of the arms and legs, a disproportionately long trunk, trident hands, midfacial hypoplasia, prominent forehead (frontal bossing), thoracolumbar gibbus, true megalencephaly, and caudal narrowing of the interpedicular spaces.
Achondroplasia is an autosomal dominant disease due to mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Most cases are due to sporadic mutations. Advanced paternal age is a risk factor.
In achondroplasia, there is a decrease in endochondral ossification, with a smaller zone of proliferating chondrocytes. Periosteal ossification, however, is not affected.
The fibroblast growth factors (FGFs) and their receptors are very important in cells growth and differentiation. The mutation in fibroblast growth factor receptors (FGFRs) result in many genetic disease. Achondroplasia is one of the most common forms of human dwarfism; it is also associated with the mutation in the FGFR3. The activation of tyrosine kinase receptors is created by two main steps. The first step is the binding of FGFs to their receptors cause the receptors to aggregate, forming adimer. In the second step, the tyrosine kinase is activated by the eggregation from step one; the phosphorylation will occurs between the tyrosine kinase and its neighbors, phosphates are added to tyrosine on the tail of the other polypeptide. The signal will be initiated; the protein is now activated. One tyrosine kinase receptor dimmer will be able to activate ten or more different intracellular proteins simultanteous. There are three main signals. The first one is the activation of the ras G protein and the MAP kinase cascade to signal to the transcription DNA. The second one is the activation of phospholipase C to make the separation of PIP2 into IP3 and DAG. The third signal is the phosphorylation of Stat1 transcription and its subsequent translocation into the nucleus. In the activation of the FGFRs, heparin has been found to have effects on the biding of FGFs to their receptors. It will help the FGFs binding together as a web and link to their receptors. There are many types of FGFRs in human body and also there will bee many types of FGFRs mutation in our body. In this article, there are three first FGFRs introduced such as: mutations in FGFR1, FGFR2 and FGFR3. Mutation in FGFR1 can cause the Pfeiffer Syndrome, a malformation syndrome, leads to the abnormal of skull and facial shape. Mutation in FGFR2 may cause three different type of syndrome such as Crouzon Syndrome, Jackson-Weiss Syndrome and Apert Syndrome. Mutation in FGFR3 can give Achondroplasia or Thanatophoric Dysplasia. The most common forms of achondroplasia are found with a very high percentage (97%) specific to FGFR3 mutation in the transmembrane of the receptors. In a normal condition of the transmembrane region of the protein, Glycine amino acid is found on DNA at the position 380. But in the mutation FGFR3, there is the absence of glycine; and at that location, there is an appearance of arginine. This is the results of a genetic mutation of glycine to arginine. The achondroplasia is caused by the mutation in FGFR3 as the “gained-of-function” mutation because the FGFRs gain their activeness. Usually, the binding of the FGF to the FGFRs will help the FGFRS becoming more active. But in the mutations of FGFRs, the FGFRs are able to be more active without binding to the FGF ligands. The FGFRs has been gain the function of the Stat1 transcription factor and its subsequent translocation into nucleus. This is the third type of signaling. Under the effects of gaining the function of Stat1 transcription factor, the more signaling of this function is the more the cell cycle is limited and inhibited, leads to the cell growth arrest. This is how “gain-of-function-mutation” affects the growth of the affected individual. The FGFRs and FGFs relate to achondroplasia as the mutation in FGFR3. Furthermore, the mutation in FGFRs is responsible to many diseases. FGFs and FGFRs have an important position in cell growth and differentiation.
Achondroplasia causes proximal shortening of the limbs, short stature, relatively enlarged head with frontal bossing, and a depressed nasal bridge. The thorax is long and narrow, and is accompanied by thoracolumbar kyphosis. There is tilting of the sacrum with associated exaggeration of the lumbar lordosis. Affected individuals are of normal intelligence. Homozygous mutations are rare, and usually affect children of two affected parents. In this case, the features of the disease are more severe, and usually causes death early in life.
Communicating hydrocephalus and spinal stenosis can occur.
A skeletel survey is useful to confirm the diagnosis of achondroplasia. Skull films demonstrate a large skull with a narrow foramen magnum, and relatively small skull base. The vertabral bodies are short and cuboidal, and there is congenitally narrowed spinal canal. The iliac wings are small and squared, with a narrow sciatic notch. The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates. Fibular overgrowth is present. The hand is broad with short metacarpals and phalanges, and a trident configuration. The ribs are short with cupped anterior ends. If the radiographic features are not classic, a search for a different diagnosis should be entertained.
The diagnosis can be made on by fetal ultrasound by progressive discordance between the femur length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended.
- Achondroplasia by Kathleen Tozer, M.D. & Bart Keogh, M.D., University of Washington Department of Radiology.
- Wikipedia listing for Achondroplasia
- Approach to Skeletal Dysplasias by Michael L. Richardson, M.D., University of Washington Department of Radiology.
- Azouz, E. M., Teebi, A. S., Chen, M.-F., Lemyre, E., and P. Glanc. "Achondroplasia, Hypochondroplasia, and Thanatophoric Dysplasia: Review and Update [Bone Dysplasia Series]," Canadian Association of Radiologists Journal 50(3): 185. June 1999.