What is achondroplasia?

• Achondroplasia is the most common form of short-limb dwarfism, a disorder in which bone tissue does not develop properly, especially the long bones of the arms and legs.
• Affects about 1 in 25,000 individuals of all ethnic groups.

Genetics

• Achondroplasia is a single gene disorder caused by mutations in the FGFR3 gene on chromosome 4.
• Two different mutations in the FGFR3 gene cause more than 99 per cent of cases of achondroplasia.
• It is a dominant genetic disease so only one copy of the FGFR3 gene needs to be mutated for symptoms to develop.
• Achondroplasia can be inherited from a parent with the disease. However, most cases of achondroplasia are the result of a new mutation in the FGFR3 gene, over 80 per cent of people with achondroplasia have parents who are unaffected.

Biology

• The FGFR3 gene encodes the instructions for making a protein called fibroblast growth factor receptor 3 (FGFR3).
• Fibroblasts are cells that make the collagen and other structural materials in our tissues and bones. They also play an important role in wound healing.
• A growth factor is a protein that stimulates cell growth.
• A receptor is a molecule on the surface of cells that binds with other molecules outside of the cell. This enables the cell to respond to external stimuli such as growth factors.
• The FGFR3 protein spans the cell membrane so that one end is inside the cell and the other is outside. This allows the protein to interact with growth factors outside the cell and receive signals for growth and development.
• FGFR3 protein in bone cells helps control bone growth by limiting a process called ossification, which controls the formation of bone from cartilage.
• The bones of embryos are made largely of cartilage, so they are soft. Ossification uses calcium to create hard, strong bone, as the child grows.
• When growth factors bind to the FGFR3 protein it is activated (switched on) and FGFR3 is able to regulate the process of ossification.
• Mutations in the FGFR3 gene lead to a change in the FGFR3 protein, specifically, the amino acid glycine is replaced with the amino acid arginine.
• This results in the FGFR3 protein being absent or damaged so that it cannot interact with external growth factors and therefore cannot control ossification.
• This results in problems during bone development where cartilage fails to turn into bone.

Symptoms

• Due to poor bone development, the bones are shortened, particularly in the thigh and upper arms, a condition known as rhizomelia.
• The thigh and upper arms are more affected because they have longer bones and larger growth plates (regions of the bones where growth occurs).
• The lower legs and forearms are affected to a lesser degree because their growth plates are smaller.
• The hands and feet are also short with unusual separation between the third and fourth digits.
• Affected individuals reach a maximum height of 120 cm (four feet).
• The torso usually develops to its proper size but the head may be larger than normal with a prominent forehead and flat nose.
• Affected children have delayed development and often take longer to learn to sit, crawl and walk than their unaffected peers. They may also develop a curved spine and bowed legs.
• Adults can suffer from back and leg pain. Abnormal development of the head may result in hearing loss and infections.
• In the worst cases, the abnormal structure of the skull and vertebrae can cause compression of the spinal cord, resulting in paralysis and breathing difficulties.

Ellie Simmonds arriving for the Royal World Premiere of ‘Skyfall’ at the Royal Albert Hall, London. Picture by Steve Vas.
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Diagnosis

• Achondroplasia is generally diagnosed by bone measurement during physical examination or after X-ray.
• Prenatal diagnosis is recommended if one or both of the parents are already affected.
• In the majority of cases, achondroplasia occurs spontaneously through mutations in the sperm or egg.

Treatment

• There is no cure for achondroplasia.
• Growth hormones can help people with achondroplasia to achieve moderate growth in some children.
• Surgery is a treatment option in some cases to increase leg length by up to 30 cm, prevent spinal compression, or correct bowed legs.
• In some people with achondroplasia it may be necessary to drain fluid from the head to:
  • relieve pressure on the brain
  • test for hydrocephalus, a condition where spinal fluid builds up inside the skull.