Achondroplasia

Introduction
Achondroplasia is a disorder of bone growth that prevents the changing of cartilage
(particularly in the long bones of the arms and legs) to bone. It is characterized by dwarfism,
limited range of motion at the elbows, large head size (macrocephaly), small fingers, and
normal intelligence. Achondroplasia can cause health complications such as interruption of
breathing (apnea), obesity, recurrent ear infections, an exaggerated inward curve of the
lumbar spine (lordosis). More serious problems include a narrowing of the spinal canal that
can pinch (compress) the upper part of the spinal cord (spinal stenosis) and a buildup of fluid
in the brain (hydrocephalus). Some people with achondroplasia may have delayed motor
development early on, but cognition is normal.

Etiology
Achondroplasia is caused by mutations in the FGFR3 gene. Inheritance is autosomal
dominant, Males and females are equally affected, as the FGFR3 gene is located on
chromosome 4 (an autosome) and not on a sex chromosome.

History
In 1994, several reports linked achondroplasia to a region near the Huntington's disease gene
on chromosome 4 (C.A. Francomano et al., Human Molecular Genetics, 3:787-92, 1994; M.
Le Merrer et al., Nature Genetics, 6:318-21, 1994; M. Velinov et al., Nature Genetics, 6:314-
7, 1994). One of the gene candidates in that region was fibroblast growth factor receptor 3
(FGFR3).
The team, led by John J. Wasmuth, a UC-Irvine professor of biological chemistry who died
in 1995, found the defective gene just six weeks after beginning its gene hunt. The search
was accelerated because his lab had intensively studied the FGFR3 gene three years before
as part of a collaborative effort to find the Huntington's disease gene.
In the paper “Mutations in the transmembrane domain of FGFR3 cause the most common
genetic form of dwarfism, achondroplasia”, researchers "detected a glycine-to-arginine
transition in the gene coding for FGFR3, resulting in an amino acid change in the
transmembrane domain of the protein," explains Leslie M. Thompson, a research associate
at UC-Irvine. The receptor is one of a family of FGF receptors that mediate cellular responses
in many tissues, including developing cartilage. "Ninety-five percent of achondroplasia is
caused by this specific change (15 of the 16 chromosomes 4 examined, had the same
mutation)," notes Rita Shiang, also a research associate at UC-Irvine. Both Shiang and
Thompson contributed equally to the work.
Thompson and Shiang believe that the paper is cited frequently because it was the first to
identify a growth factor receptor mutation responsible for a skeletal dysplasia. Now
researchers are finding such mutations involved in a number of similar diseases.
One result of the work is a simple rapid-screening test for identifying common mutations.
Thompson is quick to point out that such a screen would be used only for prenatal testing of
pregnancies at risk of having two copies of the gene mutation, which is invariably fatal.

Clinical Aspects
 Signs and Symptoms:
People who have achondroplasia have abnormal bone growth that causes the following
clinical symptoms: short stature with disproportionately short arms and legs, short fingers, a
large head (macrocephaly) and specific facial features with a prominent forehead (frontal
bossing), mid-face hypoplasia and depressed nasal bridges, trident configuration of the
hands, and genu varum.
The intelligence and life span in individuals with achondroplasia is usually normal.
Infants born with achondroplasia typically have weak muscle tone (hypotonia). Because of
the hypotonia, there may be delays in walking and other motor skills. Compression of the
spinal cord and/or upper airway obstruction increases the risk of death in infancy.
People with achondroplasia commonly have breathing problems in which breathing stops or
slows down for short periods (apnea). Other health issues include obesity and recurrent ear
infections. Adults with achondroplasia may develop a pronounced and permanent sway of
the lower back (lordosis) and bowed legs. The problems with the lower back can cause back
pain leading to difficulty with walking.
X-ray findings are rhizomelic shortening of long bones, which also become robust and
tubular bones, a narrowing of the interpediculate distance of the caudal spine, rounded ilia
and horizontal acetabula, a narrow sacrosciatic notch, proximal femoral radiolucency, and
mild, generalized metaphyseal changes. Virtually all patients with achondroplasia have
reduced foramen magnum size as determined by cranial CT examination. Reduced foramen
magnum size might cause compression of the brainstem at the craniocervical junction and
therefore results in elevated frequency of hypotonia, tetraparesia, motor developmental
delay, central apnea, and sudden death.
*Achondroplasic mothers must undergo caesarian section due to the small size of the pelvis.

Epidemiology
Achondroplasia arises in about 1 in every 25,000–30,000 individuals. That, in turn, translates
into around 250,000 affected persons worldwide.
Some populations appear to have a higher incidence of achondroplasia. For instance, it is
estimated to occur in about 1 case in 6400 births in Denmark and about 1 case in 10,000
births in Latin America. No particular race has been documented to be more commonly
affected.

Molecular Alteration
Achondroplasia is caused by mutations in the fibroblast growth factor receptor-3 (FGFR3)
gene. Mutations within FGFR3 are the only genetic changes known to cause achondroplasia.
FGFR3 has been mapped to the short arm of chromosome 4, p16.3 (4p16.3). All causal
mutations occur at the exact same location within the gene; hence, molecular testing by
targeted mutational analysis is easily done and interpreted.
Because of its dominant inheritance pattern, an individual affected with achondroplasia (and
whose partner is of average stature) has a 50% risk for each of their offspring to be similarly
affected. However, most instances of achondroplasia – perhaps 80% – arise from new,
spontaneous mutations. In turn, then, around 80% of affected babies are born to two
unaffected, average statured parents.
Achondroplasia cases display mutation at the 1138th nucleotide position. The common form
of mutation was transition; this location of the nucleotide corresponds to the 380th amino
acid of the FGFR protein (G380R). Due to this missense mutation, the amino acid at the
position changes from Glycine to Arginine resulting in protein dysfunction (transition).
Thus produced deficient proteins are incapable of inducing chondrocyte proliferation as well
as limits the growth of cartilage and long bones, hence, producing the phenotypic
characteristics of Achondroplasia.

 Normal Function of FGFR3 Gene:

The FGFR3 gene provides instructions for making a protein called fibroblast growth factor
receptor 3. This protein is part of a family of four fibroblast growth factor receptors that share
similar structures and functions. These proteins play a role in several important cellular
processes, including regulation of cell growth and division (proliferation), determination of
cell type, formation of blood vessels (angiogenesis), wound healing, and embryo
development.
The FGFR3 protein spans the cell membrane, so that one end of the protein remains inside
the cell and the other end projects from the outer surface of the cell. This positioning of the
protein allows it to interact with specific growth factors outside the cell and to receive signals
that control growth and development. When these growth factors attach to the FGFR3
protein, the protein is turned on (activated), which triggers a cascade of chemical reactions
inside the cell that instruct the cell to undergo certain changes, such as maturing to take on
specialized functions (differentiation).
Several versions (isoforms) of the FGFR3 protein are produced from the FGFR3 gene. The
different isoforms are found in various tissues of the body, and they interact with a variety of
growth factors. Many isoforms are found in the cells that form bones. Researchers believe
that the FGFR3 protein regulates bone growth by limiting the formation of bone from
cartilage (a process called ossification), particularly in the long bones. One particular isoform
of the FGFR3 protein is found specifically in cells that line the surfaces of the body (epithelial
cells), including the cells that form the outermost layer of skin, called the epidermis.

Diagnosis
Achondroplasia can be diagnosed before birth by fetal ultrasound or after birth by complete
medical history and physical examination. DNA testing is now available before birth to
confirm fetal ultrasound findings for parents who are at increased risk for having a child with
achondroplasia.

Treatment
Currently, there is no way to prevent or treat achondroplasia, since the majority of cases result
from unexpected new mutations. Treatment with growth hormone does not substantially
affect the height of an individual with achondroplasia. Leg-lengthening surgeries may be
considered in some very specialized cases.
Detection of bone abnormalities, particularly in the back, are important to prevent breathing
difficulties and leg pain or loss of function. Kyphosis (or hunch-back) may need to be
surgically corrected if it does not disappear when the child begins walking. Surgery may also
help bowing of the legs. Ear infections need to be treated immediately to avoid the risk of
hearing loss. Dental problems may need to be addressed by an orthodontist (dentist with
special training in the alignment of teeth).