What is achondroplasia?

Congenital osteosclerosis Chondrodystrophia fetalis Chondrodystrophy syndrome

Achondroplasia is a disorder of bone growth that results in abnormality of cartilage formation It is the most common cause of dwarfism. It occurs in one in every 15,000 to one in 40,000 live births. Achondroplasia is caused by a gene mutation in the FGFR3 gene (paternal age 35&above) The FGFR3 gene makes a protein called fibroblast growth factor receptor 3 that is involved in converting cartilage to bone. FGFR3 is the only gene known to be associated with achondroplasia. All people who have only a single copy of the normal FGFR3 gene and a single copy of the FGFR3 gene mutation have achondroplasia. Most people who have achondroplasia have average-size parents. In this situation, the FGFR3 gene mutation occurs in one parent's egg or sperm cell before conception. Other people with achondroplasia inherit the condition from a parent who has achondroplasia.

Causes

Symptoms : People who have achondroplasia have abnormal bone growth that causes the following
clinical symptoms:

Abnormal hand appearance with persistent space between the long and ring fingers Bowed legs Decreased muscle tone Disproportionately large head-to-body size difference Prominent forehead (frontal bossing) Shortened arms and legs (especially the upper arm and thigh) Short stature (significantly below the average height for a person of the same age and sex) Spinal stenosis Spine curvatures called kyphosis and lordosis

Related Health Problems

Breathing disorders (apnea) Recurrent ear infections Obesity Reduced muscle strength Crowded teeth Clubbed feet Fluid build up in the brain (hydrocephalus)

Diagnosis
During pregnancy, a prenatal ultrasound may show excessive amniotic fluid surrounding the unborn infant. Examination of the infant after birth shows increased front-to-back head size. There may be signs of hydrocephalus ("water on the brain"). X-rays of the long bones can reveal achondroplasia in the newborn.

In individuals who may be too young to make a diagnosis with certainty or in individuals who do not have the typical symptoms, genetic testing can be used to identify a mutation in the FGFR3 gene. Genetic testing can identify mutations in 99 percent of individuals who have achondroplasia. Testing for the FGFR3 gene mutation is available in clinical laboratories.

Treatment
No specific treatment is available for achondroplasia. Children born with achondroplasia need to have their height, weight and head circumference monitored using special growth curves standardized for achondroplasia. Measures to avoid obesity at an early age are recommended. A magnetic resonance imaging (MRI) or CT scan may be needed for further evaluation of severe muscle weakness (hypotonia) or signs of spinal cord compression. To help with breathing,

surgical removal of the adenoids and tonsils, continuous positive airway pressure (CPAP) by nasal mask, or a surgical opening in the airway (tracheostomy) may be needed to correct obstructive sleep apnea. When there are problems with the lower limbs, such as hyperreflexia, clonus or central hypopnea, then surgery called suboccipital decompression is performed to decrease pressure on the brain.Children who have achondroplasia need careful monitoring and support for social adjustment.

Prognosis
People with achondroplasia seldom reach 5 feet in height.

The prognosis for people with achondroplastic dwarfism depends on the severity of their condition. In 2 percent to 5 percent of all cases, newborns do not survive more than 12 months after birth Most people with this condition should expect to live a normal lifespan and have normal intelligence.

Pathophysiology
Achondroplasia is caused by mutations in the fibroblast growth factor receptor-3 (FGFR3) gene. At present, FGFR3 is the only gene known to cause achondroplasia. This gene has been mapped to chromosome 4, band 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. The mutations (G1138A, G1138C) cause an increased function of the FGFR3 gene, resulting in decreased endochondral ossification, inhibited proliferation of chondrocytes in growth plate cartilage, decreased cellular hypertrophy, and decreased cartilage matrix production. The nucleotide G1138A and G1138C mutations of FGFR3 account for 99% of the mutations resulting in a specific point mutation, hence an amino acid substitution. About 98% of cases have the G1138A mutation resulting from a G-to-A point change. One percent of cases have a G-to-C point change at nucleotide 1138, causing the G1138C mutation. A rare missense mutation (Lys650Met) in the tyrosine kinase region of FGFR3 causes a disorder termed severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)

Achondroplasia is the most common of a group of growth defects characterized by abnormal body proportions. Affected individuals have arms and legs that are very short, while the torso is nearly normal size. The word achondroplasia is Greek and means "without cartilage formation," although individuals with achondroplasia do have cartilage. During fetal development and childhood, cartilage normally develops into bone, except in a few places, such as the nose and ears. In individuals with achondroplasia, something goes wrong during this process, especially in the long bones (such as those of the upper arms and thighs). The rate at which cartilage cells in the growth plates of the long bones turn into bone is slow, leading to short bones and reduced height. What does a person with achondroplasia look like? A child with achondroplasia has a relatively normal torso and short arms and legs. The upper arms and thighs are more shortened than the forearms and lower legs. Generally, the head is large, the forehead is prominent and the nose is flat at the bridge. Sometimes, the large head size reflects hydrocephalus (excess fluid in the brain) and requires surgery. Hands are short with stubby fingers. There is a separation between the middle and ring fingers (trident hand). Feet are generally short, broad and flat. Most individuals with achondroplasia eventually reach an adult height of about 4 feet (1, 2). How is achondroplasia diagnosed? At birth or during infancy, achondroplasia is generally diagnosed with x-rays and a physical examination. If there is any question about the diagnosis, genetic testing using a blood sample can be done to look for a mutation (change) in the gene that causes achondroplasia. Before birth, achondroplasia may be suspected in the fetus if an ultrasound shows shortened bones and other bone abnormalities. In such cases, the health care provider may recommend amniocentesis to confirm the diagnosis. How does achondroplasia affect development? Individuals with achondroplasia usually have normal intelligence and a normal life span (1). However, affected children have a number of medical complications that can affect their development. Babies with achondroplasia have poor muscle tone, often leading to delays in learning to sit, stand and walk. Before beginning to walk, a baby with achondroplasia often develops a small hump (kyphosis) on his upper back. This is due to poor muscle tone and usually goes away after the child starts walking. Babies with achondroplasia should not be placed in umbrella-type strollers or other carriers that do not provide good back support, because lack of support can contribute to development of a hump in the back. Once walking, the child usually develops a markedly curved lower spine (lordosis or sway-back), and the lower legs often become bowed. Children with achondroplasia have narrow passages in the nose that can contribute to ear infections and, without treatment, to hearing loss. Due to a small jaw, teeth may be crowded, and upper and lower teeth may be poorly aligned. Occasionally, a baby or young child with achondroplasia may die suddenly, often during sleep. This occurs in 2 to 5 percent of affected babies (2). These deaths can result from compression of the upper end of the spinal cord, which can interfere with breathing. The compression is caused by abnormalities in the size and structure of the opening in the base of the skull (foramen magnum) and vertebrae in the neck through which the spinal cord

descends. All babies and young children with achondroplasia should be evaluated for foramen magnum compression. Adolescents and adults with achondroplasia often develop low back pain or weakness, tingling and pain in the legs. This often is due to pressure on the spinal cord from a small spinal canal (called spinal stenosis). How is achondroplasia treated? Health care providers closely monitor the growth and development of children with achondroplasia. Though there is currently no way to normalize skeletal development of children with the disorder, most complications can be effectively treated. Infants and children with achondroplasia should be thoroughly evaluated for skeletal abnormalities by a doctor experienced with the disorder. The doctor follows the childs development using special charts of head and body growth for children with achondroplasia. If the head is becoming too large, the doctor tests the child for hydrocephalus. If necessary, a neurosurgeon inserts a shunt to drain the excess fluid and relieve pressure on the brain. The child also is monitored for signs of upper spinal cord compression (due to foramen magnum abnormalities), using imaging tests such as computed tomography (CT scan or CAT scan) or magnetic resonance imaging (MRI). Possible symptoms of spinal cord compression may include snoring, sleep apnea (episodes where the baby stops breathing while sleeping) and persistent low muscle tone. When necessary, surgery can widen the opening and relieve pressure on the spinal cord. Some children also may have breathing problems caused by small facial structures, large tonsils or a small chest size. Surgery to remove the tonsils and adenoids (lymph tissue near the throat) often improves these breathing problems. If kyphosis (small hump) does not go away after a child begins walking, a back brace may be used to correct it. Surgery can correct bowing of the legs, especially if the bowing becomes severe or causes pain. Children with achondroplasia often require placement of middle-ear drainage tubes. This helps to prevent hearing loss that can occur with frequent ear infections. Dental problems caused by overcrowding of teeth may require extra routine care and braces. Children with achondroplasia tend to put on extra weight, starting at an early age. Because excessive weight can further aggravate skeletal problems, affected children should receive nutritional guidance to help prevent obesity. Physical activity can help control weight. The American Academy of Pediatrics (AAP) recommends activities, such as swimming and biking (2). Children with achondroplasia should avoid gymnastics and collision sports because of the risk of spinal complications (2). Some medical centers are evaluating the use of human growth hormone to improve the growth of children with achondroplasia. To date, some children have achieved modest increases in growth after 1 to 2 years of treatment (1, 2). However, no study has demonstrated that this treatment significantly increases eventual adult height (1, 2). Leg-lengthening surgeries can increase the height of someone with achondroplasia by up to 12 to 14 inches (1, 3). This procedure is controversial because it requires a long duration of treatment (up to 2 years) and is associated with many complications. Little People of

America (LPA), an advocacy organization for individuals of short stature and their families, recommends postponing any decisions about this surgery until the young person is able to fully participate in decision making (4). What is the cause of achondroplasia? Achondroplasia is caused by a mutation in a gene (called fibroblast growth factor receptor 3) that is located on chromosome 4 (5, 6). This gene normally helps regulate the rate of growth in long bones. Mutations in this gene result in severely limited bone growth. In a small number of cases, a child inherits achondroplasia from a parent who also has the condition. If one parent has the condition and the other does not, there is a 50 percent chance that their child will be affected. If both parents have achondroplasia, there is: A 50 percent chance A 25 percent chance A 25 percent chance have severe skeletal that the child will inherit the condition that the child will not have it that the child will inherit one abnormal gene from each parent and abnormalities that lead to early death

When both parents have achondroplasia, providers generally offer them prenatal tests to diagnose or rule out the fatal form of the disease. A child who does not inherit the condition cannot pass it on to his or her own children. In more than 80 percent of cases, however, achondroplasia is not inherited but results from a new mutation that occurs in the egg or sperm cell that forms the embryo (1, 3). Parents of children with achondroplasia resulting from a new mutation usually are normal sized. Typically, these parents have no other children with achondroplasia, and the chances of their having a second affected child are extremely small. Geneticists have observed that older-than-average fathers (40 and older) are more likely to have children with achondroplasia and certain other autosomal-dominant conditions (disorders that occur when one gene in a gene pair is abnormal) caused by new mutations (1, 3). Individuals with achondroplasia resulting from new mutations transmit the disorder to their children as previously described. Can achondroplasia be prevented? There is no way to prevent most cases of achondroplasia because they result from totally unexpected gene mutations in unaffected parents. Genetic counseling can help adults with achondroplasia and unaffected individuals who have had an affected child make informed decisions about family planning. Does the March of Dimes support research on achondroplasia and other forms of disproportionate short stature? March of Dimes grantees are studying how abnormalities in the structure or function of the fibroblast growth factor receptor 3 gene may cause the features of achondroplasia. For example, one grantee is studying interactions between this gene and a cell-to-cell signaling pathway that plays a role in bone development. The goal of this research is to develop treatments for achondroplasia and other skeletal disorders caused by this gene. Other recent grantees have been working to identify the genes that cause some of the other more than 100 forms of disproportionate short stature (1).