Achondroplasia

Also known as: Achondroplastic dwarfism

Definition Achondroplasia is a genetic disorder that causes dwarfism (short stature). It is a disorder in which bone and cartilage do not grow normally. It is the most common cause of dwarfism.

This condition leads to patients attaining a full-grown height of less than four feet. The greatest shortening occurs in the humerus (the bone between the shoulder and the elbow) and the femur (the bone between the hip and the knee). There may also be underdevelopment of the face. Achondroplasia is the most common form of inherited disproportionate short stature. It occurs in 1 in 26,000 to 1 in 40,000 live births.

Risk Factors

Those at risk of inheriting achondroplasia are children of a parent with achondroplasia and children of normal-sized parents who carry a mutated FGFR3 gene. Advanced paternal age can cause spontaneous mutations.

Etiology and Genetics

Achondroplasia is inherited as an autosomal dominant disorder, meaning that a single copy of the mutation is sufficient to cause full expression of the syndrome. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. Most cases of achondroplasia, however, result from spontaneous new mutation, so in these instances affected individuals will have unaffected parents. Advanced paternal age has been identified as a contributing factor in many spontaneous cases, and researchers using mouse models are endeavoring to identify aspects of deoxyribonucleic acid (DNA)replication or repair during spermatogenesis that could result in a predisposition to this mutation.

Homozygous achondroplasia, in which both copies of the gene carry the mutation, is a severe disorder that is invariably fatal either before or shortly after birth. Rare reports of marriages in which both partners have achondroplasia confirm the prediction that in such families 50 percent of the children will have achondroplasia, 25 percent will be unaffected, and 25 percent will die from the severe homozygous form of the condition.

Either of two mutations at nucleotide 1138 of the FGFR3 gene, found on the short arm of chromosome 4 at position 4p16.3, will result in achondroplasia. The normal product of this gene, fibroblast growth factor receptor 3, is a protein that exerts negative regulatory control on bone growth during development. The mutant protein, which has the amino acidglycine substituted for an arginine residue at position 380, appears to be overly active, thus leading to the defects in skeletal development and decreased bone growth that are characteristic of this disorder. In fact, since the FGFR3 protein is concentrated in the cartilage and connective tissue as well as the bone, the ligaments, tendons, and muscles of patients with achondroplasia are also affected.

Symptoms

Patients with achondroplasia have short stature, a long trunk, and shortened limbs, which are noticeable at birth. Adults usually reach a height of between 42 and 56 inches. An individual’s head is large and his or her forehead is prominent, and portions of the face can be underdeveloped. At birth, the legs appear straight, but as a child begins to walk, he or she develops a knock-knee or bowed-leg deformity. The hands and the feet appear large, but the fingers and toes are short and stubby; straightening of the arm at the elbow may be restricted but usually does not keep a patient with achondroplasia from doing any specific activities. Children may develop an excessive curve of the lower back and a waddling walking pattern.

Other common symptoms include weight control problems; bowed legs; middle ear infections, especially in children, which, if not treated properly, can result in hearing loss; dental problems (from overcrowding of teeth); hydrocephalus (water on the brain); and neurologic and respiratory problems. Individuals also experience fatigue, pain, and numbness in the lower back and spine. Spinal compression may occur in the upper back or where the spinal cord exits from the skull in the back of the neck; compression at this latter site may cause sleep apnea or even death if not recognized and treated early. A magnetic resonance imaging (MRI) or a computed tomography (CT) scan evaluation can help detect these complications

Screening and Diagnosis

The diagnosis for achondroplasia includes clinical evaluation and radiographs. Molecular genetic testing can be used to detect a mutation in the FGFR3 gene; such testing is 99 percent sensitive and is performed in clinical laboratories. A doctor can usually diagnose the disorder in a newborn by observing physical symptoms. To confirm that dwarfism is caused by achondroplasia, X-rays are taken.

It is important that patients follow their doctors’ advice to make sure that spinal stenosis does not develop. The physician can evaluate the strength of a patient’s extremities and bladder control. Weakness and loss of bladder control are both signs of developing spinal stenosis.

Treatment and Therapy

Unfortunately there is currently no treatment that can cure this condition. Because it is now known that achondroplasia is caused by an absence of growth factor receptor, scientists are exploring ways to create alternate growth factors that can bypass the missing receptor and lead to normal bone growth. Such treatments are still well in the future but may offer the possibility of enhanced stature to future families who have children with achondroplasia.

Treatment with human growth hormone has been used for more than a decade and effectively increases bone growth rate, at least in the first year of life. There have been few studies looking at whether children treated with growth hormone achieve greater (or normal) adult heights.

Surgery is sometimes needed to correct specific skeletal deformities. Spinal fusion is a surgery to permanently connect otherwise separate vertebrae. This surgery is performed for patients with significant spinal kyphosis.

Laminectomy is a surgical procedure to open the spinal canal to relieve pressure on the compressed spinal cord from spinal stenosis. Spinal stenosis, a narrowing of the spinal canal, is the most serious complication of achondroplasia.

In an osteotomy, the bones of the leg are cut and allowed to heal in the correct anatomical position. This procedure is used for patients with severe knock-knees or bowed legs.

While osteotomy has primarily been used to correct deformities, in recent years bone-lengthening procedures have been used for many short children, including those with achondroplasia. The procedures are lengthy, traumatic, and very demanding for both children and their families. Complications, sometimes serious, are common. One center has reported an average leg length (height) gain of about seven inches and an average increase in arm length of about four inches for achondroplastic individuals who undergo surgery. The combination of growth hormone therapy followed by lengthening surgery may provide benefit in achieving near-normal stature and proportions.

Prevention and Outcomes

Because achondroplasia is an inherited disorder, there are no preventive measures. The prognosis depends on the severity of the condition. Patients who have two copies of the deficient gene (one from each parent, also known as homozygous) generally die a few weeks to months after birth. Those with one copy (from only one parent, also known as heterozygous) have a normal life span and intelligence, although children often take longer to develop normal motor skills and there is an increased risk of death in the first year of life due to respiratory problems. Patients are usually independent in their daily life activities. Many of these patients, in fact, have gone on to do great things in life.

Bibliography

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