Pseudoachondroplasia

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Pseudoachondroplasia

Definition

Pseudoachondroplasia is moderately severe skeletal dysplasia characterized by disproportionate short stature, hypermobile joints, normal head size, and normal length and appearance at birth. Individuals with this condition are usually not diagnosed until early childhood. Complications of this disorder include early-onset arthritis of the weight-bearing joints and other orthopedic complications. This genetic disorder has autosomal dominant inheritance .

Description

Pseudoachondroplasia is a rare genetic skeletal dysplasia first described by Drs. Maroteaux and Lamy in 1959. It is sometimes also referred to as pseudoachondroplastic dysplasia and pseudoachondroplastic spondyloepiphyseal dysplasia and is one of more than 200 rare skeletal dysplasias. Skeletal dysplasias are a group of disorders that result from problems in bone growth and formation. The term dwarfism is losing favor to the more technical term of skeletal dysplasia. There are many causes of growth problems, including hormone imbalances, metabolic problems, and problems with bone growth.

Pseudoachondroplasia is one of the most common skeletal dysplasias. Individuals with pseudoachondroplasia have normal growth parameters (height and weight) at birth, and it usually is not until the second year of life that growth retardation becomes evident. During this phase, their body proportions resemble those of individuals with achondroplasia—the most common form of skeletal dysplasia. Because of this resemblance, this type is skeletal dysplasia was termed "pseudo" achondroplasia .

As the name implies, pseudoachondroplasia was once thought to be closely related to achondroplasia. However, geneticists have since learned otherwise. In appearance, individuals with pseudoachondroplasia share the same height as those with achondroplasia, but their head size is the same as that of average-size people, and they lack the distinct facial features characteristic of achondroplasia. Children with pseudoachondroplasia are usually not diagnosed until they are two or three years old when their growth parameters become abnormal. The most serious complications of pseudoachondroplasia are short stature, orthopedic problems, and early-onset osteoarthritis of the weight-bearing joints. Many individuals with pseudoachondroplasia experience significant joint pain, and undergo multiple orthopedic surgeries and joint replacements.

Pseudoachondroplasia is easily recognizable. Individuals with pseudoachondroplasia have disproportionate short stature, normal size head, normal facial features, joint laxity, and disproportionate shortening of their limbs. Most individuals with pseudoachondroplasia have a normal IQ. The early motor development of infants with pseudoachondroplasia is normal until the advent of walking when a waddling gait is often noted. Individuals with pseudoachondroplasia can have medical complications that range from mild to severe. Because of the differences in their bone structure and their joints, they are at increased risk to develop osteoarthritis at an early age (sometimes in their teens and usually by their twenties). They also have a small risk for neurologic problems caused by spinal cord compression due to abnormal vertebra and joint laxity.

The short stature of pseudoachondroplasia can be socially isolating and physically challenging. Most public places are not adapted to individuals of short stature, and this can limit their activities. Children and adults with pseudoachondroplasia can be socially ostracized due to their physical appearance. Many individuals erroneously assume that people with pseudoachondroplasia have limited abilities.

Genetic profile

Pseudoachondroplasia is caused by a mutation, or change, in the cartilage oligomeric matrix protein 3 gene (COMP) that is located on the short arm of chromosome 19 (19p13.1)

Genes contain the instructions that tell a body how to form. They are composed of four different chemical bases: adenine (A), thymine (T), cytosine (C), and guanine (G). When these bases are arranged in a specific order, they provide the instructions that a cell needs to form a protein. Every three bases codes for one amino acid. Amino acids are the building blocks of proteins.

The COMP (cartilage oligomeric matrix protein) gene provides the instruction for the formation of a particular protein that is made by cartilage cells and is then transported into the cellular matrix surrounding these cells. Cartilage plays a very important role in bone formation. Because of abnormalities in the formation of this protein, the protein cannot be transported out of the cell. This results in a deficiency of the protein in the cartilage matrix and a buildup of the protein within the cartilage cells. This leads to the development of pseudoachondroplasia. Because cartilage plays a role in the normal growth and development of bones, any problems with cartilage will lead to problems with bone growth.

Pseudoachondroplasia is caused by mutations in the COMP gene. One specific mutation accounts for approximately 30% of the cases of pseudoachondroplasia. The COMP gene is comprised of 757 amino acids. In a normal (non-mutated) gene, amino acid 372 codes for aspartic acid. In most individuals with pseudoachondroplasia, this amino acid has been deleted. Other mutations have been detected in the COMP gene, most of which are small substitutions or deletions of base pairs.

Mutations in the COMP gene are inherited in an autosomal dominant manner. Every individual has two COMP genes: one from their father and one from their mother. In an autosomal dominant disorder, only one gene has to have a mutation for the person to have the disorder. Most individuals with pseudoachondroplasia are born to parents with average stature. Their pseudoachondroplasia is the result of a de novo, or new, mutation. No one knows the cause of de novo mutations or why they occur so frequently in pseudoachondroplasia. However, once a couple has had a child with pseudoachondroplasia, there is a 4% recurrence risk to have a second similarly affected child. This increased recurrence risk is due to germline mosaicism, or the chance that the de novo mutation is present in others of their sperm and egg cells.

An individual with pseudoachondroplasia has a 50% chance of passing on their mutated gene to their children. Often individuals with short stature will marry other individuals with short stature. If the partner of a person with pseudoachondroplasia also has an autosomal dominant inherited skeletal dysplasia, then there is a 25% chance that they will have a child with average stature, a 25% chance that they will have a child with one pseudoachondroplasia gene (a heterozygote), a 25% chance that their child will have the other autosomal dominant skeletal dysplasia (a heterozygote), and a 25% chance that a child will get a double dose of the gene for pseudoachondroplasia and the gene for the other skeletal dysplasia (a double heterozygote). Babies with two skeletal dysplasias (double dose) can be much more severely affected than babies with a single pseudoachondroplasia gene. Couples with skeletal dysplasias should seek genetic counseling to understand their exact risks before undertaking a pregnancy.

Demographics

The exact prevalence of pseudoachondroplasia is unknown, but it is estimated to occur in about one in 30,000 individuals. Pseudoachondroplasia affects males and females in equal numbers. Most individuals with pseudoachondroplasia are born to parents with average stature. This is due to a new mutation that occurs on the COMP gene of the child with pseudoachondroplasia.

Signs and symptoms

Individuals with pseudoachondroplasia have disproportionate short stature, normal-sized heads, limb differences, and rhizomelic shortening of their limbs; rhizomelic means "root limb." Rhizomelic shortening of the limbs means that those segments of a limb closest to the body (the root of the limb) are more severely affected. In individuals with pseudoachondroplasia, the upper arms are shorter than the forearms, and the upper leg (thigh) is shorter than the lower leg.

In addition to shortened limbs, individuals with pseudoachondroplasia have other characteristic limb differences. They have a limited ability to rotate and extend their elbows. They also have joint laxity, particularly of the hands, ankles, and knees. Because of this joint laxity, they can be bowed legged or knock kneed and may have in-turned toes. Their hands and feet are short and broad, as are their fingers and toes. Their fingers and other joints are hyperextensible, or very flexible.

In addition to limb differences, individuals with pseudoachondroplasia have other characteristic skeletal differences. Because of malformed vertebra and lax ligaments, individuals with pseudoachondroplasia can have spinal problems, including kyphosis (hunchback), lordosis (swayback), and scoliosis .

Individuals with pseudoachondroplasia have normal facial features and a normal-sized head. This is one of the major features that differentiate pseudoachondroplasia from achondroplasia. Individuals with pseudoachondroplasia have shortening of their long bones. The average adult height of individuals with pseudoachondroplasia ranges from 32–52 in (80–130 cm).

Diagnosis

Pseudoachondroplasia is diagnosed by a combination of physical exam, x rays, and molecular testing. The characteristic findings of short stature and rhizomelic shortening of the limbs become apparent around two years of age and become more pronounced over time. In addition to being diagnosed by physical examination, individuals with pseudoachondroplasia have some specific bone changes that can be seen on an x ray. A DNA blood test to look for mutations in the COMP gene may also help clarify the diagnosis.

Unlike other skeletal dysplasias, pseudoachondroplasia cannot be diagnosed by a prenatal ultrasound or sonogram because the characteristic changes in the bones and the growth delays do not appear until the child is two years of age.

The diagnosis of pseudoachondroplasia can be made prenatally by DNA testing if the mutation for that family has been characterized. A sample of tissue from a fetus is obtained by either chorionic villi sampling (CVS) or by amniocentesis . Chorionic villi sampling is generally done between 10 and 12 weeks of pregnancy, and amniocentesis is done between 14 and 18 weeks of pregnancy. Chorionic villi sampling involves removing a small amount of tissue from the developing placenta. The tissue in the placenta contains the same DNA as the fetus. Amniocentesis involves removing a small amount of fluid from around the fetus. This fluid contains some fetal skin cells from which DNA can be isolated. The fetal DNA is then tested to determine if it contains the mutation that is responsible for pseudoachondroplasia in that family.

Prenatal DNA testing for pseudoachondroplasia is not routinely performed in low-risk pregnancies. This type of testing is generally limited to high-risk pregnancies, such as those in which both parents have pseudoachondroplasia or one in which one parent has pseudoachondroplasia and the other parent has another autosomal dominant form of skeletal dysplasia. It is particularly helpful in determining if a fetus has received two dominant skeletal mutations. Infants who have inherited two autosomal dominant skeletal dysplasias may have very severe complications that may result in death.

DNA testing can also be performed on blood samples from children or adults. This is usually done as part of a genetic work-up to establish the exact form of skeletal dysplasia. Many skeletal dysplasias can be hard to differentiate from one another, and DNA testing can often clarify the diagnosis.

Treatment and management

There is no cure for pseudoachondroplasia. All children with pseudoachondroplasia should have their height, weight, and head circumference measured and plotted on growth curves specifically developed for children with pseudoachondroplasia. The most common medical complication is early-onset osteoarthritis and other orthopedic problems. Some patients experience significant pain that can be controlled by analgesics, although the effectiveness of various forms of analgesics has not been thoroughly studied in pseudoachondroplasia. Early-onset osteoarthritis is caused by malformations of the weight-bearing joints and deficient cartilage production. Approximately 50% of patients with pseudoachondroplasia will require hip replacements. By being aware of the potential medical complications and by taking some preventative measures, it may be possible to avoid or delay the onset of some of the long-term consequences of these complications.

Weight management is extremely important for an individual with pseudoachondroplasia. Excess weight can exacerbate many of the potential orthopedic problems, such as bowed legs, curvature of the spine, and joint and lower back pain. Excess weight can also contribute to sleep apnea problems. Development of good eating habits and appropriate exercise programs should be encouraged in individuals with pseudoachondroplasia. However, because of the potential for spinal cord compression, care should be used in choosing appropriate forms of exercise.

The social adaptation of children with pseudoachondroplasia and their families should be closely monitored. Children with visible physical differences can have difficulties in school and socially. Support groups such as Little People of America can be a source of guidance on how to deal with these issues. It is important that children with pseudoachondroplasia not be limited in activities that pose no danger. In addition to monitoring their social adaptation, every effort should be made to physically adapt their surroundings for convenience and to improve independence. Physical adaptations can include step stools to increase accessibility and lowering of light switches and counters.

The two treatments that have been used to try to increase the final adult height of individuals with pseudoachondroplasia are limb-lengthening and growth hormone therapy.

Limb-lengthening involves surgically attaching external rods to the long bones in the arms and legs. These rods run parallel to the bone on the outside of the body. Over a period of 18–24 months, the tension on these rods is increased, which results in the lengthening of the underlying bone. This procedure is long, costly, and has potential complications, including pain, infections, and nerve problems. Limb-lengthening can increase overall height by 12–14 in (30.5–35.6 cm)in some skeletal dysplasias. It does not change the other physical manifestations of pseudoachondroplasia, such as the appearance of the hands and feet. This is an elective surgery, and individuals must decide for themselves if it would be of benefit to them. The optimal age to perform this surgery is not known.

Growth hormone therapy has been used to treat some children with pseudoachondroplasia. Originally, there was doubt about the effectiveness of this treatment because children with pseudoachondroplasia are not growth-hormone deficient. This doubt has proven to be justified. While this treatment seems to have some success for individuals with other forms of skeletal dysplasia, at least one study has found that it actually decreases the height of children with pseudoachondroplasia. As of 2005, growth hormone therapy is not recommended for pseudoachondroplasia.

Prognosis

The prognosis for most people with pseudoachondroplasia is very good. In general, they have minimal medical problems, normal IQ, and most achieve success and have a long life, regardless of their stature. The most serious medical barriers to an excellent prognosis are the orthopedic complications and early-onset arthritis that can limit the activities of an individual and cause significant pain. Most individuals with pseudoachondroplasia will have multiple orthopedic surgeries over their lifetime.

Successful social adaptation plays an important role in the ultimate success and happiness of an individual with pseudoachondroplasia. It is very important that the career and life choices of an individual with pseudoachondroplasia not be limited by preconceived ideas about their abilities.

Resources

BOOKS

Ablon, Joan. Living with Difference: Families with Dwarf Children. Westport, CT: Praeger Publishing, 1988.

PERIODICALS

American Academy of Pediatrics Committee on Genetics. "Health Supervision for Children with Pseudo-achondroplasia." Pediatrics 95, no 3 (March 1995): 443–451.