Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a group of genetic diseases of collagen in which the bones are formed improperly, making them fragile and prone to breaking.

Description

Collagen is a fibrous protein material. It serves as the structural foundation of skin, bone, cartilage, and ligaments. In osteogenesis imperfecta, the collagen produced is abnormal and disorganized. This results in a number of abnormalities throughout the body, the most notable being fragile, easily broken bones.

There are four forms of OI, Types I through IV. Of these, Type II is the most severe, and is usually fatal within a short time after birth. Types I, III, and IV have some overlapping and some distinctive symptoms, particularly weak bones.

Evidence suggests that OI results from abnormalities in the collagen gene COL1A1 or COL1A2, and possibly abnormalities in other genes. In OI Type I, II, and III, the gene map locus is 17q21.31-q22, 7q22.1, and in OI Type IV, the gene map locus is 17q21.31-q22.

In OI, the genetic abnormality causes one of two things to occur. It may direct cells to make an altered collagen protein and the presence of this altered collagen causes OI Type II, III, or IV. Alternately, the dominant altered gene may fail to direct cells to make any collagen protein. Although some collagen is produced by instructions from the normal gene, an overall decrease in the total amount of collagen produced results in OI Type I.

A child with only one parent who is a carrier of a single altered copy of the gene has no chance of actually having the disease, but a 50% chance of being a carrier.

If both parents have OI caused by an autosomal dominant gene change, there is a 75% chance that the child will inherit one or both OI genes. In other words, there is a 25% chance the child will inherit only the mother's OI gene (and the father's unaffected gene), a 25% chance the child will inherit only the father's OI gene (and the mother's unaffected gene), and a 25% chance the child will inherit both parents' OI genes. Because this situation has been uncommon, the outcome of a child inheriting two OI genes is hard to predict. It is likely that the child would have a severe, possibly lethal, form of the disorder.

About 25% of children with OI are born into a family with no history of the disorder. This occurs when the gene spontaneously mutates in either the sperm or the egg before the child's conception. No triggers for this type of mutation are known. This is called a new dominant mutation. The child has a 50% chance of passing the disorder on to his or her children. In most cases, when a family with no history of OI has a child with OI, they are not at greater risk than the general population for having a second child with OI, and unaffected siblings of a person with OI are at no greater risk of having children with OI than the general population.

In studies of families into which infants with OI Type II were born, most of the babies had a new dominant mutation in a collagen gene. In some of these families, however, more than one infant was born with OI. Previously, researchers had seen this recurrence as evidence of recessive inheritance of this form of OI. More recently, however, researchers have concluded that the rare recurrence of OI to a couple with a child with autosomal dominant OI is more likely due to gonadal mosaicism. Instead of mutation occurring in an individual sperm or egg, it occurs in a percentage of the cells that give rise to a parent's multiple sperm or eggs. This mutation, present in a percentage of his or her reproductive cells, can result in more than one affected child without affecting the parent with the disorder. An estimated 2%–4% of families into which an infant with OI Type II is born are at risk of having another affected child because of gonadal mosaicism.

Demographics

OI affects equal numbers of males and females. It occurs in about one of every 20,000 births.

Causes and symptoms

OI is usually inherited as an autosomal dominant condition. In autosomal dominant inheritance, a single abnormal gene on one of the autosomal chromosomes (one of the first 22 "non-sex" chromosomes) from either parent can cause the disease. One of the parents will have the disease (since it is dominant) and is the carrier. Only one parent needs to be a carrier in order for the child to inherit the disease. A child who has one parent with the disease has a 50% chance of also having the disease.

Type I

This is the most common and mildest type. Among the common features of Type I are the following:

• bones are predisposed to fracture, with most fractures occurring before puberty, people with OI type I typically have about 20–40 fractures before puberty
• stature is normal or near-normal
• joints are loose and muscle tone is low
• usually sclera (whites of the eyes) have blue, purple, or gray tint
• face shape is triangular
• tendency toward scoliosis (a curvature of the spine)
• bone deformity is absent or minimal
• dentinogenesis imperfecta may occur, causing brittle teeth
• hearing loss is a possible symptom, often beginning in early 20s or 30s
• structure of collagen is normal, but the amount is less than normal

Type II

Sometimes called the lethal form, Type II is the most severe form of OI. Among the common features of Type II are the following:

• frequently, OI Type II is lethal at or shortly after birth, often as a result of respiratory problems
• fractures are numerous and bone deformity is severe
• stature is small with underdeveloped lungs
• collagen is formed improperly

Type III

Among the common features of Type III are the following:

• bones fracture easily (fractures are often present at birth, and x rays may reveal healed fractures that occurred before birth; people with OI Type III may have more than 100 fractures before puberty)
• stature is significantly shorter than normal
• sclera (whites of the eyes) have blue, purple, or gray tint
• joints are loose and muscle development is poor in arms and legs
• rib cage is barrel-shaped
• face shape is triangular
• scoliosis (a curvature of the spine) is present
• respiratory problems are possible
• bones are deformed and deformity is often severe
• dentinogenesis imperfecta may occur, causing brittle teeth
• hearing loss is possible
• collagen is formed improperly

Type IV

OI Type IV falls between Type I and Type III in severity. Among the common features of Type IV are the following:

• bones fracture easily, with most fractures occurring before puberty
• stature is shorter than average
• sclera (whites of the eyes) are normal in color, appearing white or near-white
• bone deformity is mild to moderate
• scoliosis (curvature of the spine) is likely
• rib cage is barrel-shaped
• face is triangular in shape
• dentinogenesis imperfecta may occur, causing brittle teeth
• hearing loss is possible
• collagen is formed improperly

Diagnosis

It is often possible to diagnose OI solely on clinical features and x-ray findings. Collagen or DNA tests may help confirm a diagnosis of OI. These tests generally require several weeks before results are known. Approximately 10–15% of individuals with mild OI who have collagen testing, and approximately 5% of those who have genetic testing, test negative for OI despite having the disorder.

Diagnosis is usually suspected when a baby has bone fractures after having suffered no apparent injury. Another indication is small, irregular, isolated bones in the sutures between the bones of the skull (wormian bones). Sometimes the bluish sclera serves as a diagnostic clue. Unfortunately, because of the unusual nature of the fractures occurring in a baby who cannot yet move, some parents have been accused of child abuse before the actual diagnosis of osteogenesis imperfecta was reached.

Prenatal diagnosis

Testing is available to assist in prenatal diagnosis. Women with OI who become pregnant, or women who conceive a child with a man who has OI, may wish to explore prenatal diagnosis. Because of the relatively small risk (2–4%) of recurrence of OI Type II in a family, families may opt for ultrasound studies to determine if a developing fetus has the disorder.

Ultrasound is the least invasive procedure for prenatal diagnosis, and carries the least risk. Using ultrasound, a doctor can examine the fetus's skeleton for bowing of the leg or arm bones, fractures, shortening, or other bone abnormalities that may indicate OI. Different forms of OI may be detected by ultrasound in the second trimester. The reality is that when it occurs as a new dominant mutation, it is found inadvertantly on ultrasound, and it may be difficult to know the diagnosis until after delivery since other genetic conditions can cause bowing and/or fractures prenatally.

Chorionic villus sampling is a procedure to obtain chorionic villi tissue for testing. Examination of fetal collagen proteins in the tissue can reveal information about the quantitative or qualitative collagen defects that leads to OI. When a parent has OI, it is necessary for the affected parent to have the results of his or her own collagen test available. Chorionic villus sampling can be performed at 10–12 weeks of pregnancy.

Amniocentesis is a procedure that involves inserting a thin needle into the uterus, into the amniotic sac, and withdrawing a small amount of amniotic fluid. DNA can be extracted from the fetal cells contained in the amniotic fluid and tested for the specific mutation known to cause OI in that family. This technique is useful only when the mutation causing OI in a particular family has been identified through previous genetic testing of affected family members, including previous pregnancies involving a baby with OI. Amniocentesis is performed at 16–18 weeks of pregnancy.

Treatment

There are no treatments available to cure OI, nor to prevent most of its complications. Most treatments are aimed at treating the fractures and bone deformities caused by OI. Splints, casts, braces, and rods are all used. Rodding refers to a surgical procedure in which a metal rod is implanted within a bone (usually the long bones of the thigh and leg). This is done when bowing or repeated fractures of these bones has interfered with a child's ability to begin to walk.

Other treatments include hearing aids and early capping of teeth. Patients may require the use of a walker or wheelchair. Pain may be treated with a variety of medications. Exercise is encouraged as a means to promote muscle and bone strength. Swimming is a form of exercise that puts a minimal amount of strain on muscles, joints, and bones. Walking is encouraged for those who are able.

Smoking, excessive alcohol and caffeine consumption, and steroid medications may deplete bone and exacerbate bone fragility.

Alternative treatment such as acupuncture, naturopathic therapies, hypnosis, relaxation training, visual imagery, and biofeedback have all been used to try to decrease the constant pain of fractures.

Prognosis

Lifespan for people with OI Type I, III, and IV is not generally shortened. The prognosis for people with these types of OI is quite variable, depending on the severity of the disorder and the number and severity of the fractures and bony deformities.

Fifty percent of all babies with OI Type II are still-born. The rest of these babies usually die within a very short time after birth. In recent years, some people with Type II have lived into young adulthood.