Osteogenesis imperfecta is the most common heritable disorder of bone and occurs in all races. In Western Europe and North America it has an incidence of about 1 in 20,000. It is not a single disease but a group of disorders all of which are currently thought to be caused by defects of collagen 1. In recent years increasing numbers of abnormalities of collagen or of the DNA coding for collagen have been identified, particularly in patients with more severe variants.
The disorder may be inherited as an auotsomal recessive (generally severe cases) or in autosomal dominant manner (generally a milder disease). In this second group the disorder may arise from the beginning as a result of a new mutation. Fractures may occur with apparently minor or even unrecognized force and, when radiographs are carried out for other reasons, unrecognized fractures in various stages of healing may be found. Conversely, patients unexpectedly do not fracture with every injury. The fracture rate can vary greatly from time to time.
Some cases of the milder variants would not be recognized at all but for the presence of an unequivocal family history. One characteristic feature of OI and similar bone diseases is that fractures may occur with little or no trauma and fractures may well not be accompanied by the physical signs of bruising, swelling or contusions that would otherwise be expected. Generally bruises are much more common than fractures in genuine cases of non-accidental injury. In OI however, although bruising is a feature of the disorder, there may be paradoxically be little bruising at the site of the trauma.
The extent to which bruising is not associated with fractures may provide evidence for some form of brittle bone disease but caution is needed for several reasons. The type of fracture needs to be considered. Bruising and extensive contusion would be expected from the trauma that causes a transverse fracture of the shaft of a normal long bone but may not be seen in some fractures occurring with limited trauma such as greenstick fractures of the distal radius and ulna.
Appreciable bruising would be expected with trauma sufficient to cause a skull fracture unless the bone is abnormal. For the lack of bruising to be helpful diagnostically, it is important to have evidence that the fracture was recent at the time othe child was seen or that the child was seen by a reliable independent observers at appropriate times. Local evidence of injury may not be seen if the applied force was remote, for example, with torsion injury.
The presence or absence of other physical signs of OI needs to be assessed with some caution. Blue or grey scleras are present two-thirds of all patients with OI but mild variants of the disease with normal sclera are well recognized. Overt dentinogenesis imperfecta is seen in about half of patients with OI. Increased joint flexibility may be evident, enlargement or delayed closure of the anterior fontanel may suggest osteogenesis imperfecta or other bone diseases. An increased head circumference may be helpful. All these signs should be sought but there are patients, undoubtedly affected on the basis of family history, who have none of these physical signs.
Since the disorder reflects abnormalities of collagen formation it is not surprising that bone may appear normal radiologically, particularly at the time of the first fracture. The classical radiological abnormalities described in textbooks reflect the effects of the fractures and their immobilization rather than the fundamental disorder. Even in adults normal figures for cortical thickness and bone density may be found. The presence of excessive numbers of wormian bones may be a helpful diagnostic pointer but their absence does not include OI.
Doctors have created a classification system of the different types of OI, consisting of eight Types, so that one may know the potential symptoms as well as the severity of the type of the disease that they may have. Characteristic features of OI may vary greatly from person to person even though they may have the same type and not all characteristics are present in each person. In most cases, Types I, II, III, and IV, OI is caused by a dominant mutation of the type I collagen gene. Types VII and VIII have been recently identified to be inherited in a recessive manner. In Types V and VI the causing gene has not been identified however they are not caused by a type I collagen mutation.
The eight different classifications of osteogenisis imperfecta and the different types are used to describe how OI affects the person diagnosed. Type I is the most common and mildest type of OI and most people can lead a normal life. Type I OI may include symptoms such as bones that fracture easily, loose joints and muscle weakness, normal or near normal stature, triangular face, possible brittle teeth, hearing loss that may begin in patients early 20's or 30's, sclera usually have a blue, purple or gray tint, and tendency toward spinal curvature. The collagen structure may be normal however the amount of collagen is less than normal. Usually fractures that occur will occur before puberty.
Type II is the most severe form and usually leads to death within the first year of life. Death is usually due to respiratory problems. Symptoms of Type II OI include collagen that has improperly formed, severe bone deformities, numerous fractures that happened in the womb, during the birthing process or after giving birth, small stature with underdeveloped lungs, as well as tinted sclera. Type II osteogenisis imprefecta usually results from a new gene mutation.
Type III is also labeled severe because of the bone deformities that leave many people wheelchair bound and have a somewhat shortened lifespan. Type III is usually an isolated family incident and has very similar symptoms to Type I. These symptoms may include bones that fracture easily, barrel shaped rib cage, spinal curvature, bone deformity that is often severe, brittle teeth, triangular face, loose joints and poor muscle development, possible hearing loss, short stature, respiratory problems may be possible, and sclera that have a blue purple or gray tint. In Type III patients the collagen structure is improperly formed.
Type IV, moderately severe, is similar to Type I however persons with Type IV often rely on crutches or braces to walk. Type IV patients may or may not have symptoms such as bones that fracture easily, possible spinal curvature, barrel shaped rib cage, brittle teeth, hearing loss possible, shorter than average stature, mild to moderate bone deformity, triangular face, and sclera that may be white or near white in color. Types V, VI, VII, and VIII are all considered subtypes of Type IV and do not occur often.
Diagnosis for Osteogenesis imperfecta is primarily a clinical process. Because of this testing is usually done in conjunction with a clinical exam and a complete medical history conducted by a geneticist or an OI expert. Because there are different types of OI and differing degrees of severity, it cannot always be diagnosed at birth or during early infancy. Over 800 different mutations have been identified so far as causes for OI. Gathering information about mutations is an important avenue for learning not only about causes, but also for identifying potential cures. A mutation database is maintained by the OI Database Consortium. Ideally all mutations, regardless of which lab identifies them will be reported to the database. Consumers are urged to request that the testing results be reported to the mutation database.
The OI Foundation believes that genetic counseling should always be part of the process when genetic testing for OI is done. Testing reports are often complex and results are not always clear. Counseling can come from either the laboratory that is doing the testing, or from a geneticist or genetic counselor who is familiar with OI. Families need to understand how the tests are done, what the results mean, what the tests do not indicate and what this may mean for their future.
There are a few tests that are available at this time and here are a few. All of these tests can miss a small percentage of unusual mutations, but should detect the most common types of collagen mutations causing OI.
Collagen Biochemical Test. This test, sometimes referred to as a "skin biopsy," examines collagen proteins made by skin cells (fibroblasts) and requires a dermal punch biopsy sample (a small circle of skin, usually removed after application of a topical anesthetic.)
Collagen Molecular Testing. This type of test sometimes referred to as "DNA analysis" looks directly for the mutation in collagen by sequencing at the gene level. It requires either a blood sample or a skin sample.
Testing for Recessive OI. These tests look for defects in the genes controlling CRTAP or P3H1 and require a skin biopsy.
Prenatal Testing/Diagnosis. Undergoing prenatal diagnosis does not obligate parents to elect pregnancy termination, and the information obtained may be useful in managing pregnancy and delivery.
o Ultrasound identifies the more severe forms of OI such as Type II or Type III. Even with experience it can be difficult to identify the type before birth.
o Chorionic villous sampling (CVS) examines placental cells. It is used to test for recurrence of OI in a family with an identified mutation.
o Amniocentesis examines fetal cells shed into the amniotic fluid. It is used to test for recurrence of OI in a family with an identified mutation.
Generally osteogenisis imperfecta can be diagnosed after a thorough physical examination and a family's medical history. However it is usually difficult for a physician who is unfamiliar with the disorder to diagnose it properly. It is not always possible to diagnose OI by a physical exam alone. Radiographs may be taken or prenatal ultrasounds may be performed to diagnose OI at an early age. It may even be necessary to perform biochemical or molecular testing to ensure the correct diagnosis.
There is currently no cure for OI. There are however opportunities to manage the disease. These opportunities include exercise and many patients commonly choose water therapy or swimming because of the low amount of stress the activity places on the bones. Many patients benefit from keeping their weight healthy and eating a nutritious diet as well as staying away from smoking, alcohol, caffeine and steroidal medications where, each of these may make bones more fragile. Another consideration many patients benefit from is "rodding." Rodding consists of surgically inserting metal rods or nails into the long bones to strengthen and/or correct certain deformities that may occur. Depending on the case, patients also have several medications that may help treat or even prevent osteogenisis imperfecta. These medications include growth hormones called bisphosphonates as well as gene therapies.
Although radiology does not play a role in treatment for osteogenisis imprefecta, it does play an important role in diagnosing OI. In most cases patients are diagnosed by many fractures that are seen in radiographs. Radiographs can help determine the type as well as the severity of the disease. These radiographs should include, but are not limited to, views of the skull, chest, long bones, pelvis and thoracolumbar spine. Milder cases of osteogenisis imperfecta show thin, overtubulated bones with thinner outer layers of the bones and fewer fractures. The shorter bones are also affected but not nearly as much as the long bones. In more severe cases of OI, such as Type II and Type III, you could potentially see shortened long bones with multiple fractures that can be complicated by hyperplasic callus formations. Generally the callus is found around the femur and is usually a large dense irregular mass seen in the cortex of the bone.
There are many forms of complications that arise from OI but they are largely based on the type of OI present. They are directly related to the problems with weak bones and multiple fractures. Some of the complications may include hearing loss they are mostly common in type I and type III. Type II OI complications include heart failure, respiratory problems and pneumonias due to chest wall deformities, spinal cord or brain stem problems and permanent deformities.
Genes are the structures which pass biological information on from a parent to a child. The information contained in genes organizes the development of all the cells and tissues throughout the body. A person receives one set of genes from each parent. Because osteogenesis imperfecta is a genetic disorder, the gene which causes it can be passed on from an affected individual to his or her offspring. In dominant forms of OI, a person needs to have only one defective gene to actually develop the disorder. In recessive forms of OI, a person needs to have two defective genes, one from each parent, to develop the disorder. Sometimes OI cannot be traced back to a parent with the disorder. In these cases, the genetic defect is said to be a spontaneous mutation. This means that some unknown event has caused a gene (which functions normally in the parent) to develop a permanent defect. A person who has OI due to a spontaneous mutation can then pass on this defective gene to his or her future offspring.
Severe forms are usually diagnosed early in life but mild cases may not be noted until later in life. An appointment with your health care provider needs to be made early if you or your children have symptoms of this condition. Although it is not treatable it can be somewhat controlled. This condition effects approximately 6 to 7 per 100,000 people worldwide, but the more common types are found in 4 to 5 per 100,000 people.
There is no known way to prevent OI, although adults with OI should be carefully counseled regarding the chance of their offspring being born with the disease. In the dominant form of OI, a child who has one parent with the disease has a 50% chance of also having the disease. In the recessive form of OI, a child who has two parents with the disease has a 25% chance of having the disease, a 25% chance of being completely unaffected, and a 50% chance of being a carrier. A carrier is someone who does not have the disease itself, but "carries" the defective gene, and thus can pass it on to future offspring. A child who has only one parent with the recessive form of OI has no chance of actually having the disease, but a 50% chance of being a carrier.
The prognosis for a person with OI varies greatly depending on the number and severity of symptoms. Life expectancy is not affected in people with mild or moderate symptoms. Life expectancy may be shortened for those with more severe symptoms. The most severe forms result in death at birth or during infancy. Respiratory failure is the most frequent cause of death for people with OI, followed by accidental trauma. Despite the challenges of managing OI, most adults and children who have OI lead productive and successful lives. They attend school, develop friendships and other relationships, have careers, raise families, participate in sports and other recreational activities and are active members of their communities.
