What is osteogenesis imperfecta?
Osteogenesis imperfecta, abbreviated as OI, is a genetic disorder that appears in childhood and is characterized by abnormally fragile bones, which leads to an excessive number of fractures and other musculoskeletal problems. A number of different genetic mutations are responsible for the development of OI, and all of the genes affected play some role in coding for the production of Type I collagen, a structural protein that is essential for the normal strength and stability of bone tissue, as well as other critical tissues. These include ligaments (the fibrous bands that attach bones to other bones in the areas of joints), skin, dentin (a major component in the structure of teeth), and sclerae (the white areas of the eyes).
Because the mutation or mutations that cause the disease are so variable, or heterogeneous, OI may affect children in very different ways, from mild, asymptomatic osteopenia, a state of calcium deficiency more commonly seen in elderly adults without OI, to a severe form marked by severe fractures and death around the time of birth. The common clinical manifestations of OI include the following:
- Fractures – may occur in virtually any bone in the body, but most commonly affect long bones, such as the femur (thighbone), tibia (shinbone), humerus (upper arm), radius and ulna (bones of the forearm), due to the forces these bones withstand in normal activities or from falls
- Short stature or, in more severe forms, dwarfing - most children with the condition are significantly shorter than their peers
- Skull deformities – the back of the skull or forehead may be flattened, the back of the skull may bulge outward, and the face often appears to have a triangular shape
- Spine deformities – occurs in around 60% of affected children; thoracic (high spine) scoliosis is the most common manifestation, often resulting in respiratory problems, such as difficulty in breathing
- Joint laxity – because the ligaments are commonly affected, joints demonstrate laxity, or a relative looseness and instability, which can lead to dislocations and muscle problems
Basic facts about osteogenesis imperfecta:
- Osteogenesis imperfecta is a relatively rare musculoskeletal condition, affecting approximately 16 children out of every 1 million
- OI has been documented to affect, to some degree, virtually all ethnic groups and all geographic locations
- The disease was first described in Sweden in 1788 by a scientist named Ekman
- The discovery of an Egyptian mummy with many of the skeletal characteristics of OI suggests that the disease may have affected humans as early as 1000 BC. We have come to learn that depending on the gene or genes that are affected in a patient, many different varieties of OI occur in children, with a wide spectrum of clinical presentations. As mentioned, above, it is extremely heterogenous. However, some doctors may still utilize the classic classification system, described below:
- Type I (Tarda B) – mild; marked by blue sclerae, occasional bone fractures with activity, minimal deformity
- Type II (Congenita A) – lethal; marked by blue sclera, death before or soon after birth, due to multiple fractures, crumpled bones, severe deformity
- Type III (Tarda A, Congenita B) – severe; marked by normal (white) sclera, abnormal dentition (teeth), frequent fractures beginning at birth, significant deformity (including spine), short stature
- Type IV – moderate severity; marked by normal sclera, normal teeth, occasional fractures, moderate deformity, short stature
- There are no known ways to prevent osteogenesis imperfecta
Normal bone structure and biology
While most people think of the skeleton as an unchanging mass of solid, interconnected structures, it is actually a very dynamic set of tissues, with the bones constantly turning over cells and nutrients and changing in structural features, according to a person’s age and the demands placed upon the skeleton. When the normal early skeleton develops, it consists mainly of cartilage that is gradually filled in with stronger calcified bony tissue throughout childhood. Immature bone begins as woven bone, which cannot accommodate the forces of the normal activities of the body, such as walking or lifting objects. The tissue of the lamellar bone that replaces woven bone, on the other hand, is arranged both longitudinally and circularly so as to withstand the weight of the body and all of the additional stresses it endures. A key component of lamellar bone is type I collagen, the molecules of which cross-link together to serve as the organic matrix upon which calcium-based molecules are laid down. Whereas the calcified tissue gives the skeleton its compressive strength, preventing collapse, the collagen-based tissue gives the skeleton its tensile strength, preventing abnormal bending or torque in the bones and acting as the foundation throughout which the stiffer calcified tissue is interspersed.
What causes osteogenesis imperfecta and its clinical characteristics?
OI is a genetic disease in which the genes that code for type I collagen undergo some type of mutation or mutations. The two genes primarily affected have been identified and are named COL1A1 (found on chromosome 17) and COL1A2 (found on chromosome 7). Over 150 different mutations of various types have been shown to cause some form of OI, which explains the wide range of clinical characteristics and degrees of severity that are seen in the disease. The result of the mutation is either decreased or defective collagen, or both. Without the intricately arranged sub-architecture of the collagenous matrix, the bone tissue in OI may more closely resemble disorganized woven bone than tightly packed lamellar tissue. The more severe the sub-type of the disease, the more immature the bone structure appears and the more unstable the bones will be when subjected to physiological forces. There is also increased bone turnover at the cellular level, and the haversian canals, natural microscopic spaces within bones through which nutrients are transported, are abnormally large. Though the calcified tissue in bones is normal in molecular structure, there is less of it, causing virtually all children with OI to have generalized osteopenia, described above. This condition, combined with the abnormal supportive matrix, predisposes affected children to fractures, even from minimal trauma. The long bones of the lower extremities are the most common fracture sites, but minor falls, obviously common in all infants and young children, often lead to upper extremity long bone fractures as well. OI ultimately affects both the long bones and the axial skeleton, which includes the skull and spine. The spine may therefore undergo millions of tiny microfractures, which go undetected by the patient but gradually lead to scoliosis and varying degrees of kyphosis, the clinical name for an abnormally forward tilted spine, or hunchback.
When bones do fracture, the healing process that takes place is also abnormal. Though the long bones can produce a large amount of callus, the intermediate cartilaginous material that fills in the space between the fractured ends, the callus does not fill in sufficiently with bone tissue, leading to malunion, a condition that describes poorly healed fractures and results in a weak, unstable bone. Though the frequency of fractures decreases significantly following puberty, this frequency will ultimately pick up again in women with the condition after menopause and in men in their 60’s and later decades.
Because type I collagen is found in other tissues of the body, OI has non-skeletal manifestations as well. Cross-linked collagen is responsible for the white color of the eyes and teeth, which explains why those with OI may have translucent or bluish eyes and translucent, brownish teeth. Resulting eye problems are minimal, but the teeth may wear away easily, requiring a significant amount of dental work. Skin may also appear translucent, and may become easily distensible, almost elastic-seeming. Heart and blood vessel problems may occur, and hearing deficiencies are not uncommon for OI patients.
How is it diagnosed?
Osteogenesis imperfecta is usually diagnosed by a pediatrician or by an orthopaedic surgeon, based on clinical characteristics and the appearance of x-ray images. More severe cases are obviously identified at younger ages, on average, because the more severe manifestations become more readily apparent, even as early as the perinatal period, occasionally during the period of fetal growth with ultrasound. If a diagnosis is desired or warranted in the prenatal period, DNA analysis can be performed on the amniotic fluid. In addition, these genetic analysis techniques can be used in an older child who has mild symptoms of the disease, when a diagnosis cannot be definitively made based on clinical criteria. In more severe cases, x-rays of a child’s long bones may clearly demonstrate the generalized osteopenia common to all four classic types of OI, and the presence of multiple healed or current fractures can contribute to the diagnosis. Recently, definitive diagnosis has been aided by the use of skin biopsy, in which a small sample of tissue is taken from the skin and analyzed for the ability of fibroblasts, protein secreting cells in the skin, to produce normal amounts of type I collagen. The previously described abnormalities in the teeth, eyes and joints also contribute to the diagnostic process.
How is it treated?
Following diagnosis of OI, a number of different types of physicians may become involved in a child’s care, including pediatricians, orthopaedic surgeons, neurologists, ophthalmologists, dentists, physical therapists, and others. Such a team-based approach may seem overwhelming, but is often the best way to manage a disease with manifestations involving many physiological systems.
Orthopaedic surgeons may see a child with OI quite frequently and should manage any fractures that occur. Various treatments are employed by the surgeons, depending on the types of fractures or deformities that are present, including the use of splints or braces, casting, and, at times, surgical operations as well. The primary goal is to keep the child mobile through physical therapy, while protected through bracing or splinting, ultimately emphasizing the independent functioning and social integration of the child over time. Surgery may be appropriate for older children with deformities in their arms or legs. In such instances, an operation known as an osteotomy may be performed, in which a small wedge of bone is removed to properly realign the extremities as much as possible. Patients with spinal problems such as scoliosis or kyphosis as a result of OI may benefit somewhat from bracing, but for severe spinal curves (>45 degrees), an operation known as a spinal fusion is usually more appropriate, involving spinal segments (known as vertebrae) being held together with bone fragments and/or metal rods, in order to straighten the abnormal curve.
A number of non-orthopaedic treatments, collectively referred to as systemic therapy, have been used or researched as potential ways to decrease the symptoms of OI. For example, calcium, vitamin D, steroids, calcitonin, and growth hormones have all been tried by OI patients. One form of systemic therapy that has shown particularly promising results in early clinical studies is the use of intravenous bisphosphonates. Bisphosphonates are drugs designed to inhibit the activity of osteoclasts, the cells responsible for breaking down bone in the normal, healthy process of bone turnover. Because bone turnover is abnormally increased in OI patients, and the rate of breakdown exceeds that of bone creation, bisphosphonates can play an important role in the maintenance of bone density and bone strength. Right now, these drugs are being given by some doctors on a cyclical basis, in which children receive intravenous doses for 3 consecutive days every 3 to 4 months for several years, with very few side effects. Patients receiving the therapy have shown a number of beneficial effects, including thickening of cortical bone, increased bone mineral density (BMD), decreased bone pain, decreased fracture rates, increased ambulation, and overall decreased physical disability. Further research into this type of therapy will elucidate how long these effects may last and what the maximally effective dosing schedule should be.
The area of gene therapy is still largely theoretical, but in the future there may be a way to insert genetic material into the body to stimulate increased production of type I collagen or to replace a defective collagen gene. Ongoing research at various academic medical centers throughout the country is dedicated to the lofty goal of making such gene therapy a reality and towards improving the current treatment modalities for osteogenesis imperfecta.
Coping with osteogenesis imperfecta
Osteogenesis imperfecta can present a difficult challenge for some children and their parents. Bone fragility and the risk of fractures often affect a child’s ability to play normally like other children. Rarely, the disease can be so severe as to make fractures at a young age inevitable, regardless of activity, or even lead to perinatal death. However, the majority of cases of OI are of the mild genetic form and lasting disability can be avoided with some relatively simple preventative measures. When active treatment is necessary, it is generally fairly successful as well. Managing the condition may require some adjustments early on, but seeking continued medical guidance from your orthopaedic surgeon and maintaining a positive outlook is the best way for parents to help their children. Many people have also benefited from communication with other parents and patients with OI, as offered by some of the support groups described below.