Osteogenesis imperfecta (OI, also known as brittle bone disease or Lobstein syndrome),is a congenital bone disorder characterized by brittle bones that are prone to fracture. OI may also present with shorter height, neurological features including communicating hydrocephalus, basilar invagination, and seizures, blue sclerae, hearing loss, or other complications. The fractures themselves can cause acute or chronic pain, reduced quality of life, and depression.
People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of type I collagen. Eight types of OI can be distinguished. Most cases are caused by mutations in the COL1A1 and COL1A2 genes, both of which code for type I collagen. Diagnosis of OI is based on the clinical features and may be confirmed by collagen or DNA testing.
There is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture and maintain mobility. Treatment includes bisphosphonates, surgery, physical therapy, and physical aids.
OI occurs in about one per 20,000 live births. The frequency of OI doesn't change across groups, but certain types are more common in certain groups.
All people with OI have weak bones, which makes them susceptible to fractures. Persons with OI are usually below average height ( short stature). However, the severity of the disease varies greatly. The classic symptoms include:
- Blue tint to the whites of their eyes (blue sclera)
- Multiple bone fractures
- Early hearing loss (deafness)
Because type I collagen is also found in ligaments, persons with OI often have loose joints (hypermobility) and flat feet. Some types of OI also lead to the development of poor teeth. Symptoms of more severe forms of OI may include:
- Bowed legs and arms
- Kyphosis (S-curve spine)
Mutations in the COL1A1, COL1A2, CRTAP, and LEPRE1 genes cause osteogenesis imperfecta.
Mutations in the COL1A1 and COL1A2 genes are responsible for more than 90 percent of all cases of osteogenesis imperfecta. These genes provide instructions for making proteins that are used to assemble type I collagen. This type of collagen is the most abundant protein in bone, skin, and other connective tissues that provide structure and strength to the body.
Most of the mutations that cause osteogenesis imperfecta type I occur in the COL1A1 gene. These genetic changes reduce the amount of type I collagen produced in the body, which causes bones to be brittle and to fracture easily. The mutations responsible for most cases of osteogenesis imperfecta types II, III, and IV occur in either the COL1A1 or COL1A2 gene. These mutations typically alter the structure of type I collagen molecules. A defect in the structure of type I collagen weakens connective tissues, particularly bone, resulting in the characteristic features of osteogenesis imperfecta.
Mutations in the CRTAP and LEPRE1 genes are responsible for rare, often severe cases of osteogenesis imperfecta. Cases caused by CRTAP mutations are usually classified as type VII; whenLEPRE1 mutations underlie the condition, it is classified as type VIII. The proteins produced from these genes work together to process collagen into its mature form. Mutations in either gene disrupt the normal folding, assembly, and secretion of collagen molecules. These defects weaken connective tissues, leading to severe bone abnormalities and problems with growth.
In cases of osteogenesis imperfecta without identified mutations in the COL1A1, COL1A2, CRTAP, or LEPRE1 gene, the cause of the disorder is unknown. These cases include osteogenesis imperfecta types V and VI. Researchers are working to identify additional genes that may be responsible for these conditions.
Genetic counseling is recommended for couples considering pregnancy if there is a personal or family history of this condition.
There is no definitive test for OI. The diagnosis is usually suggested by the occurrence of bone fractures with little trauma and the presence of other clinical features. A skin biopsy can be performed to determine the structure and quantity of type I collagen. DNA testing can confirm the diagnosis, however, it cannot exclude it because not all mutations causing OI are known and/or tested for. OI type II is often diagnosed by ultrasound during pregnancy, where already multiple fractures and other characteristic features may be present. Relative to control, OI cortical bone shows increased porosity, canal diameter, and connectivity in micro-computed tomography.
An important differential diagnosis of OI is child abuse, as both may present with multiple fractures in various stages of healing. Differentiating them can be difficult, especially when no other characteristic features of OI are present. Other differential diagnoses include rickets, osteomalacia, and other rare skeletal syndromes.
How well a person does depends on the type of OI they have.
Type I, or mild OI, is the most common form. Persons with this type can live a normal lifespan.
Type II is a severe form that is usually leads to death in the first year of life.
Type III is also called severe OI. Persons with this type have many fractures starting very early in life and can have severe bone deformities. Many become wheelchair bound and usually have a somewhat shortened life expectancy.
Type IV, or moderately severe OI, is similar to type I, although persons with type IV often need braces or crutches to walk. Life expectancy is normal or near normal.
There is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture and maintain mobility. Bisphosphonates can increase bone mass, and reduce bone pain and fracture. In severe cases, bones are surgically corrected, and rods are placed inside the bones, particularly to enable infants to learn to walk.
Bone infections are treated as and when they occur with the appropriate antibiotics and antiseptics.
In 1998, a clinical trial demonstrated the effectiveness of intravenous pamidronate, a bisphosphonate which had previously been used in adults to treat osteoporosis. In severe OI, pamidronate reduced bone pain, prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced the number of long-bone fractures.
Although oral bisphosphonates are more convenient and cheaper, they are not absorbed as well, and intravenous bisphosphonates are generally more effective, although this is under study. Some studies have found oral and intravenous bisphosphonates, such as oral alendronate and intravenous pamidronate, equivalent. In a trial of children with mild OI, oral risedronate increased bone mineral densities, and reduced nonvertebral fractures. However, it did not decrease new vertebral fractures.
Bisphosphonates are less effective for OI in adults.
Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield, MD, at Shriners Hospitals for Children in Chicago. During the late 1940s, Sofield, Chief of Staff at Shriners Hospitals in Chicago, worked there with large numbers of children with OI and experimented with various methods to strengthen the bones in these children. In 1959, with Edward A. Miller, MD, Sofield wrote a seminal article describing a solution that seemed radical at the time: the placement of stainless steel rods into the intramedullary canals of the long bones to stabilize and strengthen them. His treatment proved extremely useful in the rehabilitation and prevention of fractures; it was adopted throughout the world and still forms the basis for orthopedic treatment of OI.
Spinal fusion can be performed to correct scoliosis, although the inherent bone fragility makes this operation more complex in OI patients. Surgery for basilar impressions can be carried out if pressure being exerted on the spinal cord and brain stem is causing neurological problems.
Physiotherapy is used to strengthen muscles and improve motility in a gentle manner, while minimizing the risk of fracture. This often involves hydrotherapy and the use of support cushions to improve posture. Individuals are encouraged to change positions regularly throughout the day to balance the muscles being used and the bones under pressure.
Children often develop a fear of trying new ways of moving due to movement being associated with pain. This can make physiotherapy difficult to administer to young children.
With adaptive equipment such as crutches, wheelchairs, splints, grabbing arms, or modifications to the home, many individuals with OI can obtain a significant degree of autonomy.
People affected by OI are supported by multiple organizations, including the Osteogenesis Imperfecta Foundation, the Canadian Osteogenesis Imperfecta Society, and the Children’s Brittle Bone Foundation.