Learning About Osteogenesis Imperfecta

National Human Genome Research Institute

National Institutes of Health
U.S. Department of Health and Human Services


Learning About Osteogenesis Imperfecta

What is Osteogenesis imperfecta?

Osteogenesis imperfecta (OI) is a genetic disorder that causes a person's bones to break easily, often from little or no apparent trauma. OI is also called "brittle bone disease." OI varies in severity from person to person, ranging from a mild type to a severe type that causes death before or shortly after birth. In addition to having fractures, people with OI also have teeth problems (dentinogenesis imperfecta), and hearing loss when they are adults. People who have OI may also have muscle weakness, loose joints (joint laxity) and skeletal malformations.

OI occurs in approximately 1 in 20,000 individuals, including people diagnosed after birth. OI occurs with equal frequency among males and females and among racial and ethnic groups. Life expectancy varies depending on how severe the OI is, ranging from very brief (lethal form, OI type II) to average.

There are four well-known types of OI. These types are distinguished mostly by fracture frequency and severity and by characteristic features. Three additional types of OI (type V, VI and VII) have also been identified.

The vast majority (90 percent) of OI is caused by a single dominant mutation in one of two type I collagen genes: COL1A1 or COL1A2.The COL1A1 and COL1A2 genes provide instructions for making proteins that are used to create a larger molecule called type I collagen. This type of collagen is the most common protein in bone, skin and other tissues that provide structure and strength to the body (connective tissues). OI type VII is caused by recessive mutations in the CRTAP gene.

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What are the symptoms of Osteogenesis imperfecta?

Osteogenesis imperfecta (OI) causes bones to be fragile and easily broken and is also responsible for other health problems.

Type I OI is the mildest form of the condition. People who have type I OI have bone fractures during childhood and adolescence often due to minor trauma When these individuals reach adulthood they have fewer fractures.

Type II OI is the most severe form of OI. Infants with type II have bones that appear bent or crumpled and fractured before birth. Their chest is narrow and they have fractured and misshapen ribs and underdeveloped lungs. These infants have short, bowed arms and legs; hips that turn outward; and unusually soft skull bones. Most infants with type II OI are stillborn or die shortly after birth, usually from breathing failure.

Type III OI also has relatively severe signs and symptoms. Infants with OI type III have very soft and fragile bones that may begin to fracture before birth or in early infancy. Some infants have rib fractures that can cause life-threatening problems with breathing. Bone abnormalities tend to get worse over time and often interfere with the ability to walk.

Type IV OI is the most variable form OI. Symptoms of OI type IV can range from mild to severe. About 25 percent of infants with OI type IV are born with bone fractures. Others may not have broken bones until later in childhood or adulthood. Infants with OI type IV have leg bones that are bowed at birth, but bowing usually lessens as they get older.

Some types of OI are also associated with progressive hearing loss, a blue or grey tint to the part of the eye that is usually white (the sclera), teeth problems (dentinogenesis imperfecta), abnormal curvature of the spine (scoliosis) and loose joints. People with this condition may have other bone abnormalities and are often shorter in stature than average.

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How is Osteogenesis imperfecta diagnosed?

OI is often inherited from an affected parent. The diagnosis of OI is made on the basis of family history and/or clinical presentation. Frequent fractures, short stature, a blue hue to the white part of the eye (blue sclera), teeth problems (dentinogenesis imperfecta) and hearing loss that progresses after puberty may be present.

X-rays are also used to diagnose OI. X-ray findings include fractures that are at different stages of healing; an unexpected skull bone pattern called Wormian bones; and bones in the spine called "codfish vertebrae."

Laboratory testing for OI may include either biochemical testing or DNA-based sequencing of COL1A1 and COL1A2. Biochemical testing involves studying collagens taken from a small skin biopsy. Changes in type I collagen are an indication of OI.

DNA sequencing of COL1A1 and COL1A2 is used to identify the type I collagen gene mutation responsible for the altered collagen protein. DNA testing requires a blood sample for DNA extraction. Both tests are relatively sensitive, detecting approximately 90 percent and 95 percent, respectively, of individuals with the clinical diagnosis of OI. Normal biochemical and molecular testing in a child with OI warrants additional testing of less common collagen genes (CRTAP and P3H (LEPRE1)) responsible for some of the rare recessive forms of OI.

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What is the treatment for Osteogenesis imperfecta?

There is currently no cure for OI. Treatment involves supportive therapy to decrease the number of fractures and disabilities, help with independent living and maintain overall health. OI is best managed by a medical team including the child's own doctor, and genetic, orthopedic and rehabilitation medicine. Supportive therapy is unique to each individual depending on the severity of their condition and their age.

Physical and occupational therapies to help improve their ability to move, to prevent fractures and to increase muscle strength are often useful.

Fractures are treated as they would be in children and adults who do not have OI. An orthopedic treatment called intramedullary rodding (placing rods in the bones) is used to help with positioning of legs that helps with more normal functioning when necessary.

A newer treatment with medication called biophosphonates is being used to help with bone formation and to decrease the need for surgery.

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Is Osteogenesis imperfecta inherited?

Most types of OI are inherited in an autosomal dominant pattern. Almost all infants with the severe type II OI are born into families without a family history of the condition. Usually, the cause in these families is a new mutation in the egg or sperm or very early embryo in the COL1A1 or COL1A2 gene. In the milder forms of OI, 25-30 percent of cases occur as a result of new mutations. The other cases are inherited from a parent who has the condition. Whether a person has OI due to a new mutation or an inherited genetic change, an adult with the disorder can pass the condition down to future generations.

In autosomal dominant inherited OI, a parent who has OI has one copy of a gene mutation that causes OI. With each of his/her pregnancies, there is a 1 in 2 (50 percent) chance to pass on the OI gene mutation to a child who would have OI, and a 1 in 2 (50 percent) chance to pass on the normal version of the gene to a child who would not have OI.

Rarely, OI can be inherited in an autosomal recessive pattern. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. Autosomal recessive inheritance means two copies of the gene must be altered for a person to be affected by the disorder. The autosomal recessive form of type III OI usually results from mutations in genes other than COL1A1 and COL1A2.

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NHGRI Research on Osteogenesis imperfecta

Currently, NHGRI is not conducting clinical research on OI. However, other institutes at the National Institutes of Health are conducting clinical trials listed on ClinicalTrials.gov:

  • Current NHGRI Clinical Studies
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    Additional Resources on Osteogenesis Imperfecta

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    Last Updated: August 15, 2012