Osteogenesis Imperfecta (OI) is a group of rare disorders affecting the connective tissue and characterized by extremely fragile bones that break or fracture easily (brittle bones), often without apparent cause. The specific symptoms and physical findings associated with OI vary greatly from case to case. The severity of OI also varies greatly, even among individuals of the same family. OI may be a mild disorder or may result in severe complications. Four main types of OI have been identified. OI type I is the most common and the mildest form of the disorder. OI type II is the most severe. In most cases, the various forms of osteogenesis imperfecta are inherited as autosomal dominant traits.
In all types of Osteogenesis Imperfecta, the associated symptoms vary greatly from case to case, even within families. Some affected individuals may not experience any bone fractures or only a few; other affected individuals may experience multiple fractures. OI may range from a mild disorder with few symptoms to a severe, debilitating disorder. The age of onset of fractures also varies from case to case.
Osteogenesis Type I
Osteogenesis type I is the most common and usually the mildest form of OI. In most cases, it is characterized by multiple bone fractures usually occurring during childhood through puberty. Fractures usually begin when an affected child begins to walk; fractures during the newborn (neonatal) period are rare. The frequency of fractures usually declines after puberty. Repeated fractures may result in slight malformation of the bones of the arms and legs (e.g., bowing of the tibia and femur).
A distinguishing feature associated with OI type I is bluish discoloration of the whites of the eyes (blue sclera). In some cases, individuals with OI type I may develop abnormalities affecting the middle and/or inner ears contributing to, or resulting in, hearing impairment (i.e., conductive and/or sensorineural hearing loss). Hearing loss occurs most often in the third decade of life; however, it can occur as early as the second decade or as late as the seventh.
Individuals with OI type I may have a triangular facial appearance and an abnormally large head (macrocephaly). In approximately 50 percent of cases, individuals with OI type I will experience growth deficiencies after birth (postnatal), resulting in mild short stature (e.g., affected individuals will be shorter than unaffected family members). Approximately 20 percent of adults with OI type I develop abnormal sideways or front-to-back curvature of the spine (scoliosis or kyphosis).
Additional symptoms associated with OI type I include loose (hyperextensible) joints, low muscle tone (hypotonia), and thin skin that bruises easily.
Some researchers believe that a subgroup of OI type I exists in which affected individuals experience dental abnormalities in addition to the abovementioned features.
Osteogenesis Type II
OI type II is the most severe type of osteogenesis imperfecta. Affected infants often experience life-threatening complications at, or shortly after, birth. Infants with OI type II have low birth weight, abnormally short arms and legs (limbs), and bluish discoloration of the whites of the eyes (blue sclera). In addition, affected infants may have extremely fragile bones and numerous fractures present at birth. The ribs and long bones of the legs of affected infants are often malformed.
Infants with OI type II often have underdeveloped lungs and an abnormally small upper chest (thorax) that may result in life-threatening respiratory insufficiency. In some cases, affected infants may experience congestive heart failure.
Infants with OI type II may also have a small, narrow nose; a small jaw (micrognathia); and an abnormally soft top of the skull (calvaria) with abnormally large soft spots (large fonatanelle). Affected infants may also have abnormally thin, fragile skin and low muscle tone (hypotonia).
OI type II has been subdivided into three subgroups (A, B, and C) based upon small differences in bone formation seen only on x-rays (radiographic features).
Osteogenesis Type III
OI type III is characterized by extremely fragile bones, multiple fractures, and malformed bones. Multiple fractures are often present at birth. Fractures and malformation of various bones (most often the ribs and long bones) may become worse (progressive malformation) as affected infants and children age.
Progressive malformation of various bones may result in short stature, sideways and front-to-back curvature of the spine (scoliosis and kyphosis), and malformation of the area where the bone in the back of the skull (occipital bone) and the top of the spine meet (basilar impression). In some cases, affected individuals may develop pulmonary insufficiency and respiratory problems. In severe cases, progressive bone malformation may result in affected individuals requiring wheelchairs.
Infants with OI type III may have a slight blue discoloration to the whites of the eyes (blue sclera) at birth. In most cases, the bluish tinge fades during the first year of life. Affected infants may have a triangular facial appearance due to an abnormally prominent forehead (frontal bossing) and an abnormally small jaw (micrognathia). In some cases, hearing impairment and brittle, discolored teeth (dentinogenesis imperfecta) may also be present.
Osteogenesis Type IV
Individuals with OI type IV have fragile bones that often fracture easily. Fractures are more common before puberty. Affected individuals experience mild to moderate bone malformation and are usually shorter than average. Affected individuals may develop sideways and front-to-back curvature of the spine (scoliosis and kyphosis).
Individuals with OI type IV may have a triangular facial appearance. In most cases, the whites of the eyes (sclera) are normal or pale blue during infancy. As an affected infant ages, the pale blue discoloration of the sclera fades. Affected individuals may also experience hearing impairment and brittle, discolored teeth (dentinogenesis imperfecta)
Unclassified Osteogenesis Imperfecta
Many cases of individuals with the bone abnormalities characteristic of osteogenesis imperfecta have been reported in the medical literature. However, these cases have additional symptoms that prevent them from being classified under one of the four main types of OI. Researchers have speculated that these cases may be subgroups of one of the four main types of OI, an additional type of OI (e.g., OI type V), or separate disorders. (For more information on these disorders, see the Related Disorders section below.)
In most cases, osteogenesis imperfecta types I, II, and IV are inherited as autosomal dominant traits. Most cases of OI type II occur without a previous family history of the disorder, resulting instead from a spontaneous genetic change (i.e., new mutation). The inheritance of this mutation is autosomal dominant.
Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.
Rare subgroups of OI types II and III may be inherited as autosomal recessive genetic traits. In recessive disorders, the condition does not occur unless an individual inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
Investigators have determined that most types of osteogenesis imperfecta are caused by disruption or changes (mutations) of one of two genes (COL1A1 or COL1A2). These genes carry instructions for the production of type 1 collagen. Collagen is the major protein of bone and connective tissue including the skin, tendons, and sclera.
The COL1A1 gene is located on the long arm (q) of chromosome 17 (17q21.31-q22). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 17q21.31-q22” refers to bands 21.31-22 on the long arm of chromosome 17.
The COL1A2 gene is located on the long arm (q) of chromosome 7 (7q22.1).
In 2006, researchers at the National Institutes of Health (NIH) discovered that a previously unexplained fatal form of osteogenesis imperfecta results from a genetic defect in a different gene known as CRTAP. The CRTAP gene codes for (contains the information for) cartilage-associated protein. These mutations are associated with a recessive form of the disorder. The discovery of this gene was described in an article published in the December 28, 2006, New England Journal of Medicine.
Osteogenesis imperfecta affects males and females in equal numbers. The exact number of individuals with OI in the United States (prevalence) is unknown. OI type I is estimated to occur in one in 30,000 live births. OI type II is estimated to occur in one in 60,000 live births. The overall prevalence of all types of OI is estimated at .5 per 10,000 individuals in the United States. Approximately 20,000 to 50,000 individuals in the United States have OI.
A diagnosis of osteogenesis imperfecta is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of specialized tests. Surgical removal and microscopic examination (biopsy) of the skin may be done to determine whether abnormalities of collagen are present. A blood sample may be taken and tested to detect the presence of the genetic mutation that causes OI.
In some cases, the diagnosis of OI may be made before birth (prenatally), based upon specialized tests such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). Ultrasound studies may reveal characteristic findings such as fractures or bowing of the long bones. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. Chromosomal studies performed on this fluid or tissue sample may reveal the genetic mutation that causes OI.
The treatment of OI is directed toward the specific symptoms that are apparent in each individual. Treatment is aimed at preventing symptoms, maintaining individual mobility, and strengthening bone and muscle.
Exercise and physical therapy programs have proven beneficial in strengthening muscles, increasing weight-bearing capacity, and reducing the tendency to fracture. Physical therapy in the water (hydrotherapy) has also been proven helpful since moving around in water lessens the chance of fracture. Individuals with OI should consult with their physicians and physical therapists to determine a safe and appropriate exercise program.
A procedure in which metal rods are surgically placed in the long bones to prevent fractures (rodding) is often used to treat individuals with OI. Plastic braces are replacing plaster casts as protective devices because they permit greater freedom of movement and can be used in water. Inflatable suits can provide added protection, especially to very young children.
Surgery may prove necessary for individuals with severe malformation of the bones of the spine or basilar impression. Dental procedures may be necessary to correct various dental abnormalities. Affected individuals, especially adults, should be monitored for hearing impairment often associated with OI. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For information about clinical trials sponsored by private sources, contact:
As of January 2007, there were seven clinical trials listed on www.clinicaltrials.gov investigating various treatment strategies for osteogenesis imperfecta. Among them, researchers were studying new treatment options for individuals with osteogenesis imperfecta, including bisphosphonate drugs, growth hormones, and bone marrow transplants. One of these drugs is Fosomax, which earned an FDA orphan drug designation in 2004. Another drug study is a phase IV trial involving the drug Teriparatide for the treatment of adults with this disorder.
Growth hormone (GH) therapy has proven beneficial in individuals with mild or moderate forms of OI. GH has helped improve collagen production and increased growth and bone mineral density. More research is necessary to determine the long-term safety and effectiveness of this treatment for individuals with OI.
Initial studies of the bisphosphonate drug, Pamidronate, have shown an increase in bone mineral density and a reduction in the frequency of fractures in individuals with severe forms of OI. More research is necessary to determine the long-term safety and effectiveness of bisphosphonate therapy for the treatment of OI.
Marrow mesenchymal cell therapy is currently (2006) being investigated in a clinical study that began in 2004. This involves a bone marrow transplant procedure.
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