Osteogenesis imperfecta (OI) is an uncommon (about 1/10,000 worldwide) inherited disorder caused by mutations in any of more than a dozen genes. Multiple types of OI, extreme range of severity, changes across the lifespan, in addition to dominant and recessive patterns of inheritance contribute to the complexity of OI. Identified mutations affect type I collagen genes or are in genes in the collagen or bone formation pathways. This contributes to the wide range of clinical features, beyond fragile bones, that are seen in OI patients.

Genetics and Inheritance Patterns of OI

OI is considered a "heritable" condition because it results from genetic changes. Most people with OI (>90%) have a mutation in one of the two copies of the genes (COL1A1 or COL1A2) that carry instructions for making type I collagen- the protein “scaffolding” of bone and other connective tissues. These mutations either reduce the amount of type I collagen made or alter the quality of the protein. The remaining individuals with OI have mutations in other genes and the inheritance pattern in those families may be either dominant or recessive.

A person’s genetic inheritance is composed of two copies of each gene. Each parent contributes only one of those two copies. If one altered copy of a gene is sufficient to cause a clinical condition, including OI, then the disorder can be transmitted from parent to child and the pattern of inheritance is called "dominant". Both males and females are affected, and it is clearly transmitted from parents to their children in about 50% of the pregnancies. The first time a mutation appears in the family and it is referred to as a "new dominant mutation". These usually occur in a single egg or sperm and then can be transmitted in subsequent generations. For the more severe forms of OI, the mutations commonly occur in this fashion and so may be seen only in the affected child who may not reproduce.

In some instances, when the affected child is born to unaffected parents one parent may have only some cells in which the mutation occurred, some of which are in the germ cells and can be transmitted. Those parents are considered to be mosaic for an OI mutation. This means that an OI causing mutation is present in a percentage of one parent’s cells, but does not cause any symptoms in the parent. The chance to have another child in that situation depends on the proportion of cells in the germ cells (sperm or eggs) that have the mutation. It would never be more than 50%.

In the last decade, it has been recognized that some individuals do not have mutations in COL1A1 or COL1A2 yet still have OI. In many of these individuals, it has been found that they have two altered copies of a gene, many involved in collagen processing or bone cell maturation. In these families, each parent has one copy of the altered gene and one copy of the normal copy and the condition is referred to as having "recessive inheritance". The parents are asymptomatic and both must transmit the altered copy of the gene to have an affected child, a situation that will occur in about 25% of the pregnancies. For complete discussion about the inheritance pattern of OI and recurrence risks, parents are urged to consult with a medical geneticist or a genetic counselor.

A person who has a dominantly inherited form of OI has a 50% chance of passing on the disorder to each of his or her children. An affected child will have the same mutation, and therefore the same type of OI, as the parent. Although the expression- the degree of severity, or number of fractures- may be different among family members, the chance to have an affected child remains 50% with each pregnancy. Unaffected siblings of a child with dominant OI have no greater risk of having children with OI than anyone in the general population. Unaffected siblings of a child with a recessively inherited form of OI have a 67% chance of being a carrier for the recessive mutation but are not at risk to have an affected child unless they have children with another individual who is a carrier for a mutation in the same gene or someone who has OI as a result of two mutations in the same gene. For more information on dominant and recessive forms of OI, and mosaicism, please see the factsheet on Inheritance Patterns How OI Occurs in Families.

Diagnosing Osteogenesis Imperfecta

Evidence of OI is often present at birth. In severe instances it can be seen on a prenatal ultrasound, beginning by 14 weeks of pregnancy. Milder forms might not be recognized until the child begins to walk. Unusually low bone density may lead to a young adult’s diagnosis. In the usual situation, the diagnosis of OI is suspected on clinical grounds and can be confirmed by DNA or biochemical testing. A physician, usually a geneticist, who is familiar with OI, can often make the diagnosis on the basis of the presence of fractures and other clinical features. A family history for the disorder and genetic testing can help confirm a diagnosis. Bone densitometry by itself is not diagnostic for OI but lower than expected scores suggest a need for further evaluation for OI and/or other skeletal disorders. Some of the clinical features that are considered in the diagnostic process include: bone density, spine deformity or fractures, tinted sclera (although this is seen outside of OI in children under age 18 months), wormian bones and other skull anomalies, delayed growth and excessive sweating.

Laboratory tests are available to confirm a diagnosis of OI. All forms of OI can be tested for by DNA-based tests using blood or saliva as a source of the DNA. Collagen/skin biopsy is no longer the first choice for testing. Because all genetic causes for OI have not yet been identified, a negative test does not exclude the diagnosis but should initiate reassessment. Test reports are frequently complex. Patients and families may need genetic counseling to understand them and their implications. For a list of laboratories that process OI genetic testing results, please see the factsheet on OI Testing Centers in the United States.

Because OI is an uncommon disorder, affected individuals and/or their families may be unfamiliar with the condition. Information and support provided at the time of diagnosis will help them understand their OI and participate in making treatment decisions. Adults who receive a diagnosis may be relieved that some aspects of their medical history now make sense. They will need a plan to maintain general health as they age. Parents of a child with a new diagnosis will need information about treatments and fracture care and access to resources in their community for a child with a disability.

Prenatal Diagnosis

Prenatal testing can detect all forms of OI if the genetic alterations are known. They depend on the ability to obtain a DNA sample from the pregnancy and usually take a sample of the placenta by a process known as chorionic villus sampling (CVS) at about 10 weeks after pregnancy starts. Ultrasound can detect bowing, fractures, shortening and other bone abnormalities, but even experienced professionals may not be able to pinpoint the type of OI or differentiate between OI Type II (lethal), or OI Type III (severe) or other conditions, if neither parent is affected and there is no genetic information to assist in the diagnosis. Cells obtained through amniocentesis can be used for DNA analysis. A fetal MRI does not see bone well, but may offer useful information on other topics. Parents should always be advised as to risks for miscarriage associated with a pre-natal test. Whether one of the parents has OI or prenatal testing suggests the presence of OI symptoms in the fetus, it is recommended that the couples seek genetic counseling.

Postnatal Diagnosis

The diagnostic process begins with a clinical evaluation. If the clinical evaluation indicates the possibility of OI, genetic testing of the patient follows. Unless otherwise indicated, a test for the dominant form of OI is done first, followed by the test for recessive OI. Information about pregnancy and birth is informative since a breach position at birth is common among infants who have OI. For parents who have lost a child to a severe form of OI, testing will confirm the diagnosis and help determine the chance of future affected pregnancies.

Differential Diagnosis

A variety of disorders may present with recurrent fractures due to bone fragility--that is, not everyone with fractures has OI. Other causes of brittle bones include osteomalacia, disuse osteoporosis, disorders of increased bone density and defects of bone, such as fibrous dysplasia and tumors. In determining a cause for brittle bones, it is important to use history, physical examination, laboratory diagnostics and radiographic studies to hone the differential diagnosis. If the history and physical examination do not narrow the differential diagnosis sufficiently, then laboratory tests should be employed.

Child Abuse

The question of non-accidental injury versus osteogenesis imperfecta arises most often when infants and toddlers experience unexpected or unexplained broken bones. A child with a fragile skeleton may fracture during routine care. Toddlers pulling to stand and beginning to walk are also at risk for a fragility fracture. Children who have OI may fracture from little or no apparent trauma and can bruise easily. Bruises may give the impression of greater trauma. In the interest of providing appropriate medical care, when there are no signs of neglect the possibility of mild or moderate OI or a related bone disorder should be considered. An examination and evaluation by a physician who is experienced in diagnosing OI and other rare bone disorders is warranted. Besides OI, other conditions that feature fragile bones and bruising include Ehlers-Danlos syndrome, hypophosphotasia, disorders of vitamin D metabolism, disorders of copper metabolism, and premature birth. DNA or biochemical testing may be necessary.

References

Sutton VR. Differential Diagnosis of Osteogenesis Imperfecta in Children (253-266). In Shapiro JR. (Ed.). (2014). Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease 1st edition. New York, NY: Elsevier Academic Press.

Bober MB (Ed.). (2013). Introduction to Osteogenesis Imperfecta: A Guide for Medical Professionals, Individuals and Families Affected by OI. Gaithersburg, MD: Osteogenesis Imperfecta Foundation.

Website- Information about and resources for genetic testing may be found on GeneTests (www.genetests.org) or the GTR: Genetic Testing Registry (http://www.ncbi.nlm.nih.gov/gtr/).

AttributionThank you to Dr. Peter Byers, University of Washington in Seattle for reviewing this document. February 2015.

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