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Osteogenesis imperfecta

Reviewed April 2013

What is osteogenesis imperfecta?

Osteogenesis imperfecta (OI) is a group of genetic disorders that mainly affect the bones. The term "osteogenesis imperfecta" means imperfect bone formation. People with this condition have bones that break easily, often from mild trauma or with no apparent cause. Multiple fractures are common, and in severe cases, can occur even before birth. Milder cases may involve only a few fractures over a person's lifetime.

There are at least eight recognized forms of osteogenesis imperfecta, designated type I through type VIII. The types can be distinguished by their signs and symptoms, although their characteristic features overlap. Type I is the mildest form of osteogenesis imperfecta and type II is the most severe; other types of this condition have signs and symptoms that fall somewhere between these two extremes. Increasingly, genetic factors are used to define the different forms of osteogenesis imperfecta.

The milder forms of osteogenesis imperfecta, including type I, are characterized by bone fractures during childhood and adolescence that often result from minor trauma. Fractures occur less frequently in adulthood. People with mild forms of the condition typically have a blue or grey tint to the part of the eye that is usually white (the sclera), and may develop hearing loss in adulthood. Affected individuals are usually of normal or near normal height.

Other types of osteogenesis imperfecta are more severe, causing frequent bone fractures that may begin before birth and result from little or no trauma. Additional features of these conditions can include blue sclerae, short stature, hearing loss, respiratory problems, and a disorder of tooth development called dentinogenesis imperfecta. The most severe forms of osteogenesis imperfecta, particularly type II, can include an abnormally small, fragile rib cage and underdeveloped lungs. Infants with these abnormalities have life-threatening problems with breathing and often die shortly after birth.

How common is osteogenesis imperfecta?

This condition affects an estimated 6 to 7 per 100,000 people worldwide. Types I and IV are the most common forms of osteogenesis imperfecta, affecting 4 to 5 per 100,000 people.

What genes are related to osteogenesis imperfecta?

Mutations in the COL1A1, COL1A2, CRTAP, and P3H1 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 P3H1 genes are responsible for rare, often severe cases of osteogenesis imperfecta. Cases caused by CRTAP mutations are usually classified as type VII; when P3H1 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 one of the genes described above, 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.

Related Gene(s)

Changes in these genes are associated with osteogenesis imperfecta.

  • COL1A1
  • COL1A2
  • CRTAP
  • P3H1

How do people inherit osteogenesis imperfecta?

Most cases of osteogenesis imperfecta have an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the condition. Many people with type I or type IV osteogenesis imperfecta inherit a mutation from a parent who has the disorder. Most infants with more severe forms of osteogenesis imperfecta (such as type II and type III) have no history of the condition in their family. In these infants, the condition is caused by new (sporadic) mutations in the COL1A1 or COL1A2 gene.

Less commonly, osteogenesis imperfecta has an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means two copies of the gene in each cell are altered. The parents of a child with an autosomal recessive disorder typically are not affected, but each carry one copy of the altered gene. Some cases of osteogenesis imperfecta type III are autosomal recessive; these cases usually result from mutations in genes other than COL1A1 and COL1A2. When osteogenesis imperfecta is caused by mutations in the CRTAP or P3H1 gene, the condition also has an autosomal recessive pattern of inheritance.

Where can I find information about diagnosis or management of osteogenesis imperfecta?

These resources address the diagnosis or management of osteogenesis imperfecta and may include treatment providers.

  • Gene Review: COL1A1/2-Related Osteogenesis Imperfecta (http://www.ncbi.nlm.nih.gov/books/NBK1295)
  • Genetic Testing Registry: Osteogenesis imperfecta (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0029434)
  • Genetic Testing Registry: Osteogenesis imperfecta, recessive perinatal lethal (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0268360)
  • Genetic Testing Registry: Osteogenesis imperfecta type 5 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1970414)
  • Genetic Testing Registry: Osteogenesis imperfecta type 6 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1970413)
  • Genetic Testing Registry: Osteogenesis imperfecta type 7 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1853162)
  • Genetic Testing Registry: Osteogenesis imperfecta type 8 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1970458)
  • Genetic Testing Registry: Osteogenesis imperfecta type I (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0023931)
  • Genetic Testing Registry: Osteogenesis imperfecta type III (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0268362)
  • Genetic Testing Registry: Osteogenesis imperfecta with normal sclerae, dominant form (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0268363)
  • MedlinePlus Encyclopedia: Osteogenesis Imperfecta (http://www.nlm.nih.gov/medlineplus/ency/article/001573.htm)

You might also find information on the diagnosis or management of osteogenesis imperfecta in Educational resources (http://www.ghr.nlm.nih.gov/condition/osteogenesis-imperfecta/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/osteogenesis-imperfecta/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about osteogenesis imperfecta?

You may find the following resources about osteogenesis imperfecta helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for osteogenesis imperfecta?

  • Brittle bone disease
  • Fragilitas ossium
  • OI
  • Vrolik disease

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about osteogenesis imperfecta?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding osteogenesis imperfecta?

autosomal ; autosomal dominant ; autosomal recessive ; bone formation ; cell ; collagen ; dentinogenesis ; gene ; inherit ; inheritance ; mutation ; osteogenesis ; pattern of inheritance ; protein ; recessive ; respiratory ; sclera ; secretion ; short stature ; sporadic ; stature ; syndrome ; trauma

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Byers PH. Osteogenesis imperfecta: perspectives and opportunities. Curr Opin Pediatr. 2000 Dec;12(6):603-9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/11106283?dopt=Abstract)
  • Cabral WA, Chang W, Barnes AM, Weis M, Scott MA, Leikin S, Makareeva E, Kuznetsova NV, Rosenbaum KN, Tifft CJ, Bulas DI, Kozma C, Smith PA, Eyre DR, Marini JC. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007 Mar;39(3):359-65. Epub 2007 Feb 4. Erratum in: Nat Genet. 2008 Jul;40(7):927. (http://www.ncbi.nlm.nih.gov/pubmed/17277775?dopt=Abstract)
  • Cole WG. Advances in osteogenesis imperfecta. Clin Orthop Relat Res. 2002 Aug;(401):6-16. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12151877?dopt=Abstract)
  • Gene Review: COL1A1/2-Related Osteogenesis Imperfecta (http://www.ncbi.nlm.nih.gov/books/NBK1295)
  • Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, Bächinger HP, Pace JM, Schwarze U, Byers PH, Weis M, Fernandes RJ, Eyre DR, Yao Z, Boyce BF, Lee B. CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006 Oct 20;127(2):291-304. (http://www.ncbi.nlm.nih.gov/pubmed/17055431?dopt=Abstract)
  • Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004 Apr 24;363(9418):1377-85. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15110498?dopt=Abstract)
  • Roughley PJ, Rauch F, Glorieux FH. Osteogenesis imperfecta--clinical and molecular diversity. Eur Cell Mater. 2003 Jun 30;5:41-7; discussion 47. Review. (http://www.ncbi.nlm.nih.gov/pubmed/14562271?dopt=Abstract)
  • Venturi G, Tedeschi E, Mottes M, Valli M, Camilot M, Viglio S, Antoniazzi F, Tatò L. Osteogenesis imperfecta: clinical, biochemical and molecular findings. Clin Genet. 2006 Aug;70(2):131-9. Erratum in: Clin Genet. 2006 Nov;70(5):455. (http://www.ncbi.nlm.nih.gov/pubmed/16879195?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: April 2013
Published: December 22, 2014