OVERVIEW: What every practitioner needs to know

Are you sure your patient has Osteogenesis imperfecta? What are the typical findings for this disease?

Osteogenesis imperfecta (OI) is a group of inherited genetic disorders with a wide range of clinical heterogeneity.

  • Bone fragility is the cardinal feature of osteogenesis imperfecta

  • Dentinogenesis imperfecta, hearing loss (may appear early in life or be progressive, post-pubertal), blue sclerae, joint laxity, and short stature are found to varying degrees in the different types of OI.

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No diagnostic criteria, such as are available for Marfan syndrome, have been published for the different types of osteogenesis imperfecta.

Types of Osteogenesis Imperfecta:

Type I – Mild type. Blue sclerae, bone fragility, average stature

Type II – Perinatal lethal type. Extreme bone fragility, neonatal fractures, blue sclerae

Type III – Progressive deforming type. Dwarfism (severe short stature), bone fragility with progressive deformity, blue sclerae, dentinogenesis imperfecta

Type IV – Mild deforming type. Dentinogenesis imperfecta, mild short stature, light sclerae

Osteogenesis types I-IV are inherited as autosomal dominant conditions.

Types V – XII all cause autosomal recessive OI of moderate severity.

What other disease/condition shares some of these symptoms?

Unexplained fractures may lead to a suspicion of child abuse. It is estimated that up to 7% of cases of suspected child abuse may have an underlying genetic cause resulting in bone fragility. To distinguish between osteogenesis imperfecta and child abuse, a child with unexplained fractures should have a careful family history, a detailed physical examination to look for signs of osteogenesis imperfecta, and consideration of a referral to a health care professional with experience in the diagnosis and management of osteogenesis imperfecta.

Other genetic conditions that may present with bone fragility include:

Cleidocranial dysplasia – moderate short stature, frontal bossing, aplastic clavicles, delayed tooth eruption, osteosclerosis.

Dysosteosclerosis – disproportional short stature, deafness, blindness, delayed closure anterior fontanelle, frontal bossing, delayed tooth eruption, osteosclerosis, platyspondyly.

Bruck syndrome (osteogenesis imperfecta with congenital contractures) – congenital joint contractures, including club feet, wormian bones. Sclerae may be normal or blue.

Osteoporosis-pseudoglioma syndrome – pseudoglioma causing blindness in infancy, bone fragility with unprovoked fractures, skeletal deformities.

Cole-Carpenter syndrome – shallow orbits with ocular proptosis, craniosynostosis, hydrocephalus, multiple fractures.

Hadju-Cheney syndrome – short stature, distal brachydactyly, vertebral anomalies, joint laxity, bowed fibulae, wormian bones osteopenia, conductive hearing loss.

What caused this disease to develop at this time?

OI types I – IV are caused by mutations in the genes encoding type I collagen, COL1A1 and COL1A2.

OI type V is an autosomal recessive form of OI; the causative gene has not yet been found.

OI type VI is an autosomal recessive form of OI caused by homozygous mutations in FKBP10, chromosome 17q21.

OI type VII is autosomal recessive, caused by caused by homozygous or compound heterozygous mutations in the CRTAP gene.

OI type VIII – autosomal recessive – LEPRE1 gene.

OI type IX – autosomal recessive – PPIB gene.

OI type X – autosomal recessive – SERPINH2.

OI type XI – autosomal recessive – SP7.

OI type XII – autosomal recessive – SERPINF1.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Sequence analysis of COL1A1 and COl1A2 cDNA – detects mutations in the exons of these genes.

Sequence analysis of COL1A1 and COl1A2 genomic DNA – detects mutations that alter mRNA stability or mRNA sequence (splice site changes).

Mutation detection rate varies by type of OI. Because of the wide variety of sub-types and significant clinical and genetic heterogeneity, it is recommended that a referral to a genetics center familiar with the diagnosis and management of OI be made if the diagnosis is suspected.

In types V, VI and VII OI, histological examination of bone from an iliac crest biopsy shows retained lamellar structure, reduction of cancellous bone volume and cortical width, and an increase in bone remodeling. In Type VI, but not V or VII, there is a characteristic “fish scale” appearance on polarized light microscopy.

Comprehensive DNA diagnostic testing is available for types IIB, VI-XII if autosomal recessive osteogenesis imperfecta is suspected.

Would imaging studies be helpful? If so, which ones?

A skeletal survey may be done to look for wormian bones, evidence of healing or healed fractures, bowing of the long bones, platyspondyly, or scoliosis.

If you are able to confirm that the patient has Osteogenesis imperfecta, what treatment should be initiated?

  • Physical medicine – stabilize lax joints by bracing or orthotics; physical and occupational therapy to promote improved mobility, contraction prevention, muscle toning and strengthening.

  • Analgesia for pain associated with fractures.

  • Orthopedic treatment including intramedullary rodding to anatomically position limbs to enable the best possible function.

  • Consideration of bisphosphanate therapy.

  • Treatment of hearing loss early in life, which is usually conductive, may involve surgical repair of fractures of bones in the inner ear and/or replacement of the incus. Hearing loss that develops later is generally sensorineural and may benefit from cochlear implantation.

What are the adverse effects associated with each treatment option?

Bisphophonate therapy has been investigated in both children and adults with OI. A 2009 Cochrane review found that while increased bone mineral density has been demonstrated with bisphophonate therapy, the functional effects on fracture frequency, pain and quality of life remain to be established.

What are the possible outcomes of Osteogenesis imperfecta?

The prognosis for osteogenesis imperfecta depends on the type of OI; with outcomes varying from neonatal death in type II to relatively mild phenotypes in types I and IV, with a wide range of variation in between these two extremes.

What causes this disease and how frequent is it?

If one considers all type of OI together, the estimated prevalence is 6-7 per 100,000. The two mildest forms of OI, types I and IV, account for more than half the cases, and mutations in type I collagen (OI types I, II, III and IV) account for 90% of cases with OI. Mutations in a long list of other genes involved in bone metabolism account for the remaining cases of autosomal recessive OI. These genes include FKBP10, CRTAP, LEPRE1, PPIB, SERPINH1 and 2, and SP7.

How do these pathogens/genes/exposures cause the disease?

Type I collagen is the most prevalent collagen in bone, and mutations that alter the structure of type I collagen, or the amount of type collagen synthesized, cause changes in the integrity of the bone resulting in increased fragility and fracture risk.

Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?


Are additional laboratory studies available; even some that are not widely available?


How can Osteogenesis imperfecta be prevented?

If the disease-causing mutation is known for autosomal dominant forms of OI, prenatal or pre-implantation diagnosis is an option. If a couple has had a child with an autosomal recessive form, and the disease-causing mutations in both parents are found, prenatal or pre-implantation diagnosis may also be offered.

What is the evidence?

Paterson, CR, Ogston, SA, Henry, RM. “Life expectancy in osteogenesis imperfecta”. BMJ. vol. 312. 1996. pp. 351

Plotkin, H. “Syndromes with congenital brittle bones”. BMC Pediatr. vol. 4. 2004. pp. 16(A good discussion of the differential diagnosis of fractures in the new-born period.)

Rauch, F, Travers, R, Parfitt, AM, Glorieux, FH. “Static and dynamic bone histomorphometry in children with osteogenesis imperfecta”. Bone,. vol. 26. 2000. pp. 581-9. (Discussion of how histology on iliac crest bone biopsy may add to the diagnosis of OI.)

Steiner, RD, Pepin, MG, Byers, PH. “Osteogenesis Imperfecta”. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2011. (This is a comprehensive review of Osteogenesis Imperfecta, including disease characteristics, diagnosis and testing, management and genetic counseling issues for all types of OI known at the time it was written.)

Ongoing controversies regarding etiology, diagnosis, treatment