Genetics of Osteogenesis Imperfecta Clinical Presentation

Updated: Aug 02, 2021
  • Author: Eric T Rush, MD, FAAP; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Many patients with osteogenesis imperfecta (OI), particularly individuals with the more severe forms, have acquired the disease through de novo pathogenic variants, although some patients, particularly those with mild forms, have inherited the disease from a parent. 

Patients may present with spontaneous fracture or fracture from minor trauma.

In severe cases, prenatal screening ultrasonography performed during the second trimester may show bowing of long bones, fractures, limb shortening, and decreased skull echogenicity. Lethal OI cannot be diagnosed with certainty in utero, and it is important for perinatal providers to understand the clinical variability of disease. .

Patients with OI may have joint hypermobility, especially of the small joints. Skin can also be fragile, and patients may describe easy bruising.

Unlike individuals with some other brittle bone diseases (such as inherited forms of rickets), patients with OI tend to heal avidly. However, because of the sheer number of fractures, nonunion or delayed union is not rare. 

Hearing loss is a variable feature of OI. About 50% of patients with type I OI have hearing loss by age 40 years. [47]  A North American study, by Machol et al, indicated that hearing loss occurs less often in COL1A1/COL1A2-related OI than previous research has determined, reporting a 28% prevalence. In type I OI, the rate was found to increase with patient age, while in types III and IV, no such change was seen. However, the investigators determined that in types III and IV, the risk of hearing loss is higher in the first decade of life than it is in type I. [48]



Physical examination can vary depending on the severity. Degrees of severity may vary to some extent among different affected members of the same family.

Type I - Mild, nondeforming

See the list below:

  • Patients have no long-bone deformity.

  • The sclera can be blue or white. Blue sclera may also occur in other disorders, such as progeria, cleidocranial dysplasia, Menkes syndrome, cutis laxa, Cheney syndrome, and pyknodysostosis.

  • Dentinogenesis imperfecta may be present.

  • Over a lifetime, numbers of fractures can range from 1-60 or more.

  • Height is usually normal in individuals with mild forms of osteogenesis imperfecta, but may be less than unaffected members of their family. [49]

  • People with osteogenesis imperfecta have a high tolerance for pain. Old fractures may be discovered in infants only after radiographs are obtained for other reasons other than an assessment of osteogenesis imperfecta, and they can occur without any signs of pain.

  • Exercise tolerance and muscle strength are frequently reduced in patients with osteogenesis imperfecta, even in the mild forms.

  • Fractures are most common during infancy but may occur at any age.

  • Other possible findings include kyphoscoliosis, hearing loss, [50] premature arcus senilis, and easy bruising.

Type II - Perinatal lethal

See the list below:

  • Some providers who treat large numbers of patients with osteogenesis imperfecta suggest that the diagnosis of Type II OI be made in retrospect for patients who do not survive the perinatal period, and that even patients with very severe forms of OI who nonetheless are long term survivors be classified as Type III.

  • Blue sclera may be present.

  • Patients may have a small nose, micrognathia, or both.

  • All patients have in utero fractures, which may involve the skull, long bones, and/or vertebrae.

  • The ribs are beaded, and the long bones are severely deformed.

  • Causes of death include extreme fragility of the ribs, pulmonary hypoplasia, and malformations or hemorrhages of the CNS.

Type III - Severe, progressively deforming

See the list below:

  • Patients may have joint hyperlaxity; muscle weakness; chronic, unremitting bone pain; and skull deformities (eg, posterior flattening) due to bone fragility during infancy.

  • Deformities of upper limbs may compromise function and mobility.

  • The presence of dentinogenesis imperfecta is independent of the severity of the osteogenesis imperfecta.

  • The sclera have variable hues.

  • In utero fractures are common.

  • Limb shortening and progressive deformities can occur.

  • Patients have a triangular face with frontal and temporal bossing. Malocclusion is common.

  • Basilar invagination is an uncommon but potentially fatal occurrence in osteogenesis imperfecta.

  • Vertigo is common in patients with severe osteogenesis imperfecta.

  • Hypercalciuria may be present in about 36% of patients with osteogenesis imperfecta, and adults may be at higher risk of renal calculi. [51]

  • Respiratory complications secondary to kyphoscoliosis are common in individuals with severe osteogenesis imperfecta.

  • Constipation and hernias are also common in people with osteogenesis imperfecta.

Type IV - Common variable

See the list below:

  • This type of osteogenesis imperfecta is not as clearly defined as other types.

  • Height is extremely variable with some patients having near-normal height and others having significantly short stature. [49]

  • Dentinogenesis imperfecta may be present. Some have suggested that this sign can be used to divide type IV osteogenesis imperfecta into subtypes a and b.

  • Fractures usually begin in infancy, but in utero fractures may occur. The long bones are usually bowed, although typically not as severe as patients with type III.



Osteogenesis imperfecta is an inherited disorder. In Types I-V osteogenesis imperfecta, the mode of inheritance is autosomal dominant and often involves a new dominant mutation. This accounts for between 90-95% of the total disease burden. The remaining 5-10% of patients show an autosomal recessive inheritance pattern, with both parents generally being asymptomatic carriers.

Some have proposed possible germ-cell mosaicism as an explanation for cases occurring in families with healthy parents that have more than one child with osteogenesis imperfecta. In some cases, somatic mosaicism has been noted in parents who have had multiple children with the same dominant form of osteogenesis imperfecta.