Forgotten Diseases Research Foundation

Osteogenesis imperfecta (type 5)


Osteogenesis imperfecta, or OI, is a disorder whose most obvious feature is fragile to extremely fragile bones that are prone to fracturing. There are many subtypes of OI, but brittle bones and fractures are common to all of them and are the defining feature of this family of conditions. OI is sometimes called Brittle Bone disease.

The subtypes of OI are numbered from 1 to 5. Disease severity varies, with type 1 being the mildest (life expectancy is on the average) and type 2 being the most severe (patients tend to die before birth or within weeks of birth). In mild cases, a patient may suffer only a few or no broken bones during his or her life, while in the more severe forms, bones break without apparent cause. In some cases, multiple fractures occur before birth. In addition, disease severity varies widely not only among different subtypes, but even among patients with the same subtype --- even among members of the same family. The reasons for these differences are not well understood.

OI was originally classified into 4 subgroups (1), with OI type 5 added in the early 2000s (2). Many studies published since this classification was made have argued that there are additional subtypes of OI, such as OI type 6, which is caused by a gene previously not associated with another disease or with OI (3, 4). However, a very recent paper left the classification at 5 subtypes, noting that there was considerable overlap among the candidates for new subtypes (5). The classification scheme for OI does not appear to have been finalized, however.

Clinical information

Signs and symptoms

OI 5 resembles other forms of OI and primarily affects the musculoskeletal system. Its most consistent feature is calcification (hardening) of a tissue called the interosseous membrane, or IM. The IM connects the two bones in the forearm and keeps them stable (see images at the bottom of this page). When it hardens, it loses flexibility, and a person begins to have trouble moving his lower arm. The most common problem is reduced ability to rotate the palms up and down when the arm is bent at the elbow. In a majority of cases, the defect is severe enough to cause dislocation of the head of the radius bone (see photo at right). This particular dislocation is very common in OI type V, and is absent or uncommon in other forms of OI.

Another important clinical feature of type 5 OI is the formation of calluses on bones (see photos on this page). These abnomalities are called hyperplastic calluses or hypertrophic calluses. They often form at sites where a fracture has healed, but may also form spontaneously in other places. They may cause swelling and discomfort. No one knows why they form, and they often resolve by themselves. These formations resemble tumors called osteosarcomas, and although osteosarcoma is not associated with type 5 OI, they should be investigated to ensure correct identification, especially in a person who does not have a definitive diagnosis of type 5 OI. Conversely, it may be wise to rule out osteosarcoma in a patient with bone fragility or other signs of OI.

The most common signs and symptoms of OI type 5 are as follows:

    Clinical features of OI type 5

  •  Extremely brittle bones (may break before birth or as a result of minimal or no apparent force)
  •  Hyperplastic calluses (calcified masses of tissue; often appear at the site of a fracture)
  •  Osteopenia or osteoporosis (low or very low bone density) in a person under age 50
  •  Reduced ability to turn palms up and down with forearm extended
  •  Calcification of membrane connecting the bones of the forearm
  •  Dislocation of the elbow at the head of the radius (see photos)
  •  Wormian bones (extra bone pieces in a suture in the skull)
  •  Bowing of the long bones (arm and leg bones; see images)
  •  Compression fractures of the vertebrae
  •  Delays in motor development
  •  Short or very short stature
  •  Scoliosis

OI type 5 does not appear to affect cognitive ability/IQ. A small minority of patients have heart disease. Hearing loss and blue or grey sclerae are common in other forms of OI, but are uncommon in OI type 5.

Diagnosis and Testing

OI-V is an autosomal dominant disorder caused by mutations in the gene IFITM5. The term autosomal dominant means that a disease can be passed from one affected parent to a child. Thus, many people with type 5 OI have a parent who also has the disease. When we did our literature review, we found that 40% of 105 people with OI type 5 had a parent who also had OI type 5. In the other cases, the disease occurred sporadically in a family without a history of OI. In these cases, the mutation occurred spontaneously in an egg or sperm for reasons that are not known.

Criteria for diagnosing OI type 5 were laid out in the original report of the disease (2). The authors of that study distinguished OI type 5 from other forms of OI based on the following three clinical features:

  •  Calcification of the interosseous membrane of the forearms
  •  A tendency to develop hyperplastic calluses, especially after fractures
  •  Bone biopsies that show a meshlike pattern of bone lamellation (polarized light microscopy)

The interosseous membrane (IM) is a strip of soft tissue that connects the two bones of the arm (see photo below) and stabilizes them. The term calcification means that of this tissue is replaced by calcium. The calcium hardens the tissue, and it loses flexibility. The forearm becomes stiff and painful, and loses range of motion. In addition, the forearm becomes less stable and dislocations can result (see photo and X-rays on this page). IM calcification is very common in OI type 5. We found that it occurred in 91% of 137 patients, with elbow dislocations happening to ~70% of those patients. IM calcification may not always be found in very young patients, such as those under age 10 (for examples, see references 6-9).

A hyperplastic callus is a hard mass of bony, fibrous, and cartilaginous tissue that develops around bones. These calluses are also calcified. They tend to occur at sites of fracture or injury in OI, but some occur elsewhere for no known reason. The X-ray images on this page show examples of hyperplastic calluses. A limb with one of these calluses can become very swollen.

Important note. It is important to distinguish hyperplastic calluses from tumors and tumor-like lesions. These include osteosarcomas and osteochondromas. Although these conditions are not typically associated with OI type 5, osteosarcomas are very serious nonetheless, and should be ruled out (especially at first occurrence and most especially in a patient who does not have a definitive, molecularly confirmed diagnosis). MRI and CT scans can help distingish a callus from a sarcoma (10).

The connection between IFITM5 and OI type 5 was discovered in 2012 (8, 11). Before then, people used lab testing for OI type 5 by ruling out mutations in the two collagen genes that cause most other forms of OI. Today, a diagnosis suspected on clinical features can be confirmed by finding a mutation in IFITM5. For a list of labs that perform testing, see the links at right.

Disease Management

A focus of managing all types of OI is to minimize fractures and disabilities while helping a patient live as independently as possible (12). Ideally, patients should have access to a diverse team of specialists who can help them in this regard. Surgeries (including rod insertions) are common approaches to treating OI. Other approaches include medicines that help maintain bone mineral density, such as bisphosphonates including pamidronate (13). For a full discussion on managing all types of OI, see reference 12.

Differential Diagnosis

OI type I. OI type 1 is the mildest form of OI. It is also the most common, with ~90% of OI cases classified as type 1 (5). Type I OI is characterized by bone fractures, which tend to begin around the time a child learns to walk. They become less common after puberty, but may recur after a patient has had a baby or after menopause. Fractures are rare in infants with type I OI, whereas they may even occur before birth in type 5 and other forms of OI. Other similarities between types I and V include short or very short stature, scoliosis and other problems involving curvature of the spine, bowing of the long bones, bones, and loose or hyperexensible joints. People with OI type I tend to have blue sclerae (the whites of their eyes are blue or grey). This trait occurs in OI type 5, but is relatively rare in type 5 and relatively common in type 1. The presence of one or more of the features noted above in the Diagnosis section be the best ways to distinguish OI type 5 from type 1 clinically. Genetic testing can give a definitive answer, as OI type 1 is caused by mutations in either COL1A1 or COL1A2.

OI type 4. This subtype of OI is called the moderate form, though disease severity varies from being relatively mild (only a few fractures over the course of a life) to severe (fractures present at birth). In this sense, types 4 and 5 overlap. In addition, people with OI types 4 and 5 may also have similar facial features (a triangular face and a prominent forehead, for example) and abnormal spinal curvature. However, there are key differences between the two conditions. Many people with OI type 4 have a dental condition that makes their teeth brittle and discolored. This condition is called dentinogenesis imperfecta. It does not appear to be a feature of OI 5 --- for example, in our reivew, no one among 132 cases reporting on this problem had it. In addition, people with OI type 4 do not have calcification of the interosseous membrane. Testing for genetic mutations can distinguish the two conditions, as OI 5 is caused exclusively by mutations in IFITM5. Type 4 OI is associated with a number of genes, including COL1A1, COL1A2, CRTAP, PPIB, FKBP10, SERPINF1, and WNT1.

OI type 3. This subtype of OI is called the progressively deforming form. Overall, it is more severe than type 5 OI, although the level of bone fragility varies widely. Some newborns with type 3 OI have multiple bone fractures, and they may have respiratory troubles and difficulty swallowing. Adults tend to be very short (less than 42 inches). As with type 4 OI, dentinogenesis imperfecta is common, and if it is present, it is an indicator that the patient does not have type 5 OI. Bone malformation tend to get worse with time in this form of OI, which is why it is called the progressively deforming form. In particular, the long bones of the arms and legs and the ribs become deformed. Many patients require wheelchairs. Most cases of type 3 OI are caused by mutations in COL1A1 or COL1A2, but 13 other genes are also associated with type 3.

OI type 2. This form of OI is the most severe form. Patients with type 2 OI do not generally survive longer than a few weeks, and many die before birth or around the time of birth. OI Death is usually due to respiratory and cardiac problems. Patients with OI types 2 and 5 may develop fractures before birth, but are caused by different genes. In contrast, life expectancy in type 5 is higher, with some patients in our literature survey being in their 40s and 50s. Given that the condition was first described only in 2002, it is not possible to make predictions about survival past those ages.



References

  1. 1. Sillence DO et al. (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet  16(2):101-116. Full text on PubMed.
  2. 2. Glorieux FH et al. (2000) Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res  15(9):1650-1658. Full text from publisher.
  3. 3. Glorieux FH et al. (2002) Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res  17(1):30-38. Full text from publisher.
  4. 4. Homan EP et al. (2011) Mutations in SERPINF1 cause osteogenesis imperfecta type VI. J Bone Miner Res  26(12):2798-2803. Full text on PubMed.
  5. 5. Tournis S & Dede AD (2017) Osteogenesis imperfecta - A clinical update. Metabolism  in pressdoi: 10.1016/j.metabol.2017.06.001. Abstract on PubMed.
  6. 6. Kim OH et al. (2013) Osteogenesis imperfecta type V: clinical and radiographic manifestations in mutation confirmed patients. Am J Med Genet A  161A(8):1972-1979. Abstract on PubMed.
  7. 7. Liu Y et al. (2016) Osteogenesis imperfecta type V: Genetic and clinical findings in eleven Chinese patients. Clin Chim Acta  462:201-209. Abstract on PubMed.
  8. 8. Semler O et al. (2012) A mutation in the 5'-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet  91(2):349-357. Full text on PubMed.
  9. 9. Zhang Z et al. (2013) Phenotype and genotype analysis of Chinese patients with osteogenesis imperfecta type V. PLoS One  8(8):e72337. doi: 10.1371/journal.pone.0072337. Full text on PubMed.
  10. 10. Renaud A et al. (2013) Radiographic features of osteogenesis imperfecta. Insights Imaging  4(4):417-429. Full text on PubMed.
  11. 11. Cho TJ et al. (2012) A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet  91(2):343-348. Full text on PubMed.
  12. 12. Steiner RD et al. (2005) OL1A1/2-Related Osteogenesis Imperfecta Updated 4 February 2013. GeneReviews [Internet]  Pagon RA et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2018. Full text.
  13. 13. Blouin S et al. (2017) Hypermineralization and high osteocyte lacunar density in osteogenesis imperfecta type V bone indicate exuberant primary bone formation. J Bone Miner Res  32(9):1884-1892. Abstract on PubMed.
  14. 14. Lazarus S et al. (2014) A brilliant breakthrough in OI type V. Osteoporos Int  25(4):399-405. Abstract on PubMed.
  15. 15. ShakataGaNai, Wikimedia Commons user (2017) Photograph on the Wikimedia Commons.
  16. 16. Fujino T et al. (2010)Sporadic osteogenesis imperfecta type V in an 11-year-old Japanese girl. J Orthop Sci  15(4):589-593. Abstract on PubMed.
  17. 17. Patel MS, Radiopedia contributor (no date given) Image of forearm with abcess. Image and case history on the Radiopedia.
  18. 18. ShakataGaNai, Wikimedia Commons user (2017) Photograph on the Wikimedia Commons.




Above: A girl with OI5 and a dislocated elbow (14).

Below: A hyperplastic callus in OI5 (9).




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Above: Left. An X-ray of the arms of a person with OI type 5. The image shows
numerous abnormalities, including dislocation of the elbow at the radial head (top left),
bowing of the long bones, and a hyperplastic callus (left, where the bone is most rounded.
See reference 15.



Below left: The interosseous membrane (IM) links the bones in the forearm. The radial
head is also shown in the picture (top left).
Below middle: X-ray showing a forearm with a normal interosseous membrane (Radiopedia).
Below right: X-ray showing calcification of the interosseous membrane. See reference 16.
for details.

For a larger image and copyright information, click here.



Below: An x-ray showing a hyperplastic callus behind a child's femur. The callus
callus formed after the bone had been fractured. Asterisks show the callus; the
arrow shows the location of the fracture. Source: reference 10.





Page last modified on 5 December 2017.