AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Background

Osteogenesis imperfecta (OI) is a common heritable disorder of collagen synthesis that results in weak bones that are easily fractured and often deformed. Several distinct subtypes have been identified. All of them lead to variable degrees of micromelic (short-limbed) dwarfism. Depending on severity, the bone fragility may lead to perinatal death or cause severe deformities into adulthood. A wide array of clinical manifestations of the disease may be seen. These partly depend on the genetic subtype of OI.

In OI, the modes of inheritance, family history, clinical features, and radiologic findings vary. This variability forms the basis for the current accepted classification system, which Sillence et al first proposed in 1979.

Four distinct types are identified: type I, or dominantly inherited form with blue sclerae; type II, or perinatal lethal form; type III, or progressively deforming form with normal sclerae; and type IV, or dominantly inherited with normal sclerae.

In general, type I is the mildest form of disease, whereas types IV, III, and II indicate increasing severities of disease. These types are discussed in Clinical Details.

Key imaging hallmarks help distinguish OI from its major differential diagnosis, child abuse (nonaccidental injury). The multiplicity of fractures seen in OI commonly raises a concern about child abuse. Because the radiologist plays a central role in distinguishing these 2 entities (Ablin 1998), he or she must have an understanding of OI, its genetic variability, and its imaging appearance.

Pathophysiology

The primary pathology in OI is a disturbance in the synthesis of type I collagen, which is the predominant protein of the extracellular matrix of most tissues. In bone, this defect of extracellular matrix causes osteoporosis, which leads to an increased tendency to fracture. Besides bone, type I collagen is also a major constituent of dentin, sclerae, ligaments, blood vessels and skin; therefore, individuals with OI may also have abnormalities of these structures.

The process of collagen molecule formation starts with the synthesis of procollagen. This precursor consists of a long triple-helix protein flanked by 2 propeptides at its 2 terminals. Procollagen is synthesized and then secreted into the extracellular compartment, where the amino- and carboxy-terminal propeptides are cleaved; thus, the functional collagen molecule is formed. These molecules then assemble into an ordered fibril. Mutations that interfere with expression of the collagen gene, formation of the triple helix (amino acid sequencing), or procollagen secretion, affect the structure and function of collagen fibrils, resulting in a form of OI. Electron microscopic studies in OI demonstrate a decreased diameter of the collagen fibril compared to those of normal patients as well as smaller than normal apatite crystals.

A number of genetic defects cause abnormal type I collagen synthesis leading to OI. OI generally arises from mutations in 1 of 2 genes that encode for the synthesis and/or structure of type I collagen: the COL1A1 gene on chromosome 17 and the COL1A2 gene on chromosome 7. Mutations in these genes may cause some combination of the production of abnormal collagen and decreased production of normal collagen. The variability in combinations results in the different phenotypic expressions of OI (see Clinical Details). Milder forms of OI are caused primarily by the decreased production of normal collagen, while more severe forms are caused primarily by the production of abnormal collagen. These abnormalities may be dominantly inherited or the result of sporadic mutation.

Frequency

United States

The frequency of disease in Canada and the United States is believed to be similar to that reported in Australia (see Internationally below).

International

The frequency of OI is based primarily on data from the work of Sillence et al (1979) in Australia. Type I, the most common form of OI, occurs in 1 of 28,500 births. Type II, a rare lethal form of OI, occurs in 1 of 62,500 births. Type III OI occurs in 1 of 68,800 births. No reliable data exist for the frequency of occurrence of type IV OI.

Mortality/Morbidity

Common causes of non-orthopedic morbidity in type I and type IV OI are joint hypermobility causing chronic joint pain, hearing impairment, and brainstem compression.

Children with type III OI often require orthopedic care because of their progressive deformities. Standing and walking are often impossible because of spinal compression fractures and scoliosis. Progressive thoracic deformities are associated with recurrent pneumonias often limiting the patient's lifespan.

• Type I: The life expectancy of patients with all other forms of OI is often assumed to be shortened. However, according to Paterson et al (1996), life expectancy of patients with OI type IA is the same as that of the general population. Type IA is the subtype of type I OI without dentinogenesis imperfecta (tooth abnormalities). Type IB is the rare form of type I OI with dentinogenesis imperfecta (see Clinical Details for further information). In types IB and IV, mortality is modestly increased compared with that of the general population, with no statistically significant difference in life expectancy.
• Type II: This form of OI is fatal in the perinatal period.
• Type III: Only in type III OI is life expectancy affected. However, patients with type III OI surviving beyond the age of 10 years have a better outlook than other patients with OI.

Sex

No known sex predilection is reported.

Age

The onset of fractures and deformities varies according to the type of OI that is present.

For type I, the age of onset is variable. This form most commonly appears during the preschool years when the child is starting to stand. Onset after puberty is uncommon, although fractures may recur in adulthood after menopause or after periods of inactivity, such as after childbirth.

Type II occurs in utero.

In type III, abnormalities are present at birth (ie, develops in utero) in more than 50% of patients. Fractures are frequent during the first 2 years of life.

Type IV abnormalities are present at birth in approximately 30% of patients. The onset of this form is during infancy or the preschool years.

Clinical Details

The clinical features depend on the type of OI, but bone fragility with multiple fractures and bony deformities are the common hallmark of all types.

The major presenting signs and symptoms of OI include blue sclerae, hearing loss, tooth abnormalities (dentinogenesis imperfecta), joint laxity, and abnormal skin texture (smooth and thin skin). Other features that may be common to multiple OI types include bleeding diathesis (causing easy bruising), and respiratory distress.

OI is classified into 4 distinct types: I-IV. Some cases of OI do not fit easily into any of the 4 types. A type V category has been added (Glorieux, 2000) to include a group of individuals with osteoporosis, interosseous membrane ossification of the forearms and legs, and a high frequency of hypertrophic calluses.

Type I

This prototypical and most common form of OI has the best prognosis. The mode of inheritance is autosomal dominant. Its clinical distinguishing features are blue sclerae at all ages and presenile conductive hearing loss and/or a family history of hearing loss in most patients. Bone fragility is mild, with minimal bony deformities. The stature of patients with this form is often normal or near normal. Ligamentous hyperlaxity, resulting in joint hypermobility or subluxation, is common. Approximately 20% of patients have kyphoscoliosis.

Dentinogenesis imperfecta is present in some families but not in others. Therefore, type I OI is subclassified into patients without dentinogenesis imperfecta (type IA, more common) and those with dentinogenesis imperfecta (type IB, rare). Some have suggested that these 2 subgroups are biochemically distinct and that individuals with OI type IB, whose bodies make structurally abnormal collagen, are more similar to those with OI type IV than to those with other types of OI, including type IA.

Type II

This is the most severe form of OI, characterized by extreme bone fragility leading to intrauterine or early infant death, with only rare exceptions. The cause of death is most often respiratory failure. The mode of inheritance is autosomal recessive. The sclerae are blue and occasionally dark blue or black. Clinically distinguishing features include intrauterine growth retardation, thin and beaded ribs, crumpled long bones, and limited cranial and/or facial bone ossification. Limbs are short, curved, and angulated.

Type II OI can be further subdivided into types IIA, IIB, and IIC on the basis of the radiographic features of the long bones and ribs. See Radiography below for details. Although patients with types IIA or IIC uniformly die in the perinatal period, those with type IIB survive into early childhood in rare cases.

Type III

This is the next most severe form of OI after type II, and it is the most severe form for children surviving beyond the perinatal period. Its hallmark feature is severe bone fragility and osteopenia, which is progressively deforming. The mode of inheritance is thought to be autosomal recessive. Multiple fractures and progressive deformity affect the long bones, skull, and spine and are often present at birth. Postnatal growth failure is severe. Kyphoscoliosis is common. Sclerae are normal, either having been normal from birth or progressing from pale blue in infancy to a normal appearance by adolescence.

This form is probably the best known to radiologists and orthopedic surgeons because children with type II OI tend to have severe dwarfism due to spinal compression fractures, limb deformities, and disruption of growth plates.

Type IV

This form is distinguished from type I OI by the slightly increased, though still variable, severity of bone fragility, and by the presence of normal sclerae. The mode of inheritance is autosomal dominant. Mild-to-moderate bony deformity of the long bones and spine is present, with a variable frequency of fracture. Basilar impression of the skull, with consequent brainstem compression is common and reported in 70% of patients.

Hearing loss or a family history of hearing loss is noted in this type, as is dentinogenesis imperfecta. Type IV OI is also subclassified into patients without dentinogenesis imperfecta (type IVA) and those with it (type IVB). Compared with type I OI, hearing loss is less common in type IV, and dentinogenesis imperfecta (type IVB) is more common.

Some authors have suggested a self-limiting variant of OI, known as temporary brittle-bone disease. Its clinical features are identical to those found in cases of child abuse, and this entity is further discussed in Medical/Legal Pitfalls.

Preferred Examination

The preferred examination for the initial investigation of OI is plain radiography. Indeed, most of the imaging characteristics of OI are plain radiographic findings.

Prenatal ultrasonography plays a role in the diagnosis of OI, which is one of the more common skeletal dysplasias detected by using this test. Most cases of OI are found incidentally on sonographic examinations performed for other reasons but found to have fractures or decreased calvarial ossification or compressible calvaria with transducer pressure. Most of these cases of OI are type II, and the patients have no family history of the disease.

MRI plays an adjunct problem-solving role in assessing for associated complications, such as basilar invagination.

DIFFERENTIALS

Section 3 of 11  

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• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Other Problems to be Considered

Because osteoporosis and multiple fractures are hallmark features of OI, other disorders causing multiple fractures or decreased bone mineralization might be considered.

Juvenile osteoporosis
Steroid-induced osteoporosis
Menkes (kinky-hair) syndrome
Hypophosphatasia
Battered child syndrome (syndrome X)
Temporary brittle-bone disease

RADIOGRAPH

Section 4 of 11  

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Findings

In cases of suspected OI, postnatal radiographs should include views of the long bones, skull, chest, pelvis and thoracolumbar spine.

Radiographic features depend on the type of OI and on the severity of disease. Some findings, however, may be seen across all subtypes.

General radiographic features of OI

The radiologic sine qua non of OI is generalized osteoporosis of both the axial and appendicular skeleton.

Milder forms of OI result in thin, overtubulated (gracile) bones with thin cortices, and relatively few fractures (see Images 1-2). The short tubular bones are also affected, though they are less frequently fractured.

More severe forms of OI, such as in types II and III, feature thickened, shortened long bones with multiple fractures; these forms are often complicated by hyperplastic callus formation (see Image 3). The callus is most often found around the femur and often large, appearing as a dense, irregular mass arising from the cortex of bone. This callus is associated with thickened periosteum. Its presence causes other differential diagnostic considerations including: osteosarcoma, myositis ossificans, chronic osteomyelitis, and osteochondroma.

Radiographs of the skull may reveal normal skull development in milder forms of disease. With increasing disease severity, the skull demonstrates poor mineralization and multiple wormian, or intrasutural, bones (see Images 4-5).

The chest may be small. Multiple rib fractures are often found; these can cause the ribs to become broad and deformed.

Spinal abnormalities in all subtypes include platyspondyly, and scoliosis (see Type III findings below).

Recent advances in treatment of OI with bisphosphonates have resulted in specific imaging findings. Cyclical pamidronate treatment produces sclerotic growth-recovery lines in the long bones (see Image 1 and Image 6). The amount of bone growth between doses of pamidronate can be measured by the distance between these growth lines.

Type-specific radiographic features of OI

Some radiographic findings are more specific to certain subtypes of OI than others.

Type II

This group is further categorized into 3 subtypes based on radiologic features of the long bones and ribs. In types IIA and IIB, the long bones are short and broad because of undermodeling; the bones are also crumpled. In type IIC, the long bones are thinner (cylindrical) and longer than in the other subtypes, though they are still undermodeled.

The ribs in type IIA are short and broad with continuous beading. In type IIB, beading is absent or minimal and discontinuous. In type IIC, the ribs are thin and beaded.

Type III

General findings occur, plus several specific findings, as follows.

Scoliosis of the thoracolumbar spine: As many as 25% of patients with OI have scoliosis, and the association is even higher in type III OI (see Image 7). Most have an S-shaped scoliosis.

Severe platyspondyly with vertebral compression fractures and codfish vertebrae are more common in this type than others (see Image 8).

Popcorn calcifications occur commonly in this type in the metaphyseal-epiphyseal region of long bones, most commonly at the knee and ankle. This results from repeated microfractures at the growth plate.

Soft craniofacial bones with a large, thin calvarium, causing triangular facies.

Type IV

Radiographic findings of this type are similar to the general findings and those of type I.

One feature more commonly associated with type IV than other types is basilar invagination (impression) with or without brainstem compression. This may be detected on plain radiography of the skull or cervical spine. The McGregor line can be used to assess for this complication. This is defined as the straight line connecting the upper surface of the posterior edge of the hard palate to the most caudal point of the occipital curve. Projection of the tip of the odontoid process above the McGregor line suggests the presence of basilar invagination (see Images 9-10).

The presence of a large and thin cranium with platybasia and cranial settling may lead to the appearance of the Tam O'Shanter skull.

Degree of Confidence

The detection of hallmark bone findings in OI can be made with a high degree of confidence on plain radiographs and need not be confirmed with other imaging tests.

CT SCAN

Section 5 of 11  

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• CT SCAN
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• Ultrasound
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• References

Findings

The major role of CT currently is an adjunctive problem-solving one. CT can be used to further assess for basilar impression (see Image 9 and MRI below), to evaluate the petrous bone for narrowing of the middle ear or otosclerosis, and to support bone mineral densitometry (BMD) (see Nuclear Medicine below).

MRI

Section 6 of 11  

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• References

Findings

The major role of MRI in OI is a problem-solving one. MRI is also used to image complications of OI, such as basilar impression. Although cervical spinal radiography and CT can demonstrate this abnormality well, MRI has the advantage of detecting associated compression of the spinal cord (see Image 10).

Basilar impression has a high correlation with type IV OI. In particular, type IVB OI has an increased incidence of neurologic symptoms.

Other association conditions that may be imaged better with MRI include syringohydromyelia and communicating hydrocephalus, especially if developing after fontanelle closure.

ULTRASOUND

Section 7 of 11  

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• Ultrasound
• Nuclear Medicine
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• Multimedia
• References

Findings

OI is one of the most common skeletal dysplasias detected on prenatal ultrasonography, and most cases, usually Type II OI are found incidentally.

The diagnosis of OI can be made reliably by week 17 of gestation. The diagnosis can be made by detecting morphologic abnormalities on sonograms or by analyzing collagen synthesized by chorionic villus cells after sonography-guided chorionic villus sampling.

Sonographic findings of OI during the second trimester scanning include decreased echoes from the calvarium with supervisualized (too easily seen) intracranial structures, bowing and angulation of the long bones implying platic deformities and fractures, decreased length of the long bones, and multiple rib fractures.

NUCLEAR MEDICINE

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Findings

Bone mineral densitometry (BMD) results can confirm the severity of osteoporosis in patients with OI or the presence of demineralization in mild cases of type I or type IV OI.

Currently accepted BMD measurement techniques include the following: (1) cortical radial BMD measured by using single-photon absorptiometry (SPA), (2) BMD of the lumbar spine (children > 1 y) and femoral neck (children > 6 y) BMD obtained by using dual-energy x-ray absorptiometry (DXA), and (3) lumbar spinal BMD measured by means of CT in children older than 4 years.

Degree of Confidence

BMD measurements in young children with OI are reported in only a few cases, and as such, their reliability is unknown.

INTERVENTION

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• Mri
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

New approaches to treatment of OI are aimed at improving bone mass and include the use of bisphosphonates to decrease bone resorption and increase bone formation. Intravenous pamidronate is effective in promoting bone growth and relieving chronic pain when given cyclically, eg, every 4-6 months.

Medical/Legal Pitfalls

• Some authors have suggested the existence of a self-limiting variant of OI, known as temporary brittle-bone disease.
• This variant has been described as a fundamental transient defect in collagen formation and as a cause of multiple fractures in infants younger than 6 months.
• The radiologic and clinical features of this variant are the same as those noted in cases of child abuse.
• As there is little scientific evidence to support the existence of this self-limiting entity, controversy about how to deal with cases of possible child abuse exists in the medical and legal communities.

MULTIMEDIA

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• Multimedia
• References

Media file 1:  Frontal radiograph of the leg in a patient with type I osteogenesis imperfecta (OI) shows evidence of severe osteoporosis, overtubulation of both the tibia and fibula, and a healing fracture of the transverse diaphyseal of the tibia. Also note the multiple metaphyseal growth-recovery lines about the knee in this patient who was treated with pamidronate.
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Media type:  X-RAY

Media file 2:  Frontal radiograph of the forearm in a 17-year-old female adolescent with type I osteogenesis imperfecta (OI) shows osteoporosis, bowing deformities with overtubulation of the radius, a healed ulnar fracture, and callus formation over the distal humerus. Growth-recovery lines are present in the distal radius.
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Media type:  X-RAY

Media file 3:  Healing fracture of the left humeral diaphysis with callus formation in a patient with osteogenesis imperfecta (OI).
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Media type:  X-RAY

Media file 4:  Lateral radiograph of the skull in a young female patient with type III osteogenesis imperfecta (OI) demonstrates multiple wormian bones.
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Media type:  X-RAY

Media file 5:  Osteogenesis imperfecta (OI). Corresponding anteroposterior radiograph of the skull in the same patient as in Image 4 demonstrates multiple wormian bones.
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Media type:  X-RAY

Media file 6:  Frontal radiograph of the pelvis in a 9-year-old girl with type III osteogenesis imperfecta (OI) and bilateral healing femoral fractures. Multiple growth-recovery lines are present in the femoral heads bilaterally after bisphosphonate treatment. Scoliosis and squared iliac bones are also demonstrated.
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Media type:  X-RAY

Media file 7:  Frontal radiograph in a patient with type III osteogenesis imperfecta (OI) with severe S-shaped scoliosis of the thoracolumbar spine.
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Media type:  X-RAY

Media file 8:  Lateral spinal radiograph in a 1-year-old boy with osteogenesis imperfecta (OI) demonstrates multilevel, mild platyspondyly.
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Media type:  X-RAY

Media file 9:  Sagittally reconstructed CT scan of the cervical spine in a 16-year-old female adolescent with type IV osteogenesis imperfecta (OI). Image demonstrates mild basilar invagination, with the tip of the dens above the McGregor line (red).
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Media type:  CT

Media file 10:  Midline sagittal T2-weighted MRI through the cervical spine in the same patient as in Image 9. Image demonstrates mild stenosis at the foramen magnum due to basilar invagination (effective width of foramen magnum denoted by red line).
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Media type:  MRI

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• Mri
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

• Ablin DS. Osteogenesis imperfecta: a review. Can Assoc Radiol J. Apr 1998;49(2):110-23. [Medline].
• Ablin DS, Greenspan A, Reinhart M, Grix A. Differentiation of child abuse from osteogenesis imperfecta. AJR Am J Roentgenol. May 1990;154(5):1035-46. [Medline].
• Cole WG. Advances in osteogenesis imperfecta. Clin Orthop. Aug 2002;6-16. [Medline].
• Glorieux FH, Rauch F, Plotkin H, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res. Sep 2000;15(9):1650-8. [Medline].
• Kirks DR, ed. Musculoskeletal System. Practical Pediatric Imaging: Diagnostic Radiology of Infants and Children. 3rd ed. 1998: 362-3.
• Kleinman PK. Differential Diagnosis II: Osteogenesis Imperfecta. Diagnostic Imaging of Child Abuse. 2nd ed. 1998: 197-213.
• Kornblum M, Stanitski DF. Spinal manifestations of skeletal dysplasias. Orthop Clin North Am. Jul 1999;30(3):501-20. [Medline].
• Paterson CR, Ogston SA, Henry RM. Life expectancy in osteogenesis imperfecta. BMJ. Feb 10 1996;312(7027):351. [Medline].
• Sillence D. Osteogenesis imperfecta: an expanding panorama of variants. Clin Orthop. Sep 1981;11-25. [Medline].
• Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. Apr 1979;16(2):101-16. [Medline].
• Taybi H, Lachman RS. Osteogenesis Imperfecta. Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias, 4th ed. 1996: 876-82.

Article Last Updated: Dec 2, 2005