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Nader Khandanpour, MD, PhD, FRCR • Daniel J. A. Connolly, BSc,
MRCP, FRCR • Ashok Raghavan, MD, FRCR • Paul D. Griffiths, PhD,
FRCR • Nigel Hoggard, MD, MRCP, FRCR
Osteogenesis imperfecta is a rare genetic disorder that leads to pro-
gressive skeletal deformities due to deficits in type I collagen, the
main pathophysiologic effect of the disease. In addition, it may lead
to a wide range of associated neurologic abnormalities: The central
nervous system is usually involved because of softening of bone at the
base of the skull, with resultant upward migration of the upper cervi-
cal spine and odontoid process into the skull base. Upward migration
of the spine may cause compression of the brainstem, mechanical
impingement of the spinal canal with restriction of cerebrospinal fluid
circulation, and impingement of the cranial nerves. Osteogenesis im-
perfecta also may directly involve neurovascular structures, leading
to cavernous fistulas of the carotid artery, dissection of the cervical
arteries, and cerebral aneurysms. The brain parenchyma is frequently
affected by the disease, with manifestations including cerebral atrophy,
communicating hydrocephalus, and cerebellar hypoplasia. The imag-
ing features of the disorder vary as widely as its clinical manifestations,
depending on the severity of disease. Severe forms accompanied by
debilitating skeletal fractures and progressive neurologic impairments
may lead to perinatal death, whereas milder asymptomatic forms
might cause only a modest reduction in life span. The most important
advance in medical therapy for osteogenesis imperfecta has been the
introduction of bisphosphonate therapy to slow the resorption of bone
in patients with moderate to severe forms of the disease (ie, type III or
IV). In some patients, neurosurgery may be necessary to correct the
effects of severe basilar invagination by the odontoid process.
©RSNA, 2012 • radiographics.rsna.org
malities and Neurologic
Complications of Os-
After completing this
will be able to:
tions of osteogenesis
imperfecta on im-
ages of the skull and
cations of craniocer-
vical involvement in
■List the treatment
options for osteo-
RadioGraphics 2012; 32:2101–2112 • Published online 10.1148/rg.327125716 • Content Codes:
1From the Academic Unit of Radiology, C Floor (N.K., P.D.G., N.H.), and Department of Radiology (D.J.A.C.), Royal Hallamshire Hospital, Uni-
versity of Sheffield, Glossop Rd, Sheffield, South Yorkshire, S10 2JF, England; and Department of Radiology, Sheffield Children’s Hospital, Sheffield,
England (A.R.). Received March 8, 2012; revision requested May 8 and received July 17; accepted August 21. For this journal-based CME activity, the
authors, editor, and reviewers have no relevant relationships to disclose. Address correspondence to N.H. (e-mail: Nigel.Hoggard@sth.nhs.uk).
2102 November-December 2012 radiographics.rsna.org
Osteogenesis imperfecta, also known as brittle
bone disease, is a genetic disorder affecting the
bones, joints, ears, eyes, skin, and other structures
that normally contain a substantial amount of type
I collagen. Because the main pathophysiologic ef-
fect of osteogenesis imperfecta is a reduction in
either the quality or the quantity of type I collagen,
it is categorized as a connective-tissue disease. The
collagen-encoding genes that are most commonly
impaired are COL1A1 and COL1A2; these genes
account for approximately 80% of cases of osteo-
genesis imperfecta (1–3). Some patients with os-
teogenesis imperfecta experience ligamentous lax-
ity, joint hyperflexibility, and dental abnormalities.
The annual incidence of osteogenesis imperfecta
in the United States and Canada is one in 10,000
to 20,000 births (4,5).
Seven distinct types of osteogenesis imper-
fecta have been described on the basis of specific
genetic mutations (6,7). Occurrences of osteo-
genesis imperfecta also can be classified into
four groups or types based on the clinical and
radiologic manifestations. According to the Sil-
lence classification system, type I osteogenesis
imperfecta (the most common type) is mild and
nondeforming, type II osteogenesis imperfecta
(the least common type) is a fatal perinatal form
of the disease, type III is severely deforming, and
type IV is less severely deforming. Precise classifi-
cation is difficult in some cases because the char-
acteristics of types I and IV and those of types II
and III tend to overlap.
In patients with type I disease, fractures are
much less common after puberty because ossifi-
cation is complete and the bones are stronger. In-
deed, patients with this form of disease may have
normal bone density in adulthood. The average
life expectancy of this group is slightly reduced
because of the risks of fatal bone fractures and
complications such as basilar invagination.
In utero fractures of the skull, vertebrae, and
long bones are hallmarks of type II osteogenesis
imperfecta. Other signs of this disease type in-
clude minimal vertebral ossification, beaded ribs,
and an abnormally small chest cage. Patients with
type II osteogenesis imperfecta tend to die within
the 1st year of life because of respiratory failure
secondary to pulmonary hypoplasia or because of
Type III is the most severe type of osteogenesis
imperfecta seen in children who survive the neo-
natal period. Patients with type III osteogenesis
imperfecta may have blue sclerae, a small nose,
a soft calvaria, and micrognathia. Unlike type I
disease, type III tends to progress over time if left
untreated. The average life expectancy for pa-
tients with type III osteogenesis imperfecta who
survive the 1st decade of life is slightly lower than
that for the general population (8).
The effects of type IV disease are generally
moderate, although they may vary in severity from
mild (similar to those in type I disease) to more
severe (resembling those in type III disease). The
sclerae usually appear normal in early adulthood.
The average life expectancy for patients with type
IV osteogenesis imperfecta might be slightly lower
than that for the general population (8).
The main features of each type of osteogenesis
imperfecta are summarized in the Table (9,10).
The remainder of the article describes the cra-
nial, craniospinal junction, and spinal manifesta-
tions of this disease.
Cranial complications of osteogenesis imperfecta
include a wide range of abnormalities of the skull
and brain parenchyma.
Characteristic Features of the Four Types of Osteogenesis Imperfecta
Bone FragilityColor of Sclerae
Second most severe
Routine childhood fracture
Prenatal US, perinatal death
Prenatal US, birth-related
fracture, frequent fractures
Routine childhood fracture
3–4 × 10–6
1–2 × 10–6
1–2 × 10–6
IVThird most severeNormal3–4 × 10–6
Sources.—References 9, 10.
*Events that often lead to diagnosis are described.US = ultrasonography.
†Annual incidence in the general population is given.
‡Some may be pale blue at birth but change to normal color later.
RG • Volume 32 Number 7 Khandanpour et al 2103
Figures 1–3. (1a) Lateral skull radiograph obtained in a child with type III osteogenesis imperfecta shows an
abnormally thin cranium, platybasia, basilar invagination, and multiple Wormian bones. Note the mild mandibular
prognathism and the anterior angulation of the upper and lower incisors. (1b) Posteroanterior skull radiograph depicts
multiple Wormian bones (arrows). (2) Lateral skull radiograph obtained in a patient with type III osteogenesis imper-
fecta shows marked flattening of the occiput with brachycephaly. (3) Lateral skull radiograph obtained in a 2-year-old
patient with type III osteogenesis imperfecta shows an anterior fontanel that remains wide open (arrowhead). Note the
poor mineralization of the cranium.
Skull and Skull Base Involvement
Patients with osteogenesis imperfecta may have
a triangular face shape with an unusually promi-
nent forehead (ie, frontal bossing) and, often,
mandibular malformation leading to malocclu-
sion. Generalized impairment of membranous
and endochondral bone leads to excessive
formation of Wormian bones (accessory bones
along the sutures) (Fig 1), with an abnormally
thin or thick calvaria and either premature or
delayed closure of the fontanels and sutures
(Figs 2, 3). Multiple Wormian bones may persist
into adulthood (11).
2104 November-December 2012 radiographics.rsna.org
Figure 5. Three-dimensional volume-rendered (a)
and coronal maximum intensity projection (b) im-
ages from CT angiography in a patient with type
I osteogenesis imperfecta show a 5-mm aneurysm
arising from the left middle cerebral artery bifurca-
Figure 4. Lateral skull radiograph obtained in a patient
with type III osteogenesis imperfecta depicts mild progna-
thism with resultant malocclusion of the lower and upper
incisors. Flattening of the occiput is also evident.
Premature fusion of the coronal suture restricts
anteroposterior skull growth and is followed by
compensatory overgrowth of the sagittal suture
laterally and lambdoid sutures caudally. The resul-
tant skull deformity is referred to as brachycephaly
(12) (Fig 2). The frontal fontanel is wider and re-
mains open longer than normal (Fig 3).
Patients with osteogenesis imperfecta may
be affected by mandibular prognathism (Fig 4).
Vertical underdevelopment of the dentoalveolar
structures and condylar processes are the main
contributors to this prognathism, which is usu-
ally mild (13).
Cerebral hemorrhage is a potentially fatal com-
plication of osteogenesis imperfecta. Intracranial
hemorrhages are attributed to the development
of moyamoya disease with subsequent subarach-
noid hemorrhage as well as to vertebral artery
damage, vascular fragility, spontaneous intracra-
nial hypotension, and friction between multiple
bone fragments in the skull (5,14–16). Carotid
cavernous fistulas, cervical artery dissection, and
cerebral aneurysms (Fig 5) all have been reported
to be associated with osteogenesis imperfecta
(14,17). There are numerous reports of cerebral
hemorrhages and spinal cord injuries in children
with osteogenesis imperfecta, but only a few case
reports of nontraumatic cerebral hemorrhage in
adults with the disease (18).
Patients with osteogenesis imperfecta may
develop generalized cerebral atrophy (19) (Fig
6). The pathophysiologic mechanisms associ-
ated with this process are not known; however,
impaired outflow of cerebrospinal fluid, deforma-
tion of the skull base, forces generated by neck
muscles that hold the head upright, and intracra-
nial venous outflow obstruction are hypothesized
to be causative factors (20,21). Hydrocephalus is
also common (22) (Fig 7).
Patients with osteogenesis imperfecta may
have a widened basal cistern (Fig 8), and the
sella may be located in a low ventral position
(23). There is evidence linking these abnormali-
ties to skull base deformity and abnormal man-
dibular growth (13).
RG • Volume 32 Number 7 Khandanpour et al 2105
Figures 6–8. (6) Axial T1-weighted (a) and T2-
weighted (b) brain MR images obtained in a 15-year-
old patient with type III osteogenesis imperfecta depict
cerebral atrophy that is generalized but most obvious in
the frontal and temporal lobes. (7) Axial unenhanced
CT image of the brain (5-mm section) in a patient with
type III osteogenesis imperfecta demonstrates bilateral
dilatation of the lateral and third ventricles. (8) Axial (a)
and coronal (b) proton density–weighted MR images of
the skull base in a patient with type III osteogenesis im-
perfecta show an abnormally wide basal cistern (arrow).
2106 November-December 2012 radiographics.rsna.org
Figure 9. US appearances of the brain in a neonate with type III osteogenesis imperfecta. (a) Coronal US image
shows prominence of the frontal horns of both ventricles (right lateral ventricle diameter = 28 mm, left lateral ventricle
diameter = 27 mm), an appearance suggestive of early ventricular dilatation, which may be a feature of osteogenesis
imperfecta. (b) Coronal US image shows prominent extraaxial spaces around the frontal lobes.
It has been shown that the antenatal manifes-
tations of type III osteogenesis imperfecta, such
as marked ventricular dilatation, shortening of
the long bones, and deformity of the femurs, may
be severe enough to make prenatal diagnosis pos-
sible in the second trimester (Fig 9). Prenatal
screening with US is therefore recommended in
the presence of a high familial risk for osteogen-
esis imperfecta (24).
There are reports of cerebellar hypoplasia,
which may be unilateral (25). The causative mech-
anism is believed to be in utero vascular compro-
mise due to compression of the posterior circula-
tion secondary to craniospinal anomalies (25).
Platybasia, basilar impression, and basilar in-
vagination may occur because of bone softening
in patients with osteogenesis imperfecta. These
three characteristics are distinct, and, despite
their frequent coincidence, they should be differ-
entiated when clinically assessing the craniocervi-
cal junction. Basilar invagination is a condition
in which the odontoid process protrudes upward
into the intracranial space, penetrating the fora-
men magnum (Fig 10) (26). Basilar impression,
or upward infolding of the foramen magnum rim
into the skull, may lead to medullary and cerebel-
The McRae line can be used to determine
whether basilar invagination is present. This line
is drawn from the anterior margin (basion) to the
posterior margin (opisthion) of the foramen mag-
num. The tip of the odontoid process normally
should be positioned below this line; if it is not,
then the odontoid process has crossed through
the foramen magnum into the intracranial space,
and basilar invagination is present. This condition
may lead to medullary distortion.
Figure 10. Reconstructed midline sagittal CT image of the
cervical spine of a patient with type III osteogenesis imperfecta
depicts protrusion of the odontoid process beyond the super-
imposed McRae line (straight red line), a finding indicative of
RG • Volume 32 Number 7 Khandanpour et al 2107
Figures 11, 12. Sagittal T2-weighted brain MR images obtained in a patient with type III osteogenesis imperfecta
show two alternative methods for measuring the odontoid process to determine whether basilar invagination is pres-
ent. (11) Image shows the odontoid process tip protruding 8.5 mm above the superimposed Chamberlain line (hori-
zontal yellow line), 5.5 mm beyond the maximal limit of normal location. (12) Image shows the tip of the odontoid
process protruding 13 mm above the superimposed McGregor line (horizontal yellow line), 8.5 mm beyond the
maximal limit of normal location. These findings are indicative of basilar impression; although marked platybasia is
seen, there is no basilar invagination.
It is sometimes difficult to identify the ba-
sion on images, and in such cases, an alternative
method, the Chamberlain line, may be useful.
This line is drawn between the posterior edge of
the hard palate and the posterior margin of the
foramen magnum (Fig 11). The odontoid pro-
cess normally should not project more than 3
mm above this line; if it does, basilar impression
The McGregor line, a modification of the
Chamberlain line, may be helpful for identify-
ing both the basion and the opisthion. The Mc-
Gregor line is drawn between the posterior edge
of the hard palate and the most caudal aspect of
the occiput (Fig 12). If the odontoid process is
more than 4.5 mm above this line, that finding is
indicative of basilar impression.
The McRae line is always used to identify bas-
ilar invagination, whereas the Chamberlain line
and McGregor line are used to identify basilar
impression with or without invagination. Invagi-
nation is defined by penetration of the odontoid
process through the foramen magnum, whereas
upward displacement of the posterior rim of the
foramen magnum (ie, basilar impression) may
occur without penetration of the odontoid pro-
cess through the foramen magnum.
Basilar impression and basilar invagination,
individually or in combination, may be associ-
ated with compression of the brainstem leading
to aqueductal stenosis, hydrocephalus (Figs 13,
14) (22), cord edema, and syrinx (Fig 15) (22).
Figure 13. Sagittal T2-weighted MR image of the skull
base and craniocervical junction shows platybasia in a
patient with type III osteogenesis imperfecta. Tonsillar
herniation is also seen (arrowhead), with compression of
the central canal at the junction of the medulla and the
spinal cord. A small focus of signal hyperintensity (arrow)
within the spinal cord at the level of the C2 vertebral body
is suggestive of early-stage hydrosyringomyelia.
2108 November-December 2012 radiographics.rsna.org
Figures 14, 15. (14a) Sagittal T2-weighted MR image obtained in a patient with type III osteogenesis
imperfecta depicts brainstem compression secondary to basilar impression. Note the absence of any sig-
nal abnormality suggestive of syrinx in the cervical spinal cord and the lack of cerebrospinal fluid flow at
the level of the foramen magnum (arrow). (14b) Sagittal T2-weighted MR image obtained in the same
patient 2 years later shows interim development of a syrinx (arrow) at the level of the C2 vertebral body.
(15) Sagittal T2-weighted MR image of the cervicothoracic spine in a patient with type III osteogen-
esis imperfecta depicts a syrinx extending from the C2 to the T7 vertebral level (arrows). Note the fish
mouth–like appearance of the intervertebral spaces.
These complications may necessitate surgical
decompression of the posterior cranial fossa or
foramen magnum or resection of the odontoid
process by using an anterior approach.
Conventional lateral skull radiography is usu-
ally the first-line imaging examination for de-
tecting basilar invagination. However, magnetic
resonance (MR) imaging is the optimal modality
for depicting abnormalities of the brain and spi-
nal cord. In particular, brain MR imaging is the
method of choice for evaluating tonsillar hernia-
tion, the earliest stage of development of a syrinx,
and changes in the posterior fossa, all of which
are indications for intervention. If left untreated,
causes of brainstem compression such as tonsillar
herniation may lead to rapid neurologic deterio-
ration, respiratory arrest, or sudden death (27).
Figure 16. Sagittal CT scan of the skull base shows
marked platybasia and elevation of the clivus (white
lines indicate an abnormal basal angle) in a patient
with type IV osteogenesis imperfecta. The odontoid
process does not protrude above the McRae line
(straight black line) marking the level of the foramen
magnum; thus, there is no basilar invagination.
RG • Volume 32 Number 7 Khandanpour et al 2109
Figures 17, 18. (17) Posteroanterior radiograph of the chest and abdomen in a patient with type III
osteogenesis imperfecta depicts thoracic scoliosis with rightward convexity of the spine. The thorax is
bell shaped. The ribs are broadened, and the lateral aspect of the left sixth rib shows evidence of fracture
(black arrow). Sclerosis of the superior and inferior endplates is seen, with an associated overall reduction
in vertebral body height. Note the bilateral fixation of the cervical pedicles with rods and pins, and the
ventriculoperitoneal shunt (white arrow). (18) Coronal (a) and sagittal (b) T2-weighted MR images of the
vertebral column in a patient with type IV osteogenesis imperfecta show a generalized loss of height of the
thoracic vertebrae, or platyspondyly (white arrows in b), with slight depression of the endplates (black ar-
rows in b). Note that some of the intervertebral disk spaces are almost as tall as the vertebral bodies.
Platybasia is a morphologic abnormality of the
skull base characterized by a basal angle of more
than 145° (Fig 16) (28). The basal angle is the
angle created by intersecting lines drawn from
the nasion to the tuberculum sellae and from the
tuberculum sellae along the clivus to the basion.
Abnormal bone structure, poor enchondral and
periosteal bone formation, and absence of lamel-
lar bone lead to cortical thinning in patients with
osteogenesis imperfecta. In addition, compact
bone may be largely replaced by spongiform
bone. Patients with osteogenesis imperfecta have
a wide range of radiologic abnormalities in the
spine, including diffuse osteopenia, defective cor-
tical bone formation, sclerosis of vertebral end-
plates, and biconcave vertebral bodies (Fig 17).
Patients with osteogenesis imperfecta may be
affected by severe kyphoscoliosis or marked lor-
dosis and scoliosis (29). Generalized loss of height
of the thoracic vertebrae (platyspondyly) is an-
other characteristic feature of the disease (Fig 18).
Deformity of the vertebral endplates produces a
biconvex or ellipsoid appearance of the interver-
tebral disk spaces, which resemble fish mouths on
lateral radiographs (Fig 19). In type II osteogen-
esis imperfecta, generalized osteoporosis of the
2110 November-December 2012 radiographics.rsna.org
Figure 21. Lateral radiograph of the lumbar spine in
a patient with type IV osteogenesis imperfecta demon-
strates a pars interarticularis defect in the L5 vertebral
body (arrow). Spondylolysis is seen with grade I spon-
dylolisthesis in the setting of generalized osteopenia.
Figure 20. Anteroposterior radiograph obtained in an
infant with type II osteogenesis imperfecta shows marked
shortening of the long bones, which contain multiple
fractures (an appearance sometimes described as “ac-
cordion bones”). The ribs are thin but not crumpled
and have a beaded appearance. Generalized osteoporosis
and minimal vertebral ossification are seen. Note the
small chest cage. The patient died at 1 year of age.
Figure 19. Lateral radiograph of the lower
thoracic and lumbar spine in a patient with
type III osteogenesis imperfecta shows marked
collapse of the vertebrae (black oval) due to
generalized osteopenia. The sclerotic endplates
and intervening ovoid disk spaces create a fish
mouth–like appearance that is sometimes re-
ferred to as “codfish vertebrae.”
spine, with minimal vertebral ossification, is seen
(Fig 20). There is evidence that as many as 5% of
patients with osteogenesis imperfecta suffer from
spondylolisthesis (Fig 21) (30), which has been
attributed in part to pedicle elongation (31).
Methods of Treatment
The essential pathophysiologic feature of osteo-
genesis imperfecta is increased bone turnover.
The most important advance in medical treat-
ment therefore has been the introduction of
bisphosphonate therapy for patients with a mod-
erate to severe form of osteogenesis imperfecta
(32). Bisphosphonates are effective in reducing
osteoclast-mediated bone resorption. Intravenous
pamidronate therapy administered in repeated
courses (once every 4–6 months) over several
years reduces the incidence of bone fractures and
increases bone density, vertebral body height, and
cortical bone thickness (33) (Fig 22).
In patients with severe basilar invagination,
neurosurgery may be necessary: Ventral decom-
pression, dorsal craniocervical stabilization, or
both procedures might be performed to treat the
RG • Volume 32 Number 7 Khandanpour et al 2111
effects of this condition (Fig 23) (29). Surgical
treatment has been shown to halt the progres-
sion of craniocervical junction distraction and
produce a good and sustainable long-term func-
tional outcome by affecting the degree of cranio-
medullary junction distortion (29). Immobiliza-
tion leads to disuse atrophy of the muscles and
ankylosis of the joints and therefore should be
Acknowledgment.—We acknowledge the kind help of
Glenys Everest, Medical Illustration Department at
Sheffield Hospitals, Sheffield, England, in preparing
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Orthop B 2003;12(2):77–87.
This journal-based CME activity has been approved for AMA PRA Category 1 Credit
TM. See www.rsna.org/education/search/RG.
Teaching Points November-December Issue 2012 Download full-text
Craniospinal Abnormalities and Neurologic Complications of Osteogenesis
Imperfecta: Imaging Overview
Nader Khandanpour, MD, PhD, FRCR • Daniel J. A. Connolly, BSc, MRCP, FRCR • Ashok Raghavan, MD,
FRCR • Paul D. Griffiths, PhD, FRCR • Nigel Hoggard, MD, MRCP, FRCR
RadioGraphics 2012; 32:2101–2112 • Published online 10.1148/rg.327125716 • Content Codes:
Premature fusion of the coronal suture restricts anteroposterior skull growth and is followed by compensa-
tory overgrowth of the sagittal suture laterally and lambdoid sutures caudally. The resultant skull deformity
is referred to as brachycephaly (12) (Fig 2). The frontal fontanel is wider and remains open longer than
normal (Fig 3).
Intracranial hemorrhages are attributed to the development of moyamoya disease with subsequent sub-
arachnoid hemorrhage as well as to vertebral artery damage, vascular fragility, spontaneous intracranial
hypotension, and friction between multiple bone fragments in the skull (5,14–16).
Platybasia, basilar impression, and basilar invagination may occur because of bone softening in patients
with osteogenesis imperfecta. These three characteristics are distinct, and, despite their frequent coinci-
dence, they should be differentiated when clinically assessing the craniocervical junction.
Patients with osteogenesis imperfecta have a wide range of radiologic abnormalities in the spine, includ-
ing diffuse osteopenia, defective cortical bone formation, sclerosis of vertebral endplates, and biconcave
vertebral bodies (Fig 17).
Intravenous pamidronate therapy administered in repeated courses (once every 4–6 months) over several
years reduces the incidence of bone fractures and increases bone density, vertebral body height, and cor-
tical bone thickness (33) (Fig 22).