The chromosome abnormality, deletion of 22q11.2, is one of the most common
genetic syndromes, with a prevalence of one in 4000 live
births1-3.
In the early 1990s, this defect was identified in the majority of patients
with three distinct disorders: DiGeorge syndrome, velocardiofacial syndrome,
and conotruncal anomaly face syndrome. DiGeorge syndrome, which was first
described in 19654,
as far as we know, was originally characterized by congenital cardiac defects,
hypoplasia of the thymus and parathyroid glands, and immune deficiency. In
1978, Shprintzen et
al.5 described
velocardiofacial syndrome, which is characterized by cleft palate,
velopharyngeal incompetence, congenital cardiac defects, a distinct facies,
and learning disabilities. Conotruncal anomaly face syndrome, consisting of
conotruncal congenital cardiac defects, a distinct facies, and a hypernasal
voice, was defined in
19766. Since these
initial descriptions, the discovery of substantial phenotypic overlap and a
shared chromosome deletion has led to the current belief that these previously
distinct syndromes represent a spectrum of the same disorder. More recently,
some patients with the Opitz G/BBB (hypertelorism, laryngotracheoesophageal
cleft, cleft palate, genitourinary defects, mental retardation, and congenital
cardiac defects) and Cayler cardiofacial (asymmetric crying facies and
congenital cardiac defects) syndromes have also been shown to have the 22q11.2
deletion, further broadening the phenotypic scope of this
deletion4,7.
The more inclusive term, the 22q11.2 deletion syndrome, is now used to
describe any patient with this chromosome abnormality and the wide spectrum of
associated clinical
features4,6.
Variable phenotypic expression is the hallmark of the syndrome, and it
includes skeletal findings. Upper and lower limb, vertebral (particularly
thoracic), and rib abnormalities have previously been reported and include a
variety of findings, such as polydactyly, equinovarus, and butterfly
vertebrae8. More
recently, developmental variations of the occiput and cervical spine have been
observed in a few small studies and include platybasia, incomplete fusion of
the arches of C1, Chiari type-I malformations, occipitalization of C1, basilar
impression, and
instability9-11.
During our experience with the 22q11.2 deletion syndrome, a child being
evaluated to determine the presence of a laryngeal web was incidentally found
to have multiple occipitocervical abnormalities, most notably a block fusion
of C2-C3 associated with increased occipitoatlantal and C3-C4 segmental
motion. In our subsequent retrospective review of dental lateral cephalometric
radiographs in eleven more patients with the 22q11.2 deletion who were seen at
our institution, we identified six with evidence of variations of the occiput
and cervical spine. These observations were the impetus for the current
study.
Variations of the occiput and cervical spine, either developmental variants
or congenital anomalies, appear to be common in the 22q11.2 deletion syndrome,
but a large descriptive review of this patient population has not yet been
reported. The purposes of the current study were (1) to define and determine
the frequency of variations of the occiput and cervical spine on plain
radiographs in patients with the 22q11.2 deletion syndrome and (2) to
postulate the potential clinical importance of these variations.
Between October 31, 2001, and May 31, 2003, a cross-sectional cohort of
seventy-nine consecutive patients referred from The "22q and You"
Center in the Department of Clinical Genetics at the Children's Hospital of
Philadelphia underwent clinical and radiographic evaluation of the occiput and
cervical spine. Both institutional review board approval and informed consent
were obtained. The "22q and You" Center is a multidisciplinary
center dedicated to teaching, learning, and caring for patients with the
22q11.2 deletion. It receives local, regional, national, and international
referrals and follows over 500 patients with the 22q11.2 deletion. Patients
are referred to the center on the basis of the presence of characteristics
suggestive of a 22q11.2 deletion, and the diagnosis is confirmed in all
patients by routine genetic testing based on fluorescence in situ
hybridization (FISH). Each patient who has been newly diagnosed as having the
syndrome undergoes a comprehensive, multidepartmental evaluation coordinated
through The "22q and You" Center, including referrals to
cardiology, child development and psychology, endocrinology, orthopaedics,
otolaryngology, audiology, immunology, neurology, and urology.
The patients in the current study underwent an assessment of the occiput
and cervical spine in the Department of Orthopaedic Surgery, either as part of
their initial multisystem evaluation or at a subsequent follow-up appointment.
None of the eleven patients used in our initial retrospective review of dental
lateral cephalometric radiographs were included in this study. All patients
who were less than one year of age were excluded from the current study
because occipitocervical findings in this age-group could not be accurately
assessed on plain radiographs.
The clinical evaluation included a detailed history and physical
examination focusing on neurologic symptoms potentially related to the occiput
and/or cervical spine. Radiographic evaluation included lateral plain
radiographs of the cervical spine in neutral, flexion, and extension;
anteroposterior radiographs; and open-mouth odontoid radiographs. All
radiographs were made at the time of the clinical evaluation of each patient.
A retrospective review of previous radiographs did not occur. The
target-to-film distance was standardized in all radiographs to minimize
magnification errors and errors in measurement. The lateral radiographs
(neutral, flexion, and extension) were performed in the erect position with
use of a 183-cm target-to-film distance.
Plain radiographs were evaluated to (1) define variations of the occiput
and cervical spine, either developmental variants or congenital anomalies, and
(2) identify any increased occipitocervical or cervical segmental motion. All
radiographic evaluations were performed by four of the authors (E.T.R., L.S.,
H.S.H., and D.S.D.) independently, followed by a group review of the findings.
In cases where there was a disparity in findings or measurements, agreement
was reached by consensus or the values were averaged.
Radiographic Definitions
The radiographic features that were characterized and assessed included
occipital variations (platybasia and basilar impression), atlas (C1)
variations (dysmorphic shape, open posterior arch, and occipitalization), axis
(C2) variations (dysmorphic dens, upswept lamina, and posterior elements),
fusion of C2-C3 vertebrae, and increased occipitocervical or cervical
segmental motion. Data on occipitalization, C2-C3 fusion, and increased
segmental motion were available for only seventy-one (90%) of the total cohort
of seventy-nine patients. Eight patients could not be evaluated for these
findings because of inadequate flexion and extension radiographs.
Platybasia
Platybasia is defined as flattening of the base of the
skull12,13.
This finding was confirmed radiographically in the current study by a cranial
basal angle measurement in excess of one standard deviation above the mean for
age as compared with the norms reported by Riolo et al., a standard used
previously in this patient
population14-16.
The cranial basal angle is formed by a line drawn from the nasion to the
center of the sella turcica and then to the anterior margin of the foramen
magnum (Fig. 1). On the basis
of the most stringent norms listed by Riolo et al., a basal angle of
=136° on lateral radiographs was uniformly chosen to define platybasia
in our study16.
Platybasia data were available for fifty-seven (72%) of the seventy-nine
patients in the total cohort. The cranial basal angle could not be measured in
twenty-two patients because the nasion was not visualized radiographically in
these patients.
Basilar Impression
Basilar impression is a downward displacement of the skull base at the
foramen magnum, recognized by the protrusion of the tip of the odontoid
process through the foramen
magnum12,17.
This finding was confirmed radiographically in the current study with use of
the McRae line, which is a line drawn from the anterior border to the
posterior border of the foramen
magnum12. The McRae
line is the preferred screening method for detecting basilar impression
because it can be easily identified on lateral radiographs at all
ages12,18.
It was easily reproducible in our patients.
Dysmorphic Atlas
The atlas was defined as dysmorphic in the current study on the basis of an
unusually small or thin appearance (either in the vertebrae as a whole or
isolated to the posterior arches) noted on lateral radiographs after a
consensus review by four of the authors
(Fig. 2).
Open Posterior Arch of the Atlas
Patients who had an open posterior arch of C1 in the current study
typically showed hypertrophic enlargement of the ends of the open arch on
lateral radiographs. Therefore, an open posterior arch of C1 was defined
either by (1) direct evidence of an opening on lateral radiographs
(Fig. 3) or by (2) indirect
evidence, based on the appearance of a hypertrophic or bulbous posterior arch,
a finding we termed the "bulb sign"
(Fig. 4).
Occipitalization of the Atlas
Occipitalization of the atlas, or congenital occipitoatlantal fusion, was
confirmed by evidence of an osseous fusion (anterior and/or posterior) between
the atlas and the occiput on lateral radiographs and by the atlas and the
occiput moving as a functional unit (i.e., there is no evidence of motion
between the two) on flexion and extension radiographs
(Figs. 5-A and 5-B).
Dysmorphic Dens
The dens or odontoid process was defined as dysmorphic on the basis of
unusual anatomic features noted on radiographs after a consensus review by
four of the authors. The most common appearances included (1) a short, widened
dens (Fig. 6); (2) a bulbous
dens; and (3) a dens with a posterior angled tip.
"C2 Swoosh"
Upswept lamina and posterior elements of the axis, an appearance we termed
the "C2 swoosh," was defined by an abnormal extension of the
lamina and posterior elements superiorly, as evident on lateral radiographs
(Fig. 2).
C2-C3 Fusion
Fusion of C2-C3 vertebrae was defined in the current study either as a
fusion of the posterior vertebral elements or as a complete block fusion of
the vertebrae. Fusion of posterior elements was confirmed by narrowing or
elimination of the gap between these elements and by the spinous processes of
C2 and C3 moving as a functional unit on neutral, flexion, and extension
lateral radiographs, with no evidence of motion between the two
(Fig. 3). Block fusion was
confirmed by evidence of fusion of both the posterior elements and vertebral
bodies of C2 and C3 (Figs. 5-A and
5-B).
Increased Segmental Motion
Increased occipitocervical or cervical segmental motion was defined by
measuring the amount of translation (in millimeters) between adjacent cervical
vertebrae (or between the occiput and the atlas) on lateral radiographs in
flexion and extension. Each author's measurement of the translation at a
particular vertebral level represented an average of three separate values.
All suspected cases of increased segmental motion were reviewed as a group to
reach a consensus, and, in cases where measurements differed, a final value
was determined by averaging.
Occipitoatlantal instability is defined in the literature as >1 mm of
translation at the occipitoatlantal articulation (measured from the anterior
surface of the occipital condyles to the posterior surface of the anterior
arch of the atlas) as observed on flexion and extension
radiographs18-22.
We chose a more stringent cutoff of =2 mm of translation (using the same
landmarks) to define increased occipitoatlantal segmental motion. One
millimeter can be difficult to measure accurately on plain radiographs and may
therefore have an element of interobserver variability that was not addressed
in this study.
Atlantoaxial instability is defined in the literature by an atlantodens
interval of >4 mm in children and >3 mm in adults as observed on flexion
and extension
radiographs12,23,24.
The atlantodens interval is the distance between the anterior surface of the
odontoid process and the posterior surface of the anterior arch of the atlas.
Increased atlantoaxial segmental motion was defined in the current study with
use of the same landmarks, with a uniform cutoff of >4 mm for the
atlantodens interval.
Increased subaxial (caudad to C2) segmental motion was defined in the
current study as =2 mm of translation between adjacent subaxial cervical
vertebrae as observed on flexion and extension radiographs. As with
occipitoatlantal motion, a cutoff of 1 mm was deemed too difficult to measure
accurately on plain radiographs and may therefore have an element of
interobserver variability that was not addressed in this study.
Seventy-nine consecutive patients with a genetically documented 22q11.2
deletion were evaluated for variations of the occiput and cervical spine on
plain radiographs. The thirty-five male and forty-four female patients ranged
in age from 1.6 to 46.0 years (mean, 8.4 years)
(Table I).
At least one developmental variation of the occiput or cervical spine was
observed in every patient. Excluding platybasia and increased segmental
motion, at least one variation was noted in seventy-seven patients (97%).
Table II summarizes these
findings. The mean number of variations per patient, excluding platybasia and
increased segmental motion, was 2.9 (range, zero to five variations).
Occipital Variations
There were two common occipital variations, platybasia and basilar
impression. Platybasia was observed in fifty-two (91%) of fifty-seven
patients. The mean cranial basal angle for the fifty-seven patients was
143° (range, 129° to 160°). The mean cranial basal angle for the
fifty-two patients meeting the platybasia criterion (a cranial basal angle of
=136°) was 144° (range, 136° to 160°). Basilar impression
was observed in two (3%) of the seventy-nine patients.
Atlas Variations
The most frequent developmental variations of C1 were dysmorphic shape in
fifty-nine (75%) of the seventy-nine patients, an open posterior arch in
forty-seven (59%) of seventy-nine patients, and occipitalization in two (3%)
of the seventy-one patients with adequate radiographs.
Axis Variations
The axis (C2) variations most commonly seen were a dysmorphic dens in
forty-six (58%) of seventy-nine patients and upswept lamina and posterior
elements or the "C2 swoosh" in forty-seven (59%) of seventy-nine
patients. One patient with os odontoideum was noted.
Vertebral Fusions
Fusion of C2-C3 was seen in twenty-four (34%) of the seventy-one patients
with adequate radiographs. Fifteen (21%) had fusion of the posterior elements
only, whereas nine (13%) had complete block fusion.
Increased Segmental Motion
Increased occipitocervical or cervical segmental motion was observed in
forty (56%) of the seventy-one patients with adequate radiographs
(Table III). Approximately
one-third (thirteen; 33%) of the forty patients had increased motion at more
than one vertebral level. Thirty-one patients (44%) had increased
occipitoatlantal segmental motion (Figs.
7-A and 7-B), seven (10%) had increased atlantoaxial segmental
motion, and four (6%) had increased C2-C3 segmental motion. Occipitoatlantal
translation was best observed in extension
(Fig. 7-B), and the mean value
was 3.94 mm (range, 2 to 6 mm) (normal, <2 mm). Atlantoaxial translation
was best observed in flexion and had a mean value of 5.79 mm (range, 4.5 to 8
mm) (normal, =4 mm). Increased C3-C4 segmental motion, always adjacent to a
fusion of C2-C3, was observed in eleven (15%) of the seventy-one patients with
adequate radiographs (Fig. 8).
The mean C3-C4 translation was 2.86 mm (range, 2 to 5 mm) (normal, <2
mm).
Neurologic Symptoms
Despite the high frequency of developmental variations of the occiput and
cervical spine observed in the current study, the majority of patients were
asymptomatic. Clinically obvious neurologic deficits potentially related to
the occiput or cervical spine were not observed in any patients younger than
fifteen years of age. Of the eight patients who were fifteen years or older,
three appeared to have neurologic symptoms potentially associated with
cervical myelopathy secondary to cervical spinal stenosis, such as
coordination and fine motor difficulties, radicular pain, and weakness.
Further imaging (computed tomography and/or magnetic resonance imaging) was
advised for all three patients to determine the source of the symptoms,
evidence of possible cervical spine stenosis or spinal cord compression, and
the appropriate treatment options. The patients were managed with close
clinical surveillance.
The variations of the occiput and cervical spine as seen on plain
radiographs in a cross-sectional cohort of seventy-nine consecutive patients
with established 22q11.2 deletion syndrome are common and appear to occur
primarily within the upper cervical spine. These findings represent variations
from the normal development and anatomy of the upper cervical spine that may
or may not be pathologic. They therefore potentially include both (1)
developmental variants with little or uncertain clinical importance and (2)
true congenital anomalies with potential clinical sequelae if left
untreated12,18,25.
For example, platybasia, which was seen in fifty-two (91%) of fifty-seven
patients, was the most common variation of the upper cervical spine found in
our study, but its clinical importance is
questionable12,13.
It may more appropriately be termed a variant rather than an anomaly. Although
not clinically worrisome, such variants may still be important as radiographic
markers for more serious anomalies with clinical implications.
To the best of our knowledge, this is the first extensive study with a
detailed plain radiographic description of variations of the upper cervical
spine in patients with the 22q11.2 deletion syndrome. The few earlier reports
in the literature have been limited in their
evaluation9-11,14,15,26,27.
Some studies have described isolated variations with more elaborate imaging
techniques, but they lacked adequate description of the plain radiographic
findings9,26.
Other studies have noted isolated variations on plain radiographs, such as
platybasia and open anterior or posterior arches of the cervical vertebrae,
but without a comprehensive plain radiographic review of all
findings10,11,14,15,27.
Prior studies were also limited by sample size, with reviews of fewer than
thirty
patients9-11.
In contrast, our cohort of seventy-nine patients is the largest reported
series, to our knowledge, and includes a more clinically diverse patient
population.
Several variations of the upper cervical spine not previously described in
the 22q11.2 deletion syndrome, including atlas and dens dysmorphisms, upswept
lamina and posterior elements of C2, and increased segmental motion, were
observed frequently in this study. The "bulb sign" and the
"C2 swoosh" are terms that were coined to describe two of these
findings. The "bulb sign" describes the appearance of a bulbous
posterior arch of C1 on lateral radiographs
(Fig. 4). It was typically
noted in patients with an open posterior arch of C1 and may represent a marker
for this defect. The "C2 swoosh," used to describe the presence of
upswept lamina and posterior elements of C2 on lateral radiographs
(Fig. 2), may also represent a
radiographic marker for developmental abnormalities of the upper cervical
spine. Advanced imaging may determine whether these findings truly represent
evidence of other defects.
Forty (56%) of the seventy-one patients with adequate radiographs in this
study demonstrated increased segmental motion, with one-third of them showing
increased mobility at more than one level. Increased occipitoatlantal
segmental motion was noted most often and occurred in thirty-one patients
(44%). Most cases of increased segmental motion appeared to be of primary
origin, but increased mobility also occurred secondary to vertebral fusions.
Congenital fusions of the upper cervical spine have previously been shown to
be associated with instability at adjacent vertebral
segments12,18.
Occipitalization of C1, associated with atlantoaxial
instability18,22,28,29,
was infrequent in the present study, but fusion of C2-C3 was a common finding.
Fusion of C2-C3 appears to cause increased mobility at both adjacent vertebral
segments, C1-C2 and C3-C4. Not every patient in our study with fusion of C2-C3
had evidence of increased motion at the adjacent vertebral levels, but all
eleven cases of increased C3-C4 mobility were adjacent to a fusion of C2-C3.
With so few patients currently symptomatic, it may be premature to label the
increased mobility observed in this study as true spinal instability, with its
potential risk of myelopathy. The increased segmental motion may simply
represent an increased ligamentous laxity, with little or no clinical
consequence. Advanced imaging and further observation may help to answer these
questions.
At present, the embryological explanation for the variations of the upper
cervical spine that we noted is unclear, but the findings seem to arise during
somatogenesis, when errors in cellular proliferation, migration,
differentiation, and segmentation can occur. Failure of segmentation between
the fourth occipital and first cervical somites, for example, may cause
variable fusion of C1 to the occiput and result in occipitalization of the
atlas. Fusions of C2-C3 also represent segmentation errors between the
corresponding cervical somites during the third to eighth weeks of
life30. Failure of
segmentation can occur over a spectrum, but, in younger patients, it may not
be evident as osseous fusion initially because of incomplete ossification.
This may give a false impression of adequate disc space or space between
spinous processes. Fusions can be confirmed prior to completed ossification
with flexion and extension radiographs, which demonstrate the spinous
processes of adjacent vertebrae moving as a functional unit, with no change in
the distance between processes. We consider these radiographs essential not
only for verification of vertebral fusions (particularly fusions of the
posterior vertebral elements) but also for determination and measurement of
increased segmental motion.
Recognition of the embryology behind our findings is also important in
order to differentiate changes that may be attributed to normal development.
For example, we noted evidence of an open posterior arch of C1 in many of our
patients. Normal closure of the posterior arch of the atlas may not occur
until well after birth. Typically, there is a remnant cartilaginous cleft
between the osseous posterior arches at birth. An ossification center develops
in this cartilaginous cleft around the second year of life, and the posterior
arch is usually completely ossified by the age of four
years31. A
dysmorphic dens was another common finding in the current study. Complete
ossification of the dens may not occur until the age of
twelve23, and some
dens variations, such as posterior tilting, have previously been considered
normal
variants25.
At the genetic level, deletion of 22q11.2 is one of the most frequent
causes of genetic syndromes, with a prevalence of one in 4000 live
births1-3.
The variable, multiorgan phenotype of this disorder makes it likely that
clinical findings involve the interaction of multiple genes in the deleted
region. More than thirty genes have been characterized from the typical 3 Mb
deleted region4, and
it is likely that genes that play a role in axial patterning and segmentation
or somatogenesis, such as the homeobox genes, are involved in the pathogenesis
of variations of the upper cervical
spine23,32,33.
The clinical implications of the radiographic findings in the current study
remain unclear. The majority of patients in our cohort were asymptomatic,
although symptomatic patients were older and follow-up was ongoing. Three
patients had symptoms suggestive of cervical myelopathy secondary to cervical
spinal stenosis, and all three were fifteen years of age or older. The few
previous studies of the occipitocervical region in the 22q11.2 deletion
syndrome have also noted only a small number of patients with potential
neurologic
symptoms9-11.
Asymptomatic findings may not necessarily be clinically insignificant,
however. Advanced imaging (computed tomography and/or magnetic resonance
imaging) is being pursued in our symptomatic patients to determine the source
of the symptoms, evidence of possible cervical spinal stenosis or spinal cord
compression, and the appropriate treatment options. In addition, while it
appears that plain radiographs alone are not adequate to dictate treatment
options in our patients because so few are symptomatic, worrisome findings on
plain radiographs should be appropriately pursued with more advanced imaging
to assess for cervical spinal stenosis or spinal cord compression.
At present, it is unclear which of the radiographic findings observed in
the current study can be constituted as worrisome. Abnormalities such as
basilar impression and increased segmental motion (if deemed to be true spinal
instability) have previously been shown in the literature to be matters of
concern because of an association with brainstem compression, cervical spinal
stenosis, and/or spinal cord impingement or compression, while other findings,
such as platybasia, have
not12,13,18.
Many of the other findings in this study have not been previously described,
to our knowledge. Therefore, extensive imaging or follow-up over time has not
been done to determine the effect of the abnormalities on the spinal cord or
on the rest of the central nervous system or to assess the subsequent need for
treatment.
In the current study, we attempted to define plain radiographic variations
of the upper cervical spine, either developmental variants or congenital
anomalies, in the 22q11.2 deletion syndrome. Although the discussion of
advanced imaging is beyond the scope of our current study, such imaging of the
occipitocervical region will likely be needed to clarify the importance of
many of the radiographic variations that we observed and the potential need
for the treatment of these findings.