Extract
Congenital vertebral malformations result when the normal induction and
formation of the axial skeleton is disrupted during embryonic
development1. During
early embryonic development, somites, which are transient precursors of the
axial skeleton, are formed in a process called
somitogenesis2
(Fig. 1). Disruptions in
somitogenesis cause vertebral
malformations3,
including the formation of uneven segments (hemivertebrae and wedge
vertebrae), fused segments (block vertebrae), and vertebrae with failure of
midline fusion (butterfly vertebrae). Congenital vertebral defects that result
from disruption of the induction and formation of the axial skeleton include
Klippel-Feil syndrome, spondylocostal dysostosis, Jarcho-Levin syndrome,
congenital scoliosis and kyphosis, and a wide range of syndromes and
associations (e.g., oculoauriculovertebral dysplasia [Goldenhar syndrome] and
the VATER [vertebral defects, anal atresia, tracheoesophageal fistula with
esophageal atresia, and radial and renal anomalies] and VACTERL [vertebral,
anal, cardiac, tracheoesophageal, renal, and limb abnormalities]
associations)4-10.
While there is frequently overlap in diagnostic classification for these
disorders, differences in severity and localization of defects can aid in
defining general categories. Vertebral malsegmentation can be observed
globally (as in spondylocostal dysostosis or Jarcho-Levin syndrome) or
regionally (as in the cervical vertebral fusions of Klippel-Feil syndrome) or
in one or two vertebrae (as in Alagille syndrome or some forms of congenital
scoliosis). Disruption of genes involved in axial skeletal development,
environmental insults during gestation, or a combination of these factors can
lead to vertebral defects. The availability of the human genome sequence is
aiding in the identification of genetic causes of vertebral malformations. As
discussed below, the developmental mechanisms regulating somitogenesis can
lead to segmental defects.
Congenital vertebral malformations result when the normal induction and
formation of the axial skeleton is disrupted during embryonic
development1. During
early embryonic development, somites, which are transient precursors of the
axial skeleton, are formed in a process called
somitogenesis2
(Fig. 1). Disruptions in
somitogenesis cause vertebral
malformations3,
including the formation of uneven segments (hemivertebrae and wedge
vertebrae), fused segments (block vertebrae), and vertebrae with failure of
midline fusion (butterfly vertebrae). Congenital vertebral defects that result
from disruption of the induction and formation of the axial skeleton include
Klippel-Feil syndrome, spondylocostal dysostosis, Jarcho-Levin syndrome,
congenital scoliosis and kyphosis, and a wide range of syndromes and
associations (e.g., oculoauriculovertebral dysplasia [Goldenhar syndrome] and
the VATER [vertebral defects, anal atresia, tracheoesophageal fistula with
esophageal atresia, and radial and renal anomalies] and VACTERL [vertebral,
anal, cardiac, tracheoesophageal, renal, and limb abnormalities]
associations)4-10.
While there is frequently overlap in diagnostic classification for these
disorders, differences in severity and localization of defects can aid in
defining general categories. Vertebral malsegmentation can be observed
globally (as in spondylocostal dysostosis or Jarcho-Levin syndrome) or
regionally (as in the cervical vertebral fusions of Klippel-Feil syndrome) or
in one or two vertebrae (as in Alagille syndrome or some forms of congenital
scoliosis). Disruption of genes involved in axial skeletal development,
environmental insults during gestation, or a combination of these factors can
lead to vertebral defects. The availability of the human genome sequence is
aiding in the identification of genetic causes of vertebral malformations. As
discussed below, the developmental mechanisms regulating somitogenesis can
lead to segmental defects.
The severe spinal syndrome, spondylocostal dysostosis type 1 (SCD1), was
the first vertebral segmental disorder for which a mutation was
cloned10-12.
Patients with SCD1 have mild to moderately reduced stature secondary to
truncal shortening caused by vertebral malformations. These defects are
characterized by multiple hemivertebrae, rib fusions and deletions, and a
nonprogressive kyphoscoliosis. The genetic etiology of SCD1 has been linked to
homozygous mutations of the Notch pathway gene, delta-like
313(DLL3). Scoliosis in the absence of substantial malsegmentation has
been observed in a heterozygous carrier of DLL3 mutation in one SCD1
pedigree, raising the possibility that notch pathway defects underlie this
less severe vertebral
anomaly10. A
molecular analysis of DLL3 was carried out in forty-six patients who
had congenital vertebral defects and widely varying radiographic phenotypes,
but there was no clear evidence that genetic mutations caused those
malformations14.
Spondylocostal dysostosis type 1 is a syndrome that demonstrates autosomal
recessive inheritance caused by disruption of the DLL3 gene. The
terms Jarcho-Levin syndrome and spondylothoracic dysplasia are sometimes used
interchangeably with SCD1, but these disorders have fairly distinctive
radiographic presentations. Figure
2 shows examples of SCD1 (Fig.
2, a) and SCD2 (Fig.
2, b) compared with spondylothoracic dysplasia
(Fig. 2, c).
Spondylocostal dysostosis type 1 is more prevalent than SCD2 and has been
reported to share a common vertebral radiographic appearance, with rounded and
smooth outlines of vertebral bodies in childhood, to which the term
"pebble beach
sign"10,12
has been attributed (Fig. 2,
a). The rarer SCD2 displays block-like nonrounded
vertebral malformations (Fig. 2,
b). Furthermore, patients with SCD2 do not have the
mutations in DLL3 that patients with SCD1 have. Recently, defects in
the somite gene MESP2 have been found to cause
SCD215, also
following a pattern of autosomal recessive inheritance. Radiographs originally
published by Jarcho and Levin in 1938 were recently reexamined, and the cases
presented are consistent with
SCD26,16.
Thus, "Jarcho-Levin syndrome," as originally defined, appears to
be most consistent with the current classification of SCD2. Recently,
autosomal recessive SCD due to a mutation in another Notch pathway gene,
lunatic fringe (LNFG), was reported and designated as
SCD317. In that
patient, there was extensive malsegmentation of the entire spine and more
severe truncal shortening than that seen in patients with SCD1 and SCD2. In
patients with SCD1, SCD2, or SCD3, any kyphoscoliosis is usually mild and
nonprogressive.
Patients with spondylothoracic dysplasia display extensive fusion of nearly
all vertebral bodies, reduced vertebral rostral-caudal height due to segmental
diminution, and a relative lack of distal rib fusions or anomalies
(Fig. 2, c). Thus far,
the genetic basis of spondylothoracic dysplasia remains to be elucidated. In
summary, by radiographic analysis, SCD1, SCD2, SCD3, and spondylothoracic
dysplasia all have global effects on vertebral formation but different genetic
etiologies.
Since induction and formation of the axial skeleton cannot be examined in
humans, studies of somite stages have been carried out in the mouse.
Homozygous mutations in the mouse Dll3 gene disrupts somite formation
and subsequently causes a variety of vertebral malformations, including block
vertebrae, fused vertebrae, wedge vertebrae, and
hemivertebrae18-20.
Mutations in five other genes in the mouse Notch pathway produce somite or
vertebral defects similar to those seen in Dll3 mutations, and
screening is under way to identify mutations in the human versions of these
genes, as discussed further in the following sections.
Klippel-Feil syndrome was first described in a forty-six-year-old patient
with a short neck, low posterior hairline, and limited range of motion of the
neck caused by congenital segmentation defects of the cervical
spine9,21.
Less than half of the patients with Klippel-Feil syndrome display all three
signs of this classic triad (a short neck, low posterior hairline, and limited
range of motion of the neck). Indeed, the anomalies associated with
Klippel-Feil syndrome are highly
variable22-26.
Klippel-Feil syndrome occurs in a heterogeneous group of patients who have a
congenital synostosis of some or all cervical
vertebrae27
(Fig. 3). Studies of the
incidence of Klippel-Feil anomaly have produced estimates ranging from 1 in
40,000 to 42,000
births26,28.
A female-to-male ratio of approximately 3:2 has been
reported23,29.
Although the cervical spine anomalies of affected patients are congenital,
the diagnosis of Klippel-Feil syndrome is not usually made until a later
age23. Patients
display neurological, myelopathic, and biomechanical problems. However, the
most common symptoms are pain, neurological problems, and decreased rotation
and flexion and/or extension of the cervical spine. Presentation is also
affected by the spinal level of the defect. Patients with an atlantoaxial
fusion that is found incidentally on radiographs often present at younger ages
than those with a more caudal
fusion30. Patients
with extensive fusions also tend to present at a very early age as a result of
the clearly visible deformity. In some patients, the Klippel-Feil anomaly is
associated with defects in other organ systems and is a symptom of another
named syndrome, such as Wildervanck syndrome, Rokitansky-Küster-Hauser
syndrome, or
Goldenhar4 syndrome.
In other patients, the cervical synostosis is asymptomatic and the disorder is
discovered incidentally when radiographs are obtained for an unrelated
reason22.
Regardless of the presentation, after a synostosis of the cervical spine has
been discovered, high-resolution radiographs of the cervical spine are
recommended for all patients in order to evaluate the nature and extent of the
fusion25,31.
Compared with the evaluation of adult patients, the radiographic evaluation
of the cervical spine of infants and children can be difficult. Although a
translation of one vertebral body on another may suggest instability
associated with an adjacent fused segment, pseudosubluxation of C2 on C3 or C3
on C4 may be normal in children who are younger than eight years of
age32. Furthermore,
the radiographic appearance of the cervical spine changes as a child grows,
and incomplete vertebral ossification can make fusions difficult to identify.
Finally, the radiographic appearance of fusions that are secondary to
disorders such as juvenile rheumatoid arthritis can mimic the appearance of a
Klippel-Feil
anomaly28, but the
history of the patient and the information acquired from the physical
examination should allow the clinician to easily eliminate these
possibilities.
The heterogeneity of patients with Klippel-Feil syndrome makes it more
difficult to delineate diagnostic and prognostic classes and complicates
genetic studies. The human genetic database Online Mendelian Inheritance in
Man
()
lists at least three genetic forms of Klippel-Feil syndrome with either
dominant or recessive inheritance: Klippel-Feil syndrome (148900);
Klippel-Feil deformity, conductive deafness, and absent vagina (148860); and
Klippel-Feil deformity, conductive deafness, and facial asymmetry (148870). In
addition, autosomal recessive inheritance of Klippel-Feil syndrome has been
described in a large Brazilian
pedigree33.
Recently, a study of a large Klippel-Feil pedigree has revealed that
cervical fusions and vocal impairment defects segregate with a paracentric
inversion of chromosome 8. This led the investigators to propose a
Klippel-Feil genetic locus, designated
SGM134-36.
Positional cloning of genes disrupted by the inversion at the SGM1 locus would
provide a greater understanding of the molecular and developmental mechanisms
that cause Klippel-Feil syndrome.
Scoliosis is a lateral curvature of the spine and has been defined by
etiology into congenital, neuromuscular, and idiopathic
forms37,38.
By definition, the spinal malformations leading to congenital scoliosis can be
identified at or near birth, although the full extent of spinal curvature may
not be apparent until later in development. The types of vertebral defects in
congenital scoliosis that can be identified radiographically include
hemivertebrae, wedge vertebrae, vertebral fusions and bars, and failure of
segments to fuse along the midline (Fig. 4,
a, b, and c). Congenital curves are clinically
problematic since they tend to be very rigid and resistant to correction and
because they often progress to cause large
deformities38-40.
When spinal curves are not oriented laterally, they can be diagnosed as
kyphotic (an inward dorsoventral curve) or lordotic (an outward curvature of
the spine). In the discussion below, we will apply the term congenital
scoliosis to include related kyphosis, kyphoscoliosis, and lordosis, since
they share a common developmental etiology and only the placement of the
vertebral defect(s) determines the diagnostic category.
A few epidemiological genetic studies of congenital scoliosis have been
reported. Wynne-Davies examined more than 300 cases and identified a sibling
recurrence risk of 2% to 3% in patients who displayed multiple vertebral
defects41. Mortier
and colleagues examined patients with multiple vertebral defects, including
patients with
SCD42. A few case
reports of monozygotic twins with hemivertebrae have been
reported43-46.
In addition, cases of families with multigenerational congenital scoliosis
have also been
reported47. A
recent report identified forty-nine patients, from a total of 237 patients
with congenital
scoliosis48, who
had two or more family members with either congenital or idiopathic scoliosis
(20.7% rate of familial occurrence). Because the diagnosis of
"idiopathic" scoliosis is given when a structural or neuromuscular
etiology cannot be identified, it is possible that some mild cases of
congenital scoliosis may be categorized as idiopathic scoliosis.
The complex structures of the spine are formed and patterned in a process
called somitogenesis. At approximately fourteen days in embryogenesis in
humans, the process of gastrulation generates populations of mesenchymal cells
that will form the future head, cardiac, paraxial, and lateral
mesoderm49. In a
period between day 20 and day 30, the mesenchymal cells that lie paraxial to
the future spinal cord are segmented into spherical, segmental structures
called somites (Fig. 5). These
somite segments are formed in pairs, and the process is repeated iteratively
to produce all of the somites. The somite segments are transient and later
divide into three embryonic tissues—the sclerotome, which forms the
adult vertebrae; the myotome, which forms the adult axial musculature; and the
dermatome, which contributes to the adult
dermis50. The
sclerotome undergoes another segmentation process, which leads to the fusion
of the caudal section from one somite precursor to the rostral section of its
neighbor. Thus, there are two segmentation processes in the formation of the
axial skeleton. First, somite segments are formed and then dissociate into
scleroto mal compartments. Next, these sclerotomal tissues resegment,
producing precursors to the vertebrae. These transient somites are regularly
sized and spaced, and this careful organization is essential for the normal
patterning of the spine.
Since studies of early spinal development cannot be carried out in humans,
an animal model is essential. Fortunately, somitogenesis is highly conserved
among mammals, and the mouse is a suitable model system. In the mouse, the
first somites are formed beginning eight days post coitum and the last somites
finally coalesce by thirteen days post
coitum51. The
formation of somite segments from mesenchymal cells is associated with a
drastic cellular cytoskeletal rearrangement, from mesenchymal to columnar
epithelioid cells. Each somite consists of a single-layer epithelial sphere,
bound together through tight junctions at the basal surface, and a lumen
filled with mesenchymal
cells50. As somites
mature, they dissociate into the three embryonic tissues: the sclerotome,
myotome, and dermatome. The sclerotome goes on to form the ossified bones of
the vertebrae and the ribs, but not of the pelvic girdles, limbs, or cranium.
The dermatome forms the dermis of the back, and the myotome forms the
musculature of the vertebral column and trunk. The myotome also contributes to
muscles in the tongue, extrinsic muscles of the eyes, and possibly muscles in
the limbs3.
Somitogenesis is also essential for the normal formation of other
nonmusculoskeletal components of the spine. The process of spinal nerve
outgrowth from the neural tube is tightly associated with the formation of
somites. Neural crest precursors of spinal ganglia migrate specifically
through the rostral portion of each somite, and the results of transplantation
experiments in which the rostral-caudal polarity of the somite were reversed
revealed that neurons then migrated through the regions that were formerly
rostral52. Thus,
the adult vertebral column is formed from the spinal cord and nerves (derived
from neuroectoderm), the ossified vertebral and costal bones (derived from
sclerotomal mesoderm), the spinal muscles and ligaments (derived from myotomal
mesoderm), and the intervertebral discs (derived from the
notochord)3.
The intricate process of formation and patterning of the spine requires
careful regulation. The results of recent experiments in mouse and chick
models have revealed a mechanism that regulates the iterative formation of
somites. This mechanism involves a novel biological clock, distinct from the
twenty-four-hour circadian clock cycle. This somite clock involves an internal
oscillator that controls the regular periodicity of
segmentation53-55.
Genes in the Notch signaling pathway have been shown to be expressed in an
oscillatory pattern, in synchrony with each somite
cycle56-64
(Fig. 6). Notch genes are large
transmembrane receptors that respond to signals from delta and serrate/jagged
classes of ligands. Genes in the Notch pathway are essential for the formation
of almost all organs through regulation of cell-fate determination and
embryonic patterning in animals. The Notch pathway genes that have been
observed to have oscillatory expression include Lfng, Hes1, Hes7, and
Hey2 in the mouse and hairy1 and hairy2 in the chick.
The disruption of genes in the Notch pathway through targeted or
spontaneous mutations causes somite segmentation defects and vertebral
anomalies in mice. Mutations in mouse Dll1, Dll3, Hes7, Lfng, Notch1,
and Psen1 produce severe disruptions in normal somite
patterning19,58,65-72.
The Notch ligand Dll3 is required to maintain the cyclical expression
of other Notch pathway genes, and mutations lead to vertebral
malformations73.
The Notch signaling pathway is a component of the clock that sets the pace
of segment formation, but another process is required to produce the actual
segmental boundaries. Some insights into the actual segmental process have
come from studies of chick embryos. The region where segmental boundaries
become determined in the rostral third of the presomitic mesoderm is affected
by levels of fibroblast growth factor 8 (FGF8), which is produced in the
caudal tail region of the
embryo74.
Fibroblast growth factor 8 appears to maintain cells in an immature state.
Segmental boundaries are then determined in the embryo when levels of FGF8
fall below a threshold, toward the rostral part of the unsegmented mesenchymal
cell region. When somites are formed, they already appear to be specified
toward their eventual vertebral identity. Each vertebra exhibits distinct
morphological characteristics depending on its position along the
rostral-caudal axis. The human vertebral column consists of up to thirty-three
vertebrae (seven cervical, twelve thoracic, five to six lumbar, five fused
sacral, and three coccygeal) that have distinctive morphology and development
along the rostral-caudal axis. Previous studies in the mouse have demonstrated
that this axial identity is regulated by the Hox family of transcription
factors75. The link
between the process of segmentation and Hox specification of vertebral
precursors is clearly seen when embryos are treated with FGF8. This ectopic
treatment increases the number of clock oscillations experienced by
unsegmented mesenchymal cells without altering their absolute axial position.
Cells subjected to extra Notch cycling gene waves become part of a differently
numbered somite and have a rostral shift of Hox expression. Treatment with
FGF8 leads to the formation of smaller somites, but the Hox expression shifts
in response74. In
addition, Hox genes themselves have been shown to display oscillatory
expression during somitogenesis in the
mouse76. As a final
note, recent reports have identified that genes in the Wnt signaling pathway
also display oscillatory expression and play a key role in the segmentation
clock77,78.
In summary, the process of segmentation appears to be intimately linked to the
mechanism by which individual somites acquire their individual identity.
Genetic studies have led to the identification of mutations in the Notch
pathway genes DLL3,
MESP213,15,79,
and LNFG17
that lead to the development of SCD1, SCD2, and SCD3, respectively. Detailed
radiographic studies combined with clinical genetic studies of SCD1 and other
SCD phenotypes were instrumental in the success of these efforts. Past studies
have focused on the type of vertebral dysmorphology (e.g., wedge vertebrae
compared with block vertebrae), the prognosis for curve progression, and the
role of surgical correction in patients with congenital vertebral
malformations39,40,80,81.
In genetic
studies16,82,
more information can be gained from radiographic analysis that focuses on
pattern recognition, quantification of the extent of segmental defects, and
syndromic associations than from measurement of the Cobb angle or disease
progression. Erol et al. observed that patients with multiple compared with
single vertebral malformations had development of severe spinal curves at
similar rates (a severe curve with a Cobb angle of >30° was identified
in 43% of patients with multiple defects compared with 40% of patients with
single defects)16.
Thus, a single vertebral defect caused by a nongenetic environmental insult
could produce as severe a curve as a widespread segmental defect caused by
genetic mutation. Genetic studies could help to identify populations at risk
for congenital vertebral defects, aid in the diagnostic evaluation of
syndromic versus nonsyndromic patients and, of increasing importance for many
affected families, improve genetic risk counseling. Prenatal genetic diagnosis
of SCD1 has already been
reported83. In
addition, increased understanding of the genetic causes of vertebral defects
could help to identify disruptive or protective environmental factors. For
example, epidemiological evidence has highlighted the protective value of
folates in reducing the likelihood of neural tube defects such as spina
bifida84. While
factors such as fetal alcohol syndrome have been associated with Klippel-Feil
syndrome85, we have
yet to identify factors that may reduce the incidence of congenital vertebral
defects. Ongoing genetic and developmental studies are aimed at discovering a
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