SPECIAL TOPIC

Cranial Sutures: A Brief Review

Bethany J. Slater, M.D.
Kelly A. Lenton, Ph.D.
Matthew D. Kwan, M.D.
Deepak M. Gupta, M.D.
Derrick C. Wan, M.D.
Michael T. Longaker, M.D.,
M.B.A.
Stanford, Calif.
Summary: Craniosynostosis, or the premature fusion of one or more cranial
sutures, is a relatively common congenital defect that causes a number of
morphologic and functional abnormalities. With advances in genetics and mo-
lecular biology, research of craniosynostosis has progressed from describing
gross abnormalities to understanding the molecular interactions that underlie
these cranial deformities. Animal models have been extremely valuable in im-
proving our comprehension of human craniofacial morphogenesis, primarily by
human genetic linkage analysis and the development of knock-out animals. This
article provides a brief review of perisutural tissue interactions, embryonic
origins, signaling molecules and their receptors, and transcription factors in
maintaining the delicate balance between proliferation and differentiation of
cells within the suture complex that determines suture fate. Finally, this
article discusses the potential implications for developing novel therapies for
craniosynostosis. (Plast. Reconstr. Surg. 121: 170e, 2008.)

A
lthough the term craniosynostosis was first
used by Otto in 1830 to describe the entity
of premature suture fusion,1 manifestations
of the disease have been described throughout
history. Descriptions of the cranial dysmorphisms
that result from craniosynostosis prevail across all
cultures, from the turricephalic head of the Taoist
god of long life and luck to Homer’s description
of a warrior whose head “ran to a point.”2 In mod-
ern Western history, Virchow is credited for cor-
relating these abnormally shaped skulls to prema-
ture fusion of cranial sutures.3
With advances in genetics and molecular bi-
ology, research in craniosynostosis has evolved
from describing gross morphologic abnormalities
to decoding the molecular interactions that un-
derlie these cranial deformities. As a result of these
advances, a number of genetic mutations associ-
ated with craniosynostosis syndromes have been
identified. Animal models have been extremely
valuable for improving our understanding of nor-
mal craniofacial morphogenesis and providing in-
sight into pathologic states of fusion. Research in
the field of cranial sutures is focused on dissecting
the role of perisutural tissue interactions, embry-
onic origins, signaling molecules and their recep-
tors, and transcription factors. This article pro-
vides an overview of this research and the potential
From the Department of Surgery, Division of Plastic and
Reconstructive Surgery, Stanford University School of Med-
icine.
Received for publication May 3, 2007; accepted July 3, 2007.
Copyright ©2008 by the American Society of Plastic Surgeons
DOI: 10.1097/01.prs.0000304441.99483.97
implications for developing novel therapies for
craniosynostosis.
CRANIOSYNOSTOSIS
Craniosynostosis, or the premature fusion of
one or more cranial sutures, is a relatively com-
mon congenital defect affecting approximately
one in 2000 to 2500 live births worldwide.1,4,5
The premature ossification of cranial sutures re-
sults in a number of morphologic abnormal-
ities, such as a dysmorphic cranial vault and fa-
cial asymmetry, each accompanied by functional
consequences.1,4,6,7 The most cited consequence is
that of increased intracranial pressure. Conten-
tious debate surrounds the association of cranio-
synostosis with elevation of intracranial pressure.
Although studies have documented higher intra-
cranial pressures in children with craniosynostosis,
especially those with multiple-suture involvement,8
the physiologic range of intracranial pressures in
unaffected children remains undefined. Never-
theless, concerns for visual impairment, deafness,
and cognitive deficits drive craniofacial surgeons
to intervene early in life.9
Craniosynostosis usually occurs as an isolated
condition but can also manifest in association with
a syndrome. There are over 100 craniosynostosis
syndromes that have been described and attrib-
Disclosure: None of the authors has any commer-
cial associations or financial disclosures related to
this article.

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Volume 121, Number 4 • Cranial Sutures
uted to specific mutations. In terms of morpho-
logic phenotypes, sagittal synostosis is the most
common type and is seen in 40 to 55 percent of
nonsyndromic cases.10,11 Coronal synostosis is the
second most common (20 to 25 percent), followed
by metopic synostosis (5 to 15 percent); lambdoid
synostosis is rare (0 to 5 percent).11 More than one
suture is affected in 5 to 15 percent of cases.11
After Virchow’s law, distinct morphologic
characteristics of affected skulls provide informa-
tion about which sutures are fused. Virchow pre-
dicted that when a suture fuses prematurely,
growth perpendicular to the affected suture is dis-
rupted, and compensatory growth of the skull ad-
vances parallel to the affected suture.3,12 For ex-
ample, when synostosis of the sagittal suture
occurs, growth proceeds in an anteroposterior di-
rection, leading to scaphocephaly. In contrast,
growth occurs in the mediolateral plane, resulting
in brachycephaly, when synostosis of bilateral
coronal sutures occurs.9
There have been significant advances in the
management of craniosynostosis. However, surgi-
cal intervention remains the only treatment. The
main goals of surgery for craniosynostosis include
excising the fused suture and normalizing the cal-
varial shape to increase the intracranial volume
and thus avert potential sequelae of increased in-
tracranial pressure.9 The surgical procedures in-
volved include strip craniectomies and various cra-
nial vault remodeling techniques. It is generally
recommended that surgical correction be per-
formed in early infancy, by 6 months of age.13 The
motivations for performing the surgery early in-
clude the ability of the child younger than 1 year
to completely reossify, the malleable character of
the calvaria during this age, and the tremendous
brain growth that occurs during the first year.9
Delay in correcting craniosynostosis may result in
deformity of the cranial base, facial asymmetry,
and dental malocclusion. Some have advocated
operating at later ages under certain circum-
stances. This approach may be more beneficial for
a procedure anticipated to require extensive re-
construction and blood loss, although few sur-
geons would operate later than 1 year of age.13
The surgical procedures are physiologically
challenging, and the remodeled skull vault is
prone to refusion, often requiring additional sur-
gical procedures.14 In addition, the complications
associated with surgical correction include infec-
tion, optic nerve ischemia, seizures, bleeding, and
the need for frequent blood transfusions.15,16 Mor-
tality rates have been reported to be as high as 1.5
to 2 percent.14 Improved knowledge of the ge-
netic, molecular, and tissue interactions dictating
cranial suture fusion and maintenance of patency
will facilitate improved, minimally invasive treat-
ment protocols for craniosynostosis.
MAMMALIAN SKULL VAULT
DEVELOPMENT
Research on the embryonic origins of the cra-
nial vault has led researchers to inquire about
whether origin dictates cranial suture fate. The
mammalian skull consists largely of four bones,
the frontal, parietal, squamosal, and anterior por-
tions of the occipital bone.1,10 The cranial bones
undergo intramembranous ossification from a
layer of mesenchyme located under the dermal
mesenchyme and above the meninges covering
the brain.10 The mesenchymal cell condensations
then differentiate into osteoblasts and deposit ex-
tracellular matrix. Ossification proceeds radially
from these condensations to form the skull bones.17
Cranial sutures are the fibrous tissues uniting
the cranial bones at they approximate with one
another during craniofacial development.17 The
sutures serve pivotal roles in early life, allowing for
skull deformation during birth and expansion
during brain growth and functioning as signaling
centers regulating the balance between prolifer-
ation and differentiation of the osteogenic pre-
cursors. The cranial sutures are the major growth
centers in the skull for the first few years of life.18
The mouse skull is analogous to the human
skull in many ways. In both species, the interfron-
tal (metopic) suture forms between the paired
frontal bones and the sagittal suture between the
paired parietal bones. Along the transverse axis,
the coronal sutures are situated between the
paired frontal and parietal bones, and the lamb-
doid sutures form between the parietal bones and
the interparietal bone (Fig. 1). The osteogenic
fronts of the transversely situated coronal and
lambdoid sutures overlap, whereas the midline
interfrontal and sagittal sutures abut end to end
(Fig. 2). The mouse posterior frontal suture un-
dergoes physiologic fusion (similar to the metopic
suture in humans), whereas all other sutures re-
main patent (Fig. 2). The differential fate of the
posterior frontal suture and the remainder of the
sutures has served as a useful tool with which to
compare the biology between them.
The mouse skull has been found to be of
mixed embryonic origin. Using transgenic mice
that display ␤-galactosidase activity in any cell
that is of neural crest origin, Jiang and col-
leagues discovered the cranial vault to be com-
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 Plastic and Reconstructive Surgery • April 2008

Fig. 1. Photograph of a mammalian skull. Bone and cartilage

staining with alizarin red and Alcian blue of a postnatal day–5
mouse calvaria illustrating the skeletal components and cranial
sutures. The figure depicts the frontal, parietal, and anterior por-
tions of the occipital bone. The interfrontal suture forms between
the paired frontal bones and the sagittal suture between the
paired parietal bones. Along the transverse axis, the coronal su-
tures are situated between the paired frontal and parietal bones,
and the lambdoid sutures form between the paired parietal
bones and the interparietal bone. af, anterior frontal suture; cor,
coronal suture; f, frontal; if, interfrontal suture; ip, interparietal;
lam, lambdoid suture; p, parietal; pf, posterior frontal suture; sag,
sagittal suture; so, supraoccipital; red, bone; blue, cartilage.
Fig. 2. Histologic sections of adult mouse sutures stained with
pentachrome demonstrating cranial suture anatomy. (Above)
posed of bones of divergent embryonic origins Posterior frontal suture. (Center) Coronal suture. (Below) Sagittal
juxtaposed together.19 –21 They found that the suture. The osteogenic fronts of the midline sutures, the poste-
frontal bones are neural crest derived, whereas the rior frontal suture, and the sagittal sutures abut end-to-end,
parietal bones are mesoderm derived, with a whereas the osteogenic fronts of the transverse suture and the
tongue of the neural crest– derived tissue projecting coronal suture overlap. In addition, the posterior frontal suture is
posteriorly20 (Fig. 3). Of note, both the coronal fused, whereas the coronal and sagittal sutures are patent. Yel-
and sagittal sutures, which remain patent, are low, bone.
formed at the interface of neural crest– and me-
soderm-derived tissues. In contrast, the posterior
frontal suture is composed entirely of neural
crest– derived tissues10,20 (Fig. 4). the intervening cranial suture mesenchyme, and
the overlying pericranium (Fig. 4). Several groups
have conducted experiments both in vitro and in
TISSUE INTERACTIONS vivo to establish the influence of the surrounding
Although the exact mechanisms dictating cra- tissues on suture fate.
nial suture fusion or patency remain to be eluci- Many experiments have provided evidence for
dated, numerous studies have examined the con- the potential influence of dura mater on cranial
tributions of the individual components of the sutures. Opperman et al. examined the require-
cranial suture in controlling its fate. The cranial ment of the dura mater in the development and
suture complex can be thought of as being com- maintenance of the normally patent coronal su-
posed of the dura mater underlying the suture, the ture by transplanting coronal suture complexes
osteogenic fronts of the calvarial bone plates, with or without dura mater from embryonic

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Volume 121, Number 4 • Cranial Sutures

day–19 and postnatal day–1 rats into parietal de-

Fig. 3. Mixed embryonic origin of mouse skull. X-Gal staining of
a Wnt1-Cre/R26R mouse calvaria. The blue X-Gal staining (high-
lighted in yellow) identifies neural crest– derived tissues, whereas
the nonstained regions are mesoderm-derived tissues. AF, anterior
frontal bone; F, frontal bone; IP, interparietal bone; P, parietal bone.
fects of adult rats.22 They found that in the absence
of dura mater, the coronal suture was fused ab-
normally by 3 weeks after transplantation, whereas
in the presence of dura mater, the coronal suture
remained patent.
As further evidence for the effect of dura ma-
ter, our laboratory showed that normal fusion of
the posterior frontal suture occurs in a delayed
fashion when the suture– dura mater interaction is
interrupted with an intervening silicone sheet.23
In addition, our laboratory has demonstrated that
regional dura mater may have differing influences
on the overlying suture.24 In 8-day-old rats, a rect-
angular strip of bone including the posterior fron-
tal and sagittal sutures was excised while main-
taining the integrity of the underlying dura mater.
This strip of bone was then rotated 180 degrees
and reimplanted into the calvarial defect, so that
the posterior frontal suture was situated over dura
mater previously underlying the sagittal suture
and vice versa. The authors found the sagittal su-
ture to be pathologically fused, whereas the pos-
terior frontal suture remained abnormally patent.
Thus, the results suggested that the regional dura
mater is important in determining fusion or pa-
tency in the rat model.

Fig. 4. Components of cranial sutures. Schematic illustration and tissue origins

of the mouse (above) posterior frontal suture, (center) coronal suture, and (be-
low) sagittal suture. The cranial suture complex is composed of the underlying
dura mater, the osteogenic fronts, the cranial suture mesenchyme, and the
overlying pericranium. The patent coronal and sagittal sutures are formed at the
interface of neural crest– derived tissue (blue) and mesoderm-derived tissue
(pink), whereas the fused posterior frontal suture is located entirely within the
neural crest domain. DM, dura mater; OF, osteogenic front; PB, parietal bone; PC,
pericranium.

173e

As further evidence for regional differences in
dura mater, Mooney et al. performed transplant
experiments in a rabbit model with coronal suture
synostoses.25 After coronal suturectomy in the cra-
niosynostotic rabbit model, transplantation of
dura mater allografts from wild-type rabbits into
the suturectomy sites prevented suture refusion,
whereas the control group without wild-type dura
mater developed suture refusion. The transplan-
tation of wild-type dura mater prevented refusion
at the suturectomy site and allowed for unre-
stricted craniofacial growth.
The periosteum of the skull has also been in-
vestigated to determine its importance in cranial
suture fate. After performing calvarectomy on
neonatal rabbits, it was noted that the establish-
ment of pericranial continuity postoperatively
was essential for restoration of normal sutural
architecture.26 However, in contrast to dura mater,
Opperman et al. demonstrated using embryonic
day–19 and postnatal day–1 rat coronal sutures in
a transplant model that removal of periosteum did
not lead to suture obliteration.27 From these data,
it appears that the overlying periosteum may not
be as essential for the maintenance of patency of
cranial sutures.
ANIMAL MODELS IN CRANIAL SUTURE
RESEARCH
The multifactorial nature and heterogeneity
of human craniosynostosis has led to the devel-
opment of a number of animal model systems with
which to study both normal cranial suture devel-
opment and the various molecular factors in-
volved in craniosynostosis. The mouse, rat, and
rabbit model systems have been the most exten-
sively studied. Together, these models have been
used in many of the experiments that have eluci-
dated the molecular signaling pathways involved
in cranial suture formation, development, and
maintenance.
In normal cranial suture fusion in mice, the
posterior frontal suture fuses in a predictable man-
ner between postnatal days 7 and 12. Fusion pro-
ceeds in an anterior to posterior direction and
initiates at the endocranial aspect, with the out-
ermost portion of the ectocranial table remaining
unfused.1 A number of animal model systems have
recently been studied, including (1) the stress-
induced model system; (2) pathologic suture fu-
sion, exemplified by Mooney and colleagues with
investigation of a familial craniosynostosis rabbit
strain; and (3) transgenic mouse models, includ-
ing knock-outs of various genes. The first two mod-
els are discussed below, and the transgenic models
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Plastic and Reconstructive Surgery • April 2008
are described in association with the molecular
mechanisms involved in suture morphogenesis.
A stress-induced model of craniosynostosis has
recently been used by various investigators to study
the expression of specific molecules under differ-
ent conditions. For example, Jacob and colleagues
used a murine model of intrauterine constraint,
originally developed by Koskinen-Moffett,28 to
study the expression of Indian hedgehog (Ihh),
bone morphogenetic protein-4 (Bmp-4), and
noggin.29 They found that decreased expression of
Ihh and noggin was associated with constraint-in-
duced suture fusion. Heller et al. also examined
the expression of noggin and Runx2 in the pos-
terior frontal and sagittal sutures with response to
stress induced by a microdistraction device in a rat
organ culture system.30
The rabbit model has been used for a number
of decades to study calvarial development. Many in-
vestigators have used adhesive immobilization of var-
ious sutures to create models of craniosynostosis that
appear consistent with human pathologic data.31
However, because of the delayed appearance of syn-
ostosis and the reported toxicity of the adhesive
used, a strain of rabbits with congenital craniosyn-
ostosis was developed to study cranial sutures.
Mooney et al. have extensively investigated a colony
of New Zealand White rabbits with familial, nonsyn-
dromic coronal suture synostosis.31–33 The sutural
and bone growth findings from the rabbit model
are similar to the pathologic calvarial findings in
humans.
MOLECULAR MECHANISMS INVOLVED
IN SUTURE MORPHOGENESIS
Cranial suture fusion and maintenance of pa-
tency are dependent on the interplay of an array
of transcription factors, cytokines, growth factor
receptors, and extracellular matrix molecules. It
is now known that the majority of the cranio-
synostosis syndromes are caused by mutations in
genes encoding fibroblast growth factor receptor
(FGFR)-1, FGFR-2, and FGFR-3, and the transcrip-
tion factors TWIST and MSX2.1,18 Gain-of-function
mutations are associated with the human MSX2
and FGFR genes, whereas loss of function or hap-
loinsufficiency is largely associated with the TWIST
gene.1,18 This information has led investigators to
focus on the role of these genes in regulating
proliferation, apoptosis, and differentiation of
cells within the cranial suture complex.
The FGF family consists of 22 highly conserved
proteins that regulate cellular proliferation, dif-
ferentiation, and migration. Gain-of-function mu-
tations in FGFR-1, FGFR-2, and FGFR-3 have been
Volume 121, Number 4 • Cranial Sutures
found to be associated with many human syn-
dromic forms of craniosynostosis, including Crou-
zon, Pfeifer, Apert, Jackson-Weiss, and Muenke
syndromes.18 In all these syndromes, mutation of
the FGF receptors results in increased affinity be-
tween the ligand and receptor.34 Analogues of
these syndromic forms of craniosynostosis are
present in transgenic mice and have allowed for
further investigation of the biology underlying the
associated mutations. Wang et al. generated a
knock-in mouse model with a mutation in FGFR-2 to
investigate the pathogenesis of Apert syndrome.35
They found that the mutation alters proliferation
and differentiation of osteoblasts at the midline cal-
varial sutures, and the phenotype is consistent with
the pathologic features of Apert syndrome.
The transforming growth factor (TGF)-␤ su-
perfamily is composed of multipotential cytokines
involved in a broad range of cellular processes.36
A multitude of experimental data point to the
widespread involvement of TGF-␤ signaling in cra-
nial suture biology. TGF-␤ receptor-2 (TGF-␤R2)
is expressed in the dura mater and cranial
sutures.37 Opperman and colleagues have demon-
strated inverse patterns of TGF-␤ isoform expres-
sion between fusing and patent sutures in the rat.38
During the process of posterior frontal suture fu-
sion, the reactivity for TGF-␤3 declined, whereas
that of TGF-␤1 and TGF-␤2 demonstrated contin-
ued expression. In the patent coronal suture, the
opposite was noted. TGF-␤ signaling has also been
shown to be important in craniofacial develop-
ment in mouse models from TGF-␤2 knock-out
mice39 and conditional inactivation of TGF-␤2 in
neural crest cells.40 TGF-␤2–null mice were found
to have a decrease in cranial ossification and
bone size.39 By using a conditional inactivation
of TGF-␤R2 in cranial neural crest cells, Ito et al.
showed that the loss of TGF-␤ signaling results
in severe calvaria development defects.40 Re-
cently, mutations of TGF-␤R1 and TGF-␤R2
were found to be implicated in human syn-
dromes of craniosynostosis.36
Bone morphogenetic proteins, members of
the TGF-␤ superfamily, are involved in a broad
range of developmental roles, including bone for-
mation, skeletal patterning, and limb develop-
ment. In relation to cranial suture biology, several
investigators demonstrated the critical role of
bone morphogenetic proteins and their antago-
nists in dictating cranial suture biology. In partic-
ular, in situ hybridization of mouse cranial sutures
localized expression of bone morphogenetic pro-
tein (BMP)-2 and BMP-4 to the osteogenic fronts
and BMP-4 to suture mesenchyme and dura mater
in the sagittal and posterior frontal sutures.41
Given this finding, our laboratory investigated the
hypothesis that bone morphogenetic protein an-
tagonists are differentially expressed to regulate
bone morphogenetic protein activity and thus su-
ture fate. Noggin, an antagonist of bone morpho-
genetic protein that inhibits by direct binding, is
required for various aspects of embryonic pattern-
ing. Specifically, Warren et al. found that noggin
is expressed in the suture mesenchyme of patent,
but not fusing, postnatal cranial sutures and that
it is suppressed by FGF-2.42 Warren et al. thus
concluded that the syndromic FGFR-mediated
craniosynostosis may be the result of inappropri-
ate down-regulation of noggin expression. In ad-
dition, overexpression of noggin using an adeno-
virus in postnatal day–3 mice led to patency of the
posterior frontal suture. Our laboratory has also
investigated BMP-3, another potential bone mor-
phogenetic protein antagonist that binds indi-
rectly to its ligand through a TGF-␤/activin–spe-
cific pathway, in suture patency. Using microarray,
Nacamuli et al. found BMP-3 expression to be
decreasing in normally fusing posterior frontal
sutures and increasing in normally patent sagittal
sutures over time.43
Mutations of transcription factors have also
been directly implicated in causing syndromic
forms of craniosynostosis. Liu et al. found that a
single-amino-acid substitution in the homeodo-
main of the human MSX2 gene is associated with
Boston-type craniosynostosis.44 This mutation en-
hances the affinity of MSX2, suggesting that the
mutation acts by a dominant positive mechanism.
There appears to be a dose responsiveness to MSX2
in normal craniofacial development.18 This was dem-
onstrated by the development of two different trans-
genic mouse lines that overexpressed the gene in
differing amounts. In the model with an approx-
imately twofold overexpression of the trans-
gene, suture fusion occurred,44 whereas the in-
tegration of a larger number of copies of the
transgene led to a more severe phenotype but
without craniosynostosis.45 In addition, there
has been evidence from mouse studies to sug-
gest that MSX2 is linked to the bone morpho-
genetic protein and FGF pathways.44
TWIST proteins are transcription factors with
a basic helix-loop-helix pattern. Mutations in the
transcription factor TWIST has been found to
cause Saethre-Chotzen syndrome. In addition,
TWIST expression has been localized to the mid-
sutural mesenchyme of the coronal suture in
mice.46 Data from cell culture experiments has led
to the suggestion that TWIST1 may be involved in
175e

the regulation of osteoblast proliferation and dif-
ferentiation by playing a central role in initiating
bone cell differentiation.1 In addition, it has been
noted that TWIST and FGF appear to be integrated
in the same signaling network in osteoblast dif-
ferentiation and calvarial bone formation.46,47
With recent improvements in the technology
for creating transgenic mice, a host of mice either
underexpressing or overexpressing specific pro-
teins have shed new light on molecules that play
a role in cranial suture biology. Work by Liu and
colleagues implicated the role of canonical Wnt
signaling in regulating cranial suture fate, using
mice with knock-out of Axin-2 expression.48,49
Axin-2 is a scaffold protein that negatively regu-
lates canonical Wnt signaling by mediating degra-
dation of ␤-catenin, a downstream transmitter of
Wnt. In Axin-2 knock-out mice, premature cranial
suture fusion was noted histologically. Yu and col-
leagues demonstrated that absence of Axin-2, a
negative modulator of Wnt/␤-catenin signaling,
results in unabated Wnt signaling, causing en-
hanced proliferation and differentiation of osteo-
progenitor cells.49
In an environment rich with cytokine signals,
extracellular matrix molecules may play a role in
cranial suture biology by assisting in the localiza-
tion of cytokines. Recent experiments using a bi-
glycan/decorin knock-out mouse points to the in-
volvement of extracellular matrix proteoglycans in
modulating cranial suture fate. Although the func-
tions of biglycan and decorin have not been fully
defined, they are known to bind and modulate
members of the TGF-␤ family. Wadhwa and col-
leagues found that mice deficient in biglycan and
decorin demonstrated failure to fuse the posterior
frontal suture and significant hypomineralization
of both frontal and parietal bones.50
CONCLUSIONS
Craniosynostosis is a common congenital dis-
order with significant craniofacial morphologic
consequences and potential detrimental neuro-
logic and cognitive effects. Craniosynostosis likely
results from abnormalities in the equilibrium be-
tween proliferation and differentiation of the os-
teoprogenitor cells of the cranial sutures from
perturbations in signaling, tissue interactions, or a
combination of these elements.
Although there has been progress made to-
ward elucidating the events surrounding cranial
suture fate, much of suture biology remains poorly
understood. The ultimate translational aim of
studies regarding cranial suture morphogenesis is
to produce biologically based therapeutic strate-
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Plastic and Reconstructive Surgery • April 2008
gies to prevent craniosynostosis and thus poten-
tially alleviate the devastating sequelae associated
with this condition. As we are able to determine
the specific roles of the various signaling mole-
cules involved with cranial suture fusion, these
molecules and their receptors may be used as tar-
gets of therapies for craniosynostosis. Eventually,
clinical trials with these treatments will need to be
implemented by the surgeons treating craniosyn-
ostosis.
A recent study presented by Mooney and col-
leagues illustrates the potential for developing an-
tibody-based therapies for craniosynostosis. In a
rabbit model with bilateral coronal suture synos-
tosis, local treatment with anti–TGF-␤2 antibody at
the suturectomy site significantly inhibited post-
operative resynostosis when compared with con-
trol groups.51 With the recent rapid expansion of
RNA interference technologies, the targeted sup-
pression of protein expression at the transcrip-
tional level offers a promising avenue to pursue in
the search for improved therapies for craniosyn-
ostosis. One could envision local delivery of RNA
interference to suppress the expression of mole-
cules such as the FGF receptors and/or bone mor-
phogenetic proteins. As the study of cranial suture
biology has evolved from morphologic descrip-
tions to molecular analysis, the opportunity for
treatment of craniosynostosis to progress in sim-
ilar fashion exists.
Michael T. Longaker, M.D., M.B.A.
Department of Surgery
Division of Plastic and Reconstructive Surgery
Stanford University School of Medicine
257 Campus Drive
Stanford, Calif. 94305-5148
longaker@stanford.edu
ACKNOWLEDGMENTS
This work was funded by National Institutes of
Health grant 5R01DE013194-09 and a grant from the
Oak Foundation to Michael T. Longaker.
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