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Craniosynostosis

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 University of Belgrade
School of Medicine

CRANIOSYNOSTOSIS

Darko Sarovic
ME 27/09

Mentor: Prof. Ljiljana Vujotic, MD, PhD

Institute: Clinical Center of Serbia, Neurosurgery Department,

Pediatric division

Belgrade, 2015
     1  

Table of contents
1. Introduction……………………………………………………………………….3
2. Epidemiology……………………………………………………………………..3
3. Classification……………………………………………………………………...4
4. Pathophysiology…………………………………………………………………..5
a. General mechanisms………………..………………………………....…..5
i. Dura mater and brain.….….….…………………………………...6
ii. Osteogenic fronts and suture mesenchyme……………………….8
iii. The microspicule hypothesis…………………………………...…8
b. Molecular pathways……………....……………………………………….8
i. FGF and FGFR….….……………………………………………...9
ii. TGF-β……………………………………………...…….……….10
iii. IGF……………………………………………………....……….11
iv. Other pathways…………………………………………………...11
1. BMP………………………………………………….…..12
2. RANK…………………………………………………....13
3. MSX……………………………………………………...13
4. Wnt signaling pathways………………………………….13
5. Runx……………………………………………………...14
c. Genetics…………………………………………………………………..14
i. Nonsyndromic……………………….………………………...…14
ii. Syndromic……………………….….….………………………...15
d. Extrasutural causes…….….….….….……….…………………………...15
i. Fetal head constraint……………...…….………………………..16
ii. Intrinsic brain pathology………………..….….…………………16
iii. Teratogens……………………………………..….……………...17
1. Smoking………………………………………..………...17
2. Hyperthyroidism………………………………….……...17
3. Drugs……………………………………………..………17
a. Valproic acid……………………………………..17
b. Retinoic acid………………………………….......17
c. Fertility treatment………………………………...17
d. Alcohol…………………………………………...18
iv. Antenatal complications……………………………….…………18
v. Maternal and paternal age………………………………………..18
5. Clinical presentation…....………………………………………………………...18
a. Nonsyndromic……………………………………………………………18
i. Metopic suture……………………………………………………19
ii. Coronal suture……………………………………………...…….19
iii. Sagittal suture…………………………………………………….20
iv. Lambdoid suture…………………………………………………20
1. Differentiation from positional plagiocephaly…………...21
v. Complex………………………………………………………….22
b. Syndromic………………………………………………………………..23
i. Crouzon Syndrome………………………………………………24
ii. Apert Syndrome……………………………………………….....24
iii. Pfeiffer Syndrome……………………………………………......25
iv. Saethre-Chotzen Syndrome………………………………………26
v. Muenke Syndrome……………………………………………….26
vi. Craniofrontonasal Dysplasia………………………………..........27
vii. Carpenter Syndrome……………………………………………..28
     2  

c. Complications………………….………………………………………...28
i. Increased intracranial pressure…………………………………...28
ii. Chiari malformation and foramen magnum……….……………..29
iii. Cognitive development…………………………………………..30
iv. Airway obstruction...……………………………………………..31
v. Sensory disturbances……………………………………………..32
1. Visual…………………………………………………….32
2. Auditory………………………………………………….32
6. Diagnosis…………………………………………………………………………33
a. Physical examination…………………………………………………….33
i. Inspection………………………………………………………...33
ii. Palpation…………………………………………………………33
b. Imaging…………………………………………………………………..33
i. CT………………………………………………………………..34
1. Venography………………………………………………35
ii. MRI………………………………………………………………35
iii. X-ray……………………………………………………………..36
iv. Ultrasound………………………………………………………..36
c. Genetic testing……………………………………………………………37
7. Treatment………………………………………………………………………...37
a. Surgery…………………………………………………………………...38
i. Types of surgery………………………………………………….39
1. Open surgery……………………………………………..39
2. Minimally invasive surgery………………………………40
a. Orthotic helmet…………………………………...41
3. Additional methods………………………………………41
a. Distraction osteogenesis………………………….41
b. Spring-mediated surgery…………………………42
ii. Timing of surgery………………………………………………...43
iii. Intrasurgical aspects……………………………………………...44
1. Positioning……………………………………………….44
2. Blood transfusion and fluid replacement………………...44
iv. Complications……………………………………………………45
1. Intracranial hypertension………………………………....46
2. Infections…………………………………………………46
3. Bleeding………………………………………………….46
4. CFS leak………………………………………………….46
5. Bone defects……………………………………………...47
6. Bone fixation……………………………………………..47
b. Pharmacologic treatment…………………………………………………47
8. Prognosis and outcome…………………………………………………………..48
a. Recurrence and progression……………………………………………...48
b. Aesthetic outcome………………………………………………………..49
9. Conclusion……….……………………………………………………………....49
10. Literature…………………………………………………………………………52
     3  

1. Introduction
Craniosynostosis (CS) refers to the premature closure of one or more of the sutures that
normally separates the bones of the skull. The fusion prevents symmetric and perpendicular
growth of the cranial vault and manifests itself as a deformation of head shape with
compensated growth parallel to the fused suture.1 It can occur sporadically, due to genetic
causes, mechanically2,3 and teratogenically4.
Simple CS refers to cases with only one prematurely fused suture. This is the most
common type of CS and usually presents idiopathically. Compound CS refers to cases with
premature fusion of multiple sutures. If this occurs in the setting of genetic syndromes, it is
then referred to as syndromic CS. CS without extracranial deformations is referred to as
nonsyndromic CS.6 Lastly, the rare case of nonsyndromic CS with fusion of multiple sutures
is referred to as complex CS.7
The etiology of CS can either be primary, due to defective ossification, or secondary,
due to restricted brain growth, skeletal dysplasia, or metabolic7 and hematologic disorders.8
Surgical treatment is almost always necessary to improve the aesthetic appearance and
prevent complications, such as respiratory and neurological problems, and is performed
during infancy and early childhood. Both open surgery and minimally invasive procedures,
such as endoscopy, are being used. Pharmacologic treatment is currently being researched,9
with some agents already showing promising results for select cases.10

2. Epidemiology
The overall incidence of CS is 1 in 2’000 to 2’500 births.11 Most of the patients have
nonsyndromic simple CS, of which fusion of the sagittal suture is the most frequent12 (see
table 1 below). The second most frequent is the coronal suture. A unilateral presentation of
coronal CS is twice as frequent as a bilateral presentation. Less frequent are metopic and
lambdoid involvement. Syndromic CS occurs in less than 5% of cases, and almost half of
those cases present with bilateral coronal synostosis. The most frequent is Crouzon
syndrome, occurring in 1 in 25’000 live births. Less frequent are Saethre-Chotzen, Apert,
Pfeiffer and others.13
     4  

3. Classification
There are several ways to classify CS: (a) by the number and type of sutures fused, as single
or multiple, (b) by etiology, as syndromic or nonsyndromic, and (c) by suture biology, as
primary or secondary.
By a combination of the abovementioned factors, each classification has its own
appearance and clinical picture, with inherent risks and complications, as well as a different
approach to treatment.
CS is classified as primary when the etiology is a defect in ossification, which occurs
in idiopathic CS or in certain genetic disorders (such as mutations of the FGFR-genes). This
usually presents as simple CS. Rarely does it present as complex CS. Secondary CS has a
wide differential diagnosis, and more often has extracranial manifestations than primary CS.
Primary CS is itself further subclassified according to the type of suture involved (see
table 1). Nonsyndromic CS is usually an isolated finding that presents with fusion of a single
suture, while syndromic CS is often accompanied by developmental delay and
dysmorphisms of face, skeleton, nervous system, and other anomalies. More than 180
syndromes exist that contain CS as an entity.5

Table 1. Classification of primary CS according to involved sutures and their relative

frequencies9
Type Sutures involved Frequency
Simple Single 85-95%
Scaphocephaly Sagittal 40-55%
Anterior plagiocephaly Unilateral coronal 20-30%
Trigonocephaly Metopic 5-10%
Posterior plagiocephaly Lambdoid 1-3%
Compound Multiple 5-15%
Brachycephaly Bilateral coronal 10%

There are 4 major sutures of the skull according to which CS is classified (figure 1): (1) the
metopic suture, which separates the two frontal bones, (2) the coronal sutures, which
separate the frontal bones from the parietal bones, (3) the sagittal suture, which separates the
parietal bones, (4) the lambdoid sutures, which separate the occipital bone from the parietal
and temporal bones. The appearance CS is classified according to these four sutures,
     5  

although other sutures, such as the squamous suture,14,15 are implicated in its pathogenesis,
but rarely diagnosed.

Figure 1. Illustration showing the sutures and bones of the cranial vault9

4. Pathophysiology
There are several different reasons for the appearance of CS. Firstly, the general mechanisms
of pathogenesis will be outlined. Then specific genetic causes will be explained, both the
causes of nonsyndromic and those of syndromic CS. Lastly, some other causes that have
been implicated will be outlined.

4.a. General mechanisms

The fate of cranial sutures, whether they fuse or remain patent, is complex and several
structures are involved in the process: brain, dura mater, osteogenic fronts and suture
mesenchyme (figure 2). The cranial vault forms through the processes of both
intramembranous and endochondral ossification, however sutures are sites of
intramembranous ossification;17 there is no cartilage between cranial bones, but osteoblasts
derive directly from the mesenchyme and induce ossification at the osteogenic fronts. This
requires a well-controlled balance between stimulation and inhibition of ossification.
Current research is focused on elucidating the main actors of suture fusion, so as to
understand those pathways and find ways to target them specifically through pharmacologic
therapy. It should be remembered that most of the studies on suture biology are done on
animals, mostly rodents. Despite that most evidence points to the fact that results from
animal studies can be correlated to human physiology, one should beware of directly
     6  

translating the results. There are still many aspects that are unknown; furthermore, those
studies have to be replicated on humans before a pharmacologic therapy is clinically
available.

4.a.i Dura mater and brain

The dura mater seems to be one of the main driving forces behind the progression of CS, due
to its many functions in regulating the overlying skull, but also the underlying brain. The
osteogenic fronts are affected by soluble factors secreted by the dura, but they also
themselves regulate suture biology. Signals from the dura are most important for the
maintenance of suture patency prenatally, while the osteogenic front signals dominate
postnatally.16

of suture fusion and involved parts17

SUTURES AS BONE GROWTH SITES
Figure 2. Schematic representation of progression

Fig. 4. Diagrammatic representation of a presumptive suture (A), a morphogenesis presented. (1Opperman et al., 1997, 2Most et al.,
3
fully formed suture (B), and a fusing suture (C). The color-coded regions Rice et al., 2000, 4Johnson et al., 2000, 5Marks et al., 1999, 6Rice
The reason the dura is so intricately involved in the pathogenesis of CSRoth
is12 the fact thatKim
7 8 9
of the sutures (green), osteogenic bone fronts (orange), and bone (blue) 1999, Roth et al., 1997a, et al., 1997b, et al., 1998, 10Is
11 13
are given in the accompanying key. Periosteum is colored pink. The key al., 1997, Iseki et al., 1999, Liu et al., 1999, Lemmonier et al.,
14
listsit the
is growth
derivedandfrom neuralfactors,
transcription crest receptors,
cells. The andbrain is also derived
extracellular from
Zhou et al., neural crest cells, but
2000.)
matrix components known to be present in each of the stages of suture
lacks the ability to regulate the cranial vault. As such, the dura is able to maintain patency of
cranial sutures by communicating brain growth to the cranial vault.18 It is also possible that
culture indefinitely (Bradley et al., 1996). These stud- suture to imprint the dura mater with a signal in
iesintrinsic
demonstrated in anthe
signals from alternate waybrain
hypoplastic that(corpus
once the tory to
callosum bone formation
agenesis, would
pyramidal result in absence or o
hypoplasia
sutures have been formed, they are capable of main- eration of sutures as described above by Levine e
taining themselves independent of the presence of dura (1998) (Fig. 3D). This was also seen clinically in fa
mater. However, these data support the hypothesis of sutures to re-grow at sites where sutures init
that the dura mater underlying the suture is altered failed to form (Drake et al., 1993). Interestingly,
once the suture is formed. This idea is supported by the mater transplanted from beneath normally paten
     7  

etc.), which are frequent expressions of syndromic CS, induce suture fusion through the
activation of fibroblast growth factor receptors (FGFR) via the dura.19
It has been proposed that CS is a consequence of a defective L1CAM-FGFR
interaction;20 essentially, the pathologic FGFR signaling doesn’t cause CS directly, rather, it
does so indirectly by interfering with brain development by inhibiting FGFR-induced
signaling of L1CAM, which then leads to decreased secretion of patency-maintaining factors
by the underlying dura. L1CAM is one of the factors necessary for white matter
formation,21,22,23 and a lack of its function would lead to a hypoplastic brain that then
signals, via the dura, that suture fusion should ensue. This could possibly explain why
syndromic CS, many of which have a mutated FGFR, tends to affect more than one suture.
Non-syndromic CS, which also often has a defective FGFR2, usually only affects one suture
despite the fact that the etiology is not suture-specific. This points to the fact that the
multiplicity of suture fusion and possibly the accompanying mental retardation in syndromic
CS is, at least partly, due to faulty development of the underlying brain, due to a defect in
FGFR-L1CAM signaling, rather than a consequence of the skull size or associated
hydrocephalus.20 Why white matter dysgenesis does not occur in FGFR-mutated
nonsyndromic CS was not mentioned in the review by Raybaud et al. (2007), but it suggests
that an intermediate actor in the molecular pathway is involved..
Further evidence suggesting that the dura is the main actor in suture regulation is that
the dura undergoes bone formation when transplanted under epithelium, but not under
mesodermal tissues.24 An absence of the dura induces suture fusion,25 which shows that the
dura has both stimulating and inhibiting functions. It also seems to function regionally, such
that dura that is transplanted from a patent suture to one that is undergoing fusion maintains
it and prevents progression of ossification.16,24,26 This suggests that the dura mater-suture
communication is not dependent on tensional forces, cell-cell interactions or distant
endocrine hormones. Additional evidence that the dura regulates suture biology through
soluble factors is the fact that covering the dura, with impermeable Gore-Tex, prevents the
ossification of an overlying suture.27 Another study, using an impermeable silicone
membrane, obtained the same result, with the addition that one group received only dural
separation from the calvarium, which lead to a delay in suture fusion, suggesting the
importance of an intricate connection between the two structures.28 The main soluble factors
that are implied in suture physiology will be outlined in chapter 4.a.iv.
     8  

4.a.ii. Osteogenic fronts and suture mesenchyme

The cells of the suture mesenchyme remain undifferentiated during development, while
those at the osteogenic fronts lay down bone through intramembranous ossification. FGFR2
is highly expressed in the osteogenic fronts,17 and it is one of the central mediators of suture
biology as is explained below. Also bone morphogenetic protein (BMP) 2 and BMP 4 are
intensely expressed in the osteogenic fronts, while BMP4 is also found in the
mesenchyme.29,30 However, they have not been as extensively studied in the setting of CS as
some of the other soluble factors that will be explained in further chapters.

4.a.iii. The microspicule hypothesis

The microspicule hypothesis was proposed by Burke et al. in 1995.31 It was observed that
osteoblasts are situated everywhere on the cranial vault, except across the sutural
mesenchyme. Also, osteoclasts are only found in the diploic spaces. The microspicule
hypothesis proposes that microspicules of bone bridge the suture. Since there are no
osteoclasts to remove them, if they fail to fracture, they then act as a scaffold upon which
more bone is deposited. How those microspicules come to bridge the suture in the absence
of osteoblasts was not explained in the study.

4.b. Molecular pathways

It is only in the last decades that molecular biologic research has been able to elucidate some
of the factors involved in suture biology, and how they interact. The factors that have been
most widely studied, and implicated in suture fusion, are the fibroblast growth factor (FGF),
transforming growth factor beta (TGF-β) and the insulin-like growth factor (IGF).32 Their
roles in syndromic or nonsyndromic CS, respectively, will be put into perspective in chapter
5.
Others include BMPs and Msh homeobox 2 (Msx2) protein, but their effects on cranial
suture biology have not been as extensively studied. These factors are all pro-osteogenic and
mostly act on the osteoblasts; even less studied are the factors that modulate
osteoclastogenesis and osteoclast activation, such as the cytokine receptor activator of
nuclear factor kappaB ligand (RANKL).33 The role of the Wnt signaling pathway in CS is
unclear, though some studies have implicated it in the complex interplay that leads to CS,
especially as related to FGF.34
     9  

Table 2 shows a summary of the main proteins explicitly involved in the pathogenesis
of CS.

Table 2. Molecular inducers and inhibitors of suture fusion

Maintain suture patency Induce suture fusion
TGF-β353 FGF2,35-40 3,43 443
Noggin61,62,76 FGFR1-341,44
RANK, RANKL33 TGF-β1, β247-53
Twist170 IGF-1, 255-58
Runx273,74
BMP2, 3,33,59,60 433,55
Axin1, 273-75
Msx 1,67 262-66

4.b.i. FGF and FGFR

The FGF family consists of more than 19 ligands that interact with FGF receptors (FGFRs).
Each FGF ligand can bind to several FGFRs, and each FGFR interacts with several FGFs.
Basic fibroblast growth factor (FGF-2), the most abundant ligand, has been shown to
stimulate osteoblast proliferation and differentiation,35,36 chondrocyte differentiation,36 and
enhance bone formation both in vivo and in vitro.37,38 Also, in experimental conditions,
FGF2 treatment enhanced suture fusion.39
Mehrara et al.40 showed that FGF-2 is highly expressed locally by the dura mater both
prior to and during suture fusion. There was also a deficit in FGF-2 signaling in adjacent
sutures that suggests a possible mechanism by which the cranium accommodates for brain
growth in the presence of CS.
Supraphysiologic FGF-2 signaling causes paradoxical inhibition of osteogenesis, as do
subphysiologic levels; a continuous level of a certain concentration of FGF2 induces fusion
of cranial sutures.38 It seems as if excessive FGF-2 maintains suture patency by reciprocal
FGFR2 down-regulation.41 Another function of FGF-2 is that it directly and dose-
dependently stimulates the expression of TGF-β1 in osteoblast-like cells and as such
augments its pro-osteogenic effects.42
Increased levels of FGF3 and FGF4 have been shown to infer an increased risk of
premature fusion.43
     10  

Besides FGFs, there are three main FGFRs that are involved in suture biology:
FGFR1, FGFR2 and FGFR3.
Iseki et al.41 investigated their different roles during (mouse) calvarial development.
They found that FGFR2 expression coincided with areas of rapid proliferation, and that it
was absent from areas of osteoblast differentiation, which were highly expressive of FGFR1.
FGFR3 is expressed in both osteogenic and chondrogenic regions of the skeleton, and
together with FGFR2, signals osteogenic proliferation.
Some FGFR mutations (FGFR2 in Apert) increase the affinity of the mutant receptor,
which leads to excessive signaling, increased osteoblast differentiation and premature
calvarial ossification.44

Figure 3. Pattern of expression of FGF and FGFR within cranial sutures45

FGFRs are also differentially expressed in the different cranial sutures.46 Mutations in
the different FGFRs cause fusion of different sutures. FGFR2 is the most widely distributed
across sutures, and also the most commonly mutated; mutations affect the coronal, metopic,
sagittal, and lambdoid sutures. Mutations of FGFR3 only affect the coronal and metopic
sutures, while those of FGFR1 (and also Twist1 and EFNB1) usually only affect the coronal
suture.

4.b.ii. TGF-β
TGF-β consists of three isoforms: TGF-β1, TGF-β2 and TGF-β3.47 The functions of TGF-β
are many and include stimulation of osteoblast proliferation and collagen synthesis, as well
as inhibition of osteoclast activity.48,49,50
It has been shown that TGF-β1 mRNA transcription,51 and subsequent protein
expression,52,53 by the regional dura is markedly increased before and during suture fusion,
while nonfusing sutures express low levels of TGF-β1, which implies that it is central to the
process of suture fusion.
     11  

Besides TGF-β1, TGF-β2 and IGF-1 are also highly expressed in osteoblasts at the
suture fronts of fusing sutures. Roth et al. (1997)54 showed that the TGF-β2 isoform was the
most highly expressed at fusing suture fronts of all three isoforms. Furthermore, they
showed that TGF-β3 expression was suppressed in fusing sutures and upregulated in patent
sutures, suggesting that TGF-β3 has a role in maintaining suture patency.
Greenwald et al. (1984) used adenoviruses as vectors to inject a truncated version of
FGFR1 into the dura; the result was that the preprogrammed postnatal suture fusion was
inhibited, while in utero. In vitro analysis later showed that, besides alterations in cellular
proliferation and the expression of extracellular matrix molecules, TGF-β1 synthesis was
altered as well.55

4.b.iii. IGF
Proteins and mRNAs of the two isoforms IGF-I and IGF-II have been shown to be almost
exclusively expressed in the dura mater and suture mesenchyme of fusing sutures. The
mRNA expression of the two isoforms is increased in the dura underlying the fusing suture
2-10 days prior to induction of fusion, and subsequently in the suture mesenchyme at days
15-20 during fusion. Bradley et al. (1999)56 suggested that the dura-suture interaction thus
may be mediated by a paracrine signaling through dural growth factors, such as IGF-I and
IGF-II. They also noted that osteocalcin protein (BMP4) was present in osteogenic front
osteoblasts at day 15 of suture fusion, possibly due to stimulation by IGFs.
Akita et al. (1996)57 used a hyperthyroid rat model to show that local IGF-I plays a
role in sutural bone formation, while Thaller et al. (1993)58 showed that subcutaneously
administered IGF-I induced fusion of the underlying suture.
In vitro studies show that tensile forces acting on cranial sutures upregulate IGF-I and
IGF-I receptors in osteoblast-like and fibroblast cells, central mediators of suture fusion, to
induce their proliferation.59

4.b.iv. Other pathways

The soluble factors above have been extensively studied in CS probably because they seem
to directly affect the populations of osteoblasts and chondrocytes in the cranial sutures. In
the last decade or so a number of alternative genes have been implicated, and their
subsequent proteins have been shown to affect suture biology. Their effects are mostly
indirect, through a complex network of interactions.
     12  

In figure 3 you can see a chart of most of the involved factors and how they interact
amongst each other. The chart contains the result of a cross-reference search on the online
database Pubmed for studies that explicitly investigated any form of premature fusion of
cranial sutures; only directly interacting factors have been taken into consideration. The fact
that the different sutures have varying expressions of soluble factors vastly complicates the
situation; figure 4 shows their interactions on a global level, which need not apply in its
entirety in individual sutures.

Figure 4. Chart of molecular network underlying suture biology

4.b.iv.1. BMP
The BMPs are growth factors, belonging to the TGF-β superfamily, that are able to induce
bone formation of calvaria by regulating proliferation, differentiation and apoptosis of
human calvarian osteoblasts.33 Kinsella et al. (2011)60 experimentally applied recombinant
human BMP-2 (rhBMP-2) to rabbits with induced skull defects. The treatment resulted in
bilateral coronal fusion and variable fusion of the sagittal suture. Furthermore, Xu et al.
(2013)61 showed that treatment with rhBMP-2 and platelet-rich plasma (PRP) act
osteogenically, during distraction osteogenesis, both synergistically and in isolation. Topical
administraction of noggin, a BMP inhibitor,62 prevents CS in rat models.63
     13  

4.b.iv.2. RANK
In contrast to the aforementioned factors, RANKL exerts its action on the osteoclasts,
causing an inhibition of suture fusion. In the setting of suture fusion RANK mRNA is not
downregulated, which means that the effect is modulated on the protein level. RANKL has
been shown to be decreased in the setting of suture fusion.33 Osteoblasts counteract the
function of the RANK-RANKL system by secreting a decoy receptor for RANKL called
osteoprotegerin (OPG), which inhibits osteoclast differentiation and activation by
interrupting the binding of RANKL to RANK.64

4.b.iv.3. MSX
The Msh homeobox (Msx) 2 gene codes for a transcription factor protein, and excess of it
has been shown to cause craniosynostosis in mice.65,66 From patients with trisomy of
chromosome 5 who developed CS, the location of the Msx2 gene, we have further indication
that an increase in the number of Msx2 copies leads to CS.67,68,69 Msx1 (also known as
HOX7) has been studied in the context of tooth and palate development, and although it has
been implied in CS, direct evidence is weak. Msx2 expression declines sharply after birth,
while the expression of Msx1 is maintained postnatally during skull morphogenesis.70

4.b.iv.4. Wnt signaling pathways

The Wnt signaling pathways are a group of signal transduction pathways connecting
extracellular signals to intracellular changes in metabolism. There are two Wnt signaling
pathways: (1) canonical, which involves the protein β-catenin, and (2) noncanonical. High
Wnt/β-catenin signaling stimulates differentiation of osteoblasts, but inhibits chondrogenesis
that is central to suture fusion;71 switching the fate of mesenchymal stem cells to
chondrocytes is an etiologic mechanism for craniosynostosis in mice.72 Canonical Wnt
signaling maintains suture patency by stimulating Twist1, which represses chondrocyte gene
expression that would otherwise lead to suture fusion.73 Twist1 also upregulates FGFR-2
mRNA.74 Non-canonical Wnt signaling directly inhibits canonical Wnt signaling and
induces suture fusion. Application of Wnt antagonists leads to suture fusion.75 Another
inhibitor of the canonical Wnt pathway is Axin (Axin1 and Axin2).76,77,78
     14  

4.b.iv.5. Runx
The Runt-related transcription factor 2 (Runx2) is a key transcription factor involved in
osteoblast differentiation and has been implicated in CS;79 an excess of it causes a dose
dependent ossification.80

4.c. Genetics
There are myriad soluble factors with complex interactions that affect suture biology, and
they are all coded for by certain genes. The main ones that have been implicated in the
pathogenesis of nonsyndromic and syndromic CS, respectively, will be elucidated below.

4.c.i. Nonsyndromic
Nonsyndromic CS differs from syndromic CS in that its effects are localized and disturb the
mechanisms of the ossification of the cranial sutures only. Syndromic CS is caused by
genetic defects that have effects on peripheral tissues as well, such as palate, fingers and
long bones etc. The genetic basis of single-suture craniosynostosis is complex and while a
number of genetic biomarkers have been identified, in many cases the causes remain
inconclusive.34 Several studies have found single gene mutations in nonsyndromic coronal
synostosis.81-83 However, mutations associated with simple CS remain elusive and
sometimes overlap with those causing syndromic CS. While evidence suggests a strong
genetic component exists for all forms of craniosynostosis, nature and nurture probably both
play a role in premature suture fusion for non-syndromic forms of CS.34
Mutations affect each of the calvarian sutures (coronal, sagittal, metopic, and
lambdoid) differently, suggesting that different gene expression patterns exist in each of
them.83 The expression patterns for coronal and metopic sutures are similar, whereas gene
expression in sagittal cases is less so.34 That explains why a mutation in a globally acting
gene, such as FGF2 does not affect all sutures in every case. Elucidating the patterns of gene
expression have already given some results, however, there seems to be overlap between the
sutures, which complicates investigations.
Some of the implied genes involved in the development of nonsyndromic CS are
FGF2,83 FGFR2,84,85 FGFR3 Pro250Arg,81,85,86 TGF-β receptor I and II,84 IGF1R,87
Twist1,85,88 Runx2,89 FGF7,34 SFRP4,34 and VCAM1.34
     15  

4.c.ii. Syndromic
In this chapter only the genes and growth factors responsible for syndromic CS will be
outlined; the phenotypic expression of each syndrome will be further explained in section
5.b.
As mentioned earlier, more than 180 known syndromes contain CS as an entity. Most
of them are exceedingly rare and outlining them is outside the scope of this thesis; only the
most common ones, where CS dominates the clinical picture, will be mentioned. The most
common syndromes having CS as a phenotypic expression, in decreasing order of frequency
(though incidence rates vary widely between studies), are: Muenke Syndrome, Saethre-
Chotzen Syndrome, Apert Syndrome, Crouzon Syndrome, Pfeiffer Syndrome,
Craniofrontonasal dysplasia, and Carpenter Syndrome. Table 3 lists each of the syndromes
together with implied causative mutations and incidence rates.

Table 3. Craniosynostosis syndromes and their implied mutations and incidence rates
Syndrome Mutation Incidence
90,91
Muenke FGFR3 1:10-30’00013
Saethre-Chotzen Twist173,91 1:10-50’00013
Crouzon FGFR283,90,91 & FGFR383,90,91 1:25-100’00013
Apert FGFR283,90-92 1:65-100’00013
Pfeiffer FGFR183,90,91 & FGFR283,90,91 1:100’00013
Craniofrontonasal dysplasia EFNB190 1:100-120’00094
Carpenter RAB2390,93 & MEGF893 <1:1’000’00095

The most commonly mutated genes in CS are those of the FGFR-family.83,90-92 This is
mainly due to their high expression in cranial sutures. However, the genes involved in
syndromic CS are global actors in skeletal biology, and this is the reason why syndromic CS
has manifestations outside the cranial sutures. Other implicated genes are Twist1,73,91
EFNB1,90 RAB2390 and MEGF893 (see table 3).

4.d. Extrasutural causes

Disruptions of the genes and molecular pathways involved in suture biology are not the only
reasons for premature suture fusion. Several environmental factors have been implied in the
etiopathogenesis of CS, such as drugs, mechanical forces and co-morbidities.
     16  

4.d.i. Fetal head constraint

Externally applied tensile forces have been shown to upregulate TGF-β receptors types I and
II, 96 IGF-I,59 FGFR2,96 FGF2,97 increase membrane permeability,97 and intracellular Ca2+.97
These changes induce suture fusion. Fetal head constraint has several different etiologies by
itself. Abnormal fetal lie,98 such as breech presentation, has been shown to induce early
fusion of the coronal suture.99 Uterine malformations,98,99 such as bicornuate uterus, can
induce early suture fusion by limiting the expansion of the uterus to accommodate the
growth of the fetus. Other causes include amniotic bands98 and defects in fetal
neuromuscular development.98 Plurality has an increased risk of CS due to the fact that the
uterus is more crowded;100,101 the cranium of one fetus can be pressed against a firm surface
on the twin. Sanchez-Lara et al (2010)102 showed that plurality was only a risk factor when
including cases with fertility treatments, suggesting a teratogenic effect of those drugs,
rather than a result of fetal head constraint. Macrosomia is also a cause of fetal head
constraint-induced CS.102 There is evidence that cases due to fetal head constraint
spontaneously remold, suggesting that conservative follow-up might be an option to surgical
correction in those patients.98

4.d.ii. Intrinsic brain pathology

As explained in chapter 4, the dura mater maintains suture patency by signaling brain
growth to the overlying endocranium. An absence of such signals, as can occur from a wide
variety of brain and spine pathologies, leads to a decreased expression of suture-maintaining
signals from the dura, and subsequent early fusion. When considering the pathogenesis of
CS, one should consider the brain, dura mater, and skull as a system, rather than as
independent parts.103 Martínez-Lage et al. (1996)104 proposed that neural tube defects (NTD)
induce CS through that mechanism. The malformation sac reduces the intracranial pressure
and inhibits dural brain growth signaling. The authors noted that fetal head constraint due to
diminished fetal activity, as a result of the NTD, might be a contributing factor.
Aldridge et al (2005)105 did a comprehensive analysis of patients with unilateral
coronal CS and showed that brain dysmorphology is a primary condition, and that suture
fusion is a secondary consequence. Other studies have proposed that brain dysmorphology is
an incidental finding and a secondary feature of CS.106-108
     17  

4.d.iii. Teratogens
4.d.iii.1. Smoking
Smoking is a known risk factor for CS,109-111 and it shows a dose-dependent effect.109
Second hand smoking at home has also been shown to increase risk.110 Fusion of the sagittal
suture shows the highest association with maternal smoking, while the coronal suture shows
no such effect.109 Smoking during the first trimester of pregnancy does not confer a risk,
however smoking during the second and third trimesters does, but only for mothers who
smoke more than one pack per day.110 The mechanism by which smoking increases the risk
might be intermittent hypoxemia, since studies have shown that high antenatal maternal
altitude has an effect on the development of CS.101,112

4.d.iii.2. Hyperthyroidism
Maternal thyroid disease, such as Grave’s disease, is a known risk factor, either as a direct
cause, or as a result of the treatment for the disease.7,113 Thyroid hormones have effects on
skeletal metabolism, and a surplus of the hormone could potentially upregulate ossification
in cranial sutures. Undiagnosed maternal thyroid disease might account for some cases.114

4.d.iii.3. Drugs
4.d.iii.3.a. Valproic acid
The anticonvulsant and mood stabilizing drug valproic acid is well known to cause CS, most
notably trigonocephaly.113,115-117 A possible mechanism for this effect might be that valproic
acid increases the formation of Reactive Oxygen Species (ROS),118 and ROSs have been
shown to induce chondrocyte hypertrophy in endochondral ossification.119

4.d.iii.3.b. Retinoic acid

Another well-known drug that causes CS is retinoic acid, a metabolite of vitamin A.113 It
works by suppressing osteoblast proliferation and enhancing their differentiation, which
leads to subsequent suture fusion. 120,121

4.d.iii.3.c. Fertility treatment

Several studies have found fertility treatment and procedures to increase the risk of
CS.114,117,122 Estrogen has been found to stimulate Runx2 expression in osteoblasts, and to
inhibit it in osteoclastogenesis; these effects lead to early ossification and laying down of
immature bone.123
     18  

4.d.iii.3.d. Alcohol
One study found alcohol consumption in the 2nd and 3rd trimesters to be inversely associated
with CS,124 while another one found it to be a risk factor.114 The conflicting results may be
because of different quantities or frequencies of consumption. One study showed no effect,
possibly because the timing of consumption was not taken into consideration.125

4.d.iv. Antenatal complications

Singh et al (2010) found that a history of antenatal complications, such as hypertension/per-
eclampsia, hemorrhage and urinary tract infections, were more often present in patients with
nonsyndromic metopic CS.117

4.d.v. Maternal and paternal age

There seems to be an association between CS and the age of the parents, and the coronal
suture seems to be particularly sensitive;82 studies investigating the effect of parental age on
the incidence of premature fusion for the sagittal and metopic sutures have been
negative.126,127 A high maternal age (>40) is a risk factor.128 When comparing patients with
CS to healthy controls, the average age of the fathers was significantly higher.82

5. Clinical presentation
The main goals of clinical assessment of CS are to (1) determine the presence of suture
fusion, (2) assess whether there are additional clinical features that are suggestive of a
syndromic etiology, and (3) to determine whether urgent or elective surgery is indicated.129
Urgent intervention is indicated whenever there is breathing difficulty, choking or
vomiting when feeding, irritability, or lagophthalmos during sleep.129

5.a. Nonsyndromic
The most common presentation of patients with nonsyndromic CS is elective, due to an
unusual head shape during infancy; only a small minority presents acutely and requires
urgent treatment.129
The presentation of nonsyndromic CS depends on which suture, and how many, are
affected (see table 1).
Since nonsyndromic CS, by definition, has no pathological features outside the cranial
sutures, the central cause of morbidity and mortality is premature suture fusion. Other
     19  

features of nonsyndromic CS, such as increased intracranial pressure and alterations in brain
morphology, are a consequence of the restriction on cranial vault growth imposed by the
fused suture.130

5.a.i. Metopic suture

Fusion of the two frontal bones at the metopic suture is referred to as trigonocephaly (see
figures 5 and 6); the frontal bone assumes a characteristic triangular shape due to a bony
midline ridge, there is shortening of the anterior cranial fossa, and hypotelorism.131
Neuropsychological problems, present in about a third of patients, include mental
retardation, ADHD, autism spectrum disorder (ASD), and delays in speech, language and
behavior.132,133
Normally it is the first suture to fuse, starting at 3 months and being completely closed
at 8 months.134 In about half the patients, the anterior fontanel fuses prematurely.135

Figures 5 and 6. Cranial vault development in metopic synostosis9,136

5.a.ii. Coronal suture

Fusion of the frontal with the parietal bone is referred to as anterior plagiocephaly (see
figure 7); unicoronal fusion gives an asymmetric head shape with compensatory growth in
the contralateral coronal suture, and contralateral frontal bossing. Unicoronal fusion
negatively affects cognitive development.133 Females are more commonly affected.82
     20  

Figure 7. Cranial vault development in unicoronal synostosis136

5.a.iii. Sagittal suture

Fusion of the two parietal bones leads to a deformity called scaphocephaly (see figures 8 and
9); the cranium grows in an anteroposterior direction, while lateral growth is inhibited. As
opposed to fusion of the other sutures, sagittal synostosis seems to not affect the patient’s
cognitive development.133 Males are more commonly affected.126

Figures 8 and 9. Cranial vault development in sagittal synostosis9,136

5.a.iv. Lambdoid suture

Fusion of the parietal and occipital bones leads to posterior plagiocephaly (see figures 10
and 11); the skull is asymmetric in shape, with contralateral frontal and posterior bossing,
and the ipsilateral ear is inferiorly and posteriorly deviated. Lambdoid synostosis negatively
affects cognitive development.133 Lambdoid synostosis confers the biggest risk of secondary
     21  

development of Chiari malformation, due to the restriction it puts on the development of the
posterior cranial fossa.6

Figure 10 and 11. Cranial vault development in lambdoid synostosis9,136

5.a.iv.1. Differentiation from positional plagiocephaly

Unilateral lambdoid synostosis has a similar clinical appearance as positional plagiocephaly
(PP). It is the secondary deformation of the skull due to external mechanical force from
being in a supine position for too long. It is important to differentiate the two because
positional plagiocephaly is not caused by suture fusion, and thus does not necessitate
surgery, but is treated conservatively.137
The clinical expression differs in that in PP there is ipsilateral frontal bossing and the
ipsilateral ear is anteriorly displaced, while in lambdoid synostosis there is contralateral
frontal bossing and the ipsilateral ear is posteriorly displaced (see figure 12).
     22  

Figure 12. Differential expression of lambdoid synostosis and positional plagiocephaly138

5.a.v. Complex
The most common complex, or nonsyndromic compound, synostosis is bicoronal synostosis.
Bicoronal fusion leads to a symmetric cranium with a short anteroposterior diameter, so-
called “brachycephaly” (see figures 13 and 14). Oxycephaly (also called tower head), caused
by fusion of the coronal and lambdoid sutures, leads to a high and pointed head shape; it is a
severe form of CS that more often presents in syndromic CS. Other complex synostoses,
such as Mercedes Benz-type or Z-pattern, are rare.139,140
The risk of increased ICP is proportional to the number of sutures fused, thus complex
CS confers a great risk of high ICP and all of its complications. Impaired CFS dynamics,
venous hypertension, and progressive craniocerebral disproportion are other major
complications of complex CS; these changes can lead to secondary Chiari malformation.141
Furthermore, they more often require multiple surgeries than single suture CS, and
have more developmental delays.141
     23  

Figures 13 and 14. Cranial vault development in bicoronal synostosis9

5.b. Syndromic
Syndromic CS differs from nonsyndromic in that there are manifestations outside the
cranium. Most syndromes are caused by mutations of FGFRs, and they are generally
dominantly inherited.129
Syndromes that involve mutated FGFRs have a greater cognitive deficit than both
those that do not, and nonsyndromic CS. Of all syndromes, Apert syndrome, which is in the
majority of cases caused by a gain-of-function mutation of FGFR2, has the worst cognitive
development. The cognitive deficit in syndromic CS, if simply due to the restriction put on
brain growth by the cranium, should not differ from that of complex CS. Even when
mutations other than those central to the syndrome have been excluded, syndromic CS has a
worse prognosis in terms of cognitive development; the anteroposterior neural induction by
the FGF-FGFR system is here proposed to be a possible mechanism.
Dysregulation of basic FGF (FGF2), due to its binding with FGFRs, is often involved
in syndromic CS. During anteroposterior neural induction during gastrulation, FGF signaling
(most notably FGF2) has been shown to act as a posteriorizing inducer;142 that is, it causes
the neurons of the forebrain (cerebrum) to differentiate and migrate toward the hindbrain
(cerebellum). This effect can possibly the one of the reasons for the increased incidence of
Chiari I malformations in syndromic CS, even compared to complex CS, despite having the
same clinical expression of suture fusion; a larger brain volume contained within a smaller
posterior fossa due to early suture fusion. Also, the redistribution of neurons from anterior
cerebral modules toward posterior ones could be one of the reasons for the lower
intelligence in syndrome-associated CS. This negatively affects the gray matter volume. As
     24  

mentioned previously, a defective L1CAM-FGFR interaction can be a cause of reduced

white matter volume, and another reason why patients with syndromic CS have decreased
intelligence.

5.b.i. Crouzon Syndrome

Several different mutations of the FGFR2- and FGFR3-genes cause Crouzon Syndrome,
which is characterized clinically by maxillary hypoplasia, bicoronal synostosis, shallow
orbits and exophthalmos, external strabismus, hypertelorism, beaked nose, short humerus
and femur, low-set ears, conductive hearing loss, prognathism, and dental malocclusion (see
figures 15 and 16).129,143 Most of the symptoms arise due to the disturbed development of the
first branchial arch, which is the precursor of the mandible and maxilla. A subtype also
includes partial syndactyly, but otherwise Crouzon Syndrome differs from the other FGFR2-
associated disorders in that syndactyly is absent. Acanthosis nigricans is present in another
subtype involving FGFR3. The coronal sutures are most often affected.143 However, CS may
not be present at birth, but may present during the first 2 years.144

Figures 15 and 16. Patients with Crouzon Syndrome145,146

5.b.ii. Apert Syndrome

Apert Syndrome is caused by mutations of the FGFR2-gene, and is evident clinically as
hypertelorism, exophthalmos, symmetric syndactyly of both hands and feet, cleft palate,
learning disability, low-set ears, flat or concave facial profile, conductive hearing loss, and
dental malocclusion (see figures 17-19).129,143,147,148 At birth there may only be coronal
     25  

synostosis with patent sagittal and metopic sutures that give rise to a tall head that is
shortened from front to back.143 Associated cleft palate and syndactyly require surgery.129,148

Figures 17, 18 and 19. Patients with Apert Syndrome143,149,150

5.b.iii. Pfeiffer Syndrome

Pfeiffer Syndrome is cause by mutations of the FGFR1- and FGFR2-genes. It is divided into
3 subtypes (see figures 20-22):151 Type 1 is referred to as classic Pfeiffer Syndrome, and
those patients have a normal lifespan and normal intelligence, with bicoronal synostosis,
midface retrusion, and low-grade anomalies of fingers and toes. Types 2 and 3 are more
severe and involve central nervous system pathologies, ankylosis and synostosis of the
elbows, knees and cervical vertebrae, and high-grade anomalies of fingers and toes.143,152,153
Type 2 differs from type 3 in that it has a so-called Kleeblatschädel (cloverleaf-shaped
skull), in which all sutures fuse. It is very hard to manage and the mortality rate is high. This
deformity can also present in patients with Crouzon and Apert.143
Other features include hypertelorism, underdeveloped maxilla (which can lead to
upper airway obstruction), exophthalmos (leading to corneal damage), syndactyly, cleft
palate, beaked nose, conductive hearing loss and dental malocclusion.129,143
     26  

Figures 20, 21 and 22. Patients with Pfeiffer Syndrome: type 1, 2, and 3154

5.b.iv. Saethre-Chotzen Syndrome

Twist1-mutations cause Saethre-Chotzen Syndrome (SCS). Patients present with coronal
synostosis (uni- or bilateral), hypertelorism, low-set hairline, ptosis, a prominent nose,
partial syndactyly, deformed ears, strabismus, downward sloping palpebral fissures, and
129,143
rarely cervical spine fusion (see figures 23-25). Ptosis must be corrected so as to
prevent the development of a secondary visual deficit.129 Complications are uncommon, and
the cognitive development is normal or only modestly affected.155,156

Figures 23, 24 and 25. Patients with Saethre-Chotzen Syndrome143,157

5.b.v. Muenke Syndrome

Muenke Syndrome is caused by mutations at FGFR3. Clinically it is one of the less severe
craniofacial syndromes and is expressed with coronal synostosis (uni- or bilateral)
     27  

hypertelorism, protruding forehead, sensorineural hearing loss for low frequencies, flat
cheeks, low-set ears, and enlarged head (see figures 26-28).129,143 The coronal sutures are
most often affected, but a portion of patients present without apparent CS. As with SCS,
complications are rare, but learning difficulties are more common.157

Figures 26, 27 and 28. Patients with Muenke Syndrome143,159

5.b.vi. Craniofrontonasal Dysplasia

Craniofrontonasal Dysplasia (CFND) is an X-linked disorder caused by mutations of
ephrinB1 (EFNB1). Paradoxically, it is more severe in heterozygous females than in
hemizygous males. It presents with hypertelorism, bicoronal synostosis (usually
asymmetric), bifid nasal tip, longitudinal nail splits, dry frizzy hair, a prominent gap
between the central incisors,129,143 and sometimes also sloping shoulders, asymmetric
nipples, bifid digits, and corpus callosum agenesis (see figures 29-31).160-162 Development is
normal, and treatment is usually only indicated for aesthetic reasons.143

Figures 29, 30 and 31. Clinical features of patients with Craniofrontonasal Dysplasia143,163
     28  

5.b.i. Carpenter Syndrome

Carpenter Syndrome is a very rare disorder cause by mutations of the RAB23-gene.129 It is of
interest because it is the only one of these syndromes with a recessive inheritance.1 Patients
have CS of varying sutures, and the phenotype characteristically includes polysyndactyly
(see figures 32-34).164,165

Figures 32, 33 and 34. Patient with Carpenter Syndrome166

5.c. Complications and other features

5.c.i. Increased intracranial pressure
The symptoms of raised intracranial pressure (ICP) include headaches, vomiting,
papilledema, behavioral changes and a decline in school performance. Raised ICP has
several different causes, each with different treatment. Hydrocephalus necessitates shunting,
obstructive sleep apnea is relieved by improving the airway,167 craniocerebral disproportion
is fixed by calvarial expansion, and in the setting of non-communicating hydrocephalus due
to tonsillar herniation, foramen magnum decompression might be necessary.129
Hydrocephalus complicated by increased ICP occurs at a slightly increased rate in
nonsyndromic, single-suture CS than in normal controls, while most cases occur in complex
or syndromic CS.168 Regular follow-up is advisable, particularly in patients with Twist1
mutations, which have a particularly increased risk of secondary raised ICP, and reoperation
rates for intracranial hypertension of 35-42%.169 Crouzon, Pfeiffer and Apert syndromes
have increased risks of high ICP.155 Shunt-dependent hydrocephalus is associated with
Crouzon and Pfeiffer syndromes, while Apert usually presents with non-progressive
ventriculomegaly.170
There is a negative relationship between ICP and cognitive development; the higher
the ICP, the lower the mental level;171 this, together with the increased risk of other
     29  

complications of high ICP, such as optic atrophy and blindness, clearly shows the
importance of timely treatment.13
De Jong et al. (2012)172 compared syndromic and complex CS with normal controls
and proposed that a craniocerebral disproportion is an unlikely cause of increased ICP, while
a review by Tamburrini et al (2005)173 showed it to be a significant factor in the
etiopathogenesis in nonsyndromic and complex CS.
Neither fundoscopic nor radiological findings are sensitive enough to show an
increased ICP in small children;13 The presence of papilledema in children older than 8 years
is 100% sensitive, and in those younger than 8 years its presence is a reliable indicator of
papilledema, but its absence does not rule out a high ICP.174 Intraparenchymal monitoring is
currently the gold standard and prolonged ICP monitoring gives the best estimate.13,173 The
noninvasive diagnostic tool that has shown the most promise is that of visual evoked
potentials, where an increased latency period indicates axonal injury and is correlated with
elevations in ICP.175 A low intracranial volume cannot be used to predict intracranial
hypertension.168
Persistent postoperatively high ICP is present in up to 15% of patients, which could be
due to other aspects of CS such as cerebral venous congestion, upper airway obstruction, and
hydrocephalus.173 A portion of patients have narrow jugular foramina leading to venous
outflow obstruction and raised ICP;176,177 imaging might identify these patients from those
refractory to surgery.

5.c.ii. Chiari malformation and foramen magnum

A Chiari malformation (CM) is an acquired condition caused by the inferior displacement of
the cerebellar tonsils through the foramen magnum (see figures 35 and 36). It can cause non-
communicating hydrocephalus and secondarily increased ICP due to obstruction of CFS
outflow.13 It is thought to occur in CS due to the presence of a small posterior fossa, as a
result of fusion of the lambdoid178 and cranial base sutures, coupled with hindbrain growth,
possibly due to the posteriorizing effect of FGFs on the growth of the CNS as mentioned on
page 23.
CMs are a frequent sequela of syndromic CS, being present in up to 73% of patients
with Crouzon syndrome, 82% with Pfeiffer syndrome and in all patients with the
Kleeblatschädel deformity, but only in about 2% of patients with Apert syndrome. In
nonsyndromic CS, synostosis of the lambdoid suture carries the highest risk of tonsillar
herniation.179,180 These results suggest a role for regular screening of CM in patients with
     30  

Crouzon and Pfeiffer syndromes, while it is not warranted for patients with Apert syndrome.
The incidence rate for nonsyndromic simple CS is 5.6%, and it is usually asymptomatic.181
Posterior cranial vault expansion should be the surgery of choice for this complication of
CS.179
A small size of the foramen magnum (FM) is associated with an increased risk of
CM.182 The transverse diameter of the FM is smaller in the FGFR-associated syndromes
(Crouzon, Apert, and Pfeiffer) compared with normal controls. The diameter in SCS and
nonsyndromic bicoronal synostosis is not different from normal controls. These findings
suggest a possible etiology for the development of CM, but since the incidence rates do not
necessarily coincide with the risks (notably Apert), there are obviously other factors at
play.183

Figures 35 and 36. Sagittal and transverse MRI images of Chiari malformations184,185

5.c.iii. Cognitive development

Impaired cognitive development is a rather predictable sequela of CS,186 and postponing
diagnosis and treatment leads to a worse prognosis in terms of intelligence, behavior and
learning.
Patients who undergo cranial expansion during infancy have a good prognosis;
nonsyndromic cases have normal IQs, while those with syndromic CS have an average IQ of
83. However, the majority of syndromic patients (77%) have a normal IQ.187 This shows that
the importance of a timely diagnosis and treatment, and that the future of those patients is
not as bad as commonly viewed.
     31  

Whole-vault cranioplasty gives better results in terms of school performance and IQ than
endoscopic strip craniectomy, at least for sagittal synostosis.188 As increased ICP leads to a
stunted cognitive development,171 posterior fossa decompression and correction of venous
outflow obstructions might have additional benefits for the prevention of cognitive decline.
Kapp-Simon et al (2007)189 showed that, for nonsyndromic single suture CS, fusion of
different sutures gives different expressions of cognitive impairment. For example, sagittal
synostosis more often is associated with language and speech impairment, while metopic
synostosis, which inhibits frontal lobe growth, is more often associated with behavioral
problems. Differences exist for syndromic CS as well; those with Apert syndrome have
lower IQs, while Muenke syndrome leads to behavioral issues such as social problems, and
attention problems compared with controls. In general, syndromic CS is associated with a
higher risk for developing intellectual disability, and behavioral and emotional problems
compared with a normative population.190
No studies have investigated the intellectual development in complex
190
craniosynostosis. This research is an important connection between syndromic and
nonsyndromic CS as it has a similar phenotypic expression as syndromic CS, but lacks the
molecular mechanisms, and as such can show whether the increased rate of cognitive deficit
is due to the greater mechanical restraint put on brain growth in compound CS, or a primary
defect in syndromic CS.
It is important to note that in all studies there are only a few patients that score above
average in terms of intelligence. This suggests that the standard distribution that is normally
around 100 is shifted towards lower values; patients that would otherwise score highly have
average intelligence, while those who would normally have an average score have below
average intelligence. Even the studies that followed up several years postsurgically did not
go beyond elementary school; as cognitive demands increase there might be a higher
percentage of cognitive deficits than in some studies. Future studies on older patients are
needed.

5.c.iv. Airway obstruction

Airway obstruction occurs in conjunction with syndromic CS, due to the restrictive effect it
has on the development of the face and throat, most notably the maxilla but also the larynx
and trachea. A common feature of several syndromes is midfacial hypoplasty.
The midfacial hypoplasty that occurs in many craniofacial syndromes carries with it a
high rate of respiratory difficulty. Early midface advancement successfully avoids
     32  

tracheostomy by reconstructing a large pharyngeal cavity, enlarging the airway, and

improving obstructive respiratory disorders.191 Upper airway obstructions that are refractory
to first-line surgical and medical treatment are indicated for tracheostomy.192
The risk of nasopharyngeal stenosis requiring airway management is higher in Pfeiffer
syndrome than in Crouzon and Apert syndrome.193 FGF-mutations are found in 71% of
patients with a laryngotracheal anomaly.193
Central sleep apnea is often proposed to occur in conjunction with CM, however,
Driessen et al (2013) showed that there is no connection, at least for syndromic cases, and
that instead brain stem immaturity and upper airway obstruction are the main causes.194
Growth of tonsils and adenoidal tissue might also contribute to airway obstruction and are
treated by surgical removal.143 Although, a study by Zandieh et al (2013) showed that
adenotonsillectomy does not improve the clinical picture of central sleep apnea in syndromic
CS.195

5.c.v. Sensory disturbances

5.c.v.1. Visual
Visual deficits are present in 61% of patients with syndromic CS.155 Long standing
intracranial hypertension, craniocerebral disproportion, obstructive sleep apnea lead to
eventual optic neuropathy.196 The occurrence of ptosis in SCS inhibits central maturation of
the visual system and thus must be promptly treated. Exophthalmos is present in several
syndromes, and when the patient is unable to close the eyelids, so-called lagophthalmos, that
can lead to irreversible corneal damage such as exposure keratitis and corneal ulcers.197
Exposure keratitis is acutely treated with eye drops, and longer term protection necessitates
orbital rim advancement.143 The inability of the eyes to maintain stereo-vision, as in
strabismus, causes sensory mismatch of visual information and eventual amblyopia of the
nondominant eye.196

5.c.v.2. Auditory
Auditory deficits are present in more than half of patients with syndromic CS.155 A study
investigating hearing in patients with FGFR2 mutations found sensorineural hearing loss in a
quarter of the patients, and recurrent otitis media in all of them. The sensorineural hearing
loss was evident as a prolonged latency period on auditory brainstem response and might be
due to auditory nerve compression.198 Muenke syndrome has a characteristic low frequency
sensorineural hearing loss, while conductive hearing loss occurs with the other FGFR-
     33  

related syndromes.129,199,200 Persistent childhood conductive hearing loss eventually leads to

sensorineural hearing loss, showing the importance of timely treatment.201

6. Diagnosis
The mainstay of imaging and diagnosis of CS is the CT scan with 3D reconstruction.202
Other imaging modalities include MRI, X-ray and ultrasonography (US). Complementing
these imaging methods is the physical examination.

6.a. Physical examination

The head circumference can be measured and compared to standardized charts.203 The
medical history of the mother and the pregnancy can indicate an etiology. The family history
should also be obtained, and developmental milestones should be noted.

6.a.i. Inspection
Most of the features of CS can be detected upon inspection of the patient. Usually the
diagnosis of CS is first implied from inspection, and most patients present to their doctors
when their parents notice a deformation or asymmetry of the skull and facial features.
Nonsyndromic single suture CS is not as readily diagnosed as syndromic CS, which presents
with several features suggestive of pathology. The presence of syndactyly, a cleft palate,
low-set ears and other extracranial features are suggestive of a syndromic origin (see chapter
5).

6.a.ii. Palpation
Palpation of the skull demonstrates early closure of fontanels and asymmetry of the cranial
vault and face.131

6.b. Imaging
Available imaging methods include CT, with the possibility of performing 3D reconstruction
and venography, MRI, X-ray, and ultrasound.
     34  

6.b.i. CT
CT scanning is the gold standard for diagnosing CS and planning for surgery.129 It readily
demonstrates suture patency or fusion using the bone window, and also anatomical
abnormalities of the brain, such as ventriculomegaly and agenesis of the corpus callosum,
using the soft tissue window.129 3D reconstructed CT scans (see figures 37 and 38) are both
very sensitive and specific for CS, and have been shown to reduce intraoperative risks when
employed presurgically.204
There is an increased lifetime risk of developing cancer following CT scanning,
particularly if done during infancy. It has been proposed that CT scanning is rarely indicated
for single-suture CS without other features suggestive of a syndromic etiology. Even for
compound CS, every scan should be carefully indicated.205

Figure 37. 3D-reconstructed CT showing right-sided unicoronal synostosis206

Figure 38. 3D-reconstructed CT showing sagittal synostosis206

     35  

6.b.i.1. CT Venography
CT venography is used in complicated cases where an abnormal venous drainage is
suspected.129 This method can be used prior to surgery, such as posterior fossa
decompression for CM, to identify patients at high risk of intraoperative blood loss due to,
for example, dilated veins or abundant collateral veins.207 See figure 39 for an example of
CT venography.

Figure 39. Example of CT venography208

6.b.ii. MRI
MRI is much more sensitive for soft tissues than CT and is the imaging modality of choice
for associated congenital abnormalities, such as hydrocephalus, or corpus callosum agenesis
that presents with CFND.129,206 See figure 40 for an example of MRI imaging in a patient
with CS.

Figure 40. MRI showing a CM in an oxycephalic patient209

     36  

6.b.iii. X-ray
Skull radiographs are significantly less sensitive for detecting suture patency than CT scans;
they are insensitive for detecting early cases and are not informative enough for use in
complicated cases.210 They can be of value in the screening of positional plagiocephaly
when the findings of the physical exam are inconclusive.129,206 They are also a weakly
sensitive method for detecting raised ICP through a “copper-beaten” appearance (see figure
41).211 The copper-beaten appearance occurs in normal children also, making plain
radiography an nonspecific method for determining high ICP as well.13

Figure 41. X-ray showing a typical copper-beaten appearance of the skull211

6.b.iv. Ultrasound
Ultrasonography (US) has been used to detect CS in utero (see figures 42-44), however, only
in a few, severe cases;129,212 at the time when routine ultrasounds are being done (about 20
weeks gestation), the cranial sutures (forming around 16 weeks) have not had enough time
for growth distortion to occur. Third trimester US shows suture closure in most affected
cases.213 In suspected syndromic cases, the sensitivity of the method can be increased by
examining the limbs for syndactyly.129 3D-US is a useful adjunct to regular US, and can
improve the overall sensitivity of this method.
     37  

Figures 42, 43, and 44. 2D- and 3D-US showing severe exophthalmos and a cloverleaf skull
consistent with Pfeiffer syndrome type 2214

6.c Genetic testing

Chromosomal microarray is the first-line testing for genomic alterations. If unavailable,
routine karyotyping may be considered.215
In nonsyndromic cases involving the sagittal, metopic and lambdoid sutures, causative
mutations are not usually found. As such, genetic testing is only warranted in unicoronal and
complex nonsyndromic CS.86
Based on additional clinical features, a syndromic etiology is likely the case, and
genetic testing must follow; due to the higher incidence of complications, a different
approach to treatment, and a higher rate of repeat surgery, genetic testing is always
performed in syndromic CS.86
Genetic counseling should occur both before and after genetic testing. The parents
have to first be informed of what tests are being done and why, as well as the sensitivity of
tests and that a positive result may warrant an investigation of their genes as well. Post-
testing counseling should make it clear that a negative result only implies that the genes that
were tested were not present, and that other genes causing CS might be.

7. Treatment
The mainstay of treatment for the primary pathology, premature suture fusion, is surgery.
Surgery for CS is generally considered to be safe, with both low morbidity and mortality
rates.143,216,217 Pharmacologic treatments are currently unavailable, but are being developed
and tested.10,63,218 Conservative treatment and observation are inappropriate alternatives to
surgery, as CS does not spontaneously resolve; it might have a role in the older child that has
received a late diagnosis. Orthotic molding, using helmets, has been proposed for mild
     38  

cases; however, the reduced risk of avoiding surgery might not outweigh the impairment of
cognitive development due to the limitation put on brain growth.143 They are indicated
following endoscopic strip craniectomies.

7.a Surgery
The main goals of elective surgery of CS are to (1) correct the cranial deformity, (2) prevent
future progression, and (3) prevent the development of increased ICP.129,143 The cranial
deformity is usually corrected with good aesthetic results, and the risk of subsequent
intracranial hypertension drastically falls with early and adequate surgery.130 Progression of
CS after surgery is hard to predict, with many cases requiring repeat surgery both for the
cranial defect, but particularly for associated syndactyly, which is routinely operated on in
several stages.13 The outcome of surgery for isolated nonsyndromic CS is better than for
complex and syndromic CS, possibly due to a less complex clinical picture and a lower rate
of associated pathologies.217
The development of pharmacotherapy will open up new avenues in the treatment of
CS; it will prevent repeat surgeries by inhibiting re-fusion of operated sutures, and might
eventually also treat and prevent CS while still in utero.
Acute surgery is directed at airway maintenance, support of feeding, eye protection,
and high ICP.30,130 Breathing and feeding, both features of midface hypoplasia present in
FGFR-related syndromes, can usually be treated by midface advancement. Eye protection, in
the long term, is accomplished by treating the exophthalmos with fronto-orbital
advancement. High ICP necessitates shunting.
Contraindications include patients with other congenital defects, such as heart or lung
disorders, current infections, and hematologic disorders, who are not fit enough for
surgery.218,219
     39  

Table 4. Types of surgeries for nonsyndromic CS1,220

Type Surgery
Metopic Open strip craniectomy,1,221 fronto-orbital advancement,1,221 fronto-orbital
remodelling222
Coronal Open strip craniectomy, fronto-orbital advancement,1,223,224 endoscopic strip
craniectomy1,224
Sagittal Open strip craniectomy,1,225 endoscopic strip craniectomy + helmet 1,225,226
Lambdoid Posterior vault remodeling,1,227 extended cranial vault remodeling,1 strip
craniectomy1
Complex Multiple strip craniectomy,1 cranial vault remodeling,6,228 fronto-orbital
advancement228

The choice of surgery for syndromic CS depends on the phenotypic expression. In addition
to the surgeries listed in table 4, for the treatment of individual sutures, surgeries that treat
accompanying deformities are used. For example, the hypertelorism that occurs in several
syndromes is treated by facial bipartition.229,230 Midface hypoplasia, as in Crouzon and
Pfeiffer, is corrected with midface advancement.231

7.a.i. Types of surgery

The general surgical options include open surgery and minimally invasive surgery. Each
option has its own subcategories and variations with advantages and disadvantages. Specific
methods include the use of springs and distraction osteogenesis.
Due to the complex nature of the disease, it is hard to provide a universal treatment
algorithm. The choice of surgery depends on whether the patient has nonsyndromic or
syndromic, or single or compound CS, and complications from the disease or previous
surgeries.

7.a.i.1. Open surgery

The approach to surgery depends on the age of the patient, which sutures are closed, and
how many. The advantages of open surgery are predictable and immediate outcomes, as the
desired skull shape and size can be established intra-operatively. However, since skull
manipulation disrupts the dural-calvarial interaction, future growth is unpredictable. Another
issue with surgery, and open surgery in particular, is blood loss. It is one of the main reasons
to postpone open surgery until the child is more mature, 6-12 months,143 and able to tolerate
     40  

this inevitable consequence of surgery. This delay can increase the risk of complications due
to a progression of the disorder.1 Also, open surgery performed after 6 months is associated
with a decreased rate of re-surgery as compared to open surgery performed before 6 months,
a benefit of postponing surgery that possibly outweighs the risk of progression.216,232
Examples of open craniofacial procedures include strip craniectomy, fronto-orbital
advancement, cranial vault expansion, midface advancement, posterior fossa decompression,
and facial bipartition.143
Open surgery for isolated nonsyndromic CS, such as sagittal synostosis, can be done
by extended strip craniectomy, which has shown good results and low re-surgery rates.
Some studies have shown that cranial vault remodelling gives better results than strip
craniectomy in terms of cognitive development, and lower rate of re-surgery, but with
increased operative blood loss.188,233 In light of this, a study by Panchal et al (1999)234
showed that patients undergoing strip craniectomy for sagittal synostosis, even when
performed before 4 months, did not achieve a normal cranial index (ratio between cranial
width and length) while those who underwent subtotal calvarectomy did.
Due to the increased incidence of CM in lambdoid synostosis, posterior fossa
decompression is employed for this type of CS. Complex CS, due to the higher risk of
intracranial hypertension, usually requires radical whole vault remodelling.6 Posterior fossa
decompression, in the setting of compound CS, can lower the risk of requiring anterior
surgery later on.235
Syndromic CS has additional features that necessitate open surgery, such as fusion of
several sutures and dysmorphisms of the facial skeleton, which oftentimes cannot be
corrected by an endoscopic approach.
Studies have shown that radical surgery has better outcomes due to a lower rate of re-
fusion and better cognitive development.236,237

7.a.i.2. Minimally invasive surgery

Countless studies show that minimally invasive procedures, such as endoscopic surgery,
have several benefits compared with open surgery; blood loss and subsequent transfusions
are reduced, as are the surgical times, hospital stays, and hospital costs, and the incisions are
smaller.1,143,238-242 This method, however, might not be applicable to older patients or those
with more extensive deformities.1,243
Endoscopic techniques are followed by orthotic molding using helmets, which directs
skull growth to be symmetric and round.242,244
     41  

This technique is applied earlier than open surgery, usually between 3 and 6 months,
as rapid brain growth is still a potent stimulator of skull growth postsurgically.1,143

7.a.i.2.a. Orthotic helmet

Helmets (see figure 45) are used after endoscopic strip craniectomy;1,241,242 they can be
adjusted to accommodate for skull growth, and predictably adjusts the skull shape in three
dimensions.143,238
Some authors have suggested helmets for mild cases of CS. However, restricting skull
growth in another direction, when a fused suture has already restricted it in one, might give
an esthetically pleasing outcome, but at the expense of cognitive development.
Helmets are the primary treatment for positional plagiocephaly.137

Figure 45. Patient with an orthotic helmet245

7.a.i.3. Additional methods

There are two additional methods that are used in conjunction with open surgery: distraction
osteogenesis and springs. They aid in shaping the cranial vault, by achieving results not
possible by surgery alone, and give more predictable outcomes.

7.a.i.3.a. distraction osteogenesis

Distraction osteogenesis (DO) is the process of moving two pieces of bone apart, allowing
new bone to form between them. This has its place in CS as it allows for predictable
expansion of the cranial vault and advancement of the midface; the device remains in place
until satisfactory results have been achieved (see figures 46-48). The procedure is both safe
and effective.246-248 It has several advantages: surgery for placing of the device is short,
     42  

blood loss is minimal, bone grafting becomes unnecessary, soft tissue expansion occurs, and
no intracranial dead space is formed.13,246,247,249
Distraction osteogenesis has the inherent disadvantage of requiring a second surgery
for removal. Also, wound infections, dislocation of the device and prolonged hospital stay,
as well as dural injury and CFS leak, are additional disadvantages.246,248,249 But compared to
helmets they allow more predictable advancements in any single plane of growth, and can be
used in older children.143 Posterior DO is most suitable for younger infants requiring
aggressive surgery,250 while frontofacial advancement by DO is advisable in older patients
as a deterioration of function is seen in long term follow up for patients who were younger at
the time of surgery.251 Long-term growth of the cranial vault following DO is satisfactory;
symmetric results are achieved and the growth of the child matches the growth of the
cranium, without any recurrent growth restrictions matching the original disease.252

Figures 46, 47 and 48. 3D-CT, X-ray and photograph of patient with DO apparatus in place
undergoing posterior cranial vault expansion.13

7.a.i.3.b. Spring-mediated surgery

This method is similar to DO in that an initial surgery is performed in which expansible
springs are implanted, which exert a continual expansive force across an osteotomy or patent
suture enabling the skull vault to expand.13
Springs, similar to DO, necessitate additional surgery for removal, and can be used in
older children. They give rather predictable outcomes, but less so than DO.143 However,
optimal results are achieved at younger ages.13 Lower transfusion rates, shorter
postoperative anesthesia and hospital stay are additional advantages of this method.253,254 A
possible complication includes spring detachment.254 It is considered a safe and effective
method.253,254
     43  

Figures 49, 50, and 51. Patient with Apert syndrome with implanted springs.13

Figure 49 shows the position of the springs on the calvarium by 3D-CT. Figures 50 and 51
are radiographs immediately following placement of springs, and at 6 months follow up.

7.a.ii. Timing of surgery

The timing of surgery is a matter of great conspiracy, with different advocates giving
varying guidelines. One of the causes of this disagreement is that procedures have differing
outcomes depending on when they are performed; the question is not only as to when to
perform the surgery, but also which type of procedure.
Generally speaking, early surgery carries an increased risk of postoperative growth
restriction and re-surgery rate, due to an unpredictable growth pattern,231,255 and
complications during surgery, due to decreased maturity of the patient. Benefits of early
surgery include better cognitive development,116,188,256 and less radical procedures, as the
cranial vault is still highly malleable.130
Open surgery is generally performed later, preferably after 6 months. This is both
because it is a stressful procedure and the child is more mature, but also due to the
physiology of the skull. Open surgery corrects the skull deformity and determines its shape
immediately, and less postoperative cranial growth occurs the older the child is. The ability
of the cranium to heal large cranial defects is lost by 9-11 months, and as such some authors
suggest open surgery between 6 and 9 months.13,257,258 Performing open surgery earlier
increases the risk that postoperative growth restriction is more severe and tends toward the
original pathological growth pattern.231
Minimally invasive surgery, on the other hand, is performed earlier due to its lower
risk of complications. The best results are achieved before 6 months, since at that age brain
growth is still a potent stimulator of cranial vault growth. A study by Panchal et al (1999)234
showed that open surgery performed before 13 months resulted in a normal cranial index,
and that there was no difference between surgery performed at a mean age of 2.9 months and
7.6 months. However, there was no follow up beyond 1 year, and parameters other than
cranial index were not mentioned.
     44  

Due to the low morbidity and mortality of craniofacial procedures, early surgery is
advocated among neurosurgeons. The impaired cognitive development for late surgery is
permanent, while postoperative growth restriction can be treated relatively safely with repeat
surgery.

7.a.iii. Intrasurgical aspects

Minimization of blood loss is of great importance and the roles of blood transfusions and
fluid replacement will be explained in chapter 7.a.iii.2. The use of titanium plates for
fixation is only advised for exceptional cases as they have been found to displace toward the
brain as the skull grows, which increases the rate of complications and the rate of re-
surgery.259,260 Resorbable plates are used instead.259 The anesthesia of patients with
syndromic CS can be complicated by midface hypoplasia when trying to incubate the
patient.261 Also, the induction of anesthesia might have to be modified in the presence of
intracranial hypertension.262,263 There seems to be benefits to preoperative steroids through
control of postoperative edema, earlier eye opening, and reduced hospital stay, but further
studies are needed.264 Zenker’s solution, an inhibitor of osteogenesis when applied locally
during surgery,265,266 has been shown to disrupt the blood-brain barrier,267 and damage the
cortex.268

7.a.iii.1. Positioning
The positioning of the patient depends on which surgery is to be undertaken, and the aim is
to allow for easy accessibility of the area of interest.269 For anterior surgery, the patient is
positioned in a supine position, while for posterior surgery the prone position is used.13 In
the prone position, protruding eyes must be protected, and abdominal compression must be
avoided so as not to impede venous return. The head is slightly elevated to decrease the
vascular pressure and minimize blood loss, but this slightly increases the risk of air
embolism.143,270 Complications caused by positioning are rare.271

7.a.iii.2. Blood transfusion and fluid replacement

Due to the small blood volume in infants, blood loss is a major concern during surgery. It
can be minimized with the application of vasoconstrictive agents, such as adrenaline, 7 to 10
minutes before the initial scalp incision.272 Also, preoperative iron supplements ensure
optimal hemoglobin levels during surgery.143 Preoperative erythropoietin (EPO) decreases
the need for transfusions, and has a very low risk of thrombotic complications.273 The
     45  

amount of blood lost is correlated with the weight of the patient, and the length of the
operation;274 endoscopic surgeries both cause less blood loss and are shorter than open
surgery, partly explaining why they are safer. Blood conservation strategies lower
transfusion rates about fourfold.232 Hahn et al (1981) proposed that placing parallel rows of
interrupted sutures on either side of the wound reduces blood loss by about two thirds.275
Administration of the antifibrinolytic compound tranexamic acid decreases blood loss, and
lowers transfusion rates and postoperative complications.276-279
Excessive blood loss can lead to circulatory collapse that can be prevented with blood
transfusions and fluid replacement. Prophylactic transfusions (instituted before 100 min),
rather than reactive transfusions (after 100 min), decrease the length of postoperative
hospital stays, and increase the hemoglobin concentration.280 Prophylactic transfusions are
associated with a greater volume of blood transfused, which leads to an improved
coagulation profile and lower subsequent blood loss.281
Large amounts of fluid replacement may alter the concentrations of electrolytes and
lead to complications such as hyponatremia and metabolic acidosis. Ringer’s lactate is
preferred over normal saline because it is less likely to cause metabolic acidosis, without
increasing the risk of hyponatremia.282

7.a.iv. Complications
No surgery can be done without a risk of complications. Some of the complications of
craniosynostosis surgery are non-specific and are present during any surgery, while others
are specific for craniosynostosis surgery, such as leptomeningeal cysts.220 Complications can
further be divided into acute and postoperative complications. The mortality rate is usually
less than 1%, while about 4.6-10% of patients experience acute complications, which
usually resolve without permanent damage.283-285 Complication rates are higher in repeat
surgeries, and also in cranial vault remodelling compared to endoscopic procedures, due to
their greater invasiveness.284 Children with a body weight under 10kg are at an increased
risk of postoperative cardiorespiratory and hematological complications.286 For simple
nonsyndromic CS, the highest complication rate is found in patients with metopic and
sagittal invovement.285
Acute complications include bleeding, infection, dural tear, stroke, and death.
Postoperative complications include infection, CSF leak, hematoma, intracranial
hypertension, failure of re-ossification, contour irregularity, and need for
130,215,284,287
reoperation.
     46  

7.a.iv.1. Intracranial hypertension

The type of procedure and age at surgery both influence the rate of postoperative intracranial
hypertension. This complication stems from a postoperative calvarial growth restriction and
is seen after 1.5-6.2% of primary surgeries.288,289 Repeat surgeries have increased risk. One
study investigated the risk for early surgery in syndromic CS and found postoperatively
increased intracranial pressure in 36% of cases.290 Modified strip craniectomy (MSC) carries
a higher risk than calvarial remodeling (CR).287 This complication is more often found in
patients operated on during the first year of life, possibly due to the higher rate of MSC.291

7.a.iv.2. Infections
The risk of infection is present during any invasive procedure, and rates of infection after CS
correction are 3.2-8.1%.283,292 Increased incidence of infection is seen in syndromic cases,
surgeries of longer duration, closure of skin under tension, more than 4 surgeons present
during surgery, pediatric intensive care unit (pICU) stay longer than 2 days, and the use of
ventilators after surgery.292 Fronto-facial procedures that allow for communication between
the contaminated nasal cavity and extradural space increase the risk of infection.143

7.a.iv.3. Bleeding
Blood loss and methods for its prevention are discussed in chapter 7.a.iii.2. Possible
complications of postsurgical bleeding include subgaleal and subcutaneous
hematomas.143,283,284 Intraoperative hemodynamic monitoring, hematocrit evaluation and
volume status by the anesthesiologist should be employed in order to determine transfusion
requirements and lower postoperative complications.274

7.a.iv.4. CSF leak

Operative dural tears can lead to CSF leakage. This complication occurs after 2.7% of CS
surgeries284 and the intra-extradural connection allows for bacterial contamination.143
Fortunately most leaks stop spontaneously. Dural tears are more likely to occur during
repeat surgeries, as well as with surgery utilizing metallic plates and screws.
Prophylactic placement of a lumbar drain at the end of the procedure can lower the
incidence of CFS leaks. Initial treatment is the placement of a lumbar drain. If the leak
persists, then skull base repair should ensue.143
     47  

7.a.iv.5. Bone defects

Children lose the ability to heal large bone defects between 9 and 11 months of age,257 and
as such older children require bone grafts to cover calvarial defects. Resorbable plates,
which resorb in 1 to 2 years, are available.143 Follow up is necessary since delayed
degradation of resorbable plates may occur, causing complications such as an intracerebral
foreign body granuloma.293
It is advisable to use the patient’s own bone, such as from the inner cortical surface, to
fill bone defects.294,295 Covering bony defects, compared to leaving them open, lowers the
risk of requiring repeat surgeries.295

7.a.iv.6. Bone fixation

Metallic plates and screws eventually become embedded in the bone they are intended to
stabilize and as such should be avoided, in favor of resorbable plates, whenever possible.
Transcranial and transdural movement of metallic parts occurs as the skull grows.
Eventually they can come in contact with, and damage, the underlying cortex.259,260,296 It is
still uncertain whether or not resorbable plates resorb quickly enough to avoid the same
fate.296 Secondary surgery is more often necessary and has higher rates of complications,
such as dural tears.143

7.b. Pharmacologic treatment

The development of pharmacologic therapy for CS is a new frontier that will allow for better
treatment and prevention. There are several possible benefits of a potential pharmacological
therapy. Firstly, administration postsurgically can reduce post-operative refusion and reduce
the need for secondary surgery in the setting of restricted calvarial growth. Secondly, if an
early diagnosis is made, administration of drugs can slow down the progression of suture
fusion, and both decrease the need for acute surgery and improve functional and cognitive
development. Finally, in familial cases of known heredity and early ultrasound diagnoses,
administration during pregnancy might be able to prevent the development of CS in utero.
The first step toward the development of pharmacologic therapy is to develop an
understanding of the pathophysiological mechanisms involved. As shown in chapter 4, there
is already an abundance of studies on the subject, and the next step is to make a coherent
molecular network for suture biology, from which potential therapeutic agents can be
identified and developed.
     48  

Some pharmacologic agents have already been tested, with varying results. In
syndromic FGFR-mutations the patency-maintaining molecule Noggin is inhibited, and
administration of recombinant human Noggin prevents CS in rat models.63,297,298 Aberrant
FGFR stimulation alters tyrosine kinase activation. Inhibition of tyrosine kinase, through the
use of PD173074, prevents CS in a mouse model of Crouzon syndrome.10 Administration of
U0126, which alters the signaling of FGFR2, inhibits CS in mouse models of Apert
syndrome.299 Expression of truncated FGFR-1 inhibits suture fusion, and has even been
applied in utero in rats with success.300,301 TGF-β antibodies have also shown promising
results.302,303

8. Prognosis and outcome

The prognosis differs depending on the type of CS the patient has. Generally, nonsyndromic
CS has an excellent prognosis; patients lead normal lives, have very low rates of
complications, recurrence, and resurgery.304 Esthetically they also have good outcomes.305
Syndromic CS has many features that worsen its prognosis compared to nonsyndromic CS;
higher rates of compound CS, intrinsic brain pathologies, and extracranial deformities. All
of these features lead to a worse prognosis in terms of need for surgery and resurgery,
complication rates, cognitive development, and aesthetic outcome. The syndromes, differing
in genotype and phenotypic expression, also differ in their prognosis; patients with Apert,
Pfeiffer and Crouzon syndromes require several surgeries to treat complications and re-
synostosis than do patients with Saethre-Chotzen and Muenke syndromes.143
Neuropsychological prognosis is examined in chapter 5.c.iii.

8.a. Recurrence and progression

Only about 10% of patients will require a second surgery.306 The best method for following
up on children with CS is to measure the head circumference; a fall in growth rate,
recurrence of deformity, or clinical symptoms should prompt an investigation using imaging
and an ophthalmologic exam.143 Follow-up as long as a decade postoperatively is
encouraged as the risk of recurrence is elevated for several years.307
In cases where point mutations are the cause there is usually an acute progression of
disease and a great risk of resurgery, while patients with chromosomal aberrations have a
more indolent course with a lower risk of resurgery and less complications related to CS.86
     49  

As mentioned previously in the text, increased risk of requiring another surgery is

present in syndromic CS/compound CS,141,155,182,290,307 point mutations,86 surgery performed
before 6 months,130,216,232,290 late surgery,231,255 lambdoid synostosis (CM correction),6,179,180
Twist1 mutations,169 small foramen magnum,182 bone fixation with metallic plates and
screws,143 use of distraction devices and springs,143,246,248,249 less extensive primary
surgery,287 not covering bony defects,295 patients who have already had repeat surgery,284
and female patients.308

8.b. Aesthetic outcome

Aesthetic results are better after early surgery.309 More extensive surgery, such as calvarial
remodeling compared with strip craniectomy, is also associated with better aesthetic
outcome.131,236,310 Simple CS is associated with better aesthetic outcomes after surgery than
compound CS.307 Patients with nonsyndromic CS are indistinguishable from their normal
peers at school age, at least when surgery is performed in infancy.305 Patients with metopic
synostosis and associated hypotelorism have inferior aesthetic outcomes, possibly due to
undercorrection.311,312

9. Conclusion
Nonsyndromic CS is easy to treat with surgery, and patients have excellent prognoses.
Syndromic CS is complex and much pathology is present besides fusion of sutures, which
complicates treatment and diminishes the possibilities of achieving a curative approach.
Research on CS is quickly moving forward and is already achieving very good results. The
next step in treatment, which will cause a huge leap forward, is the development of
pharmacologic therapies that have the possibility of slowing and hindering suture fusion, but
also improving postsurgical outcomes by limiting osteogenesis. Most studies seem to
suggest radical surgeries so as to prevent premature osteogenesis postsurgically and
subsequent repeat surgeries, and better cognitive development; introducing pharmacologic
therapy postsurgically will allow for more conservative primary operations with better and
safer outcomes, and a lower incidence of repeat surgeries.

The reason why it is so hard to elucidate the biochemical pathways of suture fusion is
because studies focus on one or two factors at a time. The fact that many of them interact
and that some do not have dose-dependent actions (such as the paradoxical inhibition of
     50  

fusion by supraphysiologic levels of the osteogenic FGF-2) greatly lowers the probability
that simple experiments will give a complete picture. Only once we know which are the
factors involved in the process, and how they behave in relation to suture biology, will we be
able to devise more complex experiments that examine several factors at the same time and
their interactions, both in vitro and in vivo. The results of those studies will open up the
possibility of creating pharmacologic therapies to prevent the appearance and progression of
CS. However, since some patients present with intrauterine suture fusion, for
pharmacologic, but also surgical, treatment to be successful prenatal diagnostics need to be
improved and implemented.

There seems to be disagreement on the nomenclature of classifying CS. Some studies equate
complex and syndromic CS; that is, they put all compound phenotypes in one category. The
majority of studies separates the two, and use “complex” to refer to nonsyndromic CS with
multiple suture involvement, and “syndromic” to refer to cases with both multiple involved
sutures and extracranial involvement. This thesis adopted the nomenclature used by the
majority because there is clinical value in separating patients with compound CS into
syndromic and nonsyndromic cases. In the management of syndromic CS there is a different
approach to the patient, as well as a different prognosis, and it is proposed that the
nomenclature for CS be standardized to the form used in this paper.

The high rate of coronal synostosis in syndromic cases might be due to the close proximity
of the brain to the skull in conjunction with intrinsic brain pathology. As mentioned
previously, genetic mutations underlying syndromic CS might lead to white and gray matter
abnormalities giving rise to a hypoplastic brain. Failure of growth of the brain leads to a lack
of signaling to the overlying sutures to maintain patency. The anatomical position of the
sutures, and their proximity to the brain might affect the incidence rate. The sagittal and
metopic sutures develop between the cerebral hemispheres, and the lambdoid sutures
develop between the cerebral and cerebellar hemispheres. The effect of this is that the
expanding brain exerts less force on the sutures, and there is also a longer distance for the
soluble factors to travel before they affect them. The coronal suture, on the other hand,
develops over the brain parenchyma, in close proximity, and as such has a lower threshold
for initiation of suture fusion when soluble patency maintaining factors are lacking.

An aspect that has not been commented on in CS research is the posteriorization induced by
FGF, which causes neural populations to migrate from the forebrain to the midbrain, and
     51  

from the midbrain to the hindbrain. This aspect of neurophysiology could explain the
increased incidence of CM in FGFR-related syndromes. Future studies could show whether
this effect has clinical value in CS, and whether systemic administration of pharmacologic
agents altering FGF-signaling could reduce this complication.
     52  

10. Literature
1. Baird LC, Proctor MR. Craniosynostosis. In: Albright AL, Pollack IF,
Adelson PD. Principles and Practice of Pediatric Neurosurgery – third edition.
Thieme; 2014. p237-248
2. Higginbottom Mc, Jones KL, James HE. Intrauterine constraint and
craniosynostosis. Neurosurgery 1980; 6(1):39-44
3. Martinez-Lage JF, Poza M, Lluch T. Craniosynostosis in neural tube defects:
a theory on its pathogenesis. Surg Neurol 1996; 46(5):465-9
4. Aleck K. Craniosynostosis syndromes in the genomic era. Semin Pediatr Neurol
2004; 11(4):256-61
5. Kimonis V, Gold JA, Hoffan TL, Panchal J, Boyadjiev SA. Genetics of
craniosynostosis. Semin Pediatr Neurol 2007; 14(3):150-61
6. Czerwinski M, Kolar JC, Fearon JA. Complex craniosynostosis. Plast
Reconstr Surg 2011; 128(4):955-961
7. Rasmussen SA, Yazdy MM, Carmichael SL, Jamieson DJ, Canfield MA,
Honein MA. Maternal thyroid disease as a risk factor for craniosynostosis.
Obstet Gynecol 2007; 110(2 pt 1):369-77
8. Ursitti F, Fadda T, Papetti L, Pagnoni M, Nicita F, Lannetii G et al.
Evaluation and management of nonsyndromic craniosynostosis. Acta Paediatr
2011; 100(9):1185-94
9. Senarath-Yapa K, Chung M, McArdle A, Wong V, Quarto N, Longaker M
et al. Craniosynostosis – Molecular pathways and future pharmacologic
therapy. Organogenesis 2012; 8(4):103-13
10. Perlyn CA, Morriss-Kay G, Darvann T, Tenenbaum M, Ornitz D. A model
for the pharmacologic treatment of Crouzon syndrome. Neurosurgery 2006;
59(1):210-5
11. Di Rocco F, Arnaud E, Renier D. Evolution in the frequency of nonsyndromic
craniosynostosis. J Neurosurg Pediatr 2009; 4:21-5
12. Slater BJ, Lenton KA, Kwan MD, Gupta DM, Wan DC, Longaker MT.
Plast Reconstr Surg 2008; 121(4):170e-8e
13. Derderian C, Seaward, J. Syndromic Craniosynostosis. Semin Plast Surg
2012: 26:64-75
     53  

14. Ranger A, Chaudhary N, Matic D. Craniosynostosis involving the squamous

temporal sutures: a rare and possibly underreported etiology for cranial vault
asymmetry. J Craniofac Surg 2010; 21(5):1547-50
15. Kanchan T, Krishan K, Kumar GP. Squamous suture – A rare case of
asymmetric closure with review of literature. Forens Sci Intern 2013; 231(1-
3):410.e1-3
16. Greenwald JA, Mehrara BJ, Spector JA, Warren SM, Crisera FE,
Fagenholz PJ et al. Regional differentiation of cranial suture-associated dura
mater in vivo and in vitro: implications for suture fusion and patency. J Bone
Miner Res 2000; 15(12):2413-30
17. Opperman LA. Cranial sutures as intramembranous bone growth sites.
Developmental Dynamics 2000; 219:472-485
18. Gagan JR, Tholpady SS, Ogle RC. Cellular dynamics and tissue interactions
of the dura mater during head development. Birth Defects Res C Embryo Today
2007; 81(4):297-304
19. Tokumaru AM, Barkovich AJ, Ciricillo SF, Edwards MS. Skull base and
calvarial deformities: association with intracranial changes in craniofacial
syndromes. Am J Neuroradiol 1996; 17(4):619-30
20. Raybaud C, Di Rocco C. Brain malformation in syndromic craniosynostoses, a
primary disorder of white matter: a review. Childs Nerv Syst 2007;
23(12):1379-88
21. Hall H, Walsh FS, Doherty P. Review: a role for the FGF receptor in the
axonal growth response stimulated by cell adhesion molecules? Cell Adhes
Commun 1996; 3(6):441-50
22. Doherty P, Walsh FS. CAM-FGF receptor interactions: a model for axonal
growth. Mol Cell Neurosci 1996; 8(2-3):99-111
23. Saffell JL, Williams EJ, Mason IJ, Walsh FS, Doherty P. Expression of a
dominant negative FGF receptor inhibits axonal growth and FGF receptor
phosphorylation stimulated by CAMs. Neuron 1997; 18(2):231-42
24. Levine JP, Bradley JP, Roth DA, McCarthy JG, Longaker MT. Studies in
cranial suture biology: regional dura mater determines overlying suture biology.
Plast Reconstr Surg 1998; 101(6):1441-7
25. Opperman LA, Sweeney TM, Redmon J, Persing JA, Ogle RC. Tissue
interactions with underlying dura mater inhibit osseous obliteration of
developing cranial sutures. Dev Dyn 1993; 198(4):312-22
     54  

26. Cooper GM, Durham EL, Cray JJ, Siegel MI, Losee JE, Mooney MP.
Tissue interactions between craniosynostotic dura mater and bone. J Craniofac
Surg 2012; 23(3):919-24
27. Opperman LA, Passarelli RW, Morgan EP, Reintjes M, Ogle RC. Cranial
sutures require tissue interactions with dura mater to resist osseous obliteration
in vivo. J Bone Miner Res 1995; 10(12):1978-87
28. Roth DA, Bradley JP, Levine JP, McMullen HF, McCarthy JG, Longaker
MT. Studies in cranial suture biology: Part II. Role of the dura in cranial suture
fusion. Plast Reconstr Surg 1996; 97:693-9
29. Kim HJ, Rice DP, Kettunen PJ, Thesleff I. FGF-, BMP- and Shh-mediated
signaling pathways in the regulation of cranial suture morphogenesis and
calvarial bone development. Development 1998; 125(7):1241-51
30. Marie PJ, Debiais F, Haÿ E. Regulation of human cranial osteoblast
phenotype by FGF-2, FGFR-2 and BMP-2 signaling. Histol Histopathol 2002;
17(3):877-85
31. Burke MJ, Winston KR, Williams S. Normal sutural fusion and the etiology
of single sutural craniosynostosis: the microspicule hypothesis. Pediatr
Neurosurg 1995; 22(5):241-6
32. Warren SM, Longaker MT. The pathogenesis of craniosynostosis in the fetus.
Yonsei Med J 2001; 42(6):646-59
33. Lee Jc, Spiguel L, Shenaq DS, Zhong M, Wietholt C, He TC et al. Role of
RANK-RANKL-OPG axis in cranial suture homeostasis. J Craniofac Surg
2011; 22(2):699-705
34. Stamper BD, Park SS, Beyer RP, Bammler TK, Frain FM, Mecham B et al.
Suture Craniosynostosis. PLoS One 2011; 6(10): e265557
35. Marie PJ. Fibroblast growth factor signaling controlling osteoblast
differentiation. Gene 2003; 316:23-32
36. LeeTJ, Jang J, Kang S, Jin M, Shin H, Kim DW et al. Enhancement of
osteogenic and chondrogenic differentiation of human embryonic stem cells by
mesodermal lineage induction with BMP-4 and FGF2 treatment. Biochem
Biophys Res Commun 2013; 430(2):793-7
37. Nakamura K, Kurokawa T, Kawaguchi H, Kato T, Hanada K, Hiyama Y
et al. Stimulation of endosteal bone formation by local intraosseous application
of basic fibroblast growth factor in rats. Rev Rhum Engl Ed 1997; 64(2):101-5
     55  

38. Kimoto T, Hosokawa R, Kubo T, Maeda M, Sano A, Akagawa Y.

Continuous administration of basic fibroblast growth factor (FGF-2) accelerates
bone induction on rat calvaria—an application of a new drug delivery system. J
Dent Res 1998; 77(12):1965-9
39. Moursi AM, Winnard PL, Winnard AV, Rubenstrunk JM, Mooney MP.
Fobroblast growth factor 2 induces increased calvarial osteoblast proliferation
and cranial suture fusion. Cleft Palate Craniofac J 2002; 39(5): 487-96
40. Mehrara BJ, Most D, Chang J, Bresnik S, Turk A, Schendel SA et al. Basic
fibroblast growth factor and transforming growth factor beta-1 expression in the
developing dura mater correlates with calvarial bone formation. Plast Reconstr
Surg 1999; 104(2):435-44
41. Iseki S, Wilkie AO, Heath JK, Ishimaru T, Eto K, Morriss-Kay GM. Fgfr2
and osteopontin domains in the developing skull vault are mutually exclusive
and can be altered by locally applied FGF2. Development 1997; 124(17):3375-
84
42. Noda M, Vogel R. Fibroblast growth factor enhances type beta 1 transforming
growth factor gene expression in osteoblast-like cells. J Cell Biol 1989;
109(5):2529-35
43. Grillo L, Greco D, Pettinato R, Avola E, Potenza N, Castaglia L et al.
Increased FGF3 and FGF4 gene dosage is a risk factor for craniosynostosis.
Gene 2014; 534(2):435-9
44. Lomri A, Lemonnier J, Hott M, de Parseval N, Lajeunie E, Munnich A et
al. Increased calvaria cell differentiation and bone matrix formation induced by
fibroblast growth factor receptor 2 mutations in Apert syndrome. J Clin Invest
1998; 101(6):1310-7
45. Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and
intramembranous bone development and human genetic disease. Genes Dev
2002; 16(12):1446-65
46. Coussens AK, Wilkinson CR, Hughes IP, Morris CP, van Daal A,
Anderson PJ et al. Unravelling the molecular control of calvarian suture fusion
in children with craniosynostosis. BMC Genomics 2007; 8(1):458
47. Massague J. The transforming growth factor-beta family. Annu Rev Cell Biol
1990; 6:597-641
     56  

48. Centrella M, Massague J, Canalis E. Human platelet-derived transforming

growth factor-beta stimulates parameters of bone growth in fetal rat calvariae.
Endocrinology 1986; 119:2306-12
49. Centrella M, McCarthy TL, Canalis E. Transforming growth factor beta is a
bifunctional regulator of replication and collagen synthesis in osteoblast-
enriched cell cultures form fetal rat bone. J Biol Chem 1987; 262:2869-74
50. Chenu C, Pfeilschifter J, Mundy GR, Roodman GD. Transforming growth
factor beta inhibits formation of osteoclast-like cells in long term human
marrow cultures. Proc Natl Acad Sci USA 1988; 85:5683-7
51. Mehrara BJ, Most DE, Chang J, et al. Basic fibroblast growth factor and
transforming growth factor beta-1 expression in the developing dura mater
correlates with calvarial bone formation. Plast Reconstr Surg 1999; 102:1805-
17
52. Opperman LA, Nolen AA, Ogle RC. TGF-beta 1, TGF-beta 2, and TGF-beta
3 exhibit distinct patterns of expression during cranial suture formation and
obliteration in vivo and in vitro. J Bone Miner Res 1997; 12:301-10
53. Roth DA, Longaker MT, McCarthy JG, Rosen DM, McMullen HF, Levine
JP, et al. Studies in cranial suture biology: Part I. Increased immunoreactivity
for transforming growth factor-beta (b1, b2, b3) during rat cranial suture fusion.
J Bone Miner Res 1997;12:311-21
54. Roth DA, Gold LI, Han VK, McCarthy JG, Sung JJ, Wisoff JH et al.
Immunolocalization of transforming growth factor beta 1, beta 2, beta 3 and
insulin-like growth factor I in premature cranial suture fusion. Plast Reconstr
Surg 1997; 99(2):300-9
55. Greenwald JA, Mehrara BJ, Spector JA, Warren SM, Fagenholz PJ, Smith
LE, et al. In vivo modulation of FGF-biologic activity alters cranial suture fate.
Am J Pathol 2001; 158:441-52
56. Bradley JP, Han VK, Roth DA, Levine JP, McCarthy JG, Longaker MT.
Increased IGF-I and IGF-II mRNA and IGF-I peptide in fusing rat cranial
sutures suggest evidence for a paracrine role of insulin-like growth factors in
suture fusion. Plast Reconstr Surg 1999; 104:129-38
57. Akita S, Hirano A, Fujii T. Identification of IGF-I in the calvarial suture of
young rats: histochemical analysis of the cranial sagittal sutures in a
hyperthyroid rat model. Plast Reconstr Surg 1996; 97(1):1-12
     57  

58. Thaller SR, Hoyt J, Tesluk H, Holmes R. The effect of insulin growth factor-
1 on calvarial sutures in a Sprague-Dawley rat. J Craniofac Surg 1993; 4:35-9
59. Hirukawa K, Miyazawa K, Maeda H, Kameyama Y, Goto S, Togari A.
Effect of tensile force on the expression of IGF-I and IGF-I receptor in the
organ-cultured rat cranial suture. Arch Oral Biol 2005; 50(3):367-72
60. Kinsella Jr CR, Cray JJ, Durham EL, Burrows AM, Vecchione L, Smith
DM et al. Recombinant Human Bone Morphogenetic Protein-2–Induced
Craniosynostosis and Growth Restriction in the Immature Skeleton. Plast
Reconstr Surg 2011; 127(3):1173-81.
61. Xu H, Ke K, Zhang Z, Luo X, Jin X, Liu SS, Fan Z. Effects of platelet-rich
plasma and recombinant human bone morphogenetic protein-2 on suture
distraction osteogenesis. J Craniofac Surg 2913; 24(2):645-50
62. Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT. The
BMP antagonist noggin regulates suture fusion. Nature 2003; 422(6932):625-9
63. Shen K, Krakora SM, Cunningham M, Singh M, Wang X, Hu FZ et al.
Medical treatment of craniosynostosis: recombinant Noggin inhibits coronal
suture closure in the rat craniosynostosis model. Orthod Craniofac Res 2009;
12(3):254-62
64. Kobayashi Y, Udagawa N, Takahashi N. Action of RANKL and OPG for
osteoclastogenesis. Crit Rev Eukaryot Gene Expr 2009; 19(1):61-72
65. Pelegrino KO, Sugayama S, Lezirovitz K, Catelani AL, Kok F, Chauffaille
ML. MSX2 copy number increase and craniosynostosis: copy number variation
detected by array comparative genomic hybridization. Clinics 2012; 67(8):981-
5.
66. Winograd J, Reilly MP, Roe R, Lutz J, Laughner E, Xu X et al. Perinatal
lethality and multiple craniofacial malformations in MSX2 transgenic mice.
Human Molecular Genetics 1996; 6(3):369-79
67. Wang JC, Steinraths M, Dang L, Lomax B, Eydoux P, Stockley T et al.
Craniosynostosis associated with distal 5q-trisomy: Further evidence that extra
copy of MSX2 gene leads to craniosynostosis. Am J Med Genet 2007;
143A(24):2931-6
68. Bernardini L, Castori M, Capalbo A, Mokini V, Mingarelli R, Simi P et al.
Syndromic craniosynostosis due to complex chromosome 5 rearrangement and
MSX2 gene triplication. Am J Med Genet 2007; 143A(24):2937-43
     58  

69. Shiihara L, Kato M, Kimura T, Hayasaka K, Yamamori S, Ogata T.

Craniosynostosis with extra copy of MSX2 in a patient with partial 5qtrisomy.
(Letter) Am J Med Genet 2007; 128A(2):214-6
70. Alappat S, Zhang ZY, Chen YP. Msx homeobox gene family and craniofacial
development. Cell Research 2003; 13(6):429-42
71. Rudnicki JA, Brown AM. Inhibition of chondrogenesis by Wnt gene
expression in vivo and in vitro. Dev Biol 1997; 185(1):104-18
72. Maruyama T, Mirando AJ, Deng CX, Hsu W. The Balance of WNT and
FGF Signaling Influences Mesenchymal Stem Cell Fate During Skeletal
Development. Sci Signal 2010; 3(123):ra40
73. Reinhold MI, Kapadia RM, Liao Z, Naski MC. The Wnt-inducible
Transcription Factor Twist1 Inhibits Chondrogenesis. J Biol Chem 2006;
281(3):1381-8
74. Guenou H, Kaabeche K, Mée SL, Marie PJ. A role for fibroblast growth
factor receptor-2 in the altered osteoblast phenotype induced by twist
haploinsufficiency in the Saethre-Chotzen syndrome. Hum Mol Genet 2005;
14(11):1429-39
75. Behr B, Longaker MT, Quarto N. Differential activation of canonical Wnt
signaling determines cranial sutures fate: a novel mechanism for sagittal suture
craniosynostosis. Dev Biol 2010; 344(2):922-40
76. Kikuchi A. Modulation of Wnt signaling by Axin and Axil. Cytokine Growth
Factor Rev 1999; 10(3-4):255-65
77. Yan Y, Tang D, Chen M, Huang J, Xie R, Jonason JH, et al. Axin2 controls
bone remodeling through the beta-catenin-BMPsignaling pathway in adult mice.
J Cell Sci 2009; 122(19):3566-78
78. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K,
Akiyama T. Axin, an inhibitor of the Wnt signaling pathway, interacts with
beta-catenin, GSK-3beta and APC and reduces beta-catenin level. Genes Cells
1998; 3(6):395-403
79. Gabbay JS, Heller J, Spoon DB, Mooney M, Acarturk O, Askari M et al.
Noggin underexpression and runx-2 overexpression in a craniosynostosis rabbit
model. Ann Plast Surg 2006; 56(3):306-11
80. Grevies MR, Odessey EA, Waggoner DJ, Shenaq DS, Aradhya S, Mitchell
A, et al. RUNX2 quadruplication: additional evidence toward a new form of
syndromic craniosynostosis. J Craniofac Surg 2013; 24(1):126-9
     59  

81. Renier D, El-Ghouzzi V, Bonaventure J, Le Merrer M, Lajeunie E.

Fibroblast growth factor receptor 3 mutation in nonsyndromic coronal
synostosis: clinical spectrum, prevalence, and surgical outcome. J Neurosurg
2000; 92(4):631-6
82. Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D. Genetic
study of nonsyndromic coronal craniosynostosis. Am J Med Genet 1995;
55(4):500-4
83. Mulliken JB, Steinberger D, Kunze S, Müller U. Molecular diagnosis of
bilateral coronal synostosis. Plast Reconstr Surg 1999; 104(6):1603-15
84. Hunenko O, Karmacharya J, Ong G, Kirschner RE. Toward an
understanding of nonsyndromic craniosynostosis: altered patterns of TGF-beta
receptor and FGF receptor expression induced by intrauterine head constraint.
Ann Plast Surg 2001; 46(5):546-53
85. Mulliken Jb, Gripp KW, Stolle CA, Steinberger D, Müller U. Molecular
analysos of patients with synostotic frontal plagiocephaly (unilateral coronal
synostosis). Plast Reconstr Surg 2004; 113(7):1899-909
86. Wilkie AO, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJ, et al.
Prevalence and complications of single-gene and chromosomal disorders in
craniosynostosis. Pediatrics 2010; 126(2):e391-400
87. Cunningham ML, Horst JA, Rieder MJ, Hing AV, Stanaway IB, Park SS
et al. IGF1R variants associated with isolated single suture craniosynostosis.
Am J Med Genet 2011; 155A(1):91-7
88. Seto ML, Hing AV, Chang J, Hu M, Kapp-Simon KA, Patel PK et al.
Isolated sagittal and coronal craniosynostosis associated with TWIST box
mutations. Am J Med Genet 2007; 143A(7):678-86
89. Mefford HC, Shafer N, Antonacci F, Tsai JM, Park SS, Hing AV et al.
Copy number variation analysis in single-suture craniosynostosis: multiple rare
variants including RUNX2 duplication in two cousins with metopic
craniosynostosis. Am J Med Genet 2010; 152A(9):2203-10
90. Passos-Bueno MR, Serti Eacute AE, Jehee FS, Fanganiello R, Yeh E.
Genetics of craniosynostosis: genes, syndromes, mutations and genotype-
phenotype correlations. Front Oral Biol 2008; 12:107-43
91. Ciurea AV, Toader C. Genetics of craniosynostosis: review of literature. J
Med Life 2009; 2(1):5-17
     60  

92. Park J, Park OJ, Yoon WJ, Kim HJ, Choi KY, Cho TJ, Ryoo HM.
Functional characterization of a novel FGFR2 mutation, E731K, in
craniosynostosis. J Cell Biochem 2012; 113(2):457-64
93. Twigg SRF, Lloyd D, Jenkins D, Elcioglu NE, Cooper CDO, Al-Sannaa N,
et al. Mutations in Multidomain Protein MEGF8 Identify a Carpenter Sundrome
Subtye Associated with Defective Lateralization.Am J Hum Genet 2012;
91(5):897-905
94. Craniofrontonasal dysplasia [Internet]. Orphanet: The portal for rare diseases
and orphan drugs. 2006 - [cited 2015 June 1]. Available from:
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1520.0
95. Carpenter syndrome [Internet]. Orphanet: The portal for rare diseases and
orphan drugs 2005 - [cited 2015 June 1]. Available from:
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=65759
96. Hunenko O, Karmacharya J, Ong G, Kirschner RE. Toward an
understanding of nonsyndromic craniosynostosis: altered patterns of TGF-beta
receptor and FGF receptr expression induced by intrauterine head constraint.
Ann Plast Surg 2001; 46(5):546-53; discussion 553-4
97. Yu JC, Lucas JH, Fryberg K, Borke JL. Extrinsic tension results in FGF-2
release, membrane permeability change, and intracellular Ca++ increase in
immature cranial sutures. J Craniofac Surg 2001; 12(4):391-8
98. Higginbottom MC, Jones KL, James HE. Intrauterine constraint and
craniosynostosis. Neurosurgery 1980; 6(1):39-44
99. Graham Jr JM, Badura RJ, Smith DW. Coronal craniostenosis: fetal head
constraint as one possible cause. Pediatrics 1980; 65(5):995-9
100. Graham Jr JM, Smith DW. Metopic craniostenosis as a consequence of fetal
head constraint: two interesting experiments of nature. Pediatrics 1980;
65(5):1000-2
101. Alderman BW, Lammer EJ, Joshua SC, Cordero JF, Ouimette DR, Wilson
MJ et al. An epidemiologic study of craniosynostosis: risk indicators for the
occurrence of craniosynostosis in Colorado. Am J Epidemiol 1988; 128(2):431-
8
102. Sanchez-Lara PA, Carmichael SL, Graham Jr JM, Lammer EJ, Shaw GM,
Ma C et al. Fetal Constraint as a Potential Risk Factor for Craniosynostosis.
Am J Med Genet A 2010; 152A(2):394-400
     61  

103. Aldridge K, Marsh JL, Govier D, Richtsmeier JT. Central nervous system
phenotypes in craniosynostosis. J Anat 2002; 201(1):31-9
104. Martínez-Lage JF, Poza M, Lluch T. Craniosynostosis in neural tube defects:
a theory on its pathogenesis. Surg Neurol 1996; 46(5):465-9; discussion 469-70
105. Aldridge K, Kane AA, Marsh JL, Panchal J, Boyadjiev SA, Yan P et al.
Brain morphology in nonsyndromic unicoronal craniosynostosis. The
Anatomical Record Part A: Discoveries in Molecular, Cellular, and
Evolutionary Biology 2005; 285(2):690-698
106. Hukki A, Koljonen V, Karppinen A, Valanne L, Leikola J. Brain anomalies
in 121 children with non-syndromic single suture craniosynostosis by MR
imaging. Eur J Paediatr Neurol 2012; 16(6):671-5
107. Hill CA, Vaddi S, Moffitt A, Kane AA, Marsh JL, Panchal J et al.
Intracranial volume and whole brain volume in infants with unicoronal
craniosynostosis. Cleft Palate Craniofac J 2011; 48(4): 394-8
108. Cooper GM, Mooney MP, Burrows AM, Smith TD, Dechant J, Losken HW
et al. Brain growth rates in craniosynostotic rabbits. Cleft Palate Craniofac J
1999; 36(4):314-21
109. Honein MA, Rasmussen SA. Further evidence for an association between
maternal smoking and craniosynostosis. Teratology 2000; 62(3):145-6
110. Källén K. Teratology 1999; 60(3):146-50
111. Carmichael SL, Ma C, Rasmussen SA, Honein Ma, Lammer EJ, Shaw GM.
Craniosynostosis and maternal smoking. Birth Defects Res A Clin Mol Teratol
2008; 82(2):78-85
112. Alderman BW, Zamudio S, Barón AE, Joshua SC, Fernbach SK, Greene C
et al. Increased risk of craniosynostosis with higher antenatal maternal altitude.
Int J Epidemiol 1995; 24(2):420-6
113. Cohen MM Jr. Etiopathogenesis of craniosynostosis. Neurosurg Clin N Am
1991; 2(3):507-13
114. Carmichael SL, Ma C, Rasmussen SA, Cunningham ML, Browne ML,
Lammer EJ et al. Craniosynostosis and risk factors related to thyroid
dysfunction. Am J Med Genet A 2015; 167A(4):701-7
115. Assencio-Ferreira VJ, Abraham R, Veiga JCE, Santos KCD. Cranioestenose
da sutura metópica: efeito teratogênico do valproato de sódio. Relato de caso.
Arq Neuro-Psiquiatr 2001; 59(2B):417-420
     62  

116. Lajeunie E, Barcik U, Thorne JA, El Ghouzzi V, Bourgeois M, Renier D.

Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg 2001;
95(5):778-82
117. Singh RP, Dhariwal D, Bhujel N, Shaikh Z, Davies P, Nishikawa H et al.
Role of parental risk factors in the aetiology of isolated non-syndromic metopic
craniosynostosis. Br J Oral Maxillofac Surg 2010; 48(6):438-42
118. Tung EWY, Winn LM. Valproic Acid Increases Formation of Reactive
Oxygen Species and Induces Apoptosis in Pstimplantation Embryos: A Role for
Oxidative Stress in Valproic Acid-Induced Neural Tube Defects. Mol Pharm
2011; 80(6):979-87
119. Morita K, Miyamoto T, Fujita N, Kubota Y, Ito K, Takubo K et al.
Reactive oxygen species induce chondrocyte hypertrophy in endochondral
ossification. J Exp Med 2007; 204(7):1613-23
120. James AW, Levi B, Xu Y, Carre AL, Longaker MT. Retinoic acid enhances
osteogenesis in cranial suture-derived mesenchymal cells: potential mechanisms
of retinoid-induced craniosynostosis. Plast Reconstr Surg 2010; 125(5):1352-61
121. Song HM, Nacamuli RP, Xia W, Bari AS, Shi YY, Fang TD et al. High-dose
retinoic acid modulates rat calvarial osteoblast biology. J Cell Physiol 2005;
202(1):255-62
122. Reefhuis J, Honein MA, Shaw GM, Romitti PA. Fertility treatments and
craniosynostosis: California, Georgia, and Iowa, 1993-1997. Pediatrics 2003;
111(5 Pt 2):1163-6
123. Komori T. Regulation of bone deveopment and maintenance by Runx2. Fron
Biosci 2008; 13:898-903
124. Richardson S, Browne ML, Rasmussen SA, Druschel CM, Sun L, Jabs EW
et al. Associations between periconceptional alcohol consumption and
craniosynostosis, omphalocele, and gastroschisis. Birth Defects Res A Clin Mol
Teratol 2011; 91(7):623-30
125. Alderman BW, Bradley CM, Greene C, Fernbach SK, Barón AE. Increased
risk of craniosynostosis with maternal cigarette smoking during pregnancy.
Teratology 1994; 50(1):13-8
126. Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D. Genetic
study of scaphocephaly. Am J Med Genet 1996; 62(3):282-5
     63  

127. Lajeunie E, Le Merrer M, Marchac D, Renier D. Syndromal and

nonsyndromal primary trigonocephaly: analysis of a series of 237 patients. Am
J Med Genet 1998; 75(2):211-5
128. Gill SK, Broussard C, Devine O, Green RF, Rasmussen SA, Reefhuis J.
Association between maternal age and birth defects of unknown etiology:
United States, 1997-2007. Birth Defects Res A Clin Mol Teratol 2012;
94(12):1010-8
129. Johnson D, Wilkie AOM. Craniosynostosis. Eur J Hum Genet 2011;
19(4):369-76
130. Garza RM, Khosla RK. Nonsyndromic craniosynostosis. Semin Plast Surg
2012; 26(2):53-63
131. van der Meulen J. Metopic synostosis. Childs Nerv Syst 2012; 28(9):1359-67
132. Sidoti EJ Jr, Marsh JL, Marty-Grames L, Noetzel MJ. Long-term studies of
metopic synostosis: frequency of cognitive impairment and behavioral
disturbances. Plast reconstr surg 1996; 97(2):276-81
133. Speltz ML, Collett BR, Wallace ER, Starr JR, Cradock MM, Buono L et al.
Intellectual and academic functioning of school-age children with single-suture
craniosynostosis. Pediatrics 2015; 135(3):e615-23
134. Weinzweig J, Kirschner RE, Farley A, Reiss P, Hunter J, Whitaker LA et
al. Metopic synostosis: Defining the temporal sequence of normal suture fusion
and differentiating it from synostosis on the basis of computed tomography
images. Plast Reconstr Surg 2003; 112(5):1211-8
135. David DJ, Posswillo D, Sompson D. The craniosynostosis: causes, natural
history and management. Berlin: Springer; 1992.
136. Surgery for craniosynostosis – problem [Internet]. Medscape. 2015 – [cited
2015 June 17]. Available from: http://emedicine.medscape.com/article/248568-
overview#a6
137. Laughlin J, Luerssen TG, Dias MS. Prevention and management of positional
skull deformities in infants. Pediatrics 2011; 128(6):1236-41
138. Kabbani H, Raghuveer TS. Craniosynostosis. Am Fam Physician 2004;
69(12):2863-70
139. Rhodes JL, Kolar Jc, Fearon JA. Mercedes Benz pattern craniosynostosis.
Plast Reconstr Surg 2010. 125(1):299-304
140. Schmelzer RE, Fearon JA. ‘Z-pattern’ craniosynostosis: a novel presentation
of trisutural fusion. J Craniofac Surg 2007; 18(3):568-74
     64  

141. Tamburrini G, Caldarelli M, Massimi L, Gasparini G, Pelo S, Di Rocco C.

Complex craniosynostosis: a review of the prominent clinical features and the
related management strategies. Childs Nerv Syst 2012; 28(9):1511-23
142. Doniach T. Basic FGF as an Inducer of Anteroposterior Neural Pattern. Cell
1995;83: 1067-70
143. Hayward R. Craniofacial Syndromes. In: Albright AL, Pollack IF, Adelson
PD. Principles and Practice of Pediatric Neurosurgery – third edition. Thieme;
2014. p249-266
144. Reddy K Hoffman H, Armstrong D. Delayed and progressive multiple suture
craniosynostosis. Neurosurgery 1990; 26:442-8
145. Crouzon syndrome (craniofacial dysostosis) [Internet]. TheFetus.net. 2008 -
[cited 2015 June 2]. Available from:
http://sonoworld.com/fetus/page.aspx?id=2519
146. Crouzon O. Dysostose cranio-faciale héréditaire. Bulletins et mémoires de la
Société médicale des hôpitaux da Paris 1912; 33:545-5
147. Lajeunie E, Cameron R, El Ghouzzi V, de Parseval N, Journeau P,
Gonzales M et al. Clinical variability in patients with Apert’s syndrome. J
Neurosurg 1999; 90:443-7
148. Cohen MM, Kreiborg S. Hands and feet in Apert syndrome. Am J Med Genet
1995; 57:82-96
149. Apert.org. [Internet]. Weston: Apert.org. 1999 – [cited 2015 June 2]. Available
from: http://www.apert.org/miller/
150. Huddleston A. Multiple surgeries give Idaho boy a new face and a new lease on
life [Internet]. Salt Lake City: Deseret News; 2010 [cited 2015 June 2].
Available from: http://www.deseretnews.com/article/700074214/Multiple-
surgeries-give-Idaho-boy-a-new-face-and-a-new-lease-on-life.html?pg=all
151. Cohen MM. Pfeiffer syndrome update, clinical subtypes, and guidelines for
differential diagnosis. Am J Med Genet 1993; 45:300-7
152. Anderson PJ, Hall CM, Evans RD, Hayward RD, Jones BM. The elbow in
syndromic craniosynostosis. J Craniofac Surg 1998; 9:201-6
153. Anderson PJ, Hall CM, Evans RD, Jones BM, Harkness W, Hayward RD.
Cervical spine in Pfeiffer’s syndrome. J Craniofac Surg 1996; 7:275-9
154. Pfeiffer syndrome [Internet]. Healthool.com. 2014 – [cited 2015 June 2].
Available from: http://healthool.com/pfeiffer-syndrome/
     65  

155. De Jong T, Bannink N, Bredero-Boelhouwer HH, van Veelen ML, Bartels

MC, Hoeve LJ et al. Long-term functional outcome in 167 patients with
syndromic craniosynostosis; defining a syndrome-specific risk profile. J Plast
Reconstr Aesthet Surg 2010; 63:1635-41
156. Reardon W, Winter RM. Saethre-Chotzen syndrome. J Med Genet 1994;
31:393-6
157. Saethre-Chotzen Syndrome [Internet]. The Children’s Hospital of Philadelphia.
2014 – [cited 2015 June 2]. Available from: http://www.chop.edu/conditions-
diseases/saethre-chotzen-syndrome#.VXdF9mBURyw
158. Muenke M, Gripp KW, McDonald-McGinn DM, Guadenz K, Whitaker
LA, Bertlett SP et al. A unique point mutation in the fibroblast growth factor
receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum
Genet 1997; 60:555-64
159. Muenke Syndrome [Internet]. International Craniofacial Institute. 2015 – [cited
2015 June 4]. Available from: http://www.craniofacial.net/syndromes-muenke
160. Saavedra D, Richieri-Costa A, Guion-Almeida ML, Cohen MM.
Craniofrontonasal syndrome: study of 41 patients. Am J Med Genet 1996;
61:147-51
161. Cohen MM. Craniofrontonasal dysplasia. Birth Defects Orig Artic Ser 1979;
155B:85-9
162. Kawamoto HK, Heller JB, Heller MM, Urrego A, Gabbay JS, Wasson KL
et al. Craniofrontonasal dysplasia: a surgical treatment algorithm. Plast
Reconstr Surg 2007; 120:1943-56
163. Twigg SR, Kan R, Babbs C, Bochukova EG, Robertson SP, Wall SA.
Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause
craniofrontonasal syndrome. Porc Natl Acad Sci U S A 2004; 101(23):8652-7
164. Gershoni-Baruch R. Carpenter syndrome: marked variability of expression to
include the Summit and Goodman syndromes. Am J Med Genet 1990; 35:236-
40
165. Eaton AP, Sommer A, Kontras SB, Sayers MP. Carpenter syndrome-
acrocephalopolysyndactyly type II. Birth Defects Orig Artic Ser 1974; 10:249-
60
166. Carpenter Syndrome [Internet]. Glogster.com. 2012 – [cited 2015 June 2].
Available from: http://www.glogster.com/ibekatsmiley/carpenter-syndrome/g-
6km1v72eh1bm7s7bu6mr9a0
     66  

167. Addo NK, Javadpour S, Kandasamy J, Sillifant P, May P, Sinha A. Central

sleep apnea and associated Chiari malformation in children with syndromic
craniosynostosis: treatment and outcome data from a supraregional national
craniofacial center. J Neurosurg Pediatr 2013; 11(3):296-301
168. Gault DT, Renier D, Marchac D, Jones BM. Intracranial pressure and
intracranial volume in children with craniosynostosis. Plast Reconstr Surg 1992;
90(3):377-81
169. Woods RH, Ul-Hag E, Wilkie AO, Jayamohan J, Richards PG, Johnson D
et al. Reoperation for intracranial hypertension in TWIST1-confirmed Saethre-
Chotzen syndrome: a 15-year revie. Plast Reconstr Surg 2009; 123(6):1801-10
170. Collmann H, Sörensen N, Krauss J. Hydrocephalus in craniosynostosis: a
review. Childs Nerv Syst 2005; 21(10):902-12
171. Renier D, Sainte-Rose C, Marchac D, Hirsch JF. Intracranial pressure in
craniostenosis. J Neurosurg 1982; 57(3):370-7
172. De Jong T, Rijken BFM, Lequin MH, van Veelen MLC, Mathijssen IMJ.
Brain and ventricular volume in patients with syndromic and complex
craniosynostosis. Childs Nerv Syst 2012; 28(1):137-40
173. Tamburrini G, Caldarelli M, Massimi L, Santini P, Di Rocco C. Intracranial
pressure monitoring in children with single suture and complex
craniosynostosis: a review. Childs Nerv Syst 2005; 21(10):913-21
174. Tuite GF, Chong WK, Evanson J, Narita A, Taylor D, Harkness WF et al.
The effectiveness of papilledema as an indicator of raised intracranial pressure
in children with craniosynostosis. Neurosurg 1996; 38(2):272-8
175. Thompson DA, Liasis A, Hardy S, Hagan R, Hayward RD, Evans RD et al.
Prevalence of abnormal pattern reversal visual evoked potentials in
craniosynostosis. Plast Reconstr Surg 2006; 118(1):184-92
176. Rich PM, Cox TCS, Hayward RD. The jugular foramen in complex and
syndromic craniosynostosis and its relationship to raisd intracranial pressure.
Am J Neuroradiol 2003; 24:45-51
177. Florisson JM, Barmpalios G, Lequin M, van Veelen ML, Bannink N,
Hayward RD et al. Venous hypertension in syndromic and complex
craniosynostosis: The abnormal anatomy of the jugular foramen and collaterals.
J Craniomaxillofac Surg 2015; 43(3):312-8
     67  

178. Strahle J, Muraszko KM, Buchman SR, Kapurch J, Garton HJ, Maher
CO. Chiari malformation assoiated with craniosynostosis. Neurosurg Focus
2011; 31(3):E2
179. Cinalli G, Renier D, Sabag G, Sainte-Rose C, Arnaud E, Pierre-Kahn A.
Chronic tonsillar herniation in Crouson’s and Apert’s syndromes: the role of
premature synostosis of the lambdoid suture. J Neurosurg 1995; 83(4):575-82
180. Cinalli G, Spennato P, Sainte-Rose C, Arnaud E, Aliberti F, Brunelle F et
al. Chiari malformation in craniosynostosis. Childs Nerv Syst 2005;
21(10):889-901
181. Leikola J, Koljonen V, Valanne L, Hukki J. The incidence of Chiari
malformation in nonsyndromic, single suture craniosynostosis. Childs Nerv Syst
2010; 26(6):771-4
182. Leikola J, Haapamäki V, Karppinen A, Koljonen , Hukki J, Valanne L et
al. Morphometric comparison of foramen magnum in non-syndromic
craniosynostosis patients with or without Chiari I malformation. Acta Neurochir
(Wien) 2012; 154(10):1809-13
183. Assadsangabi R, Hajmomenian M, Bilaniuk LT, Vossough A. Morphology
of the foramen magnum in syndromic and non-syndromic brachycephaly.
Childs Nerv Syst 2015; 31(5):735-41
184. Diagnosis and testing [Internet]. Mayfield Chiari Center. 2015 - [cited 2015
June 9]. Available from:
http://www.mayfieldchiaricenter.com/chiari_diagnosis.php
185. Chiari Malformation MRI Scan Images [Internet]. The Wisconsin Chiari Center.
2015 – [cited 2015 June 9]. Available from:
http://www.wichiaricenter.org/oth/Page.asp?PageID=OTH101160
186. Speltz ML, Kapp-Simon K, Collett B, Keich Y, Gaither R, Cradock MM, et
al. Neurodevelopment of infants with single-suture craniosynostosis: presurgery
comparisons with case-mathced controls. Plast Reconstr Surg 2007;
119(6):1874-81
187. Da Costa AC, Walters I, Savarirayan R, Anderson VA, Wrennall JA,
Meara JG. Intellectual outcomes in children and adolescents with syndromic
and nonsyndromic craniosynostosis. Plast Reconstr Surg 2006; 118(1):175-81
188. Hashim PW, Patel A, Yang JF, Travieso R, Terner J, Losee JE et al. The
effects of whole-vault cranioplasty versus strip craniectomy on long-term
     68  

neuropsychological outcomes in sagittal craniosynostosis. Plast Reconstr Surg

2014; 134(3):491-501
189. Kapp-Simon KA, Speltz ML, Cunningham ML, Patel PK, Tomita T.
Neurodevelopment of children with single suture craniosynostosis: a review.
Childs Nerv Syst 2007; 23(3):269-81
190. Maliepaard M, Mathijssen IM, Oosterlaan J, Okkerse JM. Intellectual,
behavioral, and emotional functioning in children with syndromic
craniosynostosis. Pediatrics 2014; 133(6):e1608-15
191. Mitsukawa N, Kaneko T, Saiga A, Akita S, Satoh K. Early midfacial
distraction for syndromic craniosynostotic patients with obstructive sleep
apnoea. J Plast Reconstr Aesthet Surg 2013; 66(9):1206-11
192. Alli A, Gupta S, Elloy MD, Wyatt M. Laryngotracheal anomalies in children
with syndromic craniosynostosis undergoing tracheostomy. J Craniofac Surg
2013; 24(4):1423-7
193. KougaT, Tanoue K, Matsui K. Airway statuses and nasopharyngeal airway
use for airway obstruction in syndromic craniosynostosis. J Craniofac Surg
2014; 25(3):762-5
194. Driessen C, Joosten KF, Florisson JM, Lequin M, van Veelen ML,
Dammers R et al. Sleep apnoea in syndromic craniosynostosis occurs
independent of hindbrain herniation. Childs Nerv Syst 2013; 29(2):289-96
195. Zandieh SO, Padwa BL, Katz ES. Adenotonsillectomy for obstructive sleep
apnea in children with syndromic craniosynostosis. Plast Reconstr Surg 2013;
131(4):847-52
196. Nischal KK. Visual surveillance in craniosynostosis. Am Orthopt J 2014;
64:24-31
197. Pereira MV, Glória AL. Lagophthalmos. Semin Ophthalmol 2010; 25(3):72-8
198. Church MW, Parent-Jenkins L, Rozzelle AA, Eldis FE, Kazzi SN. Auditory
brainstem response abnormalities and hearing loss in children with
craniosynostosis. Pediatrics 2007; 119(6):e1351-60
199. Rajenderkumar D, Bamiou DE, Sirimanna T. Audiological profile in Apert
syndrome. Arch Dis Child 2005; 90(6):592-3
200. Vallino-Napoli LD. Audiologic and otologic characteristics of Pfeiffer
syndrome. Cleft Palate Craniofac J 1996; 33(6):524-9
201. Paparella MM, Oda M, Hiraide F, Brady D. Pathology of sensorineural
hearing loss in otitis media. Ann Otol Rhinol Laryngol 1972; 81(5):632-47
     69  

202. Vannier MW, Hildebolt CF, Marsh JL, Pilgram TK, McAlister WH,
Shackelford GD et al. Craniosynostosis: diagnostic value of three-dimensional
CT reconstruction. Radiology 1989; 173(3):669-73
203. Rijken BF, den Ottelander BK, van Veelen ML, Lequin MH, Mathijssen
IM. The occipitofrontal circumference: reliable prediction of the intracranial
volume in children with syndromic and complex craniosynostosis. Neurosurg
Focus 2015; 38(5):E9
204. Taccone A, Cama A, Ghiorzi M, Fondelli MP. Diagnosis and treatment of
craniosynostosis: the usefulness of CT combined with 3-dimensional
reconstruction. Radiol Med 1989; 77(4):322-8
205. Schweitzer T, Böhm H, Meyer-Macotty P, Collmann H, Ernestus RI, Krauß J.
Avoiding CT scans in children with single-suture craniosynostosis. Childs Nerv
Syst 2012; 28(7):1077-82
206. Khanna PC, Thapa MM, Iyer RS, Prasad SS. Pictorial essay: The many face
of craniosynostosis. Indian J Radiol Imaging 2011; 21(1):49-56
207. Al-Otibi M, Jea A, Kulkarni AV. Detection of important venous collaterals by
computed tomography venogram in multisutural synostosis. Case report and
review of the literature. J Neurosurg 2007; 107(6 Suppl):508-10
208. Majoie CB, van Straten M, Venema HW, den Heeten GJ. Multisection CT
venography of the dural sinuses and cerebral veins by using matched mask bone
elimination. Am J Neurorad 2004; 25:787-91
209. Jamjoom AA, Jamjoom BA, Waliuddin AR, Jamjoom AB. Lessons from a
case of osteopetrosis oxycephaly and Chiari type I malformation: a case report.
Cases J 2009; 2:6787
210. Lupescu I, Hermier M, Georgescu SA, Froment JC. Spiral CT evaluation of
the craniosynostosis. J Neuroradiol 2000; 27(2):128-39
211. Mahomed N, Sewchuran T, Mahomed Z. The copper-beaten skull. South
African J Radiol 2012; 16(1):25-6
212. David AL, Turnbull C, Scott R, Freeman J, Bilardo CM, van Maarle et al.
Diagnosis of Apert syndrome in the second-trimester using 2D and 3D
ultrasound. Prenat Diagn 2007; 27(7):629-32
213. Delahaye S, Bernard JP, Rénier D, Ville Y. Prenatal ultrasound diagnosis of
fetal craniosynostosis. Ultrasound Obstet Gynecol 2003; 21:347-353
     70  

214. Answer to case #93 [Internet]. TheFetus.net. 2003 – [cited 2015 June 9].
Available from:
http://sonoworld.com/TheFetus/Case.aspx?CaseId=1089&answer=1
215. Agochukwu NB, Solomon BD, Muenke M. Impact of genetics on the
diagnosis and clinical management of syndromic craniosynostosis. Childs Nerv
Syst 2012; 28(9):1447-63
216. Seruya M, Oh AK, Boyajian MJ, Posnick JC, Myseros JS, Yaun AL et al.
Long-term outcomes of primary craniofacial reconstruction for
craniosynostosis: a 12-year experience. Plast Reconstr Surg 2011; 127(6):2397-
406
217. Esparza J, Hinojosa J, Garcá-Recuero I, Romance A, Pascual B, Martínez
de Aragón A. Surgical treatment of isolated and syndromic craniosynostosis.
Results and complications in 283 consecutive cases. Neurocirugia (Astur) 2008;
19(6):509-29
218. Shukla V, Coumoul X, Wang RH, Kim HS, Deng CX. RNA interference and
inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a
mouse model of craniosynostosis. Nat Genet 2007; 39(9):1145-50
219. Surgery for craniosynostosis – contraindications [Internet]. Medscape. 2015 –
[cited 2015 June 16]. Available from:
http://emedicine.medscape.com/article/248568-overview#a13
220. Craniofacial Surgery [Internet]. Long Island Neurosurgical Associates. 2015 –
[cited 2015 June 13]. Available from: http://www.lineurosurgery.com/our-
services/craniofacial-surgery
221. Delashaw JB, Persing JA, Park TS, Jane JA. Durgical approaches for the
correction of metopic synostosis. Neurosurg 1986; 19(2):228-234
222. Maltese G, Tarnow P, Tovetjärn R, Kölby L. Correction of hypotelorism in
isolated metopic synostosis. J Plast Surg Hand Surg 2014; 48(1):63-6
223. Hoffman HJ. Procedure of lateral canthal advancement for the treatment of
coronal synostosis. Childs Nerv Syst 1996; 12:678-82
224. MacKinnon S, Rogers GF, Gregas M, Proctor MR, Mulliken JB, Daki LR.
Treatment of unilateral coronal synostosis by endoscopic strip craniectomy or
fronto-orbital advancement: Opththalmologic findings. J AAPOS 2009; 13:155-
60
225. Albright AL, Towbin RB, Shultz BL. Long-term outcome after sagittal
synostosis operations. Pediatr Neurosurg 1996; 25:78-82
     71  

226. Brown L, Proctor MR. Endoscopically assisted correction of sagittal

craniosynostosis. AORN J 2011; 93:566-79, quiz 580-1
227. Pollack IF, Losken HW, Fasick P. Diagnosis and management of posterior
plagiocephaly. Pediatrics 1997; 99:180-5
228. Wagner JD, Cohen SR, Maher H, Dauser RC, Newman MH. Critical
analysis of results of craniofacial surgery for nonsyndromic bicoronal
synostosis. J Craniofac Surg 1995; 6(1):32-7; discussion 38-9
229. Balaji SM. Modified facial bipartition. Ann Maxillofac Surg 2012; 2(2):170-3
230. Sharma RK. Hypertelorism. Indian J Plast Surg 2014; 47(3):284-92
231. Shen WM, Wang G, Cui J, He JP. Skull plasty to correct congenital
craniosynostosis. Zhonghua Zheng Xing Wai Ke Za Zhi 2007; 23(4):284-7
232. Fearon JA, Ruotolo RA, Kolar JC. Single sutural craniosynostoses: surgical
outcomes and long-term growth. Plast Reconstr Surg 2009; 123(2):635-42
233. Gerety PA, Basta MN, Fischer JP, Taylor JA. Operative management of
nonsyndromic sagittal synostosis: a head-to-head meta-analysis of outcomes
comparing 3 techniques. J Craniofac Surg 2015; 26(4):2151-7
234. Panchal J, Marsh JL, Park TS, Kaufman B, Pilgram T, Huang SH. Sagittal
craniosynostosis outcome assessment for two methods and timings of
intervention. Plast Reconstr Surg 1999; 103(6):1574-84
235. Sgouros S, Goldin JH, Hockley AD, Wake MJ. Childs Nerv Syst 1996;
12(11):727-33
236. Anderson FM. Treatment of coronal and metopic synostosis: 107 cases.
Neurosurg 1981; 8(2)143-9
237. Fearon JA, McLaughlin EB, Kolar JC. Sagittal craniosynostosis: surgical
outcomes and long-term growth. Plast Reconstr Surg 2006; 117(2):532-41
238. Barone CM, Jimenez DF. Endoscopic craniectomy for early correction of
craniosynostosis. Plast Reconstr Surg 1999; 104:1965-73, discussion 1974-75
239. Murad GJ, Clayman M, Seagle MB, White S, Perkins LA, Pincus DW.
Endoscopic-assisted repair of craniosynostosis. Neurosurg Focus 2005; 19:E6
240. Shah MN, Kane AA, Petersen JD, Woo AS, Naidoo SD, Smyth MD.
Endoscopically assisted versus open repair of sagittal craniosynostosis: the St.
Louis Children’s Hospital experience. J Neurosurg Pediatr 2011; 8:165-70
241. Jimenez DF, Barone CM. Endoscopic technique for sagittal synostosis. Childs
Nerv Syst 2012; 28(9):1333-9
     72  

242. Jimenez DF, Barone CM. Endoscopic technique for coronal synostosis. Childs
Verv Syst 2012; 28(9):1429-32
243. Massimi L, Di Rocco C. Mini-invasive surgical technique for sagittal
craniosynostosis. Childs Nerv Syst 2012; 28(9):1241-5
244. Berry-Candelario J, Ridgway EB, Grondin RT, Rogers GF, Proctor MR.
Endoscope-assisted strip craniectomy and postoperative helmet therapy for
treatment of craniosynostosis. Neurosurg Focus 2011; 31:E5
245. Positional plagiocephaly, part 2: prevention and treatment [Internet]. Pediatrics
Consultant Live. 2015 – [cited 2015 June 19]. Available from:
http://www.pediatricsconsultantlive.com/articles/positional-plagiocephaly-part-
2-prevention-and-treatment
246. Sugawa Y, Uda H, Sarukawa S, Sunaga A. Multidirectional cranial
distraction osteogenesis for the treatment of craniosynostosis. Plast Reconstr
Surg 2010; 126(5):1691-8
247. Akizuki T, Komuro Y, Ohmori K. Distraction osteogenesis for
craniosynostosis. Neurosurg Focus 2000; 9(3):e1
248. Greives MR, Ware BW, Tian AG, Taylor JA, Pollack IF, Losee JE.
Complications in posterior cranial vault distraction. Ann Plast Surg 2015; epub
ahead of print
249. Akai T, Iizuka H, Kawakami S. Treatment of craniosynostosis by distraction
osteogenesis. Pediatr Neurosurg 2006; 42(5):288-92
250. Yamaguchi K, Imai K, Fujimoto T, Takahashi M, Mauyama Y, Sakamoto
H et al. Cranial distraction osteogenesis for syndromic craniosynostosis: Long-
term follow-up and effect on postoperative cranial growth. J Plast Reconstr
Aesthet Surg 2014; 67(2):e35-41
251. Gwanmesia I, Jeelani O, Hayward R, Dunaway D. Frontofacial advancement
by distraction osteogenesis: a long-term review. Plast Reconstr Surg 2015;
135(2):553-60
252. Kim YO, Choi JW, Kim DS, Lee WJ, Yoo SK, Kim HJ et al. Cranial growth
after distraction osteogenesis of the craniosynostosis. J Craniofac Surg 2008;
19(1): 45-55
253. Guimarães-Ferreira J, Gewalli F, David L, Olsson R, Friede H, Lauritzen
CG. Spring-mediated cranioplasty compared with the modified pi-plasty for
sagittal synostosis. Scand J Plast Reconstr Surg Hand Surg 2003; 37(4):208-15
     73  

254. Taylor JA, Maugans TA. Comparison of spring-mediated cranioplasty to

minimally invasive strip craniectomy and barrel staving for early treatment of
sagittal craniosynostosis. J Craniofac Surg 2011; 22(4):1225-9
255. Patel N, Fearon JA. Treatment of the syndromic midface: a long-term
assessment at skeletal maturity. Plast Reconstr Surg 2015; 135(4):731e-42e
256. Patel A, Yang JF, Hashim PW, Travieso R, Terner J, Mayes LC et al. The
impact of age at surgery on long-term neuropsychological outcomes in sagittal
craniosynostosis. Plast Reconstr Surg 2014; 134(4):608e-17e
257. Paige KT, Vega SJ, Kelly CP, Bertlett SP, Zakai E, Jawad AF et al. Age-
dependent closure of bony defects after frontal orbital advancement. Plast
Reconstr Surg 2006; 118(4):977-84
258. Utria AF, Mundinger GS, Bellamy JL, Zhou J, Ghasemzadeh A, Yang R et
al. The importance of timing in optimizing cranial vault remodeling in
syndromic craniosynostosis. Plast Reconstr Surg 2014; 135(4):1077-84
259. Fearon JA, Munro IR, Bruce DA. Observations on the use of rigid fixation for
craniofacial deformities in infants and young children. Plast Reconstr Surg
1995; 95(4):634-7; discussion 638
260. Duke BJ, Mouchantat RA, Ketch LL, Winston KR. Transcranial migration
of microfixation plates and screws. Case report. Pediatr Neurosurg 1996;
25(1):31-4; discussion 35
261. Thomas K, Hughes C, Hohnson D, Das S. Anesthesia for surgery related to
craniosynostosis: a review. Part 1. Paediatr Anaesth 2012; 22(11):1033-41
262. Orliaguet G, Meyer P, Blanot S. Anesthetic management of craniosynostosis.
Ann Fr Anesth Reanim 2002; 21(2):111-8
263. Stricker PA, Fiadjoe JE. Anesthesia for craniofacial surgery in infancy.
Anesthesiol Clin 2014; 32(1):215-35
264. Wei AT, Madsen C, Al-Sheemy A, Kumar AR. Does preoperative steroid use
implove clinical outcomes in open repair of craniosynostosis? J Craniofac Surg
2015; 26(1):226-31
265. Pawl RP, Sugar O. Zenker’s solution in the surgical treatment of
craniosynostosis. J Neurosurg 1972; 36(5):604-7
266. Brandt L, Alberius P, Ljunggren B. The use of Senker’s solution in linear
craniectomy for craniosynostosis: technical modification and reappraisal. Acta
Neurochir (Wien) 1986; 83(1-2):67-70
     74  

267. Marlin AE, Brown Jr WE, Huntington HW, Epstein F. Effect of the dural
application of Zenker’s solution on the feline brain. Neurosurg 1980; 6(1):45-8
268. McComb GJ, Withers GJ, Davis RL. Cortical damage from Zenker’s solution
applied to the dura mater. Neurosurg 1981; 8(1):68-71
269. Francel PC, Bell A, Jane J. Operative positioning for patients undergoing
repair of craniosynostosis. Neurosurg 1994; 35(2):304-6
270. Mickle JP, Faberowski LW, Black S. 841 Incidence of venous air embolism
during craniectomy of craniosynostosis repair. Neurosurg 1999; 45(3):696
271. Behnke J, Mursh K, Luhr HG, Markakis E. A stable positioning for patients
requiring large calvarial exposure for surgical correction of cranial synostosis.
Acta Neurochir (Wien) 1996; 138(9):1099-101
272. Panchal J, Uttchin V. Management of craniosynostosis. Plast Reconstr Surg
2003; 111(6):2032-48; quiz 2049
273. Naran S, Claris F, Fearon J, Bradley J, Michelotti B, Cooper G et al. Safety
of preoperative erythropoietin in surgical calvarial remodeling: an 8-year
retrospective review and analysis. Plast Reconstr Surg 2012; 130(2):305e-310e
274. Ali A, Basaran B, Yornuk M, Altun D, Aydoseli A, Sencer A et al. Factors
influencing blood loss and postoperative morbidity in children undergoing
craniosynostosis surgery: a retrospective surgery. Pediatr Neurosurg 2013;
49(6):339-46
275. Hahn JF, Trusso R, Levy WJ. Craniosynostectomy with reduced blood loss.
Neurosurg 1981; 8(2):209-11
276. Maugans TA, Martin D, Taylor J, Salisbury S, Istaphanous G. Comparative
analysis of tranexamic acid use in minimally invasive versus open
craniosynostosis procedures. J Craniofac Surg 2011; 22(5):1772-8
277. Goobie SM, Meier PM, Pereira LM, McGowan FX, Prescilla RP, Scharp
LA et al. Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a
double-blind, placebo-controlled trial. Anesthesiology 2011; 114(4):862-71
278. Dadure C, Sauter M, Bringuier S, Bigorre M, Raux O, Rochette A et al.
Intraoperative tranexamic acid reduces blood transfusion in children undergoing
craniosynostosis surgery: a randomized double-blind study. Anesthesiology
2011; 114(4):856-61
279. Song G, Yang P, Zhu S, Luo E, Feng G, Hu J et al. Tranexamic acid reducing
blood transfusion in children undergoing craniosynostosis surgery. J Craniofac
Surg 2013; 24(1):299-303
     75  

280. Bristol RE, Singh D, Hooft N, Cotugno R, Beals S, Joganic E et al. 123 Time
to first blood in craniosynostosis surgery. Neurosurg 2013; 60:160-1
281. Pieters BJ, Conley L, Weiford J, Hamilton M, Wicklund B, Booser A et al.
Prophylactic versus reactive transfusion of thawed plasma in patients
undergoing surgical repair of craniosynostosis: a randomized clinical trial.
Paediatr Anaesth 2015; 25(3):279-87
282. Zunini GS, Rando KA, Cox RG. Fluid replacement in craniofacial pediatric
surgery: normal saline or ringer’s lactate? J Craniofac Surg 2011; 22(4):1370-4
283. Nguyen C, Hernandez-Boussard T, Khosla RK, Curtin CM. A national
study on craniosynostosis surgical repair. Cleft Palate Craniofac J 2013;
50(5):555-60
284. Esparza J, Hinojosa J. Complications in the surgical treatment of
craniosynostosis and craniofacial syndromes: apropos of 306 transcranial
procedures. Childs Nerv Syst 2008; 24(12):1421-30
285. Tahiri Y, Paliga JT, Wes AM, Whitaker LA, Bartlett SP, Taylor JA.
Perioperative complications associated with intracranial procedures in patients
with nonsyndromic single-suture craniosynostosis. J Craniofac Surg 2015;
26(1):118-23
286. Goobie SM, Zurakowski D, Proctor MR, Meara JG, Meier PM, Young VJ
et al. Predictors of clinically significant postoperative events after open
craniosynostosis surgery. Anesthesiol 2015; 122(5):1021-32
287. Persing JA. MOC-PS(SM) CME article: management considerations in the
treatment of craniosynostosis. Plast Reconstr Surg 2008; 121(4 Suppl):1-11
288. Adamo MA, Pollack IF. A single-center experience with symptomatic
postoperative calvarial growth restriction after extended strip craniectomy for
sagittal craniosynostosis. J Neurosurg Pediatr 2010; 5(1):131-5
289. Cetas JS, Nasseri M, Saedi T, Kuang AA, Selden NR. Delayed intracranial
hypertension after cranial vault remodeling for nonsyndromic single-suture
synostosis. J Neurosurg Pediatr 2013; 11(6):661-6
290. Pollack IF, Losken HW, Biglan AW. Incidence of increased intracranial
pressure after early surgical treatment of syndromic craniosynostosis. Pediatr
Neurosurg 1996; 24(4):202-9
291. Thomas GP, Johnson D, Byren JC, Judge AD, Jayamohan J, Magdum SA
et al. The incidence of raised intracranial pressure in nonsyndromic sagittal
     76  

craniosynostosis following primary surgery. J Neurosurg Pediatr 2015;

15(4):350-60
292. Yeung LC, Cunningham ML, Allpress AL, Gruss JS, Ellenbogen RG, Zerr
DM. Surgical site infections after pediatric intracranial surgery for craniofacial
malformations: frequency and risk factors. Neurosurg 2005; 56(4):733-9
293. Katsuragi YT, Gomi A, Sunaga A, Miyazaki K, Kamochi H, Arai F et al.
Intracerebral foreign body granuloma caused by a resorbable plate with passive
intraosseous translocation after cranioplasty. J Neurosurg Pediatr 2013;
12(6):622-5
294. Greene AK, Mulliken JB, Proctor MR, Rogers GF. Pediatric cranioplasty
using particulate calvarial bone graft. Plast Reconstr Surg 2008; 122(2):563-71
295. Greene AK, Mulliken JB, Proctor MR, Rogers GF. Primary grafting with
autologous cranial particulate bone prevents osseous defects following fronto-
orbital advancement. Plast Reconstr Surg 2007; 120(6):1603-11
296. Weingart D, Bublitz R, Michilli R, Class D. Peri-osseous intracranial
translocation of titanium osteosynthesis plates and screws after fronto-orbital
advancement. Mund Kiefer Gesichtschir 2011; 5:57-60
297. Cooper GM, Curry C, Barbano TE, Burrows AM, Vecchione L,
Caccamese JF et al. Noggin inhibits postoperative resynostosis in
craniosynostotic rabbits. J Bone Miner Res 2007; 22(7):1046-54
298. Cooper GM, Usas A, Olshanski A, Mooney MP, Losee JE, Huard J. Ex vivo
Noggin gene therapy inhibits bone formation in a mouse model of postoperative
resynostosis. Plast Reconstr Surg 2009
299. Shukla V, Coumoul X, Wang RH, Kim HS, Deng CX. RNA interference and
inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a
mouse model of craniosynostosis. Nat Genet 2007; 39(9):1145-50
300. Ueno H, Gunn M, Dell K, Tseng A Jr, Williams L. A truncated form of
fibroblast growth factor receptor 1 inhibits signal transduction by multiple types
of fibroblast growth factor receptor
301. Greenwald JA, Mehrara BJ, Spector JA, Warren SM, Fagenholz PJ, Smith
LP et al. In vivo modulation of FGF biological activity alters cranial suture fate.
Am J Pathol 2001; 158(2):441-52
302. Opperman LA, Galanis V, Williams AR, Adab K. Transforming growth
factor-beta3 (Tgf-beta3) down-regulates Tgf-beta3 receptor type I (Tbetar-I)
     77  

during rescue of cranial sutures from osseous obliteration. Orthod Craniofac Res
2002; 5(1):5-16
303. Opperman LA, Adab K, Gakunga PT. Transforming growth factor-beta 2
and TGF-beta 3 regulate fetal rat cranial suture morphogenesis by regulating
rates of cell proliferation and apoptosis. Dev Dyn 2000; 219(2):237-47
304. Wall SA, Goldin JH, Hockley AD, Wake MJ, Poole MD, Briggs M. Fronto-
orbital re-operation in craniosynostosis. Br J Plast Surg 1994; 47:180-4
305. Panchal J, Marsh JL, Park TS, Kaufman B, Pilgram T. Photographic
assessment of head shape following sagittal synostosis surgery. Plast Reconstr
Surg 1999; 103(6):1585-91
306. Craniosynostosis [Internet]. FACES: The National Craniofacial Association.
2015 - [cited 2015 June 23]. Available from: http://www.faces-
cranio.org/Disord/Cranio.htm
307. Mossop CM, Rogers G, Boyajian M, Myseros JS, Keating RF. 124
Symptomatic recurrence following the open surgical repair of nonsyndromic
craniosynostosis: a 16 year experience. Neurosurg 2013; 60:161
308. Cohen SR, Burstein FD, Williams JK, Hudgins R, Boydston W, Simms C.
Outcome assessment in craniosynostosis: a prospective, statistical analysis of
reoperation rates.
309. Renier D, Lajeunie E, Arnaud E, Marchac D. Management of
craniosynostosis. Childs Nerv Syst 2000; 16(10-11):645-58
310. Thomas GP, Johnson D, Byren JC, Jayamohan J, Magdum SA, Richards
PG, Wall SA. Long-term morphological outcomes in nonsyndromic sagittal
craniosynostosis: a comparison of 2 techniques. J Craniofac Surg 2015;
26(1):19-25
311. Selber J, Reid RR, Gershman B, Sonnad SS, Sutton LN, Whitaker LA et al.
Evolution of operative techniques for the treatment of single-suture metopic
synostosis. Ann Plast Surg 2007; 59(1):6-13
312. Havlik RJ, Azurin DJ, Bartlett SP, Whitaker LA. Analysis and treatment of
severe trigonocephaly. Plast Reconstr Surg 1999; 103(2):381-90

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