Childs Nerv Syst (2014) 30:991–1000

DOI 10.1007/s00381-014-2411-x

REVIEW PAPER

Skull base embryology: a multidisciplinary review

Antonio Di Ieva & Emiliano Bruner & Thomas Haider &
Luigi F. Rodella & John M. Lee & Michael D. Cusimano &
Manfred Tschabitscher

Received: 11 March 2014 / Accepted: 25 March 2014 / Published online: 17 April 2014
# Springer-Verlag Berlin Heidelberg 2014

Abstract promises to expand our knowledge and enhance our ability to

Introduction The skull base represents a central and complex
bone structure of the skull and forms the floor of the cranial
cavity on which the brain lies. Anatomical knowledge of this
particular region is important for understanding several path-
ologic conditions as well as for planning surgical procedures.
Embryology of the cranial base is of great interest due to its
pronounced impact on the development of adjacent regions
including the brain, neck, and craniofacial skeleton.
Materials and methods Information from human and compar-
ative anatomy, anthropology, embryology, surgery, and com-
puted modelling was integrated to provide a perspective to
interpret skull base formation and variability within the cranial
functional and structural system.
Results and conclusions The skull base undergoes an elabo-
rate sequence of development stages and represents a key
player in skull, face and brain development. Furthering our
holistic understanding of the embryology of the skull base
A. Di Ieva (*) : M. D. Cusimano
Division of Neurosurgery, Department of Surgery, St. Michael’s
Hospital, University of Toronto, 30 Bond Street, Toronto, ON,
Canada M5B 1W8
e-mail: diieva@hotmail.com
A. Di Ieva : T. Haider : M. Tschabitscher
Centre for Anatomy and Cell Biology, Department of Systematic
Anatomy, Medical University of Vienna, Vienna, Austria
E. Bruner
Centro Nacional de Investigación sobre la Evolución Humana,
Burgos, Spain
L. F. Rodella : M. Tschabitscher
Department of Clinical and Experimental Sciences, University of
Brescia, Brescia, Italy
J. M. Lee
Department of Otolaryngology-Head and Neck Surgery, St.
Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
treat associated anomalies.
Keywords Anatomy . Comparative anatomy . Embryology .
Skull base . Encephalocele . Pharyngeal arches . Functional
craniology
Introduction
The skull base represents a central and complex bone structure
of the skull and forms the floor of the cranial cavity on which
the brain lies. Nerves and blood vessels cross skull base
foramina while the foramen magnum allows anatomical con-
tinuation between the spinal cord and the brain. Anatomical
knowledge of this particular region is important for under-
standing several pathologic conditions as well as for planning
surgical procedures. Embryology of the cranial base is of great
interest due to its pronounced impact on the development of
adjacent regions including the brain, neck and craniofacial
skeleton [1–9].
Anatomical synopsis of the skull base
Figure 1 shows the intracranial and exocranial surfaces of the
skull base. The intracranial portion of the skull base can be
divided into three parts: the anterior, the middle and the
posterior cranial fossa. Two paired frontal bones, the sphenoid
and ethmoid bone give rise to the anterior cranial fossa bearing
the ventral part of the frontal lobe (orbital gyri). The frontal
bone originates from two symmetric bones after fusion of the
metopic suture forming the main portion of this fossa and the
roof of both orbits [10]. The cribriform plate of the ethmoid
bone is located between the two frontal bones and
allows connection between the olfactory filiae and the nasal
992
Fig. 1 Intracranial (left) and exocranial (right) surfaces of the mature
skull base
cavity. Anteriorly, the ethmoid bone also comprises the crista
galli, an anchor for the falx cerebri. While the lesser wing of
the sphenoid bone marks the dorsal boundary of the anterior
cranial fossa, the body and greater wing represent the ventral
and lateral part of the middle cranial fossa. Also the squamous
part of the temporal bone and the parietal bone form the lateral
border of the middle fossa. In the middle of this fossa, a
prominent concave structure is arranged, the sella turcica,
containing the hypophysis and building the roof of the sphe-
noidal sinus. The cavernous sinus is located to both sides of
the sella, comprising important structures. The internal carotid
artery passes through the cavernous sinus in an S-shaped
manner forming the so-called carotid siphon. Branches from
this part of the internal carotid artery supply the hypophysis,
part of the dura mater, the optic chiasm, the sixth nerve and the
trigeminal ganglion [11]. Also the abducens nerve proceeds
straight through the cavernous sinus, while the maxillary,
ophthalmic, trochlear and oculomotor nerves run within the
lateral wall [12]. The maxillary nerve originates from the
trigeminal ganglion (ganglion Gasseri) where the nerve breaks
down into its three branches, the ophthalmic, the maxillary
and the mandibular nerve located within a duplication of dura
called trigeminal or Meckel’s cave. Foramina in the middle
cranial fossa allow passage towards the viscerocranium,
namely the superior orbital fissure for the ophthalmic nerve,
the foramen rotundum for the maxillary nerve and the foramen
ovale for the mandibular nerve. A variant “oval canal” has
been described, where an osseous lamina continuous with the
pterygoid plate canopies the foramen ovale [13]. The temporal
lobe is located within the middle cranial fossa supporting its
distinct shape. The posterior aspect of the sella turcica, the
dorsum sellae, the posterior part of the sphenoid bone and the
basilar part of the occipital bone represent the anterior border
of the posterior cranial fossa. Both also contribute to the
formation of the clivus, a sloped bone structure on which the
Childs Nerv Syst (2014) 30:991–1000
abducens nerve runs upwards to the cavernous sinus. After its
extradural course the sixth nerve first enters the
sphenopetroclival venous gulf to reach Dorello’s canal located
below the ligament of Gruber and finally passes through the
cavernous sinus. [14]. The posterior fossa is bounded laterally
by the temporal and the occipital bone and behind and above
by the parietal bone. It is the largest cranial fossa and contains
the cerebellum, pons and medulla oblongata and allows con-
nection to the cervical spinal cord through the foramen mag-
num [15]. Further important foramina within this fossa are the
internal acoustic canal, the vestibular aqueduct and the jugular
foramen containing the glossopharyngeal, the vagus and
the accessory nerve as well as the internal jugular vein
[15, 16].
The inferior (exocranial) surface of the skull base is not
divided in three compartments and needs to be described
separately. Besides the largest portion, the palatine process
of the maxilla, the zygomatic process of the maxilla and the
palatine bone represent the anterior external part. The middle
part of the cranial base comprises the body of the sphenoid,
the petrous part of temporal bones and the basiocciput and
extends to a virtual transverse line dividing the foramen mag-
num. The bones of the posterior part of the external skull base
correspond with the intracranial posterior cranial fossa with its
prominent occipital bone. Most prominent structures are the
foramen magnum and the occipital condyles connecting the
skull to the cervical spine [15]. Variants of occipital condyles
have been described, such as appearance of a third condyle
with occasional articulation with the dens axis, and a rare
variant of duplicated occipital condyles [2, 17–19].
Embryologic aspect of the skull base
Pharyngeal arches
Development of the vertebrate head require the formation of
the neural crest, which represents the origin for connective and
skeletal tissue of the neck, face and skull [8]. In contrast to
trunk neural crest cells, cranial neural crest cells migrate
before neural folds fuse to form the neural tube, which is not
the case for the cranial crest in non-mammalian vertebrates [8,
20]. The rostral population of neural crest cells is the major
contributor to skull formation being the origin of the whole
viscerocranium and the rostral part of the neurocranium [8, 9].
In adolescents, the coronal suture between the frontal and the
parietal bones marks the boundary between neural crest and
cranial mesoderm origin [10, 20]. Gradual migration of neural
crest cells around the embryonic pharynx leads to formation of
five pairs of embryonic arches, each containing epithelial
covered ecto- and endoderm as well as mesenchyme originat-
ing mainly from the neural crest. Neural crest cells of the first
two arches contribute to cranial skeletal elements with
Childs Nerv Syst (2014) 30:991–1000
associated connective tissue. Condensation of neural crest-
derived mesenchyme leads to sub-sequential chondrification.
After completion of chondrogenesis, dorsal extension con-
tinues until it reaches the cranial base located laterally to the
hindbrain. Arch cartilage undergoes endochondral ossifica-
tion, ligamentous ossification, and a combination of both or
remains cartilage [8]. Most parts of the skull vault and face
undergo intramembranous ossification through mesenchymal
condensation while endochondral ossification of the skull
base is predominant [8, 9, 15, 21].
Figure 2 shows the cranial view of the skull base during
12th week of fetal development.
Chondrocranium
The first skeletal structures to differentiate are cartilages of the
skull base, the sensory capsules, the viscerocranium and the
occipital bone. Development of the cranial base is regulated
by a variety of genes like genes from the Dickkopf family,
matrix metallopeptidase 9, Indian hedgehog and Sonic hedge-
hog (Shh) [22–26]. It has been stated that skull base chondro-
genesis compared to chondrogenesis of the axial skeleton is
delayed during embryological development due to its unre-
sponsiveness to Shh signaling [25]. Both mesoderm and ec-
toderm represent tissue origins for the development of the
cranial base [8, 25, 27]. Neural crest derived cells contribute
to development of parts anterior to the notochord while the
posterior skull base originates from mesoderm [8, 25, 27, 28].
Interestingly, cartilage development through mesenchymal
condensation takes place after cranial nerves and blood ves-
sels have developed resulting in a specific location of skull
Fig. 2 Cranial view of the skull
base during 12th week of fetal
development
Foramen magnum
Jugular foramen
Hypoglossal canal
Internal auditory meatus
Trigeminal passage
Carotid foramen
Sup. orbital fisssure
Optic canal
Cribriform plate
993
base foramina before bones are formed [8]. Defective devel-
opment of the cranial base has been described to be associated
with anencephaly underlining its importance in development
of the whole skull and brain [4]. The rostral tip of the noto-
chord (chorda dorsalis) reaches a location caudal to the hy-
pophysis and represents the start of the development of the
cranial base. This part of the notochord is rich in sulphated
glycosaminoglycans inducing condensation and chon-
drification of adjacent occipital sclerotome-derived
mesenchemye. This leads to the formation of the parachordal
cartilage, which by week 7 forms the basioccipital element of
the occipital bone and therefore the occipital part of the
foramen magnum. Before reaching the prechordal plate, the
notochord makes contact with the endoderm of the primitive
pharynx followed by formation of the pharyngeal
(Tornwaldt’s) bursa [29–31]. Its possible relationship to the
adjacent variable fossa navicularis has been described previ-
ously [29]. Exooccipital components chondrify thereafter and
build the rostral boundary of the foramen magnum. Deduced
from the observation on somitic contribution to its develop-
ment it is believed that the occipital bone represents a vertebral
element that has expanded to support the brain [25, 27, 28,
32–34]. Variant forms of occipital condyles have been de-
scribed as mentioned before. Hayek proposed in 1924 that a
tertiary condyle is the result of incomplete regression of the
proatlas, a hypochordal plate needed for proper development
of the occipital bone and its condyles and usually disappears
during development [35, 36]. Variant proatlas development
can furthermore lead to hypoplastic condyles and occipital
encephaloceles causing problems in the craniovertebral junc-
tion [36, 37] Below the occipital bone, deficient differentiation
Supraoccipital cartilage
Occipital bone
Meckel`s cartilage
Dorsum sellae
Parietal cartilage
Sphenoid bone
Frontal cartilage
Ethmoid bone
Nasal bone
994
can lead to ossification of the atlanto–occipital joint, a so-
called “occipitalization” of the atlas bone [38, 39]. Also intra-
cranial manifestation of the atlas has been described, where a
prominent structure broadens the margin of the foramen mag-
num [40]. Between the parachordal and the exooccipital car-
tilages, roots of the hypoglossal nerve are localized leading to
the hypoglossal canal after fusion. Rostrally, ongoing differ-
entiation leads to development of the hypophysial cartilages
located on each side of the hypophysial pouch followed by
merging of the median plane to form the primordium of the
postsphenoid around the hypophysial stalk. During formation
of skull base cartilage, the adenohypophysial pouch remains
connected to the roof of the oral cavity (Rathke’s pouch) until
further differentiation leads to closure and the formation of the
sella turcica with its hypophysial fossa [15]. In rare cases this
perforation persists, leading to formation of the
craniopharyngeal canal [41, 42]. The presphenoid cartilages,
the cartilaginous basis for the jugum of the sphenoid body,
differentiate last within the medial aspect of the cranial base
and bridge the gap between the postsphenoid and the cartilag-
inous nasal capsule, which is already well developed by the
third month of fetal development. A transient opening in the
anterior skull base anterior to the crista galli, the foramen
cecum, allows dura to pass through toward the prenasal space
located inferoposterior to the nasal bones and anterosuperior
to the nasal cartilage. A temporary fontanelle, the fonticulus
frontalis, divides the inferior frontal bone from nasal bone
[43]. These transitory spaces (foramen cecum, prenasal space
and fonticulus frontalis) regress during physiological devel-
opment. Incomplete involution cause different pathologies as
discussed later in this article. The nasal conchae ossify during
the fifth month and become part of the ethmoid bone (superi-
or/middle concha) or form a separate bone (inferior concha),
while the ossification of lateral parts of the nasal capsule
creates the orbital plate and the ethmoidal labyrinth. The rest
of the nasal capsule undergoes intramembranous ossification
(vomer, nasal bones) or remains cartilaginous (septum, alae)
[8, 15]. Ossification of the orbit excludes the most rostral part,
which forms a cartilaginous bridge to become continuous with
the presphenoid cartilage representing the caudal boundary of
the optic foramen and consequently enclosing the optic nerve.
Later, this bridge ossifies and becomes the lesser wing of the
sphenoid bone. Around the otocyst, mesenchymal condensa-
tion leads to formation of the cochlea and semicircular canals
followed by chondrogenesis around the vestibulocochlear
nerve to create the internal acoustic meatus. Adjacent chon-
drogenesis around the carotid arteries forms the carotid canals.
Passage of the jugular vein is sustained by differentiation of
parachordal cartilage around the vein to build up the jugular
foramen [8, 15, 21].
Ongoing chondrogenesis of mesenchyme connects sepa-
rate cartilages and forms a continuous framework after
9 weeks of fetal development [15]. Skeletogenesis and
Childs Nerv Syst (2014) 30:991–1000
apoptosis are important during the final process of skull de-
velopment and were shown to be regulated mainly by MMP-9
and genes from the Dickkopf (Dkk) family [22]. During week
5 of embryological development, ossification is initiated [44].
Various results considering the location of initiation of ossifi-
cation have been reported ranging from the region surround-
ing the Rathke’s pouch to areas tangent to neural structures
such as nerves [21, 44, 45]. Bilateral symmetry of ossification
is regulated by the centrally localized chordal cartilage pro-
ducing chordin, a regulator of bone morphogenetic protein 7
(BMP-7) [21]. In rare cases, fibrous dysplasia alters ossifica-
tion of the skull resulting in replacement of the bone structure
with fibrous tissue [46, 47].
Because of its central position and regulation of adjacent
differentiation during ongoing craniofacial development,
malformations like craniosynostosis will most commonly
manifest within the spheno-occipital synchondrosis [48].
Physiologically, this synchondrosis closes between the age
of 13 and 18 [49].
The skull base in vertebrates
The cranial base has important integrative and functional roles
in the skull, many of which reflect its phylogenetic history
[50]. The shape of the cranial base is therefore a multifactorial
product of numerous phylogenetic, developmental, and func-
tional interactions.
In their New Head Hypothesis (NHH), Gans and Northcutt
[51] proposed that vertebrates evolved by adding a “new
head” rostral to the notochord, made of ectodermally derived
sense organs and nervous structures, to aid in predatory be-
haviour. Subsequent work described this building of a new
head as including, among other things, an “anterior extension
of the connective tissues providing a connection among the
sensory capsules” and specifically posited that these rostral
connective tissues are neomorphic, developing from neural-
crest derived mesenchyme. The NHH predicts that the
prechordal–chordal boundary should be coincident with the
neural crest–mesoderm boundary and that connective tissues
of the prechordal head, including bone and cartilage, should
be derived from the neural crest. So far, the skeletal and
connective tissues of the rostral cranium, from fishes to mam-
malian, have been shown to be derived from the neural crest
while cranial muscles are derived from prechordal and cephal-
ic paraxial mesoderm [52, 53]. Anatomically, the cranial base
represents the most inferior area of the skull, composed of the
endocranium and lower parts of the skull roof. The
endocranium shows several differences among different clas-
ses of animals. We generally observe a reduction in the num-
ber of bones that constitute the skull base. This reduction is
accompanied by a specialization of maxillofacial skeleton.
Childs Nerv Syst (2014) 30:991–1000
The endocranium of fishes is composed of the neuro-
cranium, the jaws (or mandibular arch), the hyoid arch
and the branchial arches. In some fishes, like jawless fish and
sharks, the endocranium is cartilaginous (Chondrichthyes),
with both the upper and lower jaws being separate elements.
In other fishes (Osteichthyes), the endocranium is ossified. As
the name implies, the endocranium encases the brain and
further houses nerves and blood vessels. The neurocranium
also contains the paired sensory organs: paired nasal capsules
at the anterior, paired orbital capsules (or eye) behind those
and paired otic (or ear) capsules posterior to the orbital
capsules.
In amphibians, of the 11 bones comprising the
neurocranium, only four, the parasphenoid, the basioccipital,
the paired epipterygoids and the stapes, are distinct and un-
fused [53]. The other bones, however, are inseparably united
to others to form two larger bony units, which are delimited by
sutures externally, but are confluent on their endocranial faces.
The lateral sphenoids, which had not been recognized previ-
ously, are evident as plates, which extend from the
basisphenoid region to the roof of the skull, and from the
trigeminal nerve foramina to the rostral part of the basi-
sphenoid (optic nerve region). The other mass of bone is
placed posteriorly and consists of the exoccipitals,
paroccipitals, prootics and the supraoccipital. These elements
house the internal ear and cover the upper and lateral parts of
the brain stem. Save for the exoccipital, whose external limits
are marked by suture lines, these elements are fused entirely to
one another.
Reptilian skull base is similar to that of mammals and
includes the ethmoid, the sphenoid, the temporal and the
occipital bones. Reptiles possess an extensively chondrified
endocranium composed of parachordal cartilage and broad
orbital cartilage that directly surrounds the neural tube [54].
The basisphenoid and parasphenoid are fused, except at the
anterior end of the basisphenoid dorsally, where a slight
separation is present in the region of the trabecular attachment
to the basisphenoid. The tip of the cultriform process of the
parasphenoid is sutured anteriorly to the pterygoids, and the
process extends posteriorly between the interpterygoid vacu-
ities. At this point the cultriform process bears a ventral keel,
and in the region between the prominent internal carotid
foramina, it expands and bears five small teeth on a roughened
area. From this area, the wings of the parasphenoid expand
and pass back over the basioccipital in a squamous suture, the
full extent of which is obscured by breakage. There is a small
gap between the basioccipital and basisphenoid (known as
unossified region), which was undoubtedly filled with carti-
lage. The basioccipital is a hexagonal bone and bears paired
oval depressions on the ventral surface. The otic region shows
a fenestra ovalis. Posteriorly, the fenestra ovalis is confluent
with the jugular foramen. Anterior to the fenestra ovalis, a
deep recess is present in the skull base. It is formed principally
995
in the basioccipital, except for its anterolateral and posterolat-
eral corners. The jugular foramina are large, formed between
the exoccipital and opisthotic, and on their concave
posteromedial borders, a pair of small foramina are present.
These are confluent with the condylar canal for the passage of
the hypoglossal nerves.
In birds, the cranial base extends caudal to the optic nerve
and includes basioccipital and pre-sphenoid bones which de-
rive from mesoderm. It has different lengths among birds
resulting in neurocranial differences [55]. The ventral convex-
ity of the cranial base in avians would be topologically equiv-
alent to the retroflexion of the rats cranial base. Moreover, the
anterior portion of the avian cranial base does not ossify in
many avians, whereas in mammals this region of the cranial
base is always ossified. There is a recent hypothesis of an
additional bone, namely the intra-parietal located between
the parietal and the supraoccipital bones. Birds with greater flight
mobility have a much more rounded cranial architecture [56].
The endocranium in mammals is reduced in relative size
and number of bones compared to the condition in the ances-
tral land vertebrates [8]. The mouse has became a popular
model organism for studies of craniofacial development. In
adult mice the cranial base is composed of the ethmoid,
presphenoid, basisphenoid and basioccipital bones along with
the auditory capsules of the temporal bones. In mammals, all
four occipital elements typically fuse to form a single occipital
bone.
The skull base in anthropology and functional craniology
Cranial base has been always a major topic in anthropology
and evolution. In his famous book, Evidence as to Man’s Place
in Nature (1863), Thomas Henry Huxley [57] introduced the
importance of the cranial base suggesting pioneering geomet-
ric models to investigate the differences among human popu-
lations (Fig. 3). Because of its role as interface between vault,
face, and body, the cranial base morphology has always
represented a debated issue in evolutionary biology. Despite
the attention dedicated to its anatomy and variations, few
agreements have been achieved concerning its role in human
evolution, mostly because of its complex structure and multi-
ple functional factors involved in its morphology. The limited
information we have also on the current human populations
for many epigenetic traits like sutures, foramina, and anatom-
ical variants of the endocranial characters, further hampers a
proper knowledge of the cranial base dynamics [58].
The cranial base anatomy is a major determinant of the
cranial architecture in primates, and a major constrain of the
overall cranial form [7, 59]. During human evolution, cranial
base morphology has been deeply influenced by both facial
and brain variations [60, 61]. The flexion of the cranial base
has been hypothesized to be a relevant factor in the
encephalization process associated with human evolution,
996
Fig. 3 In 1863, Thomas Huxley demonstrated the importance of the
cranial base as major determinant of the cranial architecture. He used
geometrical models and cranial base superimposition to compare human
groups, stressing that future development of these techniques will be
necessary to understand the complex organization of the cranial anatomy
because of its role in spatial packing of the brain mass.
Nonetheless, there are major disagreements in this sense,
mostly because of difficulties in quantitative and comparative
approaches when dealing with homology and anatomical
references [62, 63]. In terms of ontogenetic changes, the
flexion of the cranial base is almost completed at the second
year [64]. However, the morphogenesis of this area is ex-
tremely complex, not linear, and formed by stages of flexion
and retro-flexion [6, 65]. Such morphogenetic complexity
generates operational problems in terms of developing com-
parative studies among primates.
An important biomechanical interaction within the face is
represented by the ethmo–maxillary complex [66]. The cranial
base matures earlier than the facial block, and in this sense it
constraints the following splanchnocranial morphogenesis
[67]. On the other hand, the structural relationships between
endocranial base and vault are probably influenced by the
redistribution of growth forces exerted by meningeal tensors
like the falx cerebri and tentorium cerebelli [68]. It has been
Childs Nerv Syst (2014) 30:991–1000
hypothesized that dismorphologies and craniosynostosis are
actually the result of morphogenetic imbalance between the
cranial base and such connective tensors [69].
The constraints associated with the cranial base produced
some co-evolution between its traits and characters, and it has
been hence interpreted as an evolutionary anatomical unit
[70]. Nonetheless, because of the multifactorial influences,
at evolutionary and ontogenetic levels, in functions as well
as in structural relationships, the cranial base cannot be
regarded as an integrated morphological unit. As a matter of
fact, at least considering the modern human variation, the
three endocranial fossae display a scarce reciprocal integration
in terms of morphology [71]. Similarly, the midsagittal ele-
ments display a scarce integration with the lateral elements
[72]. Such limited integration within the components of the
cranial base is the result of the multiple and independent
influences of the other cranial districts on the morphology of
the cranial fossae. Low integration practically means that
every part has a relatively independent morphogenesis and
common patterns influencing the whole cranial base are weak.
Thus, the morphology of a specific area of the cranial base is
not informative on the possible morphology of other areas,
because its morphogenesis is not channelled through few
global processes, but rather moulded by many local influ-
ences. The anterior fossa is strongly constrained by the orbital
and upper face structures [66, 73, 74]. The morphology of the
middle fossa is associated with the mandibular anatomy and
biomechanics [72]. The posterior fossa is sensitive to the
parieto–occipital integration schemes and by the cerebro-
cerebellar dynamics [75, 76]. Apart from these specific cranial
interactions, the cranial base is also largely influenced by other
functional components like speech (phonation system) or
posture (head position and balancing). This multifactorial
system, in terms of evolutionary patterns, has generated mo-
saic changes in the different hominid lineages, instead of
linear, homogeneous, or gradual variations [77].
As predicted by Huxley, biostatistics has now developed
further his geometrical models by using computer science
both to investigate anatomy (digital anatomy and biomedical
imaging) and to analyze its variation (geometric morphomet-
rics) [78]. Such techniques have been soon applied to evaluate
cranial integration in ontogeny and evolution [79]. In shape
analysis, geometric coordinates are superimposed as to mini-
mize shape differences, and then the correlation between the
coordinate variation is analyzed through multivariate statistics
and functions for spatial interpolation [80–82]. If we analyze
the endocranial base in adult humans by this way, we can
recognize and quantify the underlying relationships associated
with the observed morphological variability (Fig. 4) [71]. As
mentioned, the morphological integration of the endocranial
base is poor and there are no strong correlation patterns
characterizing the overall phenotypic differences. However,
the structure of the shape variation displays two main patterns,
Childs Nerv Syst (2014) 30:991–1000 997

which, despite their limited strength, must be intended as the
principal vectors of variability. Considering the endocranial
view in two dimensions, the first component is associated with
widening and enlargement of the temples and shortening of
the posterior fossa. The second component is associated with
antero-posterior shortening of the temples and lengthening of
the middle fossa. In lateral projection, the first component is
associated with flexion of the cranial base, stretching of the
sphenoid and shortening of the posterior fossa. The second
component is associated with flattening of the cranial
base and stretching of the sphenoid. If we analyze the
whole structure in three dimensions, the first component
is associated with narrowing and heightening of the
endocranial base, while the second component is linked
to reduction of the posterior fossa with heightening and
flexion of the cranial base. Of the whole transformation,
these two 3D components explain 15 % and 12 % respec-
tively. Hence, together they account only for the 27 %
of the variability, while the rest of the variance associ-
ated with other minor scattered patterns.
The limited integration involves also a scarce influence of
size: in adults, dimensions have a limited influence on
endocranial shape. Males are generally larger than females,
and sexual differences are generally related to this minor
allometric component: men use to have relatively shorter
anterior fossa and longer and taller sphenoid. It is worth noting
that in all these analyses the median elements (foramina, sella,
petrous apex) display a remarkable stability in their spatial
position.
Skull base embryology: clinical implications for congenital
defects of the anterior skull base
Congenital defects of the skull base are rare anomalies that can
result from altered embryogenesis and has significant clinical
implications in the pediatric population. As it has been
discussed in this paper, formation of the skull base and facial
skeleton results from a complex interaction of cellular prolif-
eration and regression involving migration of neural crest cells

Fig. 4 The endocranial variation

in adult humans can be analysed
by using a system of geometric
coordinates to evidence the main
spatial patterns generating the
phenotypic variability. Color
maps show such patterns (PC1
and PC2: first and second
principal components of
variation) in upper and lateral 2D
projections, on deformation grids
based on a thin-plate spline
interpolation functions (red:
dilation; blues: compression).
Wireframes show the same
patterns in 3D (upper and lateral
views), and the mean differences
between males (blue links) and
females. Models have been
symmetrized. Data after Bruner
and Ripani [71] computed with
PAST 2.14 (http://nhm2.uio.no/
norlex/past/download.html), and
MorphoJ 1.05f (http://www.
flywings.org.uk/MorphoJ_guide/
frameset.htm?changelog.htm)
998
through ectodermal and mesodermal derived structures.
Anteriorly, as the frontal bone, nasal bone, ethmoid bone
and nasal capsule fuse, potential spaces are created which
normally regress by birth. Persistence of these spaces includ-
ing the fonticulus nasofrontalis (region between frontal and
nasal bones), pre-nasal space (region between nasal bones and
nasal capsule) and the foramen cecum (region between frontal
and ethmoid bone) may lead to the herniation of intracranial
contents or glial tissue forming either encephaloceles or glio-
mas. Alternatively, ectodermal and mesodermal tissue may be
entrapped in these spaces, which lead to the formation of
dermoids.
From a clinical standpoint, dermoids are the most common
midline congenital nasal mass and can present as a non-
pulsatile cyst, sinus or fistula on the external nose. Because
of its embryologic origins, 30 % of dermoids can communi-
cate with the dura and proper imaging is required to determine
their exact attachment site. On the other hand, gliomas repre-
sent herniated glial tissue along the skull base and facial
skeleton fusion planes but do not have any communication
with the cerebrospinal fluid (CSF). As such, they also present
clinically as non-pulsatile masses and can be either extranasal
(60 %), intranasal (30 %), or combined (10 %). Furthermore,
up to 15 % of gliomas can have attachments to the dura [83].
Encephaloceles are by definition a herniation of brain
tissue that maintains a connection to the subarachnoid space
that contains CSF. If the tissue also contains meninges, they
are referred to as meningoencephaloceles. Traditionally,
encephaloceles have been classified as being either occipital,
sincipital, or basal [84]. In North America and Europe, occip-
ital encephaloceles are the most common and are often asso-
ciated with other congenital disorders. They can vary in size
but can be large enough to involve the foramen magnum and
be associated with microcephaly. Sincipital encephaloceles
refer to encephaloceles which are visible on the face. They
occur either at or anterior to the foramen cecum, a small
foramina located in the frontal–ethmoidal suture between the
frontal bone and the crista galli of the ethmoid bone [85].
These malformations typically extend to the facial skeleton
and can be further subclassified as being either interfrontal,
nasofrontal, naso-ethmoidal, or naso-orbital depending on its
exit point [86]. Clinically, these lesions may present as pulsa-
tile masses of variable size which can cause significant facial
deformities. Finally, basal encephaloceles refer to defects and
herniations isolated solely to the skull base and thus are not
visible on the face. Instead, the intracranial contents extend
intranasally and patients can present clinically with symptoms
of nasal obstruction, CSF rhinorrhea or even meningitis.
Based on the anatomical location along the skull base, basal
encephaloceles have been classified as being either
transethmoidal (with or without involvement of the foramen
cecum), spheno-ethmoidal, sphenomaxillary, spheno-orbital,
trans-sphenoidal, and transtemporal. Surgical management of
Childs Nerv Syst (2014) 30:991–1000
all encephaloceles involves removing the herniated brain tis-
sue and reconstructing the bony defect. Ultimately, this re-
quires an intimate knowledge of the embryologic origins of
the skull base anatomy.
Conclusion
Being one of the most complex bones known, the skull base
undergoes an elaborate sequence of development stages and
represents a key player in skull, face and brain development as
discussed in this review paper. Achieving its distinct form was
obligatory in human evolution allowing encephalisation and
brain augmentation. Its intricate anatomical properties togeth-
er with the extensive interplay during embryologic develop-
ment with adjacent regions pose a great challenge for holistic
understanding of the skull base. Rapidly increasing knowl-
edge of its embryological development formed the corner-
stone of understanding different skull base pathologies and
its underlying pathophysiology, ultimately improving surgical
treatment.
References
1. Ross C, Henneberg M (1995) Basicranial flexion, relative brain size,
and facial kyphosis in Homo sapiens and some fossil hominids. Am J
Phys Anthropol 98:575–593
2. Tubbs RS, Salter EG, Oakes WJ (2005) Duplication of the occipital
condyles. Clin Anat 18:92–95
3. Ross CF, Ravosa MJ (1993) Basicranial flexion, relative brain size,
and facial kyphosis in nonhuman primates. Am J Phys Anthropol 91:
305–324
4. Lomholt JF, Fischer-Hansen B, Keeling JW, Reintoft I, Kjaer I (2004)
Subclassification of anencephalic human fetuses according to mor-
phology of the posterior cranial fossa. Pediatr Dev Pathol 7:601–606
5. Jeffery N (2005) Cranial base angulation and growth of the human
fetal pharynx. Anat Rec A: Discov Mol Cell Evol Biol 284:491–499
6. Jeffery N, Spoor F (2002) Brain size and the human cranial base: a
prenatal perspective. Am J Phys Anthropol 118:324–340
7. Lieberman DE, Ross CF, Ravosa MJ (2000) The primate cranial
base: ontogeny, function, and integration. Am J Phys Anthropol
Suppl 31:117–169
8. McBratney-Owen B, Iseki S, Bamforth SD, Olsen BR, Morriss-Kay
GM (2008) Development and tissue origins of the mammalian cranial
base. Dev Biol 322:121–132
9. Nie X (2005) Cranial base in craniofacial development: developmen-
tal features, influence on facial growth, anomaly, and molecular basis.
Acta Odontol Scand 63:127–135
10. Di Ieva A, Bruner E, Davidson J, Pisano P, Haider T, Stone SS,
Cusimano MD, Tschabitscher M, Grizzi F (2013) Cranial sutures: a
multidisciplinary review. Childs Nerv Syst 29:893–905
11. Iaconetta G, Fusco M, Cavallo LM, Cappabianca P, Samii M,
Tschabitscher M (2007) The abducens nerve: microanatomic and
endoscopic study. Neurosurgery 61:7–14, discussion 14
12. Harris FS, Rhoton AL (1976) Anatomy of the cavernous sinus. A
microsurgical study. J Neurosurg 45:169–180
Childs Nerv Syst (2014) 30:991–1000
13. Skrzat J, Walocha J, Srodek R, Nizankowska A (2006) An atypical
position of the foramen ovale. Folia Morphol 65:396–399
14. Umansky F, Elidan J, Valarezo A (1991) Dorello’s canal: a microan-
atomical study. J Neurosurg 75:294–298
15. Standring S (2008) GRAY’S anatomy — the anatomical basis of
clinical practice. Churchill Livingstone Elsevier, Edinburgh
16. Lam A, Holbrook E (2013) Skull base anatomy and CSF rhinorrhea.
Adv Oto-Rhino-Laryngol 74:1–11
17. Koblmüller L (1934) A case of condylus tertius. Anat Anz 71:305–
352
18. Allen W (1880) On tertiary occipital condyle. J Anat Physiol 15:60–
68
19. Bolk L (1921) Different forms and origniation of Condylus tertius.
Anat Anz 54
20. Jiang X, Iseki S, Maxson RE, Sucov HM, Morriss-Kay GM (2002)
Tissue origins and interactions in the mammalian skull vault. Dev
Biol 241:106–116
21. Santaolalla-Montoya F, Martinez-Ibarguen A, Sanchez-Fernandez
JM, Sanchez-del-Rey A (2012) Principles of cranial base ossification
in humans and rats. Acta Oto-Laryngol 132:349–354
22. Nie X, Luukko K, Fjeld K, Kvinnsland IH, Kettunen P (2005)
Developmental expression of Dkk1-3 and Mmp9 and apoptosis in
cranial base of mice. J Mol Histol 36:419–426
23. Young B, Minugh-Purvis N, Shimo T, St-Jacques B, Iwamoto M,
Enomoto-Iwamoto M, Koyama E, Pacifici M (2006) Indian and
sonic hedgehogs regulate synchondrosis growth plate and cranial
base development and function. Dev Biol 299:272–282
24. Riccomagno MM, Martinu L, Mulheisen M, Wu DK, Epstein DJ
(2002) Specification of the mammalian cochlea is dependent on
Sonic hedgehog. Genes Dev 16:2365–2378
25. Balczerski B, Zakaria S, Tucker AS, Borycki AG, Koyama E,
Pacifici M, Francis-West P (2012) Distinct spatiotemporal roles of
hedgehog signalling during chick and mouse cranial base and axial
skeleton development. Dev Biol 371:203–214
26. Nie X, Luukko K, Kvinnsland IH, Kettunen P (2005)
Developmentally regulated expression of Shh and Ihh in the devel-
oping mouse cranial base: comparison with Sox9 expression. Anat
Rec A: Discov Mol Cell Evol Biol 286:891–898
27. Couly GF, Coltey PM, Le Douarin NM (1993) The triple origin of
skull in higher vertebrates: a study in quail-chick chimeras.
Development 117:409–429
28. Evans DJ, Noden DM (2006) Spatial relations between avian cranio-
facial neural crest and paraxial mesoderm cells. Dev Dyn 235:1310–
1325
29. Cankal F, Ugur HC, Tekdemir I, Elhan A, Karahan T, Sevim A
(2004) Fossa navicularis: anatomic variation at the skull base. Clin
Anat 17:118–122
30. Miller RH, Sneed WF (1985) Tornwaldt’s bursa. Clin Otolaryngol
Allied Sci 10:21–25
31. Miyahara H, Matsunaga T (1994) Tornwaldt’s disease. Acta
Otolaryngol Suppl 517:36–39
32. Couly GF, Coltey PM, Le Douarin NM (1992) The developmental
fate of the cephalic mesoderm in quail-chick chimeras. Development
114:1–15
33. Muller F, O'Rahilly R (1994) Occipitocervical segmentation in staged
human embryos. J Anat 185(Pt 2):251–258
34. Kuratani S (2005) Craniofacial development and the evolution of the
vertebrates: the old problems on a new background. Zool Sci 22:1–19
35. Hayek H (1927) Analyses of the proatlas, epistropheus, atlas and
occipital bone. Morph Jahrb 58
36. Tubbs RS, Lingo PR, Mortazavi MM, Cohen-Gadol AA (2013)
Hypoplastic occipital condyle and third occipital condyle: review of
their dysembryology. Clin Anat 26:928–932
37. Nath HD, Mahapatra AK, Gunawat P (2012) A torcular
encephalocele with proatlas defect and os-terminale. Asian J
Neurosurg 7:84–86
999
38. Jacquement (1850) Abnormal articulation of occiput and axis. Bull
Soc Anat Paris 25:49
39. Al-Motabagani MA, Surendra M (2006) Total occipitalization of the
atlas. Anat Sci Int 81:173–180
40. Sauser G (1934) Intracranial Manifestation of the last occipital ver-
tebra. Sonderdruck Zeitschr Anat Entwicklungsgeschichte 104
41. Arey LB (1950) The craniopharyngeal canal reviewed and
reinterpreted. Anat Rec 106:1–16
42. Currarino G, Maravilla KR, Salyer KE (1985) Transsphenoidal canal
(large craniopharyngeal canal) and its pathologic implications. AJNR
Am J Neuroradiol 6:39–43
43. Hedlund G (2006) Congenital frontonasal masses: developmental
anatomy, malformations, and MR imaging. Pediatr Radiol 36:647–
662, quiz 726–647
44. Vermeij-Keers C (1990) Craniofacial embryology and morphogene-
sis: normal and abnormal. Churchill Livingstone, Edinburgh
45. Stricker M, Van der Meulen J, Raphael B, Mazzola R (1990)
Craniofacial growth and development. Churchill Livingstone,
Edinburgh
46. Davies ML, Macpherson P (1991) Fibrous dysplasia of the skull:
disease activity in relation to age. Br J Radiol 64:576–579
47. Bowers CA, Taussky P, Couldwell WT (2014) Surgical treatment of
craniofacial fibrous dysplasia in adults. Neurosurg Rev 37:47–53
48. Smartt JM Jr, Karmacharya J, Gannon FH, Teixeira C, Mansfield K,
Hunenko O, Shapiro IM, Kirschner RE (2005) Intrauterine fetal
constraint induces chondrocyte apoptosis and premature ossification
of the cranial base. Plast Reconstr Surg 116:1363–1369
49. Scheuer L (2002) Application of osteology to forensic medicine. Clin
Anat 15:297–312
50. De Beer G (1937) The development of the vertebrates skull.
Clarendon Press, Oxford
51. Gans C, Northcutt RG (1983) Neural crest and the origin of verte-
brates: a new head. Science 220:268–273
52. Noden DM (1978) The control of avian cephalic neural crest cyto-
differentiation: I. Skeletal and connective tissues. Dev Biol 67:296–
312
53. Hanken J, Gross JB (2005) Evolution of cranial development and the
role of neural crest: insights from amphibians. J Anat 207:437–446
54. Kuratani S (1989) Development of the orbital region in the chondro-
cranium of Caretta caretta. Reconsideration of the vertebrate
neurocranium configuration. Anat Anz 169:335–349
55. Marugan-Lobon J, Buscalioni AD (2009) New insight on the anato-
my and architecture of the avian neurocranium. Anat Rec 292:364–
370
56. Milner AC, Walsh SA (2009) Avian brain evolution: new data from
Palaeogene birds (Lower Eocene) from England. Zool J Linnean Soc
155:198–219
57. Huxley TH (1863) Evidence as to man’s place in nature. Appleton,
New York
58. Bruner E, Averini M, Manzi G (2003) Endocranial traits. Prevalence
and distribution in a recent human population. Eur J Anat 7:23–33
59. Lieberman DE, Pearson OM, Mowbray KM (2000) Basicranial
influence on overall cranial shape. J Hum Evol 38:291–315
60. Strait DS (1999) The scaling of basicranial flexion and length. J Hum
Evol 37:701–719
61. Bastir M, Rosas A, Stringer C, Cuetara JM, Kruszynski R, Weber
GW, Ross CF, Ravosa MJ (2010) Effects of brain and facial size on
basicranial form in human and primate evolution. J Hum Evol 58:
424–431
62. McCarthy RC (2001) Anthropoid cranial base architecture and scal-
ing relationships. J Hum Evol 40:41–66
63. Ross CF, Henneberg M, Ravosa MJ, Richard S (2004) Curvilinear,
geometric and phylogenetic modeling of basicranial flexion: is it
adaptive, is it constrained? J Hum Evol 46:185–213
64. Lieberman DE, McCarthy RC (1999) The ontogeny of cranial base
angulation in humans and chimpanzees and its implications for
1000
reconstructing pharyngeal dimensions. J Hum Evol 46:185–213 36:
487–517
65. Jeffery N, Spoor F (2004) Ossification and midline shape
changes of the human fetal cranial base. Am J Phys
Anthropol 123:78–90
66. Enlow DH (1990) Facial growth. WB Saunders, Philadelphia
67. Bastir M, Rosas A, O'Higgins P (2006) Craniofacial levels and the
morphological maturation of the human skull. J Anat 209:637–654
68. Moss ML, Young RW (1960) A functional approach to craniology.
Am J Phys Anthropol 18:281–292
69. Moss ML (1959) The pathogenesis of premature cranial synostosis in
man. Acta Anat 37:351–370
70. Strait DS (2001) Integration, phylogeny, and the hominid cranial
base. Am J Phys Anthropol 114:273–297
71. Bruner E, Ripani M (2008) A quantitative and descriptive approach
to morphological variation of the endocranial base in modern
humans. Am J Phys Anthropol 137:30–40
72. Bastir M, Rosas A (2005) Hierarchical nature of morphological
integration and modularity in the human posterior face. Am J Phys
Anthropol 128:26–34
73. Bruner E (2007) Cranial shape and size variation in human evolution:
structural and functional perspectives. Childs Nerv Syst 23:1357–
1365
74. Masters MP (2012) Relative size of the eye and orbit: an evolutionary
and craniofacial constraint model for examining the etiology and
disparate incidence of juvenile-onset myopia in humans. Med
Hypotheses 78:649–656
Childs Nerv Syst (2014) 30:991–1000
75. Gunz P, Harvati K (2007) The Neanderthal “chignon”: variation,
integration, and homology. J Hum Evol 52:262–274
76. Jeffery N (2002) Differential regional brain growth and rotation of the
prenatal human tentorium cerebelli. J Anat 200:135–144
77. Bastir M, Rosas A (2009) Mosaic evolution of the basicranium in
Homo and its relation to modular development. Evol Biol 36:637–654
78. Zollikofer CPE, Ponce de León MS (2005) Virtual reconstruction: a
primer in computer-assisted paleontology and biomedicine. Wiley-
Liss, New York
79. Bookstein FL, Gunz P, Mitteroecker P, Prossinger H, Schaefer K,
Seidler H (2003) Cranial integration in Homo: singular warps anal-
ysis of the midsagittal plane in ontogeny and evolution. J Hum Evol
44:167–187
80. Bookstein F (1991) Morphometric tools for landmark data.
Cambridge Univ. Press, Cambridge
81. Zelditch ML, Swidersky DL, Sheets HD, Fink WL (2004) Geometric
morphometrics for biologists. Elsevier, San Diego
82. Slice DE (2007) Geometric morphometrics. Annu Rev Anthropol 36:
261–281
83. Whitaker SR, Sprinkle PM, Chou SM (1981) Nasal glioma. Arch
Otolaryngol 107:550–554
84. Ingraham FD, Matson DD (1943) An unusual nasopharyngeal
encephalocele. N Engl J Med 228:815–820
85. Lewinska-Smialek B, Szaro P, Ciszek B (2013) Anatomy of the adult
foramen cecum. Eur J Anat 3:142–145
86. Suwanwela C, Suwanwela N (1972) A morphological classification
of sincipital encephalomeningoceles. J Neurosurg 36:201–211