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The human calvaria: A review of embryology, anatomy, pathology, and

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Childs Nerv Syst
DOI 10.1007/s00381-011-1637-0
REVIEW PAPER
The human calvaria: a review of embryology, anatomy,
pathology, and molecular development
R. Shane Tubbs & Anand N. Bosmia &
Aaron A. Cohen-Gadol
Received: 21 October 2011 / Accepted: 17 November 2011
# Springer-Verlag 2011
Abstract
Introduction The human skull is a complex structure that
deserves continued study. Few studies have directed their
attention to the development, pathology, and molecular for-
mation of the human calvaria.
Materials and methods A review of the medical literature
using standard search engines was performed to locate stud-
ies regarding the human calvaria.
Results The formation of the human calvaria is a complex
interaction between bony and meningeal elements. Derail-
ment of these interactions may result in deformation of this
part of the skull.
Conclusions Knowledge of the anatomy, formation, and
pathology of the human calvaria will be of use to the
clinician that treats skull diseases. With an increased under-
standing of genetic and molecular biology, treatment para-
digms for calvarial issues may change.
Keywords Calvaria . Neurocranium . Dura . Suture .
Craniosynostosis
R. S. Tubbs (*) : A. N. Bosmia
Department of Neurosurgery, Children’s Hospital,
Ambulatory Care Center,
1600 7th Avenue South,
Birmingham, AL 35294, USA
e-mail: shane.tubbs@chsys.org
A. A. Cohen-Gadol
Goodman Campbell Brain and Spine,
Department of Neurological Surgery, Indiana University,
Indianapolis, IN, USA
Introduction
The objective of this paper is to discuss the embryological
development and anatomy of the human calvaria and to
provide an overview of pathologies associated with this
structure. The pathogenesis of calvarial malformations will
also be discussed, in particular craniosynostosis.
Embryology and anatomy
The cranial skeleton is composed of an assortment of neural
crest- and mesoderm-derived cartilages and bones that have
been highly modified during evolution. Recent advances in
human genetics have increased understanding of the ways
particular gene perturbations produce cranial skeletal mal-
formations [7], including those malformations that affect the
human calvaria (Figs. 1, 2, and 3), which is also referred to
as the “skullcap.” The skull of the embryo starts developing
between days 23 and 26 of gestation. It can be divided into
the neurocranium, which surrounds the brain and develops
from the surrounding mesenchyme, and the viscerocranium,
which is derived from the first three branchial arches and
forms the facial skeleton. The neurocranium can be further
subdivided into the cranial base; the chondrocranium, which
refers to the cranial base bones that originate from the para-
xial mesoderm and undergo endochondral ossification; and
the cranial vault, which is also known as the membranous
cranium or calvaria [8]. The term “calvaria” is Latin and
specifies the “upper part of the head”, which encapsulates
the brain and is separate from the bones of the face and
lower jaw. This part of the skull consists of a large part of
the frontal bone, most of the two parietal bones, and usually

Fig. 1 Drawing from Vesalius’s De humani corporis fabrica published
in 1543 illustrating the removed calvaria (bottom right)
small parts of the temporal and occipital bones [12]. Raam
et al. offer a less specific description of the calvaria, stating
that the adult calvaria is comprised of eight flat cranial
bones [9]. In addition to the individual bones of the calvaria,
the calvarial sutures are significant structures to consider.
Fig. 2 Drawing of the lateral skull and this segment of the human
calvaria
Childs Nerv Syst
Fig. 3 Posterior view of the human calvaria noting sutural bones
(Wormian)
The calvarial sutures are bands of fibrous connective tissue
that prevent premature bone separation and allow for uni-
form growth of the cranium during brain development [9].
The calvarial bones are intramembranous in origin. As
the cerebral and cerebellar hemispheres grow, the calvarial
bones are drawn outward, in part, by the expanding
meninges, the outer layer of which is osteogenic and re-
sponsible for production of the inner table of each flat bone.
The growing brain does not actually push the bones out-
ward; this would create an untenable compressive force on
the vascular osteogenic tissues. Rather, each flat bone is
suspended, with the existent traction forces, within a wide-
spread sling of the collagenous fibers of the enlarging inner
(meningeal) and outer (cutaneous) periosteal layers (Fig. 4).
As these membranes grow in an ectocranial direction ahead
of the expanding brain, the bones are carried with them and
thus displaced [4].
During the fifth week of gestation, mesenchymal tissue
surrounds the cranial end of the notochord and the neural
tube, forming the architectural foundation for the skull from
which the three main components of the skull develop: the
chondrocranial base, the vault, and the facial bones. Chon-
drification of the mesenchyme begins in the spheno-
occipital region during the seventh fetal week. It also
extends into the nasal region, periotic capsule, and pharyn-
geal arches, reaching a peak at about the 10th week. The
fetal cranial roof is derived from mesenchyme, which forms
a connective tissue capsule for the forebrain. The bones of
the roof (frontal, parietal, temporal, and interparietal occip-
ital) ossify from bone centers that appear in the connective
tissue membrane by the eighth to ninth week. These centers
rapidly spread and expand the neurocranial cavity to accom-
modate the enlarging forebrain [10]. The embryological
development of the individual bones that, in whole or in
part, constitute the calvaria is important to note.
Childs Nerv Syst

suture). The union of four primary centers around the foramen

magnum forms the cartilaginous portion. These centers are the
basioccipital anterior to the foramen magnum, the lateral or
exoccipitals on either side of the foramen magnum, and the
supraoccipital posterior to the foramen magnum (the inferior
squama below the mendosal suture) [10].
At 9 to 10 weeks, a single ossification center in the tectum
synoticum (the chondrocranial roof connecting the auditory
bullae) gives rise to the supraoccipital segment. At this stage,
there are also single ossific nuclei in each lateral occipital
cartilage and in the midline basioccipital segment. There is a
single ossification center in the membranous interparietal
segment as well. At 12 weeks, ossification is more advanced
in the supraoccipital segment than in the interparietal segment.
These segments fuse medially but are separated laterally by
the mendosal sutures. By 14 weeks, progressive union of the
supraoccipital and interparietal segments has reduced the
mendosal sutures to narrow slits. In some fetal skulls, there
is a vertical midline stripe of unossified membrane along the
superior margin of the interparietal segment. Similar unossi-
Fig. 4 Lateral view of a neonatal skull illustrating the loosely opposed fied strips may occur elsewhere along the margins of the
bones making up the lateral calvaria interparietal segment. These membranous remnants may os-
sify late in fetal life or persist at term. In the latter event, they
The frontal bone develops in membrane from dual ossi- usually ossify during the first postnatal year. Rarely, the inter-
fication centers, one on either side of the midline. The parietal segment arises from two or more centers that fail to
centers appear in the vertical plate above the orbital arch fuse [10]. At term, a prominent synchondrosis separates the
by the end of the eighth fetal week. By 14 weeks, there is lateral and basioccipital segments on each side. Progressive
considerable bone formation in both the vertical and hori-
zontal portions of the frontal bone. At 18 weeks, progressive
ossification narrows the space between the medial margins
of the centers and continues at a steady rate. At term, the
frontal (metopic) suture is relatively narrow; rarely, a
metopic fonticulus (fontanelle) is present. The metopic su-
ture usually disappears by the end of the second postnatal
year, although it may persist throughout life [10].
The parietal bone ossifies in membrane from a single
central nucleus by the end of the eighth week. Ossification
proceeds radially from the central focus toward the periphery
of the bone. By 14 weeks, there is extensive ossification of
both parietal bones that continues along all margins through-
out fetal life. Nonetheless, at term, the cranial sutures adjacent
to the parietal bones are relatively broad, particularly in the
parietotemporal region. The anterior fonticulus (fontanelle) is
prominent (Fig. 5), but the posterior and lateral fonticuli are
small. Occasionally, there is a sagittal fonticulus. Rarely, the
parietal bone ossifies from two centers oriented craniocau-
dally. If these centers fail to fuse, an anomalous horizontal
parietal suture results. Sometimes there is one linear strip of
unossified membrane along the margins of the parietal bone
that ossifies during the first postnatal year [10].
The occipital bone has a dual origin from membrane and
cartilage. The membranous component gives rise to the inter- Fig. 5 Bird’s eye view of an infant calvaria noting the anterior
parietal segment (the superior squama above the mendosal fontanelle

narrowing of the synchondroses results in their complete
obliteration at 2 to 4 years of age. The supraoccipital seg-
ment is separated from the lateral occipital segments by the
broad innominate synchondrosis, which becomes obliterated
at the same time [10].
The temporal bone consists of three components at birth:
the squamosal and tympanic portions, which are derived
from membrane, and the petrous portion, which is derived
from cartilage. The temporal squama ossifies from a single
center that appears in its inferior half during the eighth fetal
week. Ossification advances superiorly, laterally toward the
zygoma, and inferiorly to form the post-auditory process,
which fuses with the tympanic ring. The post-auditory pro-
cess separates the tympanic segment from the petromastoid
segments [10]. During the ninth week of gestation, an osse-
ous center in the outer wall of the tympanic segment gives
rise to the tympanic ring, which is open superiorly. The ring
encloses the tympanic membrane and fuses with the squama
shortly before birth.
The cartilaginous petrous segment begins to ossify at 16
to 17 weeks of fetal life. Ossification develops from multiple
centers clustered in four principal areas (opisthotic, pro-otic,
pterotic, and epiotic) and advances rapidly. There is progres-
sive fusion of the individual bone centers and almost com-
plete ossification of the otic capsule by the 23rd week [10].
The calvaria differs from the cranial base in embryonic
origin as well as in its ossification scheme. Membranous
bones of the skull, their intervening sutures, and underlying
dura mater are derived from cranial neural crest (CNC) cells.
They ossify in a fibrous membrane, the ectomenix, through
an intramembranous ossification pattern. Centers of ossifi-
cation begin to form in specific areas of the ectomenix after
the second month of gestation. With the ongoing condensa-
tion of these centers, ossification proceeds to form the
cranial vault bones. The margins of those developing bones
host specialized bone-forming cells (osteoprogenitor cells
and osteoblasts) and are termed “osteogenic fronts” [8].
Mesenchymal cell proliferation and subsequent differentia-
tion into osteoblasts occurs at the margins, and the bone
grows in a radial fashion until the osteogenic fronts approxi-
mate each other and sutures form between the bones. The
sutures act as flexible joints between the developing bones and
allow the skull to change shape and grow during development.
Maintenance of growth at the osteogenic fronts at the edges of
the sutures requires a fine balance between proliferation and
differentiation. Also, apoptosis has a role ensuring that the two
osteogenic fronts remain separated [3]. In short, both the
mesoderm and ectomesenchyme, which is derived from
the CNC, contribute to the cranial skeletogenic mesenchyme
that gives rise to the calvaria [6]. During fetal and early
postnatal development of the calvarial bones, only a single
cortical table exists in most locations, but by the sixth year,
Childs Nerv Syst
development of a middle diploic layer has separated it into
the laminae interna and externa. Because deposition on the
inner and outer periosteal sides slightly exceeds resorption
on endosteal surfaces, the cortical plates proportionately
thicken [4]. Thus, the calvaria is unilaminar until the diploë
appear and form a trilaminar calvaria. In an adult, the inner
table of the calvaria is thinner than the outer table, which
accounts for the increased incidence of inner table fracture
compared to outer table fracture in head trauma [1].
The ectomeninx also develops into an outer periosteum
and inner dura. Dura mater appears between days 51 and 53
of gestation. The site of suture formation corresponds to the
location of major dural reflections. Dural reflections are
bands of dural attachment to the skull base that conform to
the early recesses of the brain. These reflections do not
ossify intracranially. Biomechanical models propose that
tension forces generated by expansion of the cranium on
these bands direct calvarial development and suture location
[8]. By 9 weeks, the cartilaginous base of the skull is well
formed, and the early dura is attached anteriorly to the crista
galli and cribriform plates, anterolaterally to the sphenoid
wings, and posterolaterally to the petrous ridges. These
major sites of dural attachment relate to the reflections of
the dura that conform to the early recesses in the developing
brain. A longitudinal dural reflection develops between the
cerebral hemispheres to become the falx cerebri; a band of
dura reflects off the sphenoid wing into the early insular
sulcus, between the major frontal and parietotemporal
regions of brain outgrowth, to become the major antero-
lateral dural band; and the dural reflections off the petrous
ridges develop between the cerebrum and cerebellum to
become the tentorium cerebelli, the major posterolateral
dural band. Between 12 and 16 weeks, intramembranous
ossification progresses in the central zones between the
major reflective bands of the dura. From these central
points, the mineralization spreads centrifugally towards the
major bands within the dura. By 16 weeks, the radiating
centers of ossification have almost reached the sites of
reflective bands in the dura. These latter sites remain unossi-
fied as regions of connective tissue between the outspreading
islands of membranous bone. Biomechanical forces in the
areas of major reflections of the dura apparently limit ossifi-
cation in these regions [11].
Studies have shown that the dura mater and cranial
sutures provide crucial regulatory signals for calvarial de-
velopment. Cranial sutures function as signaling centers for
bone growth and remain patent postnatally to accommodate
cranium expansion [6]. The normal dura consists of outer
and inner layers. The outer layer is a very dense fibrous
membrane that is tightly attached to the inner table of the
calvaria and serves as its periosteum. The inner layer is
comprised of less dense fibrous connective tissue lined on
Childs Nerv Syst
its inner aspect by a layer of mesothelial cells that are in
direct contact with the arachnoid layer of the leptomeninges
[1]. The dura is the guiding tissue in the morphogenesis of
the calvaria, with the sutures developing at the sites of band-
like reflections in the dura. The configuration of the dura in
turn conforms to that of the developing brain and to the
attachments of the dura at the cranial base, itself partially
influenced by the early form of the brain. Thus, the major
normal determinant of the presence and position of the
cranial sutures is the early form and growth of the brain [11].
The postnatal growth of the calvaria proceeds very rapidly
during the first year and is followed by a much slower growth
rate until approximately the seventh year [1]. The growth of
skull bones is driven primarily by the expanding growth of
the brain. The brain grows rapidly in utero and during the
first 3 years of life. An infant born at term has nearly 40% of
his or her adult brain volume. The infant’s brain volume
increases to 80% by 3 years of age. Correspondingly, the
size of the cranium of an infant born at term is 40% of adult
size; by 7 years, this increases to 90% of adult size [7]. As
the brain increases in mass between birth and 3 to 4 years of
age, the outward displacement of cranial bones results in
adaptive deposition of bone at the sutural margins to accom-
modate the increased volume of the cranial cavity [9]. In-
deed, a principal site for growth response is the sutural
interface of each separate bone. As the bones are drawn
apart by their displacement movements, the osteogenic sutural
membranes produce membranous bone in amounts equal to
the extent of displacement, thereby enlarging the circumfer-
ence of each bone and sustaining constant articular contact [4].
Term infants thus have well-formed skull bones separated
by sutures and fontanelles, which close at different times.
Mature suture closure occurs by 12 years of age, but com-
pletion continues into the third decade of life and beyond [7].
Local interactions between the dura and sutures are inti-
mately involved in suture development and patency. Experi-
mental studies in rats involving transplantation of early
embryonic calvaria into postnatal rats with bone defects
showed normal suture formation even when the underlying
dura mater was removed before transplantation. However,
these newly formed sutures were unable to remain patent
without the dura, and the space between the bones
was obliterated by bone. However, more mature sutures in-
corporating dura were able to maintain patency. These results
concluded that the dura mater is essential for the immature
suture to develop normal suture architecture, but once the
suture has developed, it is less dependent upon the dura mater.
In another experiment, neonatal dura underlying bone induced
bone formation when transplanted into subcutaneous tissue,
but the dura underlying sutures behaved differently. It resisted
ossification and formed only cartilage. Overall, these findings
indicate that different feedback interactions and tissue signaling
pathways exist between the sutures and the dura in different
stages of development [8].
Molecular associations
Other experiments demonstrate the functions of genetic
regulation, growth factors, and transcription factors on su-
ture patency. The role of fibroblast growth factor receptors
(FGFR-1, -2, -3, -4) and transforming growth factors of the
beta super-family (TGF-1, -2, -3) have been noted in suture
morphogenesis. These are heparin-soluble factors that elicit
various cellular functions in different tissue systems as
mediators of differentiation, proliferation, and cell migra-
tion. FGFRs are effective by activating a tyrosine kinase
pathway. Current evidence supports a role for FGFR-2 in
promoting proliferation and for FGFR-1 in osteoblast dif-
ferentiation in the cranial suture. FGFR-2 is absent from the
suture and the dura, but highly expressed in bone fronts. On
the other hand, FGFR-3 is found mostly in cartilaginous
tissues and acts as an inhibitor of proliferation during chon-
drogenesis. FGFR-4 is not shown to be expressed in cranio-
facial structures, but is highly expressed in brain tissue [8].
TGF-1, -2, and −3 are present in the approaching bone
fronts and dura, but they are not found in the suture mesen-
chyme. TGF-1 and −2 are shown to play a role in obliterating
sutures, whereas TGF-3 is expressed in non-fusing sutures.
These growth factors are suggested to play a large role in
calvarial bone growth at the sutures as well as in their patency
[8]. TGF-β signaling stimulates osteogenic progenitor cell
proliferation and can induce premature suture obliteration in
cultured fetal rat calvaria. TGF-β signaling within the im-
mature dura mater (in newborn and immature animals)
possesses the ability to induce repair of calvarial bone, while
diminished TGF-β signaling within the mature dura mater
fails to repair calvarial defects [6].
In an experiment to investigate the role of TGF-β signal-
ing in regulating the fate of cranial neural crest (CNC) cells
during calvarial development, tissue-specific Tgfbr2 gene
ablation was performed using Cre/loxP recombination ex-
clusively in the CNC lineage. Loss of Tgfbr2 in the CNC
cells results in calvarial defects with 100% phenotype pen-
etrance. Disruption of TGF-β signaling in the CNC severely
impairs cell proliferation in the dura mater, consequently
resulting in agenesis of the calvaria. Thus, TGF-β signaling
within the CNC-derived dura mater provides essential in-
ductive instruction for both CNC-derived and mesoderm-
derived calvarial bone development [6]. During skull devel-
opment, TGF-β ligand and its type II receptor are co-
localized within the craniofacial mesenchyme and may reg-
ulate its differentiation. A high level of TGF-β IIR mRNA
expression is apparent in the meninges surrounding and

covering the developing brain, suggesting an important
functional role of this receptor in regulating the develop-
ment of the dura mater [6].
Genetics of malformations and pathology
The calvaria can undergo various pathological changes. The
effects on the calvaria are not the only elements of these
disorders to consider; associated clinical findings and sys-
temic effects are discussed to help differentiate among these
disorders that involve the calvaria. Skeletal dysplasias may
manifest as a generalized decrease in calvarial density, as in
hypophosphatasia and osteogenesis imperfecta; a generalized
increase in calvarial density, as in osteopetrosis; or a focal
increase in density, as in frontometaphyseal dysplasia.
Diffusely decreased or increased calvarial density is usually
associated with a process that affects the entire skeleton [5].
In the neonate, severe thinning of the calvaria and de-
creased calvarial density may signify, in order of increasing
rarity, osteogenesis imperfecta, achondrogenesis, hypophos-
phatasia, or Menkes syndrome. Types of achondrogenesis
include achondrogenesis type IB, a recessive lethal chon-
drodysplasia caused by mutations in the diastrophic dyspla-
sia sulfate transporter, or DTDST, gene on chromosome 5,
and achondrogenesis type II, a lethal disorder caused by
dominant mutations in the type II collagen gene, COL2A1.
A diagnosis of achondrogenesis is more likely when the
patient also exhibits areas of absent ossification in the axial
skeleton, micromelia, and hydrops. Menkes syndrome is a
rare X-linked recessive disorder of copper metabolism
caused by mutations on chromosome Xq13.3, which enco-
des a copper-transporting adenosine triphosphatase. Key
differential features for Menkes syndrome are osteopenia,
mental retardation, micrognathia, metaphyseal spurs that are
most obvious in the femora, urinary tract abnormalities, and
high serum copper levels [5]. The calvaria can also be
affected in the setting of amniotic band syndrome. Amniotic
bands may cross the calvaria at any level to produce variable
skull deformities [5].
Craniosynostosis
A significant disorder affecting the calvaria is craniosy-
nostosis. Craniosynostosis is the premature fusion of
one or more of the cranial sutures. It can occur as part
of a syndrome or as an isolated defect. Craniosynostosis
is called “simple” when only one suture is involved and
“compound” when two or more sutures are involved [7].
If craniosynostosis occurs due to an intrinsic suture defect, it
is termed “primary craniosynostosis”, while craniosynostosis
resulting from another medical condition is termed “secondary
Childs Nerv Syst
craniosynostosis” [9]. Syndromic craniosynostosis is less
common, occurring in only 20% of cases of craniosynostosis,
even though more than 150 syndromes with craniosynostosis
have been identified. In syndromic craniosynostosis, multiple
sutures are involved [7]. The major complications associated
with uncorrected craniosynostosis include increased intra-
cranial pressure, asymmetry of the face, and malocclusion.
Furthermore, asymmetry of the orbits leads to strabismus
[7].
The terms “scaphocephaly” and “dolichocephaly” both
denote calvarial elongation in the anteroposterior diameter,
which results from premature sagittal synostosis. This is the
most common type of synostosis, accounting for up to 50%
of cases, and is more common in males. Sagittal synostosis
is frequently inherited as an autosomal dominant trait [5].
Brachycephaly signifies abnormal calvarial widening in the
transverse diameter. This condition typically arises when
coronal or lambdoid synostosis limits anteroposterior
growth. Among females, there is a slightly higher incidence
of bilateral coronal synostosis, in which the ipsilateral frontal
bone is flattened, and the orbit is deformed with elevation of
its superior lateral angle, resulting in “harlequin eye”; and the
midline of the face is skewed with respect to the midline of the
skull base. The incidence of associated anomalies is higher
with bilateral coronal synostosis than with sagittal synostosis
[5].
In the infant skull, the differential diagnosis for focal
osteopenia is limited. Localized areas of defective ossification
occur in the lacunar skull. True convolutional markings occur
later, after sutural closure. The term “lacunar skull” signifies a
dysplasia of the membranous bone with well-defined lucent
areas in the calvaria that correspond to non-ossified fibrous
bone. The lacunae are bounded by normally ossified bone.
The appearance resolves spontaneously by age 6 months and
is not related to the degree of concurrent hydrocephalus.
Lacunar skull is associated with neural tube defects, especially
myelomeningocele with Chiari II malformation, and less com-
monly with encephalocele. The multiple well-defined areas of
relative lucency in the cranium must be distinguished from the
increased convolutional markings that develop with pansy-
nostosis at an older age [5].
The differential diagnosis for increased bone density
includes, in order of increasing rarity, sclerosing bone dys-
plasias such as osteopetrosis, pyknodysostosis, and cranio-
diaphyseal dysplasia. Pyknodysostosis can be distinguished
from the others by a thick calvaria, wide lambdoid sutures
and fontanelles, and multiple Wormian bones. Other diag-
nostic features of pyknodysostosis include short limbs, hy-
poplasia of the mandible, and an obtuse mandibular angle.
Craniodiaphyseal dysplasia is thought to have dominant
transmission. In the newborn, craniodiaphyseal dysplasia
is characterized by severe osteosclerosis with overgrowth
of the skull, facial bones, and mandible. Obliteration of the
Childs Nerv Syst

paranasal sinuses and basal skull foramina and thickening of Apert’s syndrome, or acrocephalosyndactyly, is an auto-
the diaphyses appear later, and sclerosis in the remainder of somal dominant disorder that occurs in one of every
the skeleton is less marked. Osteopetrosis is a heterogeneous 160,000 live births. Apert’s syndrome is also caused by
group of osteosclerotic bone dysplasias in which the entire nucleotide alterations causing amino acid substitutions at
skeleton is unusually dense. Impaired bone resorption the FGFR2 gene on chromosome 10. Craniosynostosis and
results in abundant osteoid and narrow, fibrotic medullary symmetric syndactyly of the extremities are hallmarks of
spaces. Dominant osteopetrosis, which has a benign course this syndrome. The clinical features include a misshapen
and late manifestation, has been localized to chromosome skull caused by coronal suture synostosis, wide-set eyes,
16p13.3. Mutations in autosomal recessive osteopetrosis midface hypoplasia, choanal stenosis, and shallow orbits.
have been localized to the ATP6I gene, which mediates Intracranial anomalies include megalocephaly, hypoplastic
acidification of the bone–osteoclast interface. The malignant white matter, and agenesis of the corpus callosum. Cardiac
autosomal recessive form of osteopetrosis manifests at birth, anomalies, including atrial septal defect and ventricular
and the intermediate autosomal recessive form manifests in septal defect, and renal anomalies such as hydronephrosis
the first decade of life. Sclerosis initially affects the basal occur in 10% of these patients [7].
bones; later, the calvaria becomes dense and thick. The
facial bones are usually relatively less dense. In congenital
osteopetrosis, hematologic derangements, due to the dimin- Other associations
ished hematopoietic compartment, arise early and result in
early death. The bones are fragile and prone to fracture and In addition to increased or decreased density of the calvarial
show a high susceptibility to osteomyelitis. Neural and bones, the absence of the calvarial bones (i.e., acalvaria) can
vascular foramina are narrow, causing cranial nerve palsies
by neural compression [5].
Fibroblast growth factor and fibroblast growth factor recep-
tor (FGFR) regulate fetal osteogenic growth and are expressed
in cranial sutures in early fetal life. These factors possibly
influence fetal suture patency. Mutations in the FGFR1 gene
cause Pfeiffer’s disease, and mutations in the FGFR2 gene
cause Apert’s syndrome and Crouzon’s disease, which are
two diseases involving syndromic craniosynostosis [7].
The etiology of non-syndromic craniosynostosis is un-
known, and the condition is sporadic in most instances.
Familial non-syndromic craniosynostosis, which affects 2% to
6% of infants with sagittal synostosis and 8% to 14% of infants
with coronal synostosis, is transmitted as an autosomal domi-
nant disorder [7]. Many patients with syndromic craniosy-
nostosis have a family history of abnormal head shape.
Crouzon’s disease and Apert’s syndrome occur more frequently
than the other syndromes associated with craniosynostosis [7].
Crouzon’s disease is inherited through an autosomal
dominant pattern. Nearly 60% of cases are new mutations,
and many are associated with paternal age older than
35 years. Crouzon’s disease occurs in one of every 25,000
live births and accounts for 5% of cases of craniosynostosis.
Nucleotide alterations causing amino acid substitutions at
the FGFR2 gene on chromosome 10 lead to the Crouzon
phenotype. Clinical findings include brachycephalic cranio-
synostosis, significant hypertelorism, proptosis, maxillary
hypoplasia, and beaked nose. Intracranial anomalies include
hydrocephalus (Fig. 6), Chiari I malformation, and hind-
brain herniation (70%). Additionally, pathology of the ear
and cervical spine is common. Infants with Crouzon’s dis- Fig. 6 Child with hydrocephalus and hugely expanded calvaria from
ease do not have anomalies of the hands and feet as infants Baille’s text The Morbid Anatomy of Some of the Most Important Parts
with Apert’s syndrome do [7]. of the Human Body published in 1793

occur. Criteria for diagnosis of acalvaria include the absence
of calvarial bones with normal development of the chondro-
cranium and presence of the cerebral hemispheres. It is
important differentiate acalvaria from acrania in utero by
transvaginal sonography, as the brain can be normal and
potentially treatable in acalvaria. Acrania accompanies an-
encephaly and exencephaly, which are the immediate differen-
tial diagnoses; in both, the base of the brain and facial
structures are intact. In anencephaly, the brain is absent above
the orbit with bulging eyes and a frog-like appearance. In
exencephaly, a large amount of disorganized brain tissue arises
from the base of the cranium. Most cases of acrania eventually
progress to anencephaly as a result of slow degeneration of the
unprotected brain secondary to mechanical and chemical trau-
ma on exposure to amniotic fluid. In acalvaria, the usually
intact overlying skin protects the brain against this process
[2].
Severe osteogenesis imperfecta or congenital hypophos-
phatasia may cause inadequate visualization or ossification
of the calvaria, generating an erroneous diagnosis of acal-
varia [2]. Hypophosphatasia is a heterogeneous disorder
characterized by low or absent serum alkaline phosphatase
activity caused by deficient activity of tissue-nonspecific
alkaline phosphatase (TNSALP). The TNSALP gene is lo-
cated on chromosome 1p34–36.1. The congenital form is
autosomal recessive and lethal. The autosomal dominant
form is milder and manifests later in life. Hypophosphatasia
typically appears as decreased ossification of the skull and
vertebrae or as isolated plates or islands of unusually thin
calvarial bone [5]. Osteogenesis imperfecta is a bone dys-
plasia characterized by osteoporosis and osseous fragility.
Dominant-negative mutations within the COL1A1 and
COL1A2 genes cause molecular defects in type I collagen,
resulting in decreased collagen matrix in the skin and bones.
The autosomal dominant types I and IV are the least severe
forms. The autosomal recessive type III is more severe and
manifests in early infancy. The autosomal dominant type II
is a lethal condition that manifests at birth. Most cases of
type II osteogenesis imperfecta arise as new mutations.
Diagnostic features of osteogenesis imperfecta include multi-
ple Wormian bones along the lambdoid suture and decreased
ossification of the skull base [5].
Causes of calvarial defects are, in order of increasing rarity,
burr holes, parietal foramina, large fontanelles, neurofibroma-
tosis, Langerhans cell histiocytosis, cranium bifidum, metas-
tases, leptomeningeal cyst, and osteomyelitis [5].
Parietal foramina result from delayed or incomplete ossifi-
cation of the parietal bone and typically occur as an isolated
autosomal dominant trait or as part of a syndrome. The un-
derlying genetic anomaly has been identified as chromosome
11p deletions with mutation of the ALX4 gene. The calvarial
defects may be so large as to extend to the midline and may
Childs Nerv Syst
be palpable. During the first few months of life, ossification
along a midline bar may separate confluent parietal defects
into paired parasagittal defects, which may persist into adult
life [5].
The term “cranium bifidum” denotes an abnormal osse-
ous defect through which there may be herniation of the
meninges and brain tissue. It occurs with midline malforma-
tions such as myelomeningocele, meningoencephalocele, or
dermal sinus. Herniation through the calvaria may be the
result of defective induction of the bone or failure of prima-
ry neural tube closure [5].
Cleidocranial dysplasia is an autosomal dominant syn-
drome affecting membranous bone. The locus for this dys-
plasia has been isolated to the short arm of chromosome 6.
The abnormalities are caused by mutations in the CBFA1
gene, a transcription factor that activates osteoblastic differ-
entiation. Cleidocranial dysplasia is characterized by wid-
ening of the fontanelles with broad lateral cranial diameter
and multiple Wormian bones along the lambdoid sutures;
closure of the sutures and fontanelles occurs late. Associated
skeletal anomalies include absent or hypoplastic clavicles, a
widened pubic symphysis, multiple spinal anomalies, and
hypoplastic middle and distal phalanges [5].
The term “cephalohematoma” signifies a traumatic sub-
periosteal hematoma of the calvaria. Because the outer layer
of the periosteum and the sutures bound the cephalohema-
toma, it cannot cross the midline. This restriction distin-
guishes it from subgaleal hematoma, which does cross the
midline deep to the galeal aponeurosis. Cephalohematomas
occur in approximately 1% to 2% of live births, are almost
twice as common in males than in females, and are more
common in children of primiparous mothers. The incidence
increases after forceps extraction. Cephalohematomas man-
ifest as unilateral or bilateral firm, tense, soft-tissue masses
that usually increase in size after birth, and resolve sponta-
neously. Most cephalohematomas calcify peripherally and
gradually incorporate into the calvaria [5].
The term “leptomeningeal cyst” signifies a well-defined
bone defect that may arise when traumatic laceration of the
dura exposes the bone to the pulsations of the cerebrospinal
fluid within the subarachnoid space. Pulsatile pressure ero-
sion then gradually widens the fracture line. Leptomenin-
geal cysts develop following 0.6% of skull fractures and are
most common in children under 3 years of age. The differ-
ential diagnosis includes eosinophilic granuloma and infec-
tion. Calvarial involvement in eosinophilic granuloma is
rare in young infants. When present, it manifests as solitary
or multiple lucent areas in the calvaria. In eosinophilic
granuloma, typical beveled edges do not occur in the infant
cranium prior to development of the diploic layer. Lastly,
osteomyelitis manifests as overlying soft-tissue edema and
poorly defined infiltrating margins [5].
Childs Nerv Syst
Conclusions
Knowledge of the anatomy, formation, and pathology of the
human calvaria will be of use to the clinician that treats skull
diseases. With an increased understanding of genetic and
molecular biology, treatment paradigms for calvarial issues
may change.
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