• Growth and development of an individual can be
divided into prenatal and the post natal periods.
• The prenatal period of development is a
dynamic phase in the development of a human
• During this period the height increases by
almost 5000 times as compared to only three
fold increase during post natal period.
5 principal stages in craniofacial
• Germ layer formation and initial organization of
• Neural tube formation and initial formation of the
• Origins ,migration and interactions of cell
population, especially neural crest cells
• Formation of organ system especially the
pharyngeal arches and primary and secondary
• Final differentiation of tissue .
The prenatal life can be arbitrarily divided
into 3 periods
• Period of ovum
• Period of embryo
• Period of fetus
Period of ovum
• This period extends approx 2 weeks from
the time of fertilization.
• During this period the cleavage of the
ovum and the attachment of the ovum to
the intra uterine wall occurs.
• Human development begins when a
sperm fertilizes an oocyte resulting in the
formation of zygote.
• The zygote undergoes cleavage, a series
of mitotic divisions as it moves along the
uterine tube towards the uterus.
• Due to continuous cleavage it turns into a
ball of cells when it enters the uterus after
3 days of fertilization, known as morula.
• A fluid filled space develops within the
morula, called Blastocele and the entire
structure is now known as blasocyst.
• At the end of first week and beginning of
second week after the fertilization,
blastocyst adheres to the surface of the
endometrium and implantation begins and
inner cell mass forms a bilaminar disc.
Period of embryo
• This period extends from 14th
day to 56th
day of intra uterine life.
• During this period the major part of the
facial and the cranial region develops.
• Bilaminar disc comprised of epiblast and
• The epiblast is made of columnar cells and
separated from cytotrophoblast by a space
called amniotic cavity.
• During the 3rd
week,gastrulation phase, a narrow
trough with slightly bulging sides develops in the
midline of the epiblast known as primitive streak.
• During this stage only epiblast cells migrate in
the primitive streak and forms all the three germ
• Early in the third week one more important
structure develops known as notochord,
which is basically formed by the cells in
primitive node and pits which proliferate
towards cranial end until they reach
prechordal plate, which is the future
• It is the process of development of the neural
plate, neuroectoderm and finally foldings to
produce the neural tube.
• Neural tube is the primordium of the central
• The anterior region of the neural tube enlarges
to form the forebrain,midbrain,and the hind
• Eight bulges develop in the hind brain known as
rhombomeres. Each specific rhombomere give
rise to specific neural crest cells which migrate
to a specific location.
• Very high levels
of ethanol during
this period causes
deficiency of the
midline tissue of
the neural plate
as fetal alcohol
Role of neural crest cells in the
• Development of the face depends not only
on the underlying brain and its
rhombencephalon but also on the
adjacent secondary neural crest tissue
arising from the dorsal margins of the
neural folds at a very early stage of
• Fundamental to facial formation is the
differentiation, development and migration
of the secondary germ layer tissue
designated neural crest ectomesenchyme.
• This transitory pleuripotent tissue arises
from the lateral marginal crests of the
neural primordium and undergoes an
•The neural crest /neural plate is a transient
structure which can be subdivided into 4
Cranial neural crest –give rise to
various structure of chondrocranium
Trunk neural crest —melanocytes
and dorsal root ganglion
Vagal and sacral neural crest
---parasympathetic ganglia of gut
Cardiac neural crest —melanocytes
,neurons and connective tissue.
• Neural crest cells originating in the mid
brain and the from the first two
rhombomeres are important in providing
mesenchyme needed for development of
face ,first pharyngeal arches structure .
• According to Lumsden and Keynes the hindbrain
is itself is composed of segments with 8 subunits
called as Rhombomeres.
• Neural crest cells destined to 1st
migrate from the rhombomere 1 and 2 and
those for 2 and 3 arches migrate from the
rhombomeres 4 and 6,7 respectively.
• Neural crest cells from R8 migrate to 4 and 6
• Most of the cells of R3 and R5 undergo cell
death by apoptosis
• The even no. rhombomeres contain exit point for
cranial nerves V,VII and IX which will innervate
the branchial arches 1 ,2 and 3.
• Thalidomide and isotretinoin have severe
influence on the neural crest migration
which lead to various craniofacial
• Neural crest cells migrating from the
rhombomeres express the homeobox
(HOX) genes that were expressed in the
rhombomeres of origin.
• HOX genes produce transcription factors
that bind to the DNA of other genes and
regulate the gene expression.
• These genes are important in determining
the identity and spatial arrangements of
body regions and they also help to
determine the pattern and positions of
structures developing within the
• The expression of HOX genes are
mediated through two main group of
• Growth factor family and the
steroid/thyroid/retinoic acid super family.
COTROL AT CELLULAR LEVEL
GROWTH FACTOR FAMILY
ACID SUPER FAMIILY
These are the vehicles through which homeobox genes
information is expressed in the coordination of cell migration
and subsequent cell interactions that regulate the growth.
Neural crest cells
form the majority
of the facial and
also contribute to
• Mutation in fibroblast growth factor (FGF)
receptor genes are known to affect the suture
development in humans and such mutations
have been found to occur in Apert and Crouzon
• In suture formation the FGF is thought to provide
a signal from the duramater preventing the cells
from undergoing premature ossification at
presumptive sutures and the FGF receptor
mutation disrupts these progenitor osteoblast
cells to differentiate and causes fusion to occur
• Msx-1 and Msx-2 are implicated in craniofacial
development and in particular in the initiation,
developmental position(Msx-1) and further
development(Msx-2) of the tooth buds.
• Bone morphogenetic proteins (BMPs) have been
found to have multiple roles not only in bone
morphogenesis(BMP-5) but appear to induce
• The mutation in the Msx gene have been
reported to be associated with hypodontia.
Vulnerability of neural crest cells
Deficiency of Superoxide dismutase and catalase
enzymes responsible for scavenging free radicals
that damage cells
Exposure of teratogenic compounds
such as alcohol and retinoic acid
Pathogenesis of treacher collins’ syndrome
cell death in
Altered neural crest
Generalized lack of
of maxilla and
Pathogenesis of hemi facial microsomia
Early loss of neural crest cells
Cells migrating to lateral and
lower part of the face (longest
path) are most affected. these
cells are also important in the
formation of great vessels.
Cells migrating to
central face tend to
Defect in lower third of the
face associated with tetra
logy of Fallot
Midline face defects
Period of the fetus
• This phase extends from 56th
day of intra-
uterine life till birth.
• In this period ,accelerated growth of the
craniofacial structure occurs resulting in
an increase in their size as well as change
in proportion between the various
Development of the oral structures
• Development of face occurs primarily
between 4-8 weeks.
• The growth of the cranial ,facial and oral
structures begins around the 21st
• At this stage the embryo is about 3mm in
size and head begins to take shape.
• there is progressive increase in the size of
the embryonic disc, yet the head and tail
end of the disc remain relatively close
• This results in the bulging of the disc
upward into the amniotic cavity produces
two folds known as head and tail folds.
• In between these ,there is a depression
called the stomodeum,the floor of which is
formed by the buccopharyngeal
membrane which separates the
stomodeum from the foregut.
The buccopharyngeal membrane begins
to break down at this stage to allow
continuity between pharynx and the
stomodeum (primitive oral cavity).
Remnants of the
seen between the
of the first
. Human Age: 29 days
Early in the
fourth week of
the cranial and
1/2 of the
The branchial arches
• Differentiation of the face takes place early
in the prenatal life, specifically between
the 5-7 weeks after the fertilization.
• In the 4th
week after the conception, the
future face and the neck region located
under the forebrain of the future embryo
• Five branchial arches are formed
appearing as rounded, tubular
enlargements and are bounded by the
clefts and grooves that help in defining
• Mid and lower facial region develop in
part, from the first two, named the
mandibular and the hyoid arches.
By the time that
closes, the first
. Human Age: 27 days
The first, second,
third and fourth
arches are visible
sixth arch does
not form an
The maxillary and
prominences of the first
arch contribute the
upper and lower jaw.
The external ear forms
from tissues of the first
and second arches.
The third and fourth
arches form very little of
the external surface of
the neck, their tissues
lying deep in the
. Human Age: Sixth week
just dorsal to the
cleft is the
ear, the otic pit.
Human Age: 27 days
The clefts that
arches on the
of the embryo
Human Age: 29 days
Human Age: 29 days
and in part
Human Age: 29 days
relationship of the
and aortic sac to
the pharynx and
Human Age: 27 days
The first pharyngeal
arch has both a
maxillary and a
prominence. Dorsal to
the first arch is an
elevation formed by the
ganglion, the sensory
ganglion for the nerve
that supplies tissues
derived from the first
Human Age: 29 days
Each of the
supplied by a
The cells that
contribute to the
are derived from
cells and from
cells of which
contribute to the
formation of the
of cranial nerves
V, VII, IX, and X.
Human Age: 29 days
Derivatives of the pouches and
Development of the face
• The human face is first characterized by an
invagination or the dimple in the surface
ectoderm layer appearing just below the
• As this pit deepens, it forms the outline of the
oral cavity and the tissue mass immediately
surrounding this oral pit will form the future face.
• In the 4th
week the posterior boundary of the oral
pit comes into contact with the developing
• As the oral ectodermal plate meet the
endodermal lining of the gut, the
membrane disintegrate and the continuity
between the oral cavity and the
gastrointestinal tract is first gained.
• At 5th
week face appear crowded between
the rapidly growing forebrain and the heart
which occupy most of the chest cavity at
forms a downward
overlaps the upper
part of the
projection is called
In the inferior
portion of the
area of the
thickens to form
• The growth of the heart affects the
development of the face, not only because
of the importance of the blood supply to its
development but because the face during
its early period of rapid growth and
organization is crowded between the
enlarging forebrain and the pulsating
• Due to migration and proliferation of neural
crest cells into the pharyngeal arch the paired
structures develop surrounding the stomodeum
known as maxillary process and mandibular
• One of the first events in the formation of facial
structures is fusion of medial ends of the
mandibular process in the midline to form the
chin and the lower lip.
• Medial and lateral
nasal process are
formed due to
periphery of nasal
• The center of
due to loss of
leads to formation
of nasal pits which
are the precursors
of the nostrils and
the nasal cavities.
• Before the fusion of the medial and lateral
nasal process the nasal pit undergoes
• The raised anterior borders of the nasal pit
form the horse shoe shaped structures
with the open side below.
• As they grow forward, the inferior ends of
the horseshoes come into contact with
• The distance between these two pits
remains constant during these period
however pit themselves increase in height
• Since the tissue underlying the each
nostril represents the first separation of
the nasal cavity from the oral cavity, it has
been regarded as the primary palate.
• Due to proliferation of underlying
mesenchyme in the max.prominences it
moves medially toward each other and
toward the medial nasal process.
• The medial nasal process of both side
also fuse with each other and form
• This segment is important as it gives rise
to the philtrum, four incisor teeth, alveolar
bone and gingiva surrounding them and
• A no of facial prominences fuse between 7
to 10 weeks and give rise to a no. of
• The fusion between the medial nasal
process and the maxillary process is a
multi step procedure.
•Initially there is
border of max.
process and the
lateral border of
the medial nasal
form a lamina—
known as nasal
• Upon contact
adhesion of two
epithelial sheets occur
and they become
fused into a single
• Then degeneration of
the sheets occurs,
resulting in connective
through it. and finally
formation of upper lip
• At the posterior limit of the epithelial fin,
the epithelial sheets split apart and
produces an opening between the nasal
pits and roof of the nasal cavity.
• These posterior openings are future
internal nares and is the posterior limit of
the primary palate.
merge in the
• Later the nasal cavity enlarges posteriorly
to form a space overlying the entire oral
• the oral and nasal cavity are separated by
the secondary palatal shelves which are
termed “secondary palate” as they are
secondary to the primary palate.
Development of tongue
Development of the tongue
• The development of the tongue is of
considerable interest because of its importance
in functional matrix, its role in epigenetic and
environmental influences on the osseous
skeleton as well as its role in dental
• Can be studied under following headings
• Connective tissue
• The tongue
arise in the
of the first
• During the 4th
week of i.u life paired lateral
thickenings of mesenchyme appear on the
internal aspect of the first pharyngeal arch
to form lingual swellings, a centrally
located swelling also develops known as
• The lingual swelling grow and fuse to form
the mucosa of anterior 2/3 of the tongue
• Posterior 1/3 develops from hypo
pharyngeal eminence derived from 3 and
• Around the 5th
week of i.u life, the ventral
aspect of the 2nd
arches elevate into an united single
prominence known as copula which
degenerate without significant contribution
• Around the fused lingual swellings there is
epithelial proliferation into the underlying
mesenchyme takes place. Degeneration
of the central cells of this horse shoe
shaped lamina forms a sulcus, the
liguogingival groove, which frees the body
of he tongue from the floor of the mouth
except for the midline frenulum of the
The junction of
the anterior two-
posterior third of
the tongue is at
is the site at
Development of connective tissue
• Connective tissue develop from local
• Tongue muscle develop from the occipital
myotomes and are supplied by hypoglossal
• Taste buds arise by inductive interaction
between epithelial cells and invading gustatory
nerve cells from the chorda tympani,
glossopharyngeal and the vagus nerve. the
fungiform papillae are first to be develop at 11
weeks i.u. the circumvallate papillae develop at
2 -5 months i.u.
Development of palate
• The palate begins to develop early in the six
week and the process is completed in 12 week.
• The entire palate develops from 2 structure –the
primary palate and the secondary palate.
• The primary palate is the triangular shaped part
of the palate anterior to the incisive foramen
which arises from the fusion of two medial nasal
will form the
of the palate,
• Later the lateral palatine shelves of the
maxilla become elongated and the
tongue becomes relatively smaller and
• This allows
and to fuse
• The median palatine raphe is the clinical
remnant of fusion between palatine shelves.
• The lateral palatine process also fuses with the
nasal septum and the primary palate.
• The fusion between the palatine shelves and the
nasal septum proceeds in an antero-posterior
direction beginning in the ninth week.
Pathogenesis of cleft lip and cleft
• This occurs when mesenchymal
connective tissue from different
embryological structure fail to meet and
merge with each other.
• The common form of cleft lip is a result of
failure of fusion of the median nasal
process with the max process.
• It may be unilateral or bilateral and may
extends into the alveolar process.
• Cleft palate is the result of failure of the
lateral palatine process to fuse with each
other ,with the nasal septum or with the
• Even at this early stage the growth pattern
of the face is downward and forward as it
grows out from between these two organs.
• Important related occurrences are the
flexures that occur during the 4th
the region of the future neck.
• The brain flexes ventrally, then dorsally
and as a result the head becomes more
Further growth of the face:--
Development of the skull
• The skull is formed by mesenchymal
connective tissue around the developing
• The development of the skull is
considered in two components-
base of the skull
and derived from
skeleton of face and
Derived from neural
Each component has some structure that form by
endochondral ossification (cartilaginous component)
and other structures that form by intramembranous
ossification (membranous component) .
• Consists of several cartilages that fuse and
undergo endochondral ossification to give rise to
base of the skull.
• The cartilaginous junction between two bones
are called synchondroses.
• The new cartilage cells continually form in the
center of the synchondroses,move peripherally
and then undergo endochondral ossification
along the lateral margins.
The bone formed by this process are
• Occipital bone
• Body of the sphenoid bone
• Ethmoid bone
• Petrous and mastoid part of the temporal
• These arises by the intramembranous ossification of the
mesenchyme around the developing brain.
• Sutures (syndesmoses) are uncalcified dense sheets of
connective tissue that separate the bones of the calvaria.
• These sutures are also derived from two sources-neural
crest cells (sagittal suture) and paraxial mesoderm
• When sutures come together they form a region of
dense connective tissue known as FONTANELLES.
• They help the calvaria to change the shape during birth
by a process called MOLDING.
The bones formed by this process are
• Flat bones of calvaria.
• Superior portion of the frontal ,occipital
and parietal bones.
• Includes the facial skeleton arises from the
-includes middle ear
process of temporal
bone,the hyoid bone and
the laryngeal cartlilages.
—includes maxilla ,zygomatic
bone, the squamous temporal
bone and the mandible.
except for the mand
condyle,and the midline of the
Development of mandible and TMJ
• The template for the mandible is laid down by
meckle’s cartilage of the first pharyngeal arch.
• Initial intramembranous ossification occurs at 6
week post conception, the earliest of bones to
• The primary ossification center is located at the
side of bifurcation of the inferior alveolar nerve
into the incisive and the mental nerve.
• Then it spreads anteroposteriorly on the lateral
aspect of the meckle’s cartilage to encompass
the cartilage which later disintegrates.
• Secondary cartilage develops at the site of
coronoid and condylar process and at the angle.
• By 11 weeks secondary cartilage has developed,
forming the condylar head which is separated
from the temporal bone by a fibrous connective
tissue. and commencement of ossification of this
cartilage takes place at 18-19 weeks.
• The cartilaginous head of the condyle enveloped
in the fibrous covering that is continuous with the
joint capsule, persists and function as a growth
center until about the 25 year of post natal life.
• Each half of the mandible develops as a single
skeletal system in which meckle's cartilage serves
as an initial template but does not contribute
directly to the formation of mandible.
• As the two halves of the mandible continue to
grow fibrous connective tissue known as
symphyseal cartilage unite the two halves of the
mandible and serve as a growth site until the
first year after birth by which time it is calcified.
• The angle of the mandible at birth is about 130
degree with the condyle,thus nearly in the line
with the body.
• Later all these cartilages, together with the
ventral most tip of the meckle’s cartilage, ossify
endochondrally to conjoin with the membranous
bone of the body of the mandible.
• Forward growth
Deposition of new
bone along the
anterior surface of
Accretion along the
post. border of the
ramus extending from
condyle to the angle of
Development of the
dentition and the
Development of maxilla
• A primary intramembranous ossification
center appear for each maxilla in the 8th
week IU at the termination of infraorbital
nerve just above the canine tooth dental
• two further itramembranous premaxillary
centers appear anteriorly on each side in
week and rapidly fuse with the
primary maxillary center.
Prenatal changing relationship between
maxilla and mandible
• During intra uterine development, the
relative size of the maxilla and the
mandible vary widely.
• Initially the mandible is considerably larger
than the maxilla, a predominance later
diminished by the relatively greater
development of the maxilla, changing the
jaw relationship from angle class III to
• At about 8 weeks post conception, the maxilla
overlaps the mandible. subsequently the
mandible grows more rapidly, equaling the
maxilla by 11 weeks post conception.
• Mandibular growth then lags between the 13th
weeks, due to a change over from
MECKLE’S cartilage to the condylar secondary
cartilage as the main growth center of the
• At birth the mandible is generally retrognathic to
the maxilla ,although the two may be of equal
•Fibroblast growth factor (FGFs) and fibroblast
growth factor receptors (FGFRs) play a important
role in the skeletal dysplasia by controlling the
cellular events such as proliferation ,differentiation,
•FGFR-1 and FGFR-2 are expressed in prebone
and precartilage regions including craniofacial
•FGFR-3 is expressed in cartilage growth plates of
The fetal period—3—9 month
• Craniofacial changes—by the 3rd
assumes more human appearance.
• During the fetal period the head increases in
length from approx. 12 to 74mm and height from
20 to 100mm thus maintaining a fairly constant
ratio of width to length but not to the height.
• Prior to 5th
month the height increase is greatest
where as length and width increases are
• At birth the cranial vault is approx.8times larger
than the face.
• In the embryonic period the cranium to face ratio
may be as high as 40:1 dropping at 4 months to
5:1 because of the differentially more rapid facial
growth during this period.
• The cranium then grows faster in the late
prenatal months to attain 8:1 ratio at birth.
which again changes to 2:1 in adults due to post
natal facial growth.
• At the same time the no of skeletal bones is
reduced from 45 separate bones at birth to 22 in
Development of teeth
• By the 7th
week, the epithelial labial lamina
develops on the perimeter of the max. and the
mand. process .
• This wedge of epithelial cells penetrates the
underlying connective tissue to separate the
tissue of future alveolar ridge from the lip.
• At the same time a second lamina lingual to the
labial lamina appears and grows into the
alveolar ridge.—known as dental lamina which
at regular intervals will give rise to enamel organ
which will ultimately develop into tooth.
Molecular regulation of tooth
• Tooth development represents a classic
example of epithelium and neural crest derived
• Bud stage---regulation center —bud epithelium
• Cap and bell stage (enamel knot)-- regulation
• BMPs,FGFs ,sonichedgehog,MSX1and 2
interact in complex pathway to produce cell
differentiation and patterning for each tooth.
Development of the salivary gland
• All three major glands develop during 6—8
weeks due to proliferation of the oral mucosa
epithelium into the underlying mesenchyme.
• The connective tissue around the developing
glands forms the capsule as well as grow into
the glands to subdivide them into the lobules.
• The acini of the mucous gland become
functional during the 6th
week where as serous
gland become functional by birth,
• The clinician’s requirement of the anticipated endpoint of
growth and development of the face to determine
whether orthosurgical intervention is desirable is one of
the great challenges with which developmental biologists
• The hope of biomimetic intervention by genetic
engineering and molecular factors signaling utilization in
controlling growth, once considered only a remote
possibility is now becoming ever more realistic.
• With the increasing identification of growth factors
,genes, and chromosomes responsible for the
development of the face orthodontists are now in a better
position to advise patterns of the ultimate outcome of
prognosis of various dentofacial malformation and
malocclusions of their progeny.
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development—Seminar in orthodontics,March
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• Bernard G.Sarnat---growth pattern of the
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the mammalian skull vault—Dev.Biol 2002 ,vol-
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agenesis in humans—Nature Genet.2000-
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