2010

Congenital
craniofacial
malformations
Dr. T. Balasubramanian M.S. D.L.O.
This e book describes various craniopharyngeal malformations, their mode of
inheritance and their classification. An attempt is also made to discuss the
variations which are possible in these patients

drtbalu
Drtbalu’s otolaryngology resources
2/21/2010
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Congenital craniofacial malformations

By

Dr. T. Balasubramanian

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Introduction:
Craniofacial malformations are usually caused by misregulation
of normal tissue patterning. These malformations are usually
defined by their effect on the gross anatomy of the area and
the phenotypic abnormalities documented. Work is in progress
to elucidate the molecular basis for these phenotypic
abnormalities.
Inside the uterus signals for growth and differentiation of
the fetus are usually relayed from outside the cell, through the
plasma membrane and cytoplasm, into the nucleus. These
signals regulate and co-ordinate genetic expression and tissue
differentiation, similarly from the nucleus information passes
outwards to alter the Cytoplasmic structures, modulating the
cellular response to the incoming signals, and also serves to co-
ordinate the activities of other cells nearby as well as distant
ones.
These signals are also known as Ligands. Ligands are of two
types:
Diffusible Ligands: Growth factors classically belong to this
group. Ligands belonging to this group are highly diffusible in
the lipid matrix. They help in signal transmission from the
outside. These Ligands begin signal transduction process by
binding to specific receptors present over the cell membrane.

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These receptors are known as transmembrane receptors.

These receptors have three portions:
a. Extracellular domain: This is present over the exterior of
cell membrane. This is where the diffusible ligand is
supposed to get attached.
b. Transmembrane domain: This portion of the receptor
spans the whole thickness of the cell membrane. It is in
physical contact with the extracellular domain present
outside.
c. Intracellular domain: This domain is present within the cell
and is responsible for changes that occur within the cell.
This domain is in physical contact with the transmembrane
domain.
Binding of a ligand to the extracellular domain will cause
phosphorylation of the intracellular domain leading on to
phosphorylation of intracellular substrates and also alters the
activity of other intracellular proteins.

Stationary Ligands: This in comparison to the diffuse Ligands

doesn’t usually diffuse into the cell. Examples of these Ligands
include matrix associated proteins. Classic matrix associated
proteins include the fibroblast growth factors (which are
responsible for the growth and differentiation of fibroblasts),

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Bone morphogenic factor (causing tissues to differentiate into

bones).
These Ligands thus cause changes in protein activity, controls
cell proliferation, migration, differentiation, symmetry and
sometimes even apoptosis. Co-ordination of all these cellular
process is a must for development of facial skeleton.
Derangements of this co-ordinated signaling process can lead
to craniofacial malformations.

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Diagram showing cell signaling process

Embryology of face and jaws:

Tissues giving rise to face and jaws are derived from three
sources:

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a. The ectodermal layer that provides the surface cover. This

layer also interacts with mesodermal layer helping to
pattern the developing structures.
b. Neural crest layer that provides for most of the facial
mesenchyme.
c. The paraxial / prechordal mesenchyme contribute to the
development of craniofacial musculature.
The first sign of development of face is the formation of a small
pit called as stomodeum. Stomodeum lies just below the
developing brain. The ectoderm that overlies the developing
forebrain extends into the stomodeum. At the stomodeum it
lies adjacent to the developing foregut. The junction between
the ectoderm and the adjacent endoderm is known as the
oropharyngeal membrane. The line of attachment of the
oropharyngeal membrane corresponds to the future
Waldayer’s ring.

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Figure showing development of nasal placodes

This oropharyngeal membrane undergoes spontaneous
dissolution during the 4th week of gestation. This dissolution
permits communication between the mouth and foregut. The
Waldayer’s ring connects the nasopharyngeal tonsil, lingual
tonsil and the palatine tonsils.
It is during this 4th week of intrauterine gestation the neural
crest cells start to migrate to the developing face from the

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lower portion of forebrain and upper midbrain areas. These

neural crest cells are a vital source for facial connective tissue
(which includes cartilage, bone and ligaments). Since these
migrating neural crest cells arise from different portions of the
developing brain they carry with them different developmental
programmes according to their site of origin. Mutations
involving these migrating neural crest cells may cause various
anamolies involving the facial structures.
This 4th week of gestation is really crucial in the development
of facial structures. It is during this period that 5 processes
develop to surround the developing stomodeum. A single
unpaired frontonasal process lies in the midline just above the
stomodeum (future mouth). Embryologically this process arises
from the forebrain. Paired maxillary prominences lie on either
side of stomodeum superiorly and paired mandibular
prominences lie on either side of stomodeum inferiorly. These
two paired processes arise from the first branchial arch.
It is during the embryological window spanning between 4 –
8 weeks, the median frontonasal process give rise to median
facial structures, and the paired maxillary and mandibular
arches / processes give rise to lateral facial structures. Hence it
should be borne in mind that malformations usually involve
either median or lateral structures separately or the junctional
areas.

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Development of nose and nasal cavity:

At the end of the 4th week paired ectodermal thickenings
appear on the surface of the frontonasal process, just
superolateral to the stomodeum at 1 o’clock and 11 o’clock
positions. These thickenings known as nasal placodes gives rise
to the future nose and nasal cavity. Lens placodes also develop
during the same embryological window. Developments of
nasal and lens placodes are dependent on the paired Box gene
Pax 6. In the absence of this gene neither the nasal nor the lens
placode can develop.
During the 5th week of gestation the mesenchyme present
over the margins of nasal placodes begins to proliferate to form
horse shoe shaped projections. The medial limbs of the horse
shoe projections are known as nasomedial process, and the
lateral limbs are designated as nasolateral process. The
nasomedial processes are larger than nasolateral processes.
Tissues surrounding the optic and nasal placodes enlarge
causing the nasal pit area to form recess known as nasal pits.
These nasal pits give rise to future nose and nasal cavities.

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Figure showing nasomedial and nasolateral processes

Figure showing development of maxillary process

Figure showing branchial arches

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During the 4th and 5th weeks of gestation the mandibular

processes begin to enlarge on both sides, merging with each
other in the midline. This merger takes place between 6th to 8
weeks forming the mental area of the lower jaw. Incomplete
fusion of this area leads to the formation of the dimple in the
chin area. The paired maxillary processes grow towards each
other and towards the paired nasomedial processes. The
maxillary processes eventually give rise to lateral 2/3 of upper
jaw. It also gives rise to the upper dentition except for the
incisors. The nasolateral processes at the 6th week merges with
the maxillary process to form the ala of the nose.
At the junction between the maxillary and the lateral nasal
process lies the nasolacrimal groove. These grooves extend
between the developing nose and eyes. The ectodermal lining
of this groove give rise to nasolacrimal ducts and nasolacrimal
sacs. The nasolacrimal ducts extends from the medial corners
of the eye up to the inferior meatus in the lateral nasal wall.
Cheeks and corners of the mouth develop from fusion of
maxillary and mandibular processes. Development of upper lip
is usually complete by the 8th week of intrauterine life. The
nasomedial processes merge with the superficial regions of
maxillary processes. This line of merger is known as the lines of
fusion. These areas are represented as furrows / folds after
completion of development. The nasomedial processes also

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merge with each other across midline to form the

intermaxillary segment. This fusion displaces the frontonasal
prominence posteriorly. Hence the frontonasal prominence
doesn’t contribute to the definitive upper lip, jaw or nasal tip.
During the 7th week Pinna begins to develop. It develops from
6 mesenchymal hillocks which form around the first pharyngeal
groove. Three of these hillocks (auricular) develop from the
first pharyngeal arch and the other three develop from the
second pharyngeal arch. These 6 auricular hillocks merge with
each other to form the pinna. The groove between these
hillocks gives rise to the external auditory canal.
After the formation of facial structures is completed,
mesodermal tissue from the first and second arches begin to
invade to give rise to the muscles of facial expression and
muscles of mastication. The relative size of these facial
structures undergoes change during life. The mid portion of
the face remains underdeveloped during embryogenesis but
completes its development much later. The mandible also is
relatively small but catches up in proportional size later.

Signaling process responsible for the development of face:

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Development of face is dependent on molecular signals for

normal patterning and growth to take place. These molecular
signals include:
1. Mesodermal and ectodermal interactions – This is highly
critical for normal tissue patterning to occur.
2. Hedgehogs – These are three in number i.e. sonic
hedgehog, Desert hedgehog and Indian hedgehog. These
hedgehogs play a vital role in the development of brain
and face in vertebrates. Among these three protein
molecules the most extensively studied is the sonic
hedgehog. This molecule could also be considered to be a
morphogen as it is responsible for the normal
development of facial structures. Lewis Wolpert designed
a model known as French flag model to illustrate the
morphogenic effects of sonic hedgehog. Sonic hedgehog
diffuses into the developing tissues effecting different
effects on the stem cells depending on its concentration.
French flag model proposed by Wolpert represents the
various effects of morphogen concentration on the
developing tissues. These effects are conveniently
represented by the different colors of the French flag.
High concentrations of sonic hedgehog activate a blue
gene, while lower concentrations activate a white gene.
The default state of the cell is described as red color.

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Diagram showing the French flag model

3. Fibroblast growth factors – are heparin binding proteins

capable of biding to cell surface associated heparin sulfate
proteoglycans. This binding is essential for molecular
signal transduction into the cell. In humans 22 different
types of fibroblast growth factors have been identified to
be responsible for facial development.
4. Retinoic acid signaling – This is a metabolite of vitamin A.
It is responsible for signals controlling cell proliferation and
differentiation.
5. Aristaless like homeobox genes – These genes are
responsible for neuronal development.

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As far as facial development is concerned, the sonic hedgehog

is the morphogenic organizer; fibroblast growth factors are
responsible for mesenchymal growth. Facial malformations are
known to occur due to deficiency or excess of molecular
signaling.
It has been demonstrated in experimental animals that
reduced retinoic acid signaling caused a reduction in sonic
hedgehog and fibroblast growth factors causing hypoplastic
forebrain, fused eyes and absence of structures developed
from the frontonasal process. Timely replacement of retinoic
acid prevented this malformation from occurring. On the
contrary excess stimulation by sonic hedgehog causes excessive
fronto nasal growth, leading on to widening of the frontonasal
process. This process in turn leads to the failure of palatal
shelves to abut causing cleft palate. Excess fronto nasal growth
may also lead to duplication of midfacial structures.

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Diagram depicting faulty signaling mechanism and its effect

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Diagram depicting molecular biology of cleft palate

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Development of palate: Palatal development usually begins

between the 7th and 10th weeks of intrauterine life. Its origin
generally begins from three primodia, unpaired median
palatine process and a paired lateral palatine process. These
processes fuse in midline to form the palate. The median
palatine process originates from the nasomedial process. The
median palatine process grows posteriorly to form a triangular
primary palate which is bony in nature. In adults this zone is
known as the premaxillary component of the maxilla. It gives
rise to the upper 4 incisor teeth. The incisive foramen forms
the posterior extent of the premaxilla.

Diagram showing development of palatine processes

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The lateral palatine process begin appear during the 6th week
of gestation and grows downwards vertically on either side of
the tongue.
Factors responsible for palatal development include:
1. Ectodermal – mesenchymal interaction
2. Epidermal growth factor
3. Transforming growth factor α
The development of palatal process begins with the hydration
of hyaluronic acid within the palatal shelves. This process
causes an intrinsic shelf elevating force causing the palatal
shelves to elevate from their early vertical position to a
horizontal position above the dorsum of the tongue.

Development of nasal cavities and nasal septum:

Development of nose usually begins during the 5th week of
gestation as nasal pits. These pits begin to deepen towards the
oral cavity. By the 7th week of gestation only a thin oronasal
membrane separates the nasal and oral cavities. The oronasal
membrane eventually breaks down and these two cavities
communicate with each other through the future choanal area.
The fusion of palatal processes lengthens the nasal cavity
pushing the choanal orifice posteriorly. Nasal septum develops
from the frontonasal process to reach the palatal shelves.

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Anteriorly the septum is continuous with the primary palate.

Fusion of palatal plates begin posterior to the incisive foramen
and extends in anterior and posterior directions.

Development of facial skeleton: Facial skeleton develops from

the cartilage of nasal capsule. The bony portions of the facial
skeleton appear around the nasal capsule and may also replace
it in parts. The lateral ethmoidal masses develop from
enchondral ossification of the nasal capsule. The frontal
process of maxilla, premaxillary bone, nasal bones, lacrimal
bones and palatine bones are formed by membranous
ossification of the roof and lateral wall of the nasal capsule.
The vomer develops from the perichondrium of the septal
process. Finally nearly the entire nasal capsule except for a few
portions becomes ossified / atrophied. The remaining part of
the nasal capsule includes the anterior portion of the nasal
septum and the alar cartilages that surround the nasal
vestibule. The sepal cartilage in the midline at birth is directly
continuous with the cartilaginous skull base.
The skull base ossifies from three centers:
1. Basiocciput
2. Basisphenoid
3. Presphenoid

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4. Mesethmoidal centre (Develops during the 1st year after

birth). This center gives rise to the perpendicular plate of
ethmoid.
At birth the septal cartilage is not ossified, the lateral ethmoidal
masses are ossified. The cribriform plate is still cartilaginous or
fibrous. Radiologically the whole face at birth would appear
like a midline radiolucent strip with lateral ethmoidal masses.
This may even mimic a midline defect of face in plain
radiographs.
The nasal septal cartilage extends along midline from
anterior nares to the presphenoid bone. Anteriorly and
inferiorly the septal cartilage is attached to the premaxilla by
fibrous tissue. Posteriorly the septal cartilage is continuous
with the cartilage of skull base. Inferiorly the lower edge of
septal cartilage is slotted into the vomerine groove. After birth
the unossified portion of septal cartilage (posterosuperior
portion) extends between the perpendicular plate of ethmoid
and vomer. This portion of the septal cartilage is known as
sphenoidal tail of septal cartilage. The ossifying portion of the
perpendicular plate of ethmoid is separated from the facial
skeleton by the unossified cartilage of the cribriform plate of
ethmoid and the sphenoidal tail of the cartilaginous portion of
nasal septum. Later the perpendicular plate of ethmoid bone
unites with the vomerine groove below. When this union takes

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place the vomerine groove gets converted into a tubular

vomerine tunnel. This tunnel should radiologically not be
confused with the bony canal around dermal sinus or
encephalocele.

Diagrammatic representation of various centers of ossification

of face

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The nasal septum appears differently according to the patient’s

age in imaging. Hence caution must be exercised before
interpreting midline defects of face.

This Coronal CT of a 4 month old infant shows the following

features:
1 – Unossified cribriform plate
2 - Ossified lateral ethmoidal centers
3 – Ossified vomer

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Coronal CT of 5 month old infant shows the following:

1 – Wide midportion of nasal septum (septal diamond)
2 - Ossification of palatal shelves

Coronal CT of 6 month old infant showing a bilamellar nasal

septum (arrow) “vomerine groove”.

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Features of facial skeleton in less than 1 year old infant:

1. Lateral ethmoidal centers are ossified
2. Nasal septum and anterior cranial fosse are not ossified in
midline
3. Cribriform plate is not ossified in infants less than 2
months of age
4. Crista galli gets ossified only from the age of 2
5. Ossification centers in crista, cribriform plate, and
perpendicular plate of ethmoid lead to the formation of a
bony “crystal cross” during the 4th month after birth. The
whole process of this ossification is complete by the 11
month
6. Nasal septum is wide at the midpoint of its vertical height.
This is known as the septal diamond. Septum usually
buckles in this area
7. Ossified vomer shows a “v” or “y” shaped superior border
in this age group
8. There is no midline ossification in children under the age
of 1. This should not construed as a radiological
abnormality
9. The ethmoidal labyrinth is asymmetric. This accounts for
the asymmetry of the foveal region.

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Coronal CT image of 8 month old infant showing a partially

ossified crista galli

Coronal CT image of 9 month old infant showing crystal cross

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Coronal CT image of an infant showing:

Y shaped ossification of vomer (yellow arrow).
1 – Bilamellar ossification of perpendicular plate of ethmoid

Torus Palatinus:
This is a benign thickening of cortical and medullary bone of
hard palate. It is covered by pale and thin mucosa. It usually
aligns along the median intermaxillary / interpalatine suture
line. It protrudes downwards from the apex of the palatine
arch. It extends symmetrically on both sides. These tori have a
triangular / diamond configuration. The nasal aspect of hard
palate is spared. Usually the following regions are spared:
1. Region of palatal rugae
2. Region of greater palatine foramen
Torus maxillaris are multiple hyperostoses arising from the
alveolar portion of maxilla, usually in the molar region.

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Figure showing Torus palatinus

If torus maxillaris arises from the lingual surface of dental arch

it is known as Torus maxillaris internus. This usually arises
opposite to the roots of the molars. Torus maxillaris externus
arises from the buccal aspect of the superior alveolar ridge.

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CT scan showing torus palatinus

Torus mandibularis is unilateral / bilateral hyperostosis

occurring along the lingual surface of the mandible between
the alveolar border and mylohyoid line. Usually they are
commonly present close to the apex of second premolar
opposite to the mental foramen. Torus maxillaris and torus
mandibularis are commonly found in patients with torus
palatinus. These tori may be associated with thick posterior
wall of glenoid fossa. Tori usually grow as the patient grows
and stabilizes when the patient reaches the age of 30. Tori are
usually found in 2% of new born children. It is twice as
common in females.
Classification of torus palatinus:
Torus palatinus may be classified into 4 types:

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Flat torus: This is a smooth, symmetrical, and broad based,

convex exostosis seen involving the palate close to the midline.
It is oriented along the interpalatine and intermaxillary suture
line.
Spindle torus: This is usually a midline palatine ridge containing
prominent median groove. It is bilateral in origin. It is also
known as cresta palatine.
Nodular torus: These are multiple exostoses involving the
palate. They appear as multiple discrete protuberances.
Lobular torus: This is a mushroom shaped exostosis involving
the palate. This usually arises from a single base but may form
multiple secondary nodules. These nodules are separated by
deep grooves.
Exostosis may cause stretching of mucosa leading on to
ulceration. Dentures may be ill fitting.

Facial clefts:
These are usually caused by:
1. Deranged development of frontonasal process
2. Failure of frontonasal process and lateral nasal processes
to fuse.

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Insufficient development of frontonasal and nasomedial

processes results in:
1. Hypoplasia of nose
2. Absence of nose & intermaxillary segment
3. Rectangular defect in the middle third of the face
4. Absence of incisors
5. Absence of primary palate
6. Secondary palatal clefts
7. Hypertelorism
The above said are the features of holoprocencephaly.
Failure of two nasomedial processes to merge in midline
produces the rare true midline cleft lip, cleft palate and
Hypertelorism. This is classically associated with clefting of
primary palate, diastasis of median incisors, double frenulum of
upper lip, dehiscence of skull base and basal encephaloceles.
True midline cleft is a feature of Mohr syndrome.
Failure of nasomedial processes to fuse with maxillary
processes in one or both sides will cause the rather common
unilateral / bilateral cleft lip and palate.
Failure of the nasolateral process to merge with the maxillary
process causes an oblique facial cleft extending from the inner
canthus of the eye to the nose. This cleft may also be
associated with bilateral cleft lip and palate.

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Failure of merger of mandibular and maxillary processes usually

causes transverse facial cleft. This condition is also known as
macrostomia / wolf mouth. Transverse clefts may be an
isolated occurrence or be part of syndromes such as Hemifacial
microsomia.

Figure showing cleft palate

Clefts that occur away from the known lines of fusion are
caused by amniotic band syndrome.

Cleft lip / Palate:

Clefts involving lip and palate account for nearly 90% of all
facial clefts. These clefts may involve lip only, lip and palate,
palate only. They can be unilateral / bilateral. Non syndromic
cleft lip and palate is really common.

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Pathogenesis of cleft lip / palate: Both genetics and

environment play a role in the development of cleft lip / palate.
The risk of clefting of lip / palate is 4% if one parent or one
sibling is involved. This percentage increases to 20% if both
one parent and one sibling are affected. This indicates role
played by hereditary factors. Administration of B6 and folic acid
during the 1st trimester of pregnancy reduces the risk of cleft lip
/ palate. Teratogens have been linked with facial clefting.
These include cortisone, phenytoin, and salicylates. Maternal
smoking during 1st trimester is a well known risk factor.
Studies have shown that there were significant elevation of
lactate dehydrogenase and creatinine phosphokinase in
amniotic fluid of clefted fetuses. Genes responsible for non
syndromic orofacial clefting has been identified. These genes
are named as OFC1, OFC2 and OFC3.
Clinical features of cleft lip / palate: In addition to the aesthetic
problems cleft palate also causes functional problems since it
interferes with sucking and speech.
Other features include midfacial regression, dental
malocclusion and Eustachian tube dysfunction.
Cleft lip:
Clefts involving the lip could be complete, incomplete,
unilateral, or bilateral. Distortions caused to the lip tissue due

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to clefting vary with the severity. Complete unilateral clefts

involving lip extends from the floor of the nostril through the lip
to a point just below the nostril. Lip is shortened on both sides
of the cleft. This shortening is usually asymmetrical, greater
shortening occurring on the medial side of the cleft. The
normal landmarks of lip like the vermilion skin border and
vermilion mucosal borders are distorted. The vermilion tapers
upwards along the cleft towards the nasal cavity. The
underlying lip muscles do not decussate but runs parallel to the
cleft and gets inserted into the base of the ala. This distortion
of muscle causes a bulge in the segment of lip lateral to the
cleft. This bulge is known as the orbicularis bulge. Patients
with incomplete cleft show less degree of tissue distortion. The
central lip segment i.e. prolabium has no underlying muscle but
only fibrous tissue.

Unilateral cleft lip

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Bilateral cleft lip

Oblique facial cleft

Macrostomia

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Changes in maxilla associated with cleft palate:

Maxilla in patients with cleft palate shows varying degrees of
Hypoplasia. This causes midfacial Hypoplasia. On the side of
the cleft the anterior hemimaxilla shows a narrowed curvature
(arch collapse) and upward tilting of premaxillary segment. The
inferior end of the nasal septum usually lies on the side of the
cleft, while the anterior nasal spine of the maxilla is always on
the non cleft side. These asymmetric changes in the maxilla
have been attributed to the pushing effect of the tongue.
Changes in the Nose in patients with facial clefts:
In unilateral clefts on the ipsilateral side the angle between
the medial and lateral crura is obtuse. The ala is displaced
caudally with the absence of alar facial groove. The alar facial
attachment is at an obtuse angle. The naris is retro displaced
causing an increase in its circumference. The nasal septum is
deflected towards the side of the cleft. The nasal pyramid also
deviates to the side of the cleft.
In patients with bilateral clefts the nose appears shortened.
The columella is deficient centrally with splaying of alar
cartilages. The nasal septum may be in midline. These
distortions create flat blunted nose with wide nostrils.
Malformations associated with facial clefts:

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Associated malformations are common in patients with

isolated cleft palate than in those with combined clefting of lip
and palate. Anomalies include facial, ear, eye, skeletal system,
urogenital and cardiovascular system.

Median cleft lip and associated syndromes:

This is a rare anomaly related to midline craniofacial –
cerebral dysraphism. A high percent of median cleft lip
syndrome are products of twin gestation, the other twin is
usually normal. A considerable number of these patients may
feature orofacial digital syndrome. Neurological symptoms are
not part of this group of syndromes. IQ of these patients has
no relationship with the severity of clefting.
Midline craniofacial dysraphisms fall into 2 groups:
Group A:
Inferior group: Clefting primarily involves the upper lip with or
without the involvement of the nose. This group is associated
with basal encephaloceles, callosal agenesis, and optic nerve
dysplasias such as optic pits, colobomas, megallopapilla, and
Morning glory syndrome.
The lip defect may range from:
1. small notch

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2. Vertical linear cleft

3. Small triangular deficiency of vermillion border of upper lip
with absent labial tubercle. This is infact the true midline
cleft of lip.

Group B:
Superior group: Clefting primarily involves the nose with or
without involvement of forehead or upper lip. This group is
characterized by hypertelorism, a broad nasal root, median
cleft of the nose, and median cleft involving the premaxilla.
These patients have increased incidence of frontonasal and
intraorbital encephaloceles, anophthalmos, microphthalmos
and callosal lipomas.
Characteristic features of patients belonging to this group
include:
1. Hypertelorism
2. Cranium bifidum occulta frontalis
3. Widow’s peak hair line
4. Midline clefting of nose with / without associated clefting
of lip and premaxilla
5. Notching of ala nasi

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DeMyer classification of Group B midline clefts:

Type I facies: This type is characterized by Hypertelorism,
median complete clefting of nose, absence, Hypoplasia or
median clefting of upper lip and pre maxilla, cranium bifidum.
Type II facies: This type is associated with
1. Hypertelorism
2. Median cleft nose
3. There is no median clefting of upper lip and premaxilla
4. Cranium bifidum may be present or absent
Type III facies: This type is characterized by

1. Hypertelorism
2. Median cleft nose and upper lip with or without
premaxillary clefting
3. No median cleft palate
4. No cranium bifidum
Type IV facies: Is featured by
1. Hypertelorism
2. Median clefting of nose
3. No clefting of upper lip, premaxilla or palate
4. No cranium bifidum

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Sedano classification: This classification attaches importance to

notching of ala nasi.
Type A facies: This type is characterized by
a. Hypertelorism
b. Broadening of nasal root
c. Deep facial groove / true cleft of nose and upper lip
d. Anterior cranium bifidum may be present
Type B facies: Features of this group include

a. Hypertelorism
b. Broad nasal root
c. Deep facial groove / true cleft of nose and upper lip
d. Anterior cranium bifidum may or may not be present

Type C facies: Features of this group includes

a. Hypertelorism
b. Broad nasal root
c. Nasal alar notching unilateral or bilateral
d. Anterior cranium bifidum may / may not be present
Type D type includes features of both B and C.

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Transverse facial clefts: These clefts represent the failure of

maxillary and mandibular processes to form the corner of the
mouth and cheek.

Clefts involving the lower lip and mandible:

Midline clefts involving the lower lip and mandible are very
rare in humans. These clefts could vary between a simple
notch involving the vermilion border of lower lip to a complete
cleft of lower lip, mandible and all the associated supporting
structures. Complete clefting may involve the tongue, neck
hyoid and manubrium sternum.
Clefting involving the neck may be associated with cysts,
chords, contractures and midline dermoids. Lower midline
clefts may also be associated with clefting of upper lip and
nose.
Mutations involving sonic hedgehog and homeobox genes
have been associated with clefting of lower lip, mandible and
neck. It has also been proved that exposure to plant alkaloid
jervine causes this type of clefting due to inhibition of end
organ response to sonic hedgehog.

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Amniotic band syndrome: Rupture of amnion causes a series of

events known as amniotic band disruption complex. In this
syndrome bands of amnion may form causing disruption to the
normal development, changes in the morphology of the fetus
and may also cause disruption of previously formed parts also.
Facial clefts in these patients may be caused by a strand of
amnion present between the developing facial processes
preventing their fusion. This causes clefting. Sometimes
amniotic bands may cleave through a non fusion region causing
clefting in non fusion areas. The timing of rupture of amnion is
important in the pathogenesis of facial clefting. Facial clefting
is common when amnion ruptures within first 45 days.
Ruptures occurring later than 45 days are not known to cause
facial clefting. Defects involving the central nervous system
and skull are also common when rupture occurs within 45 days
of gestation. CNS defects include anencephaly, cephalocele
and hydrocephalus.

Nasal dermal sinuses / cysts / Heterotopias / cephaloceles:

In embryonic stage the developing frontal bones are
separated from each other by a small fontanelle called as
fonticulus frontonasalis. The nasal bones are separated from
the adjacent cartilaginous nasal capsule by a prenasal space.
This potential space extends from the brain to the nasal tip.

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Small midline diverticula of dura normally extend anteriorly

into the fonticulus frontonasalis and inferiorly into the prenasal
space.

Diagram depicting embryology of frontal area of face

The prenasal space gets obliterated due to the development of

upper lateral nasal cartilage from the nasal capsule, along with
the development of ethmoidal bone. At the level of skull base
the ethmoid bones and the frontal bones close together over a

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strand of dura leaving a small opening known as foramen

caecum. Through this foramen a small vein usually passes.
If the dural diverticula becomes adherent to the ectoderm it
may not regress, on the contrary could pull the ectoderm as it
retracts creating an ectodermal tract extending from the
glabella to the crista galli. This tract may sometimes extend
further upwards in to the interdural space between the two falx
cerebri.
Similarly a persistent tract may extend from the external
surface of the nose under the nasal bones / through them into
the prenasal space & into the cranial cavity through the crista
galli. This tract is usually associated with a wide foramen
cecum, and distortion of the crista galli.

MRI showing dermoid tract extending from dorsum of nose

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Pit over the dorsum of nose indicates the dermoid tract

opening

Sometimes these tracts may become adherent to the brain

tissue itself. Sometimes remnants of these tracts form
epidermoid cysts, dermoid sinuses or fibrous cords.

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Formation of nasal encephaloceles and nasal gliomas:

Nasal gliomas and encephaloceles arise from a similar
mechanism described above. Histologically it is pretty
impossible to differentiate these two entities. If the dural
diverticula contain leptomeninges, CSF and neural tissue it
would constitute a glabellar or nasal menigoencephalocele.
If this developing structure gets pinched off from the brain
tissue, and gets isolated from the cranial cavity and forms a
heterotopic focus of meninges and brain tissue at the level of
glabella and nose.

Figure showing encephalocele

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Figure showing intranasal encephalocele

Dermoids and sinuses involving the skull:

Dermoids involving skull are usually related to neural tube
closure, and lines of sutures of skull bones. Dermoids involving
skull are classified into:
1. Midline dermoids: Commonly affects anterior fontanelle,
glabella, nasion and vertex.

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2. Fronto temporal dermoids: affects sphenofrontal,

frontozygomatic and sphenosquamosal sutures.
Commonly frontotemporal dermoids are single slow
growing asymptomatic lesions clustering around the
eyebrows.
3. Parietal dermoids: affects squamosal, coronal, lambdoid
and parietomastoid sutures.
4. Orbital dermoids: are commonly single, slow growing
masses involving the orbit. These masses occur commonly
lateral to the midaxis of the globe.

Nasal dermal sinuses: are small epithelium lined tubes arising

from a small opening situated along the dorsum of the nose.
This sinus may also reach the intradural space also. These
sinuses can coexist with nasal dermoids and epidermoid cysts.
These sinuses could be part of certain syndromes like
Hemifacial microsomia, frontonasal dysplasia, oro-facial-digital
syndrome type I, or part of VATER syndrome (vertebral defects,
imperforate anus, tracheo oesophageal fistula, radial and renal
dysplasia).
Nasal dermoid cysts and epidermoid cysts usually cluster
around the midline area just superior to the tip of the nose, the
junction of upper and lower lateral cartilages and near the
medial canthus.

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Nasal dermoid cyst just above the nasal tip

Epidermoid cysts are more common over the glabella nasion
area whereas dermoid cysts are common over the bridge of the
nose. Nasal dermal cysts and sinuses are detected early in life
sometimes as early as 3 years of age. There may be associated
intermittent discharge from these masses with widening of the
dorsum of the nose. There may be associated episodes of
recurrent meningitis, or behavioral change due to frontal lobe
abscesses. The ostium of the sinus may be very small and may
become visible only on applying pressure over the dorsum of
the nose. Fluid may extrude out of this ostium when pressure
is applied over the dorsum of the nose.

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Commonly nasal dermoids are confined to skin. Intracranial

extension of these sinuses is common in patients with multiple
anomaly syndromes.
Surgical resection of these cysts is indicated for the following
reasons:
1. Cosmesis
2. To avoid / treat complications like local infections
3. To avoid / treat meningitis
4. To prevent later development of cerebral abscess
Imaging usually clearly visualizes the complete tract and any
infections associated with it. The ostium and tract usually
appears as isodense fibrous channels, dermoid cysts and its
channels usually appear radiolucent. Uncomplicated dermoid
cysts usually appear like a radiolucent mass in images,
surrounded by a well defined capsule. Signs of inflammation
around the mass will clearly be evident as radio dense areas.
Demonstration of enlarged foramen cecum, or distorted crista
galli during imaging usually suggests intracranial extension.
Nasal gliomas (Heterotopia):
These are congenital masses of glial tissue occurring either
intranasally or extranasally close to the root of the nose. They
may or may not be connected to the brain by glial tissue. They
don’t contain CSF filled spaces. Gliomas are usually solid

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masses of glial tissue. The differentiating feature between

gliomas and encephalocele is the present of CSF in the latter.
Nasal gliomas are usually classified into:
1. Extranasal: gliomas lie external to the nasal bones / nasal
cavities. These gliomas classically appear over the dorsum
of the nose on either side of midline. Sometimes these
gliomas can be found close to the inner canthus of the eye.
These masses are not pulsatile and don’t show cough
reflex. These masses don’t show increase in size when the
jugular vein is compressed (negative Furstenberg sign).
Due to their progressive increase in size Hypertelorism is
common in these patients due to splaying of nasal bones.
2. Intranasal: gliomas lie within the nose and nasopharyngeal
cavities. They usually present as large polypoidal
submucosal masses. These masses can lead to nasal
obstruction, obstruction to nasolacrimal duct causing
epiphora. These intranasal gliomas are usually firm in
consistency, and are situated medial to the middle
turbinate where as nasal polypi are soft and lie
inferolateral to the middle turbinate. As a routine nasal
gliomas are present in infancy in contrast to nasal polypi
which present rather late.
3. Mixed: These gliomas contain both extranasal and
intranasal components. These two components

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communicate via a defect in the nasal bones or around

their lateral edges.
Histologically, these gliomas resemble reactive gliosis rather
than neoplasia.

Non nasal heterotopias: Gliomas / Heterotopic brain tissue

have been identified in non nasal sites like orbit, hard palate,
soft palate, pterygopalatine fossa, nasopharynx, tongue, upper
lip and lungs. Histologically non nasal gliomas show advanced
cellular differentiation in to neural components.

Epignathus teratoma: These are congenital teratomas of

oropharynx seen commonly in females. These teratomas are
more frequent in children of younger mothers. These children
have history of elevated levels of alpha fetoprotein and
polyhydramnios due to swallowing difficulties inutero.
These tumors are classically single masses attached to the
skull base in the midline of posterior wall of nasopharynx close
to Rathke’s pouch. Large tumors may extend intracranial via
the craniopharyngeal canal and could extend inferiorly to
involve palate and oral cavity.

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Epulis: The term Epulis is derived from the Greek word

meaning “on the gum” or “gum boil”. Congenital epulis is a
rare tumor affecting the gingiva of infants. These lesions could
be single / multiple and are common in girls than boys. These
lesions commonly involve the upper jaw more frequently.
These lesions are not associated with Hypoplasia of teeth.
These lesions may undergo spontaneous resolution. It does not
recur after surgical resection. Histologically these lesions
appear as large cells with eosinophilic cytoplasm.

Cephaloceles:
These are congenital herniations of intracranial contents
through a cranial defect. If the herniations contain only
meninges then it is known as cranial menigocele, if the content
is brain then it is known as menigoencephalocele. These
cephaloceles can be classified according to the site of
herniations.
1. Occipital cephalocele
2. Cephaloceles of cranial vault
3. Sincipital cephaloceles
4. Basal cephaloceles
5. Cephaloceles associated with cranioschisis

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Sincipital encephaloceles: These are situated in the anterior

part of the skull. Since this falls within the realm of
otolaryngologist this has been taken up for detailed discussion
here. This type of encephalocele can be further subdivided into
interfrontal and frontoethmoidal types.
Interfrontal cephalocele: This usually presents as midline mass
anteriorly above the frontonasal suture. The skull defect lies
between two frontal bones.
Frontoethmoidal encephalocele: These cephaloceles pass out
through a defect at the junction of frontal and ethmoidal bones
anterior to cribriform plate of ethmoid. These encephaloceles
can further be sub classified into naso frontal, naso orbital and
naso ethmoidal subtypes depending on the exact point of
herniations. In almost all these patients the crista galli was
found to be normal and the edge of the defect was funnel
shaped. These cephaloceles usually demonstrate two ostia i.e.
internal and external. Commonly the internal ostium is single
opening centered close to foramen cecum anterior to crista
galli. The external ostia may be single / multiple present in
different locations.
Classification of external ostia:
Boonvisut classified external ostia into type I and II. Type I
ostia is a single opening present between two adjacent bones.
Type II ostia are multiple ostia clustered in the same region.

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Fronto nasal type of encephalocele: This cephalocele emerges

from the bony canal between the frontal and nasal bones. In
these patients frontal bones would be seen to be displaced
superiorly, while the nasal bones /frontonasal process of
maxilla / nasal cartilages are displaced inferiorly. This
displacement creates space for expansion of the mass. In these
patients normal relationship of bones of nose is maintained.
This expansile mass usually lies in the glabellar region or root of
the nose. The mass can be small / larger than the size of the
head of the infant. As the mass enlarges in size it causes
distortion of the orbit leading on to increased interpupillary
distance i.e. telecanthus. The size of the mass is directly
proportional to intracranial tension. The size of the internal
ostium does not determine the size of the mass. Most
frontonasal cephaloceles are firm / solid. If they are firm they
don’t manifest transmitted pulsations, or show increase in size
on respiration. If these masses are cystic in nature they can be
compressed, and shows transmitted pulsations. They also
increase in size during inspiration. These masses usually grow
as the child grows. Cystic masses usually show
disproportionate increase in size due to accumulation of CSF
inside these masses. If these cystic masses are covered with
skin, it may rupture leading onto CSF leak.

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Internal carotid artery may lie perilously close of the internal

ostium. This anatomical aspect should be borne in mind while
operating on these patients.
Naso ethmoidal cephalocele: Cephaloceles belonging to this
category exits out of the skull through a bony canal between
the nasal bones and nasal cartilage. The nasal bones and
frontonasal process of maxilla remains attached to the frontal
bone in these patients. The nasal cartilages, septum and
ethmoid bones are displaced postero inferiorly. The bony
defect is usually circular and is present between the orbits and
increases inter orbital distance. The cribriform plate is normal
in position in relation to orbits. The dorsum of nose is widened.
These patients also have hydrocephalus commonly.
Naso orbital cephalocele: These cephaloceles emerge from a
bony canal lying between the medial wall of orbit between
lacrimal and maxillary bones. Fronto nasal process of maxilla is
abnormal and is displaced antero medially. This process forms
the anterior margin of the defect. The lacrimal bone and
lamina papyracea are displaced posterolaterally and forms the
posterior margin of the defect. These cephaloceles commonly
induce abnormalities of facial skeleton. These patients have
Hypoplasia of frontal and maxillary sinuses.

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Basal cephaloceles: These cephaloceles protrude through skull

base. These include spheno orbital, spheno maxillary and
spheno pharyngeal cephaloceles. These cephaloceles are
usually not visible externally unless they grow in size enough to
protrude through the nose / mouth.
Spheno orbital cephaloceles: protrusion occurs via the superior
orbital fissure and presents posterior to the orbit. Infants with
this type of cephaloceles manifest with proptosis. Protrusion of
eye ball increases when the patient performs Valsalva
maneuver.
Sphenomaxillary cephaloceles: This type of cephaloceles exit
the skull via the superior orbital fissure extends inferiorly into
the inferior orbital fissure to extend into the pterygopalatine
fossa.
Sphenopharyngeal cephaloceles: These cephaloceles exit from
the skull between sphenoid and ethmoid bones. This group can
further be subdivided into anterior and posterior groups.
Anterior group is also known as trans ethmoidal cephalocele.
Cephaloceles of this type extend downward anteriorly through
a skull defect along the cribriform plate of ethmoid bone. The
herniated sac may extend into the nasal cavity and paranasal
sinuses. Sella is not involved in this group of patients.
Posterior group is known as trans sphenoidal cephalocele.
These cephaloceles exit through defects in the sella to enter the

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nasal cavity. If these patients have associated cleft palate these

masses could present as oropharyngeal mass. Patients with
trans sphenoidal cephalocele have associated hypopituitarism,
Hypertelorism, and optic nerve coloboma.

Dacryocystoceles: These are distended lacrimal duct / sac due

to imperforate naso lacrimal system. These patients manifest
with nasal obstruction. These cysts present as bluish mass
close to the medial canthus of the eye. They are usually
unilateral in nature. Lacrimal production is fully mature at
birth. Tear secretions begin immediately after birth.
Imperforate naso lacrimal duct causes formation of
Dacryocystoceles. Incidence of dacryocystocele is very high in
preterm infants.
Facial / branchial arch syndromes: First and second arch
syndromes manifest as hypoplasia of maxillary and mandibular
arches. Variations of these syndromes are caused by
differences in the time of insult with respect to neural cell
migration. Neural crest cells destined to the first and second
arches begin to migrate during the 6th – 7th somite stage of the
embryo. Exposure to retinoic acid at this stage or just before
would cause Goldenhar syndrome.
Goldenhar syndrome: Also known as Oculo-Auriculo-Vertebral
syndrome. This syndrome is characterized by incomplete

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development of ear, nose, soft palate, lip, and mandible. This

syndrome commonly involves one side of the body. This
condition also goes under the name Hemifacial Microsomia.
This is the second most common facial birth defect ranking next
only to cleft lip and palate. Curiously males are commonly
affected than females.
This condition was first described by Goldenhar. He
described a triad of epibulbar choristomas, preauricular skin
appendages, and mandibulofacial dysostosis. To this triad
Gorlin added vertebral anomalies which were found commonly
in these patients and rechristened this syndrome as Oculo-
Auriculo-Vertebral dysplasia. He also included Hemifacial
microsomia, transverse facial clefts in this syndrome.
Development of Oculo-auricular-vertebral complex takes place
during the 4th week of gestation.
Pathogenesis of Goldenhar syndrome:
1. It could result from interference to blood supply to this
region, probably the primordial stapedial artery could be
the culprit.
2. Any local hemorrhage in this area can lead to this
syndrome
3. Impaired interaction between neural crest cells with the
mesoderm of the 1st and 2nd arches
4. Mutations involving Msx genes.

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Clinical features:
1. Facial asymmetry is commonly seen in 70% of these
patients. This may not be appreciable at birth but will
clearly manifest within the first 4 years of life.
2. Hypoplasia of face may be predominantly horizontal /
vertical / mixed. Predominant hypoplasia could be clearly
seen along the oblique line extending between the
malformed pinna and the angle of the mouth.
3. Right side of the face is commonly affected
4. In the upper third of face zygoma and lateral portion of
the maxilla are affected
5. Orbits usually are symmetrical with a normal inter orbital
distance
6. Nose and the columella deviate to the hypoplastic side
7. In lower portion of the face mandible is more severely
affected. Mandibular hypoplasia causes the most facial
distortion in these patients. The ramus of the mandible is
severely hypoplastic in comparison with the body. This
adds more to the asymmetry.
8. Temporo mandibular joints get displaced antero inferiorly
9. Muscles of mastication are severely hypoplastic, in
proportion to the mandibular hypoplasia.
10. Skin tags may be found between the malformed ear
and the corner of the mouth

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11. Mouth usually has short transverse dimension

(microstomia).
12. Cleft lip and cleft palate are common in these
patients
13. Tongue and palatal muscles may be paralyzed /
hypoplastic
14. Palate usually deviates to the affected side
15. Velopharyngeal insufficiency is common in a large
majority of these patients
16. Dental maturation is usually asymmetric in these
patients with defective primary enamel

Deformities of Ear: Can be classified for the sake of

convenience and better understanding into deformities
involving the external ear, middle ear and inner ear.
Microtia: This term is applied to a pinna which is small /
distorted. Non syndromic Microtia occurs in 0.01% of all new
born. More than 3% of patients with Goldenhar syndrome
have Microtia. Microtia in Goldenhar syndrome is commonly
unilateral. Severity of malformation of external canal is usually
proportional to that of Microtia.

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Figure showing severe Microtia with non developed external

auditory canal

Malformations involving middle ear: This usually parallels

severity of Microtia and mandibular hypoplasia. Radiologically
ossicles of middle ear are abnormal in 70% of these patients.
Only about a third of patients with Goldenhar syndrome have
normal hearing, the rest show sensorineural / mixed /
conductive hearing losses of varying degrees.
Malformations involving inner ear: Cochlea & vestibule may be
abnormal / absent in these patients. The internal auditory
canal may be shorter, narrower and inclined upwards. 7th
nerve palsy is seen in 50% of these patients and correlates with
the degree of Microtia.

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Deformities involving eye: Characteristic ocular abnormalities

seen in patients with Goldenhar syndrome include:
1. Epibulbar choristomas
2. Colobomas of upper eye lid – Seen in 70% of patients with
Goldenhar syndrome. These colobomas usually occur at
the medial third of the upper eyelid.
3. Impaired ocular mobility – May include estropia, exotropia
and Duane’s retraction syndrome caused by hypoplasia of
oculomotor nerve or its nuclei.
Esotropia is a type of squint in which one / both eyes turn
inwards giving a cross eyed appearance.
4. Dacryostenosis
5. Limbal dermoids
Deformities involving skull:
Plagiocephaly – This deformity which involves the frontal bones
are seen in 20% of patients with Goldenhar syndrome. Frontal
bone in this condition on the side of the Hemifacial Microsomia
shows deformity.

Treacher Collins syndrome:

This condition is also known as Mandibulofacial dysostosis.
Features of this syndrome include:
1. Malar bone hypoplasia

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2. Hypoplasia of ramus of mandible

3. Antimongoloid slant of palpebral fissures
4. Obliteration of fronto nasal angle
5. Colobomas of lateral third of lower eyelid
6. Abnormal eye lashes
7. Inferior extension of hair line on to cheeks
8. Malformed pinna / external auditory canal
9. Hypoplasia of orbit
Genetics: This is an autosomal dominant syndrome seen in 1 in
50,000 live births. Offending gene has been identified as TCS
gene (Treacher Collin syndrome gene) at chromosome 5q31.

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Differences between Goldenhar syndrome and Treacher Collins

syndrome:
Goldenhar syndrome
Mandibles asymmetric
bilaterally
Colobomas common in upper
eyelid
No Antimongoloid stance of
palpebral fissures
Malar hypoplasia uncommon
Lack of clear cut inheritance
pattern
Choristomas and skin tags
frequent
Treacher Collins syndrome
Mandibles symmetric
bilaterally
Colobomas common in lower
eyelid
Antimongoloid stance of
palpebral fissures seen
Malar hypoplasia common
Inherited as an autosomal
dominant trait
Choristomas and skin tags rare

Branchio Oto renal syndrome: (Ear pits deafness syndrome)

Melnick-Fraser syndrome
This syndrome is characterized by:
1. Anomalies involving ear
2. Hearing loss
3. Preauricular pits
4. Branchial fistulae
5. Lacrimal duct stenosis
6. Renal dysplasia

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The term Branchio is used to refer second branchial arch

anomalies.
Genetics: This syndrome is inherited as autosomal dominant
trait with high degree of penetration. Gene involved in this
mutation is EYA 1 gene.

Nager Acrofacial dysostosis syndrome:

This type of mandibulofacial dysostosis is associated with radial
defects. Cranio facial defects include mandibular and malar
hypoplasia. These patients also have malformed pinna,
external auditory canal and conductive deafness. The palpebral
fissures are downwardly slanted with absent eyelashes in the
medial third of lower eyelids.
These patients also manifest microstomia and cleft palate. A
tongue shaped extension of hair can be seen extending up to
the level of cheek.
Radial defects include absent thumb and other abnormalities
of the hand.

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Pierre Robin Syndrome:

Features of this syndrome include:
1. Micrognathia – Abnormally small lower jaw
2. Glossoptosis – downward displacement of tongue
3. Cleft palate
4. More common in girls
Clinical features:
These patients have –
1. Feeding / breathing difficulties because of Micrognathia
2. Recurrent attacks of cyanosis
3. Cleft palate
This condition should not be considered to be a syndrome at all
as they can occur in other syndromes / isolated sequential
manner. Apt word to describe this condition could be Pierre
Robin sequence.
Pierre Robin sequence has classically been observed in the
following syndromes:
1. Stickler syndrome
2. Velo-cardio facial syndrome
3. Fetal alcohol syndrome
4. Treacher syndrome
It can also occur in an isolated manner.

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Children affected by this syndrome often reach their full

developmental size. Their growth rate is slightly below normal
because of the inherent chronic hypoxia these children suffer
from. Lack of adequate nutrition due to feeding disability also
adds to their woes.

Premature cranial synostosis:

This condition is characterized by premature closure of one or
more cranial sutures. The cause could be multifarious.
Classification:
Can be classified into:
1. Primary cranial synostosis – This condition occurs in the
absence of underlying brain / metabolic disorder. This
type of cranial synostosis can occur in isolation (non
syndromic) or as part of syndromes.
2. Secondary cranial synostosis – occurs as a result of
reduced intracranial volume, hydrocephalus shunting, or
cerebral insult. Metabolic synostosis is also included in
this group. This is caused by Rickets, hypophosphatasia,
hyperthyroidism and idiopathic hypercalcemia.
The cranial sutures becomes narrower gradually and the
fontanelles smaller and shallower. Closure of these sutures
does not involve the entire depth in one go but occur gradually.

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Fusion starts ideally from the inner endosteal layer and occurs
in an orderly manner where as the outer enchondral layer may
show variations in fusion rates. The fontanelles close early.
Their closure calendar is as given below:
1. Posterior fontanelle closes by 8th week
2. Anterior fontanelle by 15 – 18 months
3. Antero lateral fontanelle by 3rd month
4. Posterior fontanelle by 2 years
5. Mendosal suture closes within weeks after birth
6. Metopic suture starts to close during the 2nd year and
fuses completely by the age of 3.
7. The sagittal, coronal and lambdoid sutures may close very
late. They may last till early adulthood.

Lateral view of skull showing various sutures

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Superior view of skull showing various sutures

Various skull shapes which are caused due to suture closure

variations:
Scaphocephaly: This skull shape also goes by the name Canoe
head / Dolicocephaly. In these patients the skull gets elongated
in an antero posterior direction, causing a relative narrowing in
a transverse dimension. This condition is usually caused by
premature closure of sagittal suture. Other rare causes include
head deformity due to prematurity, soft bones, the infant
assuming a prolonged decubitus position as in the case of those
in neonatal intensive care units.

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Trigonocephaly: This deformity is also known as axe skull / keel

shaped skull. This type of skull has sharp anteriorly directed
ridge over the frontal bone. This condition is commonly caused
by metopic synostosis.

Brachycephaly: This condition is signified by abnormal

widening of transverse diameter of the skull with shortened

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antero posterior dimension. This condition is caused by

premature closure of coronal / lambdoid sutures causing
shortening of antero posterior dimension.

Oxycephaly: This condition is also known as Turricephaly /

Tower head. This condition is characterized by superior
elongation of the skull. This condition is usually associated with
bilateral coronal / bilateral lambdoid synostosis. This
premature fusion causes redirection of growth of brain
anteriorly towards the anterior fontanelle complex or
posteriorly towards the posterior fontanelle complex.
Plagiocephaly: This condition is characterized by asymmetry of
skull. This asymmetry could be caused due to:
1. Positional deformation
2. Unilateral suture synostosis
3. Asynchronous synostosis of multiple sutures

Clover leaf skull: In this condition the skull appears like a clover
leaf. In these patients this type of skull causes severe
constriction to normal brain growth. This type of skull is
commonly seen in syndromic forms of craniosynostosis.

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Non syndromic primary craniosynostosis: This category

constitutes 85% of all primary craniosynostosis. In this category
premature closure of Sagittal, coronal, and metopic sutures are
more common, while premature closure of lambdoid suture is
least common.
Premature Sagittal stenosis is the most common form of
craniosynostosis in this category. It constitutes nearly 70% of
all craniosynostosis in this category. Nearly 10% of these cases
are familial with autosomal dominant inheritance. It is
common in male children (70% more common). Suture closure
in these patients occurs soon after birth restricting transverse
growth of the skull, hence these patients manifest with
scaphocephaly. A prominent palpable projection / ridge may
mark the area of premature closure. Compensatory growth
involving coronal / lambdoid sutures may cause frontal or
occipital bossing (prominence). The anterior fontanelles in
these patients are often found closed. Orbits in these patients
are found to be not involved and the forehead will be seen
projecting farther than that of the orbit. In these patients
fortunately concurrent abnormalities of brain are not common.
Premature unilateral coronal synostoses are the second
commonest of Non syndromic primary craniosynostosis. These
patients form 20% of this category. Most of these cases occur
sporadically, with a slight female preponderance. Unilateral

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synostosis causes growth restriction on one side only leading

on to flattening of forehead, orbit and zygoma on the affected
side. Eye and eyebrows on the affected side is displaced
upwards and backwards causing (Harlequin eye). These
patients show contralateral compensatory bossing involving the
frontal bone. This leads to displacement of contralateral eye
inferolaterally. Maxilla on the side of involvement may show
hypoplasia in the vertical plane. Pinna on the side of hypoplasia
will be seen to be displaced antero inferiorly. Anterior
fontanelle is found to be deviated to the opposite side.
Majority of these patients also have wry neck (torticollis).
Premature Metopic synostosis constitutes 5% of all Non
syndromic primary craniosynostosis. This condition is inherited
as an autosomal dominant trait. These patients have closure of
metopic sutures prematurely. This leads to hypoplasia of
frontal bones. These patients have symmetric lateral sloping of
forehead. Even though crista galli is intact in these patients,
ethmoidal sinuses show marked hypoplasia. Medial walls of
orbit show extensive thickening and increased vertical height.
Intracranial anomalies, hypoplasia of frontal lobes of brain are
also seen in these patients.

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Syndromic craniosynostosis (Craniofacial dysostosis):

This group includes syndromes that manifest with
craniofacial synostosis as one of its dominant components.
About 60 syndromes with craniosynostosis have been
described. Classifications of craniofacial dysostosis are based
on the name of the describing author, place where this
syndrome was first identified. These syndromes are caused by
faulty genes involved in Fibroblast Growth Factor Receptor.
Classical nomenclature for these syndromes includes:
1. Crouzon syndrome
2. Apert syndrome
3. Boston syndrome
4. Jackson Weiss syndrome
Among these syndromes only the Apert syndrome manifests
consistent genetics.
Pathophysiology:
Pathophysiology of craniofacial dysostosis can be understood
by studying in detail the underlying molecular genetics of these
syndromes. For premature closure of cranial sutures Fibroblast
Growth Factor Receptors play an important role. There are 4
types of Fibroblast Growth Factor Receptors that are coded by
unlinked genes (FGFR1-FGFR4). Among these genes FGFR 1, 2,
and 3 are linked to cranial suture closure. These genes encode

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tyrosine kinase receptors. These receptors are located over the

cell membrane and have a three part structure. The three parts
include:
1. Extracellular portion
2. Transcellular / Bridging portion
3. Intracellular portion
These receptors are controlled / activated by Ligands which
gets attached to the extracellular portion. In craniofacial
dysostosis mutations that occur in Fibroblast Growth Factor
Receptor genes create abnormal proteins that allow the
receptors to function even in the absence of Ligand stimulation,
otherwise put these mutant genes are always on (energized
state) causing premature closure of cranial sutures.

Cruzon syndrome: This is considered to be one of the most

frequently occurring craniofacial dysostosis. It was first
described by Cruzon in 1912. This condition is inherited as an
autosomal dominant trait with variable penetration.
This syndrome is characterized by bilateral coronal synostosis
with a brachycephalic / oxycephalic vault. The sagittal and
lambdoid sutures may also be affected. These sutures are not
fused immediately after birth, but progressively undergo fusion

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after the 1st year of birth. These patients have maxillary

hypoplasia, shallow orbits, and Hypertelorism. These patients
have partially obstructed nasal passages. Associated
intracranial abnormalities are also common in these patients.
Hydrocephalous if present is progressive in nature needing
surgical intervention.
List of other abnormalities:
1. Arnold chiari malformation
2. Calcified stylohoid ligament
3. Exophthalmos
4. Mandibular prognathism
5. Exposure keratitis of cornea
6. External auditory canal atresia
7. Jugular venous stenosis
Apert syndrome: This syndrome is also known as
acrocephalosyndactlyly type I. This is an autosomal dominant
type of cranio facial dysostosis. This condition is characterized
by symmetric syndactylism of hands / feet. These patients also
show bilateral coronal synostosis.
Other abnormalities seen in these patients include:
1. Midfacial hypoplasia
2. Bulging of eyes
3. Brain compression due to lack of intracranial space

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4. Cleft palate
5. Choanal stenosis
6. Eustachian tube dysfunction
7. Otitis media
8. Hydrocephalus
9. Fusion of cervical vertebrae
10. Ankylosis of elbows, hips and shoulders

Pfeiffer’s syndrome: This syndrome is autosomal dominantly

inherited form of craniostenosis. These patients have
Brachycephaly, short anterior fossa, prominent supra orbital
bar, Hypertelorism, Antimongoloid stance of eyes and a flat
nasal bridge.
Cohen’s classification: Cohen classified Pfeiffer’s syndrome into
three types.
Type I: is classic Pfeiffer’s syndrome with a good prognosis
Type II: is characterized by severe intracranial malformations
with poorer prognosis with clover skull deformity
Type III: is characterized by severe intracranial malformations
with poor prognosis without clover skull deformity.

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