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 2010 drtbalu Drtbalu’s otolaryngology resources 2/21/2010
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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
2010
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