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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

Congenital Craniofacial Malformations

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This e book describes the various congenital craniofacial malformations, their mode of inheritance and classification.

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Page 1: Congenital Craniofacial Malformations

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

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 Treacher Collins syndrome Mandibles asymmetric bilaterally

Mandibles symmetric bilaterally

Colobomas common in upper eyelid

Colobomas common in lower eyelid

No Antimongoloid stance of palpebral fissures

Antimongoloid stance of palpebral fissures seen

Malar hypoplasia uncommon Malar hypoplasia common Lack of clear cut inheritance pattern

Inherited as an autosomal dominant trait

Choristomas and skin tags frequent

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.