Congenital craniofacial malformations
Dr. T. Balasubramanian M.S. D.L.O.
This e book describes various craniopharyngeal malformations, their mode of inheritance and their classification. An attempt is also made to discuss the variations which are possible in these patients
drtbalu Drtbalu’s otolaryngology resources 2/21/2010
Congenital craniofacial malformations
Dr. T. Balasubramanian
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 coordinate 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.
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),
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.
Diagram showing cell signaling process
Embryology of face and jaws: Tissues giving rise to face and jaws are derived from three sources:
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.
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
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.
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.
Figure showing nasomedial and nasolateral processes
Figure showing development of maxillary process
Figure showing branchial arches
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
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:
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.
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.
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.
Diagram depicting faulty signaling mechanism and its effect
Diagram depicting molecular biology of cleft palate
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
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.
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
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
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
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
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”.
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.
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
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.
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.
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:
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.
Insufficient development of frontonasal and nasomedial processes results in: 1. 2. 3. 4. 5. 6. 7. Hypoplasia of nose Absence of nose & intermaxillary segment Rectangular defect in the middle third of the face Absence of incisors Absence of primary palate Secondary palatal clefts 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.
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.
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
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
Bilateral cleft lip
Oblique facial cleft
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:
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
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
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
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.
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.
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.
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
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
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.
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
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.
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.
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.
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
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
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.
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
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.
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.
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.
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
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
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 OculoAuriculo-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.
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
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.
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.
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
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.
Differences between Goldenhar syndrome and Treacher Collins syndrome: Goldenhar syndrome Mandibles asymmetric bilaterally Colobomas common in upper eyelid No Antimongoloid stance of palpebral fissures Malar hypoplasia uncommon Lack of clear cut inheritance pattern Choristomas and skin tags frequent Treacher Collins syndrome Mandibles symmetric bilaterally Colobomas common in lower eyelid Antimongoloid stance of palpebral fissures seen Malar hypoplasia common Inherited as an autosomal dominant trait Choristomas and skin tags rare
Branchio Oto renal syndrome: (Ear pits deafness syndrome) Melnick-Fraser syndrome This syndrome is characterized by: 1. Anomalies involving ear 2. Hearing loss 3. Preauricular pits 4. Branchial fistulae 5. Lacrimal duct stenosis 6. Renal dysplasia
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.
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.
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.
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
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.
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
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.
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
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.
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
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
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
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.