10-16-01 Cleft Lip and Palate Part 1

7/26/2019 10-16-01 Cleft Lip and Palate Part 1

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INTRODUCTION

The goals of cleft lip and palate treatment arenormal speech, hearing, occlusion, and restorationof facial form with minimal disruption of maxillofa-cial growth. The ideal timing and technique of repairto achieve the best possible outcome remain contro-versial. Treatment protocols vary significantly amongcenters, although the consensus is that a multi-

disciplinary team approach is most likely to achievethose goals. Recent surveys of cleft care in Europeand the U.S. highlight the wide range and variety oftreament protocols and outcomes. A comprehen-sive comparison of the various treatments with longterm prospective studies is still needed to validate theapproach chosen.

In addition to the multidisciplinary team approach,other recent advances in cleft care include improvedunderstanding of craniofacial embryogenesis and the

genetics of orofacial clefting, improved prenataldiagnosis, nasoalveolar molding, primary cleft nasalrepair, distraction osteogenesis, and alveolar cleftrepair with recombinant bone morphogenic protein(rhBMP-2).

HISTORY

Cleft Lip

Still and Georgiade1expertly review the evolutionof cleft lip and palate surgery (Fig 1). Galen used theterm lagocheilos to describe the congenital cleft lipin 150 AD. The first cleft lip repair was reportedlyperformed by an unidentified Chinese physician inabout 390AD. The Flemish surgeon Yperman (12951350) is credited with the original description of aprocedure to incise and suture the cleft margins,reinforcing the closure with harelip needles securedby a figure-of-8 tie.

Cleft Lip and PalatePart 1: Embryology, Anatomy, Epidemiology,

and Clinical AssessmentAmanda A Gosman MD

Fig 1.Various methods of cleft lip repair. (Reprinted with permission from Still JM Jr, Georgiade NG: Historical Review of Managementof Cleft Lip and Palate. In: Georgiade NG (ed),Symposium on Management of Cleft Lip and Palate and Associated Deformities.St Louis, Mosby, 1974. Vol 8, Ch 3.)


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Early techniques of CL repair involved a straight-line closure, such as in the operations proposed byRose2and Thompson.3The concept of closure of thecleft lip by local flaps was introduced by Malgaigne4in1843. Mirault5modified Malgaignes method by bring-ing the lateral flap across the cleft. Miraults variation

utilized the principle of filling the medial deficit with alateral flap; all subsequent methods of lip closure areessentially based on this concept.

In the 1930s and 40s, Blair-Brown6and Brown-McDowell7dominated the field of cleft lip surgery.Their techniques are based on a triangular flapbrought into the lower portion of the lip.LeMesurier8 and Tennison9 independently modi-fied the technique of lateral flap tissue transferredinto the lower portion of the lip. LeMesuriersinnovation consisted of a quadrilateral flap8whereas

Tennisons involved a triangular flap;9

both intro-duced tissue into the lower part of the lip and sharedthe advantage of producing a pouting of thetubercle. Subsequently Wynn10 and Davies11

described variations of triangular flaps introducedinto the upper lip. These repairs enjoyed a greatdeal of popularity in the 1950s and early 60s.

In 1955 Millard12developed the concept of lat-eral flap advancement into the upper portion of thelip combined with downward rotation of the medialsegment. His technique preserves both the Cupidsbow and the philtral dimple and places the tension

of the closure under the alar base, thereby reducingflare and promoting better molding of the underly-ing alveolar process. Millards repair and its modifi-cations remain the most popular methods for clo-sure of the unilateral cleft lip.

Cleft Palate

The first record of a palatal operation dates to 500ADand was prompted by inflammation of the uvula.Because for centuries perforations of the palate were

thought to be linked with syphilis, progress in the treat-ment of congenital palatal defects was slow.In 1552 Jacob Houlier proposed suturing pala-

tal clefts, and 12 years later Ambroise Par illus-trated obturators for palatal perforations.13In 1764Le Monnier, a French dentist, successfully repaireda cleft velum with hot cautery of the cleft edgesand a few sutures.13,14 Eustache in 1783 describedto the Academy of Surgery of Paris his operationfor suturing the split velum, and added that this

method could be applied in cases of congenitalsplit of the velum. It was not until some 30 yearslater, however, that von Graefe15 and Roux16

introduced their respective methods for closure ofthe congenital cleft soft palate. Von Graefe15pro-duced inflammation of the velar margins before

bringing them together in his palate suture, and iscredited with the first velar repair of a cleft in1816.14 In America, velar closure was pioneeredby JC Warren17 of Boston in 1824. In 1834Dieffenbach18closed both the hard and soft pal-ates by means of relaxing mucoperiosteal incisionsthrough bone. In 1861 von Langenbeck19

described the use of mucoperiosteal flaps in cleftpalate closure.

Multiple variations of mucoperiosteal flap clo-sure were subsequently devised in an effort to

improve speech outcomes. Veau (1931) advocatedposteriorly based unipedicled mucoperiosteal flapclosure of the hard palate.20 The speech resultswith his treatment protocol, which included closureof the soft palate musculature, separate closure ofnasal and oral mucosa, and fracture of the hamu-lus, were superior to those obtained with the vonLangenbeck procedure.19,21 Popular variations ofvon Langenbecks bipedicled flap repair are theVeau-Wardill-Kilner V-Y pushback20,22,23 and thetwo-flap palatoplasty.24

Kilner22

and Wardill23

independently modified Veaustechnique in their description of the V-Y pushback.The pushback techniques were designed to lengthenthe palate by flap retrodisplacement and release of themuscular attachment to the posterior hard palate inorder to achieve velarpharyngeal closure. In 1969Kriens25described the intravelar veloplasty which repo-sitions the abnormal velar musculature to reconstructthe levator sling. This popular technique has beenincorporated into different repair protocols.

In 1986 Furlow26published the double-opposingZ-plasty technique. The levator muscle is reorientedtransversly and the palate is lengthened by the Z-plasty design. A recent international survey reportedthat Furlows technique is the most common one-stage palate repair.27

EMBRYOLOGY

Advances in genetics, molecular biology, anddevelopmental anatomy have resulted in an improved


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understanding of craniofacial embyrogenesis and thepathogenesis of orofacial clefting. Traditionally facialdevelopment has been described by the formation,migration, and fusion of five facial prominences orproceses; the frontonasal, the bilateral maxillary, andthe bilateral mandibular.

The classical theory of embryogenesis was espousedby Dursey28and His29in the 19thcentury. It describesformation of the primary palate as a fusion of themedial and nasal prominences of the frontonasal pro-cess with the maxillary prominences during weeks 47 of gestation. The formation of the secondary palateis described as the fusion of the two lateral palatalprocesses of the maxillary prominences during gesta-tional weeks 512. This model of facial developmentinvolves the assembly of formed structures (processes)based on a simplified description of external morphol-

ogy. Recently the facial prominences or processes

were described as complex arrangements of develop-mental fields under genetic control, not single autono-mous or anatomic units.30

Early embryonic development is genetically con-trolled through the production of growth factors thattarget specific embryonic cell populations and guidetheir differentiation, migration and morphogenesis31

(Table 1). In addition to the presence, concentra-tion gradients and diffusion patterns of growth fac-tors, normal development is regulated by intercellularcommunication and selective cell membrane per-meability. Disruption of gene-controlled, growth-factormediated cell differentiation, migration, and fusionmay result in congenital malformations.31

In Carstenss neuromeric model of developmen-tal fields, the face is conceptualized as a series ofgenetically defined developmental fields, each with

a specific cellular content and a recognizable func-

TABLE 1Signaling and Growth Factors

(Reprinted with permission from Marazita ML, Mooney MP: Current concepts in the embryology and geneticsof cleft lip and cleft palate. Clin Plast Surg 31:125, 2004.)


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tional matrix.32 Each field develops from a specificanatomic zone of the embryo called a neuromere,which is based on a segmented model of the embry-onic nervous system. Unique patterns of geneexpression determine the anatomic boundaries ofeach zone within the neural tube of the embryo.

Many of the genes within a specific zone share anidentical base pair sequence called a homeobox (hox).The neuromeric zones can be mapped during thecourse of development by their hox and other zone-specific genes. Facial development is described asthe formation, migration, coalescence, and interac-tion of separate genetically based developmentalfields.30 Disruption of a neuromeric zone will resultin abnormalities in the developmental field originat-ing from that zone and will mechanically disruptnormal interactions with adjacent fields, resulting in

field mismatch.The segmental model of the embryonic nervous

system creates a genetic map that is organized intodiscrete neuromeres according to craniocaudal posi-tion along the neuroaxis. The forebrain (prosen-cephalon) is defined by 6 prosomeres (p1-6) whichare mapped by genes such as sonic hedgehog (Shh),wingless (Wnt), and Lim-1.30 The midbrain is definedby 2 mesomeres. The hindbrain (rhomboencephalon)is coded for 12 rhombomeres and is mapped by aseries of hox. The 6 pharyngeal arches and first 4

cervical somites share a common coding with the 12rhombomeres. The neural crest, ectoderm, andmesoderm outside the neural tube follow the samepattern of organization as the neuromeres. Neuralcrest cells originating from a specific location in theneural fold share the same genetic code as the corre-sponding neuromere within the neural tube.32

During week 3 of gestation, the 3 primary germlayersendoderm, mesoderm, and ectodermcomprise the trilaminar disc. At this time neuroecto-derm gives rise to the neural plate and forms thebilateral neural folds and neural tube in the processof neurulation. In the margin of the neural fold,neural crest cells differentiate from ectoderm in acranio-caudal fashion. These pluripotent cells giverise to many diverse cell and tissue types. Hall3335

suggests that neural crest cells should be considereda fourth germ layer in vertebrates.

Neural crest cells migrate and undergo populationexpansion in a segmental pattern predetermined inpart by interactions with prosomeres, rhombomeres,

prechordal plate mesoderm (PCM) and paraxialmesoderm (PAM).3032 The neural crest cells migrateinto the developing pharyngeal arches and provideprecursors of the different tissue types that make upthe structures of the head and neck. This process isdependent on inductive homeobox gene signaling.

Carstens divides facial fields into two general cat-egories,A fields andB fields,that reflect the codingorigin of the endoderm, mesoderm, and neural crestof which they are composed.30 TheA fieldsare allstructures associated with the prechordal platemesoderm (PCM) which gives rise to the mesodermalstructures anterior to the sphenoid. These fields areperfused by the terminal branches of the internalcarotid artery and are coded for by prosomeres p6 forthe nose and p5 for the orbit. The PCM is penetratedby neural crest cells and placodes which induce it to

form various structures. The nasal placodes invagi-nate into PCM and neural crest cells migrate on themedial and lateral margin of the placodes.

The fusion of the twoA fieldcomplexes give riseto the anterior columella, philtrum, premaxilla, infe-rior turbinates, piriform rim and ethmoid complexes.The septum, nasal bones and alar cartilage developwithin this functional matrix. Failure ofA fieldfusionresults in midline defects may give rise to midlinemalformations such as holoprosenceophaly and mid-line orofacial clefts such as isolated cleft palate.30

Midline defects which result in the duplication of

structuresie, septumdue to failure of fusion sup-port the bilateral basis of developmental field theory.The concept of a single frontonasal prominence failsto convey the complex bilaterality of central facialembryology.

The B fields are derived from paraxial mesodermand share rhombomeric coding. The most cephaliczone of PAM forms the structures of the head andneck. B fields structures formed from the first pha-ryngeal arch share coding with rhombomeres r2 andr3. The mandible and its associated structures are

derived from r3 and the anterior facial skeletonincluding the maxilla are derived from r2. B fieldsstructures formed from the second pharyngeal archshare coding with rhombomeres r4 and r5 (Fig 2).

Primary Palate

During week 4 of gestation the primitive craniofa-cial complex is formed. The structures of the pri-mary palate include the lip, labial musculature, nos-


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tril sill, and hard palate anterior to the incisive fora-men, including the adjacent alveolus and dentiton.The primary palate forms around the developingnasal placodes during weeks 5 7. The process iscontrolled in part by fibroblast growth factors (FGFs),

bone morphogenic proteins (BMPs), sonic hedgehog(SHH), and retinoic acid.30,31As the forebrain elevates,the maxilla (B field) grows forward to merge with themedial and lateral nasal prominences (A fields) thatsurround the invaginating nasal placode.

The primitive nostril has a transient epithelial bridgeor nasal fin that connects the medial and lateralnasal processes. The nasal fin breaks down to formthe primary nasal choana that allows migration of

mesenchyme between the medial and lateral lip seg-ments. Lip closure is preceded by the production ofa medially directed tissue bridge (Simonarts band)from the p5 lateral nasal mass. This band crosses theprimary nasal choana and fuses with the p5 medialnasal mass,32and through it the B field-derived lat-

eral lip elements (containing r2 and r4 mesenchyme)reach theA field-derived prolabial (A0) elements con-taining p5 mesenchyme.32 Lip closure is completedas the lateral lip element (B) fuses with theA fieldnasal elements and pulls the prolabial element (A0)down into position (Fig 3). Failure of bridge forma-tion results in a complete cleft lip.

Fig 3. Lip embryology. Epithelial bridge (Simonarts band)formation from A1 to A2 across the gap of the primary choane isrequired for the lateral lip elements B to reach the midline p5

prolabium fields A0 and pull them downward. (Reprinted withpermission from Carstens MH: Functional matrix cleft repair:principles and techniques. Clin Plastic Surg 31:159, 2004.)

Failed or incomplete B fieldmigration results in acleft lip with a Simonarts band. If B fieldcontact withA0 is disrupted, downward distraction of the prolabiumis interrupted an an incomplete cleft lip results.32

Clefts of the primary palate are due to a neural crestcell defect resulting in a deficiency state in the lateralzone of theA field at the inferolateral piriform fossawhere it interfaces with the medial maxilla (B field).

Schendel, Pearl, and DeArmond36

hypothesizedthat some of the morphologic deformities associatedwith cleft lip may cause a failure of mesenchymalreinforcement of the facial processes at a criticaltime in development. The authors obtained 66muscle biopsies from cleft lip infants at the time oflip repair and noted a non-neurogenic muscle atro-phy that varied in severity, with muscle fibers nearthe cleft being most atrophic and disorganized. Theyconcluded that the abnormal muscles in cleft lip

Fig 2.Soft tissue fields of the midface. The vestibular epitheliumis from p6 non-neural ectoderm of the neural fold with supportingvestibular dermis provided by neural crest from the caudalprosencephalon (p3 zone) populates the sub-ectodermal planeand creates the dermis. The skin of the forehead, nose, col-umella, and philtrum is made from p5 epidermis; its dermis isprovided by PNC (p2 zone). Upper face skin (V2) = r2 ectoderm+ r2 RNC dermis. Lower face skin (V3) = r3. Upper facialmuscles = r4 paraxial mesoderm. Lower facial muscles = r5

paraxial mesoderm. Facial muscles have two planes. Deeporbicularis oris (DOO) exploits plane between p5 philtrum andr2 mucosa and is continuous. Superficial orbicularis oris (SOO)interfaces with p5 dermis and is discontinuous in upper lip. BothDOO and SOO are continuous in lower lip. (Reprinted withpermission from Carstens MH: Functional matrix cleft repair:principles and techniques. Clin Plast Surg 31:159, 2004.)


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deformities reflected either myopathy in the facialmesenchymal mitochondrion or at least a delay inmaturation.

Raposio and colleagues37studied the ultrastructureof orbicularis oris muscle in unilateral cleft lip patientsand detected structural alterations such as variation infiber size, increased number of mitochondria, andabnormal glycogen deposits in all specimens. Theauthors speculate that these changes are the result ofincreased oxidative metabolism and an undefinedgenetic inflammatory condition of the muscle.

Mooney et al38used 3D computer reconstructionto investigate normal and cleft lip anatomy in 29fetuses ranging in age from 1821 postgestationalweeks. The orbicularis oris muscle in the normalfetal sample with discernible lip fibers increased sym-metrically in both fiber density and complexity from

1221 weeks. In contrast, the unilateral CL/P fetalspecimens with discernible lip fibers exhibited a 3.5-week delay in overall muscle development, asym-metrical fiber distribution, and abnormal fiber inser-tions. Qualitatively there were no significant differ-ences noted in orbicularis oris muscle thickness orvolume between the normal and CL/P specimensthrough 21 weeks. These findings suggest that theorbicularis muscle deficiency noted clinically in CL/Pneonates may be a result of perinatal functiondysmorphogenesis rather than congenital mesenchy-mal reduction or deficiency.

Using ultrasound, Mooney et al39,40 also reportedsubclinical anomalies in the orbicularis oris muscle inunaffected relatives of cleft probands. Theseobservations support the role of mesenchymal defi-ciency during primary palatogenesis in the develop-ment of abnormal muscular morphology. Mesenchy-mal deficiency may also contribute to the delayedossification of primary palate seen in fetusus with clefts.41

Secondary Palate

The structures of the secondary palate include thehard palate posterior to the incisive foramen, the softpalate (velum), the alveolus and associated dentitionposterior to the incisive fissure. During week 5 ofgestation, palatal shelves begin to develop from theoral margin of the maxilla (B fields). The palatalshelves rotate and elevate from a vertical position oneither side of the tongue into a horizontal position.This process is slightly delayed in female embryos.42

Palatal shelf elevation may result from several differ-

ent mechanisms, including changes in shelf vascular-ity, increased tissue pressure, rapid differential mitoticgrowth, changes in connective tissue matrix resultingin increased hydration and swelling, cranial flexion,and mandibular descent and growth pulling thetongue forward.4247 Palatal shelf growth and eleva-

tion may be in part mediated by FGF8 and SHH,which are found along the medial edge of the max-illa.46 The right palatal shelf assumes a horizontalposition before the left palatal shelf, leaving the leftside vulnerable to interruption or interference. Thismay explain the preponderance of left-sided clefts inmammalian species.

In normal palatogenesis, the palatal shelves makeadhesive contact with each other and with the fusedmidlineA field structures (vomer) at the incisive fora-men. Apoptosis of epithelial edges is necessary formidline fusion, which progresses in an anterior toposterior direction.30 The cell adhesion moleculesyndecan, TGF-3, and N-cadherin are thought toplay a role in orchestrating shelf elevation, epithelialapoptosis, and differentiation.31 Ossification of thepalate proceeds from the lateral palatine processesduring week 8.

The soft palate is formed during week 9 by themigration of mesenchymal mesoderm from the firstand fourth pharyngeal arches into the posterior hardpalate. This results in mixed innervation ofvelopharyngeal muscles by CNV2 (tensor veli palatini)

and CNX (levator veli palatini) and others.

31

Secondary palate clefts may result from failures inpalatal shelf development, elevation, contact with eachother, contact with midline vomer, adhesion, and fusion.Tongue obstruction to shelf movement may occur dueto abnormal mandibular development or retrognathia.Wide clefts may result when palatal shelves remain in avertical position due to failure of elevation. Carstensconceptualizes palatal closure as a zipper that engagesthe two palatal shelves (B field) and the midline (Afileld) vomer at the incisive foramen and which requirescontinuous contact between structures as fusion pro-

ceeds posteriorly. Any developmental defeciency ormechanical deviation in theA or B fieldsthat preventsthe zipper from engaging all three componentsorthat causes secondary disengagement of the zipperwill create a complete or incomplete secondary palatalcleft, respectively.30

Fetuses with cleft palate without cleft lip have a U-shaped vomer without the vertical osseous footplatethat normally descends to the palatal plane.48 It isunclear whether the vomer development is abnor-


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mal due to the cleft palate or the cleft palate resultsfrom abnormalA field development.

Clefts of the primary palate may be caused byfield deficiencies that lead to secondary palate clefts.Cleft palate associated with cleft lip is usually a sec-ondary event that occurs subsequent to the primarypalate cleft, therefore cleft lip with or without cleftpalate is generally considered to be a variation of thesame developmental anomaly. Cleft palate withoutcleft lip is a midline defect and is considered to be adistinct entity with different embryonic, genetic, andanatomic characteristics from cleft palate associatedwith cleft lip.

ANATOMY

Cleft Lip and NoseThe anatomic deformities associated with cleft lip

and nose have been well described in the literature.The specific forces that cause the cleft deformity areless well understood. Whether the deformation isdue to intrinsic deficiency of the involved structuresor to a distortion of normal structures by extrinsicforces is still a matter of debate. Most likely the cleftlip and nasal deformity is some combination ofintrinsic deficiency and extrinsic forces. An under-standing of the pathologic anatomy and embryology

of clefts is critical to achieving a physiologic recon-struction of the functional matrix. Accurate restora-tion of deformed structures to their correct anatomicposition will optimize functional and aesthetic out-come as well as reduce the severity of secondarydeformities and altered facial growth.

The following description of anatomic elements inunilateral cleft liphave been adapted from Millard49

and others.5052

Cleft (Lateral) Side:

The premaxilla is outwardly rotated and project-ing.

The maxilla on the cleft side is hypoplastic andretropositioned.

The vertical height of the lip is decreased.

The superficial portion of the orbicularis oris muscleparallels the cleft margin and abnormally insertsinto the cleft side alar base.

The deep portion of the orbicularis is interruptedbut does not abnormally insert.

In incomplete clefts the muscle does not cross thecleft unless the bridge is at least one-third theheight of the lip.

Muscle continuity is disrupted in a microform cleft.

Simonarts band is a skin bridge without musclethat crosses the nasal sill.

Non-Cleft (Medial) Side:

The philtrum is shortened.

Two-thirds of the Cupids bow, one philtral col-umn, and a dimple hollow are preserved.

The musculature between the philtral midline andthe cleft is hypoplastic.

The superficial portion of the orbicularis oris muscleabnormally inserts on the cleft margin and baseof the columella.

The pathologic anatomy of thebilateral cleft lipis similar to that of the unilateral cleft. In additionthere is more shortening of the columella, and theprolabium is unique in that there is absence of philtralremnants and muscle elements.

The typical anatomy of the unilateral cleft lipnose49,5466has been characterized as follows (Fig 3):

The inferior edge of the septum is dislocated outof the vomer groove and presents with the nasalspine in the floor of the normal nostril.

The septum is deviated to the non-cleft side andconvex on the cleft side, impinging on the airway.

The base of the columella deviates toward thenon-cleft side.

There is unilateral shortness in the vertical heightof the columella.

The nasal tip is deviated to the non-cleft side, andthe dome is depressed on the cleft side.

The cleft side lower lateral cartilage is attenuated,its medial crus lower in the columella and itsdome separated and inferior to the opposite alarcartilage. The lateral segment is flattened andspread across the cleft at an obtuse angle.

The lateral crus is caudally displaced on the cleftside.


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The cleft side ala buckles inwardly (M configura-tion).

The alar rim is distorted by a skin curtain (withoutcartilage) that droops over the alar rim like a web

and further reduces the apparent height of thecolumella.

The cleft side alar base is rotated outwardly in aflare.

The alar-facial groove on the cleft side is absent.

The cleft side piriform margin and alar base aremore posterior than on the non-cleft side.

The vestibular lining is deficient on the cleft side.

There is a vestibular web inside the cleft sidenostril.

The nostril floor on the cleft side is widened.

The following are characteristic components ofthebilateral cleft lip nasal deformity:6769

A short deficient columella.

Inferiorly displaced medial crura with depressionof alar domes.

A bifid nasal tip.

Lateral displacement of both alar domes withbilateral dislocation of the lateral crura from theseptum.

Hooding of the alar rims.

Lateral displacement of alar bases with flattening

of alar-facial angle. Bilateral alar flaring.

Bilateral vestibular webs.

Slaughter and coworkers70detail the blood sup-ply of unilateral and bilateral cleft lip. Cleftinginterrupts the normal anastomoses between thesuperior labial artery, anterior ethmoidal artery,posterior septal artery, and greater palatine arteryto various degrees. In complete bilateral cleft lipthe dominant blood supply to the prolabium is via

the posterior septal artery, without other collaterals.Despite this alteration in blood supply, ischemiafrom surgical repair is seldom seen. The prolabiummay be quartered and lifted to the nasal spinewithout significant compromise to its circulation.

Using 3D stereophotogrammetry, Hood and col-leagues71 compared the soft tissue features ofinfants with unrepaired unilateral cleft lip (UCL),unrepaired unilateral cleft lip and palate (UCLP),

and normal controls. The authors found signifi-

cant differences between the UCL and UCLP

groups as well as between the cleft and controlgroups. The UCL group was similar to the control

group and both were significantly different fromUCLP for the parameter measurements of nasal

width, cleft side alar wing length, and horizontal

nasal tip displacement. Significant differencesbetween both cleft groups, and each cleft group

and the control group, were found for the param-

eters of cleft-side nostril dimensions, alar wingangulation, columellar angle, alar base to corner

of mouth, alar base width, soft tissue defect in

nose and lip, and cleft border philtrum. Theyconcluded that the use of UCL patients as controls

for UCLP studies is inappropriate.

Other notable findings include71

Increased intercanthal distance in UCLP but notin UCL patients.

Increased nasal floor width on the non-cleft sidefrom dislocation of the non-cleft side ala relative

Fig 4.The unilateral cleft nasal deformity. a.Nasal tip deviated.

b.Alar cartilage displaced caudally. c.Angle between medial

and lateral crura more obtuse. d.Buckling in lateral crura. e.

Flattened alar facial angle. f.Deficiency in bony development.

g.Widened nostril floor. h.Columella and anterior caudal

septal border deviated. i.Posterior septum convex on cleft

side causing varying degrees of obstruction. (Reprinted with

permission from Spira M, Hardy SB, Gerow FJ: Correction of

nasal deformities accompanying unilateral cleft lip. Cleft

Palate J 7:112, 1970.)


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to the columellar base. Because the non-cleftside nostril is often used as a reference duringprimary nasal correction, this abnormal increasein nostril dimension must be taken into accountlest it contribute to secondary nasal deformity.

Significantly shorter philtral column on the non-cleftside in UCL (but not UCLP) patients than in con-trols. Significant shortening of the philtral columnon the cleft side in both UCL and UCLP patients.

Zemann et al72 used a computer-aided 3D-operation simulator (3D Cosmos) to analyze facialasymmetry in 3D-CT scan-derived models of 21

patients with unrepaired unilateral cleft lip and pal-ate (Fig 4). The infraorbital rims were displaced

craniocaudally (caudal in 47%, cranial in 33%) and

horizontally (posterior in 71%) on the cleft side. Thecleft side lateral piriform aperture was dislocated lat-erally (100%), dorsally (52%), and caudally (58%).Lateral translocation of the maxillary segment wasnoted in 100% of patients.

Fig 5.Midface asymmetry in patients with unilateral cleft of lip,alveolus and palate - frontal view. (Reprinted with permissionfrom Zemann W, Santler G, Krcher H: Analysis of midfaceasymmetry in patients with cleft lip, alveolus and palate at theage of 3 months using 3D-COSMOS measuring system. JCraniomaxillofac Surg 30:148, 2002.

On the basis of an anatomic study, Mulliken etal73report that the normal vermilion is widest at thepeaks of Cupids bow. On sagittal section beginning

anteriorly at the white roll and proceeding orally, thevermilion mucosa exhibits progressively increasingepidermal thickness and size of rete ridges, decreas-ing melanin, more superficial capillaries, and anabrupt transition from keratinized to nonkeratinizedsquamous epithelium (red line of Noordhoff74). In

unilateral cleft lip specimens there isdecreased ver-milion width on the medial side of the cleft andnormal to slightly increased width of vermilion later-ally. The entire prolabial vermilion component ofbilateral cleft lip specimens is hypoplastic. Theauthors73endorse Noordhoffs74recommendation ofa lateral vermilion flap to augment the deficientmedial vermilion in cleft lip repair.

Muscle Anatomy

The modern trend toward radical muscle mobi-lization in the surgical repair of unilateral cleftlip51,7577is based on evidence of the importanceof the muscle anatomy in both the lip and nasaldeformity. A pictorial summary of cleft muscleanatomy is found in Fig 5 from Millard.49,67

The normal orbicularis oris muscle is composed ofa superficial and a deep component. Lightoller78

designated these components as the pars marginalisand the pars superficialis.

Nicolau51details the specific characteristics of thedeep and superficial portions of the orbicularis oris

(Fig 6). The deep component originates from themodiolus and its continuous horizontal fibers crossthe midline to the opposite commissure just superfi-cial to the labial mucosa. The deep componentfunctions in catching food with a general sphinctericactivity and works in association with the other mus-cular loops of the oropharynx. Its lower border curlsupon itself, forming the vermilion by everting themucous membrane. Mulliken73concluded that theanterior projection of the pars marginalis of theorbicularis oris muscle gives rise to the white roll atthe cutaneous-vermilion junction.

The superficial orbicularis oris muscle functions infacial expression and speech.51 It originates from themuscles of facial expression and consists of an upperand lower bundle. The lower or nasolabial bundlederives its fibers from the depressor anguli oris muscleand inserts in the skin forming the philtral ridges.The upper or nasal bundle represents the commoninsertion of the fibers of the zygomaticus major andminor, levator labii superioris, levator labii superioris


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alaeque nasi, and transversus nasi and inserts intothe anterior nasal spine, the septo-premaxillary liga-ment, and the nostril sill, passing deep to the alarbase.51According to Nicolau,51in the cleft lip defor-mity the deep sphincteric part of the muscle doesnot reach the extremity of the interrupted vermilion.

The muscle fibers are not distorted by the cleft, butsimply interrupted. They end on either side of thecleft at the point where the skin/vermilion ridgewhite roll of Gilliesbecomes thin.

Mulliken et al73detailed the gross and microscopicanatomy of the white roll in infants with normal andcleft lips. The white roll narrows and disappearssuperiorly along the medial and lateral border of theunilateral cleft. The deficiency of the white roll was

more severe in the more complete clefts; no whiteroll was seen in the prolabial segment of complete

bilateral clefts. A normal or hypoplastic white rollwas seen in the prolabium of incomplete bilateralclefts. Where the white roll is absent, there ishypoplasia and disorientation of the underlyingpars marginalis component of the orbicularis orismuscle.

Fara50describes the anatomy of superficial orbicu-laris oris muscle in the unilateral cleft lip. On thecleft side the medial nasolabial bundle is misdirectedvertically, parallels the cleft margin, and attaches tothe nostril and the periosteum of the piriform aper-ture. Contraction results in a marked lateral bulge.The cleft disrupts the normal bilateral insertion of thenasolabial bundle and the fibers crossing through thepreserved philtral ridge on the non-cleft side parallelthe cleft and insert into the cleft edge and columella.The nasal bundle on the cleft side exerts a lateraland upward force which contributes to the cleft sidenasal deformity. The nasal bundle on the non-cleftside appears normal, as its most medial insertionpoint is the nasal spine. Nevertheless, its unopposed

Fig 7. Anatomy of the lip musculature.

Fig 6. The soft tissue deformity in (A)unilateral and (B)bilateral

cleft lip. (Reprinted with permission from Millard DR Jr: CleftCraftThe Evolution of Its Surgery. I. The Unilateral Defor-mity. Boston, Little Brown, 1976; and Cleft CraftThe Evolu-tion of Its Surgery. II. Bilateral and Rare Deformities. Boston,Little Brown, 1977.)


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lateral and upward pull might contribute to the ante-rior septal deformity.

Dado and Kernahan79review the anatomic andhistologic findings in clinical cleft lip specimens anddescribe differences between their observations andFaras.50 The authors note that the muscle bulge in

complete and incomplete cleft lips consists of a hap-hazard arrangement of muscle fibers running trans-versely, obliquely, and anteriorly to posteriorly. Incontrast to Faras report, Dado and Kernahan79foundno distinct muscle bundles paralleling the cleft mar-gin and inserting into the alar base and columella.

Delaire80 identified the importance of the paranasalmuscle in the cleft deformity and their influence onfacial growth. The normal course of the paranasalmuscle spans around the ala to the anterior nasalspine. The interruption of the paranasal muscle

insertion in cleft patients contributes to the nasaldeviation and requires reconstruction. Joos81 fur-thers Delaires concepts using MRI studies to dem-onstrate that the lateral nasal muscles, particularly atthe spina nasalis, run in a stepwise manner dorsallythrough the nasal floor and insert into the nasal sep-tum. This explains why the caudal septum deviatesto the non-cleft side, where the muscles insert, in aunilateral cleft lip deformity.

On the basis of microsurgical dissections,Breitsprecher et al82 conceptualize the muscles offacial expression as the integration of a 3-dimensional

system of 5 muscle slings. The perinasal, perioral,oromandibular, orozygomaticomaxillary, andorobuccopharyngeal slings are bilateral, symmetricstructures that utilize the anterior nasal spine, carti-laginous septum, and medial alar cartilages as their

center points. The muscle slings connect the carti-laginous septum with the zygomalicomaxillary suturesystem and the periosteal growth fields of the nasalbones, maxilla, and mandible. In the complete cleftlip deformity all muscle slings, their symmetry, powervectors, and perichondrial and periosteal attachments

are disturbed, as follows:

On the non-cleft side, the muscle insertions tothe maxilla and nasal cartilages are normal exceptfor the pars marginalis of the orbicularis oris, whichhad an abnormal connection to the nasal spineand base of the septal cartilage.

The center point muscle insertions are dislo-cated toward the non-cleft side.

The muscle mass on the non-cleft side was greaterthan on the cleft side.

On the cleft side the orbicularis oris paralleledthe cleft margin and had a pathologic maxillaryinsertion at the lateral osseous cleft margin fromthe alveolus up to the piriform fossa.

The size and composition of the nasal cartilageswere normal but misshapen and dislocated tothe non-cleft side according to the position of theanterior nasal spine and the pathologic powervector of the facial muscles.

Cleft Nasal DeformityHogan83saw the unilateral cleft nasal deformity as a

tilted tripod (Fig 7). Maxillary hypoplasia on the cleftside (the short limb of the tripod) results in the charac-teristic bending of the nasal septum and alar cartilages.

Fig 8.The tilted tripod.A, The normal nose.B, Tilting effect resulting from maxillary hypoplasia with secondary deformity of the septum andcleft ala. C, More dramatic convex deformity and vertical bending of the septum, causing it to bend toward the normal nostril. (Reprintedwith permission from Hogan VM: The tilted tripod: A theory of unilateral cleft lip nasal deformity. In: Hueston JT (ed), Transactions ofthe Fifth International Congress of Plastic and Reconstructive Surgery, Melbourne, 1971. Butterworths, Australia, 1971.)


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Fisher and Manns84 model of the cleft nasaldeformity simplifies the lobule into four arches. Theaccessory cartilages join the lateral crus to the edgeof the piriform aperture and contribute to a continu-ous cartilaginous arch from the base of the columellato the piriform margin. This cartilaginous ring is des-

ignated as the oblique arch because of its obliqueand vertical position relative to the alar rim, whichlies horizontally. The soft tissue of the alar rim com-poses the horizontal arch. The paired oblique andhorizontal arches of the model respond predictablyto extrinsic changes in their skeletal foundation.

Maxillary hypoplasia and the posterolateral dis-placement of the piriform rim distort the nasal tipand ala via the oblique arch that connects thenasal cartilage with the maxilla via the accessorycartilages. This relationship is seen in the isolated

cleft lip nasal deformity (without cleft lip). The nasaldeformity is more severe when accompanied by cleftlip because of the unopposed and pathologic actionof the orbicularis.

According to this model, the vestibular web iscaused by a vestibular fold created by posterolateraltethering of the oblique arch and outward rotationof the overlying ala, which exposes the vestibularlining on inferior view. The authors conclude thatthe abnormal position and extrinsic forces acting onthe nose can reproduce the cleft nasal deformity,but that hypoplasia and intrinsic deficiency of nasal

structures cannot be excluded.84Byrd85 found a hypoplastic lower lateral cartilage

in a stillborn infant with complete cleft lip and pal-ate. The cleft-side lower lateral cartilage showedhypoplasia of both medial and lateral crura com-pared with the non-cleft side (Fig 8 ).85

Park and colleagues86argue that the lateral crus ofthe lower lateral cartilage on the cleft side is nothypoplastic. During primary rhinoplasty of 55 uni-lateral cleft lip nose patients, the authors measuredthe lateral crus of the lower lateral cartilage on both

sides. On the cleft side, the midportion of the lateralcrus appeared to be thicker and wider than in thenoncleft side. No histologic differences were foundbetween the lateral crura of either side. They con-cluded that the cleft lip nasal deformity is caused byexternal factors rather than intrinsic factors.

Li et al87analyzed the cartilaginous framework ofthe cleft nasal deformity in 6 stillborn infants andreported pathologic displacement of the cleft sidelower lateral cartilage in a ventral, lateral, and cau-

dal direction (Fig 9). The nasal length was greater onthe cleft side, with loss of the normal overlap betweenthe lower and upper lateral cartilages. The upperlateral cartilage on the cleft side and the nasal dor-sum were deviated to the non-cleft side. The authorsdid not find a statistically significant difference in sizeor weight of the lower lateral cartilages and con-cluded that the cleft nasal deformity is secondary todisplacement and not hypoplasia.

Cleft Palate

The normal hard palate is composed of the pre-maxillary portion of the maxilla anterior to the inci-sive foramen, the palatine process of the maxilla,and the palatine processes of the palatine bone. Thepalate separates the oropharynx and nasopharynx.The oronasal surface is covered with a dense muco-periosteal layer. In the normal palate the vomer isfused to the midline.

The soft palate (velum) is made up of 6 pairedmuscles involved in velopharyngeal closure. These

muscles interdigitate to form a muscle sling that sepa-rates the oropharynx and nasopharynx; this separa-tion is necessary for proper phonation, swallowing,and breathing. The muscles of the normal velum areas follows:

Levator veli palatini (LVP): Originates from tem-poral bone and eustachian tube. The mainbundles of these bilateral muscles interdigitate atthe midline behind the palatal aponeurosis to

Fig 9.Lower lateral cartilages of left complete cleft lip and palatein stillborn infant demonstrating hypoplasia of both the medialcrus and lateral crus on the affected side. (Reprinted withpermission from Byrd HS, Salomon J: Primary correction of theunilateral cleft nasal deformity. Plast Reconstr Surg 106:1276,2000.)


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form a sling. A small bundle of fibers runs in an

anterolateral direction and inserts on the palatineaponeurosis via a number of fine tendons.87.5 TheLVP muscle elevates the velum and pulls it poste-riorly; it may also contribute to medial move-ment of the lateral pharyngeal wall.

Tensor veli palatini (TVP): Arises from membra-nous wall of eustachian tube, its tendon passesaround the pterygoid hamulus and gives rise tothe palatal aponeurosis, which fuses to the poste-rior hard palate. Opens the eustachian tube.

Uvulus: Extends behind the levator to the tip of

the uvula. Elevates and shortens the uvula. Palatopharyngeus: Arises from posterior pharynx,

passes through posterior tonsillar pillar and insertson velum. Depresses the velum.

Palatoglossus: Originates from tongue, passesthrough anterior tonsillar pillar, and inserts onanterior velum. Depresses the velum.

Superior constrictor: Broad muscle courses ante-riorly within the pharyngeal wall to attach to the

velum. Moves the lateral pharyngeal wall towardthe midline.

The greater palatine artery (from the maxillaryartery) and greater palatine nerve (CN V) via greaterpalatine foramen respectively perfuse and innervate

the hard palate. The nasopalatine nerve (CN V)communicates with the greater palatine nerve at theincisive foramen to supply the premaxilla. The lesserpalatine artery (from the maxillary artery) and nerve(CN V) via the lesser palatine foramen supply the softpalate. The ascending pharyngeal artery (externalcarotid) and ascending palatine branch of the facialartery contribute to blood supply of lateralvelopharyngeal structures. The muscles of velum areinnervated by the pharyngeal plexus (CN IX, X, withcontributions from CN XI), except for the tensor veli

palatini which is supplied by CN V.Veaus20 original description of the pathologicanatomy in cleft palate is still valid today. Figure 10illustrates the normal and cleft palate anatomy.88

In unilateral clefts the non-cleft side of the palateis fused with the vomer, while in bilateral clefts thereis no fusion between the palate and the vomer. Non-cleft lip-related clefts of the secondary palate aremidline deformities associated with a high and hypo-plastic vomer.

In soft palate clefts, the levator veli palatini andother velar muscles do not join at the midline to

form a sling, but run parallel to the cleft margin andabnormally insert into posterior margin of hard pal-ate. The disruption of normal muscle insertion invelar clefts leads to impaired velopharyngeal andeustachian tube function. Necropsies of 22 stillborninfants, 18 of whom had palatal clefts, showed theforemost pathologic features of the cleft velum werehypoplasia and atypical insertion of the muscles ofvelopharyngeal closure, which correlated with sever-ity of the cleft.89 Mutual conjugation of the levatorand tensor muscles anteriorly with the palatopharyn-

geus muscle posteriorly was typical of cleft palate.89

Lindman and colleagues90compared the levatorveli palatini muscle morphology of infants with cleftpalate and normal adults. The LVP muscle fromcleft infants had a smaller mean fiber diameter, largervariability in fiber size and form, a higher proportionof type II (fast) fibers, more fast myosin heavy chain(MyHC) protein isoforms, and a lower capillary densitythan that of normal adult controls. One-third of cleftsamples contained only a small amount of muscle tis-

Fig 10.The measurement and position of the cartilages of the leftunilateral cleft lip nose. DCC,distance between the caudal edgesof the alar cartilages in the craniocaudal plane; DDV,distancebetween the highest parts of the domes of the alar cartilages in thedorsoventral plane; DAM,distance from the angle of the alarcartilage to the midline; WLC,width of the lateral crura at themidpoint; WMC,width of the medial crura at the midpoint.(Reprinted with permission from Li AQ, Sun YG, Wang GH, et al:Anatomy of the nasal cartilages of the unilateral complete cleftlip nose. Plast Reconstr Surg 109:1835, 2002.)


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sue or none at all. It is unclear whether these differ-ences are due to the different stages of maturationbetween the infant and adult samples, changes in func-tional demand with growth, or the pathology of thecleft. Both the cleft infant and adult samples lackedmuscle spindles, which are sensory receptors for theregulation of tension and speed of contraction.90

The role of muscle spindles in palatal muscle has notbeen determined. Kuehn91 reported a lack of musclespindles in human LVP, but Liss92found numerous small

and unusual muscle spindles. Animal studies have sug-gested that the motor and proprioceptive innervationof LVP muscle spindles may be abnormal or congeni-tally absent in cleft palate patients.93Abnormal inner-vation of the cleftneurogenicpalate can result invelopharyngeal insufficiency.

CLASSIFICATION

A common classification terminology for clefts hasbecome widespread, but despite the development

of numerous diagrammatic classification schemes,none have become standard.

Terminology

The American Cleft Palate-Craniofacial Associa-tion (ACPA) common classification for clefting usesthe terms primary and secondary palate to definethe cleft.94 The primary palate includes the struc-tures anterior to the incisive foramen (lip and alveo-

lus) and the secondary palate includes structures pos-terior to the incisive foramen (hard palate, soft pal-ate, and uvula). Any cleft of the primary or second-ary palate can be complete (involving the entire ana-tomic structure) or incomplete (involving only part ofthe anatomic structure). Any cleft of the primary orsecondary palate may be bilateral or unilateral.

Several notable cleft variations are inadequatelydifferentiated in this basic system of classification.They include the following:

Microform(forme fruste) cleft lip deformity is amild incomplete cleft lip characterized by (1) aband of fibrous tissue or furrow extending fromthe vermilion to the nasal floor; (2) a vermilionnotch; (3) some degree of ipsilateral vertical lipshortness; (4) ipsilateral alar deformity.

Isolated cleft lip nasal deformityis character-ized by the classic features of the cleft lip nasaldeformity but is not accompanied by an overt lipcleft.

Submucous cleft palate is a deformity of thesecondary palate that was first described byRoux95in 1825. Calnan96listed the three diag-nostic signs of submucous cleft palate as follows:a bifid uvula, notching of the posterior border ofthe hard palate, and muscular diastasis of the softpalate with an intact mucosal layer. All threesigns do not need to be present for a diagnosis ofsubmucous cleft palate.97,98 In fact, in a study byVelasco and colleagues99the only consistent find-

Fig 11.Anatomy of theA,normal and B,cleft palate. a,tensor palati; b,hamulus; c1and c2,palatopharyngeus, horizontal and verticalfibers; d,levator palati; e,superior pharyngeal constrictor. (Reprinted with permission from Ross RB, Johnston MC: Cleft Lip and Palate.Baltimore, Williams & Wilkins, 1972. Ch 5, pp 68-91.)


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ing of submucous cleft palate was notching in thehard palate. The development of velopharyngealinsufficiency (VPI) is the only indication for surgi-cal intervention.

Binderoid complete cleft lip and palateis a term

used by Mulliken to describe a cleft variant asso-ciated with nasolabiomaxillary hypoplasia andorbital hypotelorism.100 This deformity has alsobeen called a pseudomedian cleft101 and hasbeen described by Noordhoff as median facialdysplasia102in cleft lip and palate. It is charac-terized by a flat nasal bridge, hypoplastic septaland alar cartilages, deficient columella, poorly-defined Cupids bow, diminutive premaxilla, thinvermilion mucosa bilaterally, short lateral lip seg-ments, absence of a labial frenulum and anteriornasal spine, and oligodontia.100,102 Head circum-

ference and intelligence are normal and there isno associated holoprosencephaly or brain abnor-mality.

Median cleftis a midline cleft of the lip +/- palatethat is frequently associated with other midlinedevelopmental defects, particularly of the CNS.This rare deformity is considered to be part of theholoprosencephaly spectrum usually with associ-ated nasal deformity and hypertelorism.

Cleft Diagrams

Kernahans striped Y diagrammatic classifica-tion103 (Fig 11) is popular but incomplete. In thisscheme each limb of the Y has three boxes. Stip-pling of a box signifies a cleft in that area, and cross-hatching means a submucous cleft.

Diagram key:

boxes 1 and 4 represent the lip

boxes 2 and 5 represent the alveolus

boxes 3 and 6 represent the hard palate anterior

to the incisor foramen boxes 7 through 9 represent the palate posterior

to the incisor foramen

box 9 represents the soft palate.

Smith, Khoo, and Jackson104proposed a modifi-cation of Kernahans striped Y classification that moreaccurately describes all varieties of cleft with analphanumeric system, as follows (Fig 12):

All right-sided clefts are designated by numeralswithout prime and left-sided clefts by numeralsthat are primed. For example, 1 means a com-plete right cleft lip and 1 means a complete leftcleft lip.

Incomplete cleft lips vary from microform to one-third to two-thirds, and these are classified as acand ac for right and left, respectively.

Fig 12. The striped Y system in various types of cleft palate.(Reprinted with permission from Kernahan DA: The striped Y. Asymbolic classification for cleft lips and palates. Plast ReconstrSurg 47:469, 1971.)


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Lips with Simonarts band are classified as d.

The alveolus is documented as 2 or 2. No allow-ance is made for minor degrees of clefting of thealveolus, as this has little bearing on manage-ment.

The palate anterior to the incisive foramen andposterior to the alveolus is documented as 3 or3.

The secondary palate is subdivided into three seg-ments based on the anatomic segments involvedin the cleft. The number 4 denotes a cleft up tothe palatine process of the maxillary bone, 5 is acleft up to the palatine process of the palatinebone, 6 is a cleft including the soft palate only,and the letter a denotes a submucous cleft.

Ortiz-Posadas and coworkers105 developed amathematical scheme for cleft classification that yieldsa numeric score. Different types of primary andsecondary clefts are scored according to cleft sever-ity, cleft width, and bilaterality. Aesthetic features ofthe lip and nose are assessed separately. Wide-spread acceptance of a classification scheme thataccounts for cleft width or palatal segment separa-tion would improve the accuracy of outcome com-parisons.

Despite its lack of completeness, the Veau classifi-cation described in 1931 is commonly used in theliterature to compare the outcomes of cleft palaterepair.106Veaus classification includes:

Class I Cleft of soft palateClass II Cleft of hard and soft palateClass III Unilateral complete cleft lip and palate

Class IV Bilateral complete cleft lip and palate

EPIDEMIOLOGY

The overall incidence of oral clefts (excluding bifiduvula) is estimated to be 1 in 750 live births, makingclefts the second most common congenital defect afterclubfoot.107 The most common type of oral cleft is abifid uvula, occurring in 2% of the population.108

A survey by Fraser and Calnan109 found 21% ofcases had isolated cleft lip, 46% had cleft lip and

palate, and 33% had isolated cleft palate. CL/P isunilateral in 80% of patients and bilateral in 20%. Asfor site of occurrence, left-sided clefts were twice asfrequent as right-sided clefts and 6 times more fre-quent than bilateral clefts, for a 6:3:1 ratio.110 Iso-lated cleft lip without cleft palate is typically unilateral(80%) and on the left side (70%).111 Approximately10% of cleft lips are incomplete.111 Bilateral CL isassociated with CP in 86% of cases, whereas 70% ofunilateral lip clefts are accompanied by cleft palate.112

Cleft lip with or without cleft palate (CL/P) showsevidence of racial heterogeneity. A 1993 U.S. sur-vey found oral clefts in about 1 in 700 total births,with the highest incidence among Native Americans(3.6 in 1000).113The mean incidence in Japan isapproximately 2.1 in 1000 live births; in China, 1.7in 1000; in Western European whites, 1 in 1000;and in African-Americans, 0.41 in 1000.114116 Arelatively high incidence of CL/P has been reportedin Scandinavian countries117120eg, 1.41.5 per1000 births in Denmark.

Fig 13. The modified Y system in various types of cleft palate.(Reprinted with permission from Smith AW, Khoo AKM, JacksonIT: A modification of the Kernahan Y classification in cleft lipand palate deformities. Plast Reconstr Surg 102:1842, 1998.)


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A recent study of the epidemiology of clefts in Paki-stan lists an incidence of CL/P of 1.91 per 1000 births.121

Unlike previous reports from different populations,isolated cleft lip occurred more frequently than CLPand isolated CP in the Pakistani population, at 42%,34%, and 24% respectively. In Glasgow,122 CP was

more prevalent than either CLP or isolated CL. It islikely that environmental factors play a role in theincidence and distribution of cleft types among differ-ent populations with varying susceptibilities.

There appears to be less racial heterogeneity inisolated cleft palate (CP), which has an average inci-dence of 0.5 in 1000 births among the races. Theincidence of submucous clefts of the palate is 1 in1200 to 1 in 2000 births. Unlike other isolated cleftsof the secondary palate, the incidence of uvular cleftsvaries with race, being highest in Native Americans (1

in 9 births) and relatively low in whites (1 in 80 births).111

Fogh-Andersen117also reported in his thesis thatCL/P occurs more frequently in males, whereas CPoccurs more frequently in females. Males predomi-nate in isolated cleft lip without cleft palate (60%) andwith cleft palate (67%).111 In contrast, complete cleftsof the secondary palate are twice as common in femalesas in males, and the incidence of isolated soft palateclefts is approximately the same for the sexes.111

Bagatin123 surveyed 9720 schoolchildren fromYugoslavia and discovered submucous cleft palate in5 and cleft uvula in 232, for an incidence of submu-cous cleft palate of 0.05% or 1 in 1944. An earlierstudy by Weatherley-White et al124found 9 cases ofsubmucous cleft palate in 10,836 children, for an

incidence of 1 in 1200.Gosain and colleagues125investigated the relation-

ship between isolated cleft lip and submucous cleftpalate. In a double-armed prospective trial, a studygroup of 25 consecutive infants with isolated cleft lipwere compared with a control group of 25 infantswithout facial cleft. The overall prevalence of submu-cous cleft palate in the study group patients was 56%.No submucous cleft palate was found in the controlgroup. Among 17 patients with cleft lip and alveolarcleft the prevalence of submucous cleft palate was

53%, leading the authors to recommend careful evalu-ation for submucous cleft palate and VPI in infantswho appear to have an isolated cleft lip.

RISK ASSESSMENT

Fraser126summarizes the standard risks of CL/P andCP given several family situations (Table 2). Becausethe frequency of isolated cleft palate is not increased

TABLE 2

Counseling Risks for Cleft Lip with and without Cleft Palate (CL CP) and Cleft Palate (CP)for Various Situations

(Reprinted with permission from Fraser FC: Etiology of Cleft Lip and Palate. In: Grabb WC, Rosenstein SW, Bzoch KR (eds), Cleft Lipand Palate. Surgical Dental, and Speech Aspects. Boston, Little Brown, 1971.


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in relatives of patients with cleft lip +/- cleft palate andvise versa, the consensus is that CL/P constitutes agenetically different entity from isolated CP.126

The frequency of CL/P is about 4% in siblings andchildren of patients and drops off exponentially, notlinearly, as the degree of relationship decreases. On

the other hand, the 4% frequency in siblings of affectedcases with normal parents increases to about 9% infamilies that have 2 affected children (Table 3).126

TABLE 3Frequency of Cleft Lip with and without Cleft Palate

(CL+/-P) in Relatives of Persons with CLP and ofCleft Palate (CP) in Relatives of Persons with CP

(Reprinted with permission from Fraser FC: Etiology of Cleft Lipand Palate. In: Grabb WC, Rosenstein SW, Bzoch KR (eds), CleftLip and Palate. Surgical Dental, and Speech Aspects. Boston,Little Brown, 1971.)

The risk to relatives also increases with severity of

the cleft. While siblings of a child with unilateral CLhave a cleft risk of about 2.5%, when the affectedchild has unilateral cleft lip and palate the risk tosiblings becomes 4.2%, and with bilateral CLP, it is5.7%.127

When CL/P occurs as part of a syndrome, the CL/P recurrence risks are considerably higher.120 Geneticcounseling for patients with orofacial clefts dependson whether the cleft is syndromic, nonsyndromic,familial, or non-familial.

ETIOLOGY

In a review of the etiology of facial clefting, Jones128

traces the epidemiologic history of cleft lip and pal-ate to the work of Fogh-Anderson129in the 1940s,which indicated that CL/P is distinct from isolatedCP but both tend to cluster in families. Fogh-Anderson129found the disorder to be familial twiceas often in CL/P as in CP alone, and Joness128seriesconfirms these numbers. The concordance rate of

CL/P in monozygotic twins is 36% versus 4.7% indizygotic twins.130 Overall, approximately 33%131to36%128of cases of CL/P or CP have a positive familyhistory.

Orofacial clefts can occur as part of a mendeliansyndrome, as part of a phenotype resulting from

chromosomal anomalies, or as a result of exposureto a teratogen. Orofacial clefts are part of the phe-notype of more than 300 syndromes. Approximatelyhalf of these syndromes are due to mendelian inher-itance of alleles at a single genetic locus.31 Themajority of orofacial clefts, however, are not associ-ated with a syndrome, and only a few have a knownetiology.

Many different genetic and environmental factorshave been implicated in the complex etiology oforofacial clefts. Recent studies of the etiology of

nonsyndromic clefts focus on candidate genes asso-ciated with craniofacial development, genes influ-enced by environmental teratogens or deficiencies,and genes associated with syndromic clefts.

Genetic Factors

Cleft deformities are either syndromic ornonsyndromic. Approximately 30% of oral clefts areassociated with a syndrome and 70% are non-syndromic.132 A cleft is syndromic if there is morethan one malformation involving more than one

developmental field. A cleft is nonsyndromic if thereis only one defect or multiple anomalies that are theresult of a single initiating event or primary malfor-mation.133

Syndromes

Syndromic oral clefts may occur as part of amendelian disorder (ie, resulting from a single genedefect); may arise from a chromosomal abnormal-ity; as part of a syndrome associated with a known

teratogen; or as part of an uncharacterized syn-drome. The London dysmorphology databaseincludes 171 syndromes with cleft lip: 64 are auto-somal recessive syndromes, 35 are autosomal domi-nant syndromes, and 6 are X-linked syndromes.130

Syndromes with oral clefts in the phenotype havebecome an important tool for elucidating the com-plex genetics of nonsyndromic oral clefts. Some ofthe major syndromes associated with oral clefts arelisted in Table 4.133


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To determine the frequency of multiple malfor-mation syndromes among patients with oral clefts,Jones128 derived data from 963 consecutive patientsgrouped by cleft type. A child was considered tohave a syndrome if in addition to the cleft there weretwo or more major malformations or three or moreminor malformations not explained by the family

background. Data analysis showed that syndromeswere clearly more common in isolated CP (41.8%)than in CL/P (13.8%). For the 79 syndromic CL/Ppatients, recognizable patterns of malformation wereidentified in 57%.128

In Christensens120 review of cleft epidemiology inDenmark, 6.4% of patients with CL/P had an associ-ated syndrome whereas 15.1% of patients with CPhad an associated syndrome.

Pierre Robin Sequence

A combination of anomalies that were once con-sidered a syndrome are now known as the PierreRobin sequence (PRS). The constellation of findingsin Pierre Robin is considered a sequence and not a

syndrome because it is thought that one malforma-tion or extrinsic factor causes this pattern of anoma-lies. However, PRS is frequently associated with morethan 18 different syndromes and shows great etio-logic heterogeneity.

The characteristic features of PRS are micrognathia,glossoptosis, and airway obstruction. An associatedU-shaped cleft palate is present in about 50% ofcases.134,135 Randall136,137 contends that retrogenia, notmicrognathia or retrognathia, better describes thecondition of the jaws in the disorder, as it is theposterior displacement of the chin that predisposes

to glossoptosis.The glossoptosis in Pierre Robin can begin a vicious

sequence of events: airway obstruction, increasedenergy expenditure, and decreased caloric intakefrom impaired feeding. Afflicted infants typically failto thrive because of respiratory and feeding difficul-ties. Prone positioning is often effective conservativetreatment to open the airway by reducing theobstruction caused by the glossoptosis. For infantsthat do not improve with conservative treatment,distraction osteogenesis now provides an alternative

to tracheostomy for addressing airway obstruction.The embryologic cause of PRS is either failure of

the tongue to descend or restriction of mandibulardevelopment. The position of the tongue preventshorizontal movement of the lateral palatal shelvesand results in cleft palate. The sequence has alsobeen associated with oligohydramnios and amnioticbands. The sequence occurs in 1 in 2000 to 1 in3000 births. The most common syndrome with PierreRobin sequence is Stickler syndrome.111

Stickler Syndrome(Hereditary Arthro-ophthalmopathy)

The most common recognized disorder in the cleftpalate population is the Stickler syndrome. It accountsfor 17.524% of patients with syndromic cleft pal-ate.138 The characteristic pattern of anomaliesincludes Pierre Robin sequence (cleft palate,glossoptosis, and retrogenia/micrognathia), ocularabnormalities, hearing loss, and arthropathies.

TABLE 4Some Major Syndromes Associated with Cleft Lip

and/or Palate

(Reprinted with permission from Batra P, Duggal R, Parkash H:

Genetics of cleft lip and palate revisited. J Clin Pediatr Dent27(4):311, 2003.)


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Approximately 25% of cases exhibit a midline cleftpalate.139

Stickler syndrome is an autosomal dominant dis-order of collagen connective tissue. It has variableexpression and is subdivided into types 1 and 2 onthe basis of the vitreoretinal phenotype in the eye.

The systemic features of both types are similar.Approximately 75% of affected individuals have type1 and demonstrate linkage to the COL2A1 genewhich encodes type II collagen.139 The type 2 Stick-ler phenotype is associated with mutations in theCOLIIA1 gene which encodes the a1 chain of typeXI procollagen.139

The ocular malformations typically begin in thefirst decade of life and can ultimately progress toblindness if untreated. Children with Pierre Robinsequence should have ophthalmologic screening and

routine follow-up to prevent visual impairment.

Van der Woude Syndrome

Van der Woude syndrome (VDWS) is an autoso-mal dominant disorder with a variable phenotype.The syndrome is characterized by bilateral lower lippits, cleft lip with or without palate (2/3) or isolatedcleft palate (1/3), and hypodontia.140143 Van derWoude syndrome is the most frequent cause ofsyndromic CL/P and accounts for 2% of all CL/Pcases.142,144 The genetic penetrance of this syndrome

is 70100%140,141and expressivity is variable. VDWSis familial in 61% of patients.142,145

The VDWS locus has recently been mapped tothe interferon regulatory factor-6 (IRF6) gene at1q32.146,147 Mutations at this site are the cause ofVDWS. This locus is now being investigated for itsinvolvement in nonsyndromic oral clefts.

Ectrodactyly-Ectodermal-Dysplasia-CleftingSyndrome

Ectrodactyly, ectodermal dysplasia, and clefting(EEC) syndrome has a variable phenotype but is mostcommonly characterized by the lobster claw anomalyof all four extremities, bilateral cleft lip and palate,and ectodermal dysplasia (abnormal hair, teeth, skin,nails, and/or lacrimal ducts).111

Hay-Wells syndrome, also known as ankylo-blepharon-ectodermal dysplasia-clefting or AEC syn-drome, is characterized by ectodermal dysplasia, cleftlip/palate, and congenital adhesions between the eye-

lids. Both EEC syndrome and Hay-Wells syndromeare variable autosomal dominant disorders that canbe caused by mutations in the gene p63 localized to3q27.130,148,149 The p63 gene is being investigated asa candidate gene in the etiology of non-syndromicoral clefts.

Velo-Cardio-Facial (Shprintzen) Syndrome/22q11Deletion

Velo-cardio-facial (VCFS or Shprintzen) syndromeis an autosomal dominant disorder with an estimatedincidence of 1 in 4000 live births.150 The constella-tion of anomalies is variable but almost alwaysincludes velar dysfunction, which ranges from a com-plete secondary palate cleft to velopharyngeal insuf-ficiency with a normal-appearing palate. Other char-acteristic findings include abnormal facies (maxillary

excess, malar flattening), cardiovascular abnormali-ties, and developmental delay. The carotid arteriesare frequently tortuous and medially displaced tothe posterior pharyngeal wall, which can cause con-cern when performing a pharyngeal flap orpharyngoplasty.

Genetic studies have associated VCFS with a chro-mosomal deletion at 22q11.151 Other syndromeshave been associated with a deletion at 22q11,including DiGeorge syndrome (DGS) and conotruncalanomaly face syndrome (CAFS). The overlap and

variation in the phenotype associated with the 22q11deletion has given rise to the inclusive CATCH 22syndrome, which is an acronym for all of the associ-ated anomalies found in VCFS, DGS, and CAFS:cardiac defects, abnormal facies, thymic hypoplasia,cleft palate, and hypocalcemia. The diagnosis canbe made by means of fluorescence in situ hybridiza-tion (FISH) testing.

Vantrappen et al151 reviewed 130 cases of VCFSdiagnosed by the presence of the 22q11 deletion.Because of the variable phenotype, severity of anoma-lies, and age of presentation, many patients were not

appropriately diagnosed until adulthood. Theauthors recommend that all children who presentwith velopharyngeal dysfunction, which is one onthe most consistent findings in VCFS, should bescreened for the 22q11 deletion.

Blepharo-Cheilo-Dontic Syndrome

In 1996 Gorlin and others152 coined the termblepharo-cheilo-dontic syndrome for a distinct con-


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dition characterized by abnormalities of the eyelids(euryblepharon, ectropion of the lower eyelids,distichiasis of the upper eyelids, lagophthalmia), teeth(oligodontia and conical crown form), and cleft lipand palate. This entity is believed to have autosomaldominant inheritance with variable expressivity.

Treacher Collins Syndrome

Treacher Collins syndrome (TCS) is an autosomaldominant disorder with an incidence of approximately1 in 50,000 live births.153 The phenotype of TCS ishighly variable and includes zygomatic and man-dibular hypoplasia, colobomas, downsloping palpe-bral fissures, ear malformations, and cleft palate (in28-35% of affected individuals).147 The TCS gene(TCOF1) has been localized to chromosome 5q32-

q33.1.147

Oral clefts can also be seen as part of the pheno-type of several chromosomal disorders, including Tri-somy 13, 18,and 21.

Children born with anomalies in more than onedevelopmental field should undergo diagnosticgenetic testing with chromosomal analysis. Althoughmany infants born with multiple malformations mayhave an identifiable syndrome that can be confirmedby chromosomal analysis or mendelian inheritancepattern, many do not have a known genetic abnor-mality.

Associated Anomalies

Children with clefts may have associated anoma-lies even if they do not have an identifiablesyndromic disorder. Data on the type and fre-quency of anomalies associated with oral cleftscan facilitate the early diagnosis and treatment ofpotentially life-threatening conditions such as car-diovascular anomalies. The investigation of con-current malformations is also important in the

search for new teratogens involved in clefting, sinceteratogenesis frequently involves the induction ofmultiple anomalies.154

Associated anomalies are most commonly reportedin patients with cleft palate. Central nervous systemmalformations and cardiac abnormalities are tradi-tionally associated with oral clefts. An estimate ofprevalence of associated anomalies is typically derivedfrom hospital records, whereas estimates from popu-lation-based epidemiologic studies are quite different.

Natsume et al155conducted a population-basedsurvey of congenital anomalies associated withorofacial clefts in over 700,000 infants born in childdelivery facilities in Japan. The reported prevalenceof associated anomalies was 11.4% in infants withCL, 16.2% in infants with CLP, and 20.7% in infants

with CP.Shaw et al154evaluated population-based epi-

demiologic data from 3.6 million California birthsin 1983-97. Of the 2343 CP cases, 71% hadadditional anomalies. Of the 4072 CL/P cases,59.8% had additional anomalies. The authors rec-ommend that infants born with orofacial cleftsshould be screened for other organ system malfor-mations. For both CP and CL/P the estimatedrelative risks were highest for malformations of therespiratory system and lowest for spina bifida.

There was no increased frequency of cardiac mal-formations among infants/fetuses with CP or CL/P.In contrast, Milerad et al156 reported that heartmalformations occurred 16 times more frequentlyamong infant with clefts in their population-basedstudy from Sweden.

Hagberg and others157 reviewed the records of251 patients with cleft lip/palate born in Stockholmbetween 1991 and 1995. When children with PierreRobin sequence were excluded, additional malfor-mations were present in every sixth newborn with acleft. Additional malformations were more frequent

in newborns with bilateral clefts. Children with cleftsand other malformations tended to have lower birthweight and were born earlier than children with cleftsonly. The authors recommend screening of pretermcleft children with low birth weight for other birthdefects.

In a clinical series of 78 patients,Wyse et al158

observed that midline clefts have a close associa-tion with anomalies of the central nervous system,while congenital heart anomalies and predomi-nantly conotruncal defects such as tetralogy of Fallot

are more prevalent in patients with either unilat-eral or bilateral cleft lip and palate.158 Approxi-mately 87% of children with congenital heart dis-ease and oral clefts have anomalies of other sys-tems.

Median cleft lip and isolated cleft palate can beseen with other midline developmental disorders.Holoprosencephaly (HPE) is a variable disorder thatranges from mild anomalies of midline developmentto failure of forebrain division with associated cyclo-


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pia. The incidence of HPE in early pregnancy isabout 1 in 250, but the majority of these fetuses aremiscarried and the incidence in live births is relativelylow at 1 in 15,000.147 Many of the infants born withHPE exhibit cleft palate.

Ugar and Semb159compared the prevalence of

cervical spine anomalies among Norwegian childrenwith and without oral clefts and report a significantlygreater frequency of vertebral anomalies in childrenwith clefts (CP, BCLP, UCLP), especially those withCP, compared with non-cleft children. The percent-age of cervical vertebral anomalies was 25.6% in theCP group, 18.2% in the total cleft group (CP, BCLP,UCLP), and 9.1% in the control group. Whether theincreased prevalence of cervical vertebral anomaliescorresponds to an elevated risk of neurologic injury,particularly during surgery, is not clear.

The timing of embryogenesis of the face and ofmany of the organ systems that produce anomaliesassociated with clefting, including the cervical ver-tebrae, is the same. Exposure to teratogens, envi-ronmental insults, and defective gene products thatcome into play during these common periods ofembryogenesis are all potential causes of clefts andtheir associated malformations.

Nonsyndromic clefts

Investgations into the etiology of nonsyndromic

clefts have taken several different approaches. Somestudies have focused on genes responsible forsyndromic clefts. Some have used genome scans forgenetic linkage in families with multiple cases ofnonsyndromic clefts. Others have focused on link-age and association analysis to map candidate geneloci. Candidate genes are identified by links to aspecific genomic region or by their biologic role rela-tive to craniofacial development or modification ofenvironmental factors. Many of these studies haveyielded contradictory results, and researchers havedeployed genome scans to simultaneously search formultiple regions of interest.

The theory of etiologic heterogeneity has super-seded the multifactorial/threshold theory for oralclefts. There is recent evidence of the influence of amajor gene or genes on the inheritance of clefting.Segregation analysis and familial recurrence risk pat-tern analysis are consistent with either a major genelocus involvement or relatively few loci interacting tocause orofacial clefts.31 Table 5 summarizes the

results of a meta-analysis of candidate genes, chro-mosomal regions, and genome scan analysis associ-ated with nonsyndromic orofacial clefts.31

TABLE 5

Evidence for Genes and Regions PotentiallyInvolved in Non-syndromic Orofacial Clefts

(Reprinted with permission from Marazita ML, Mooney MP:Current concepts in the embryology and genetics of cleft lip andcleft palate. Clin Plast Surg 31:125, 2004.)


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Nopoulous and associates160compared the brainstructure and cognitive ability of men withnonsyndromic cleft lip and/or palate (NSCLP) to agroup of controls. The magnetic resonance imaginganalysis of the men with NSCLP demonstrated sig-nificant abnormalities in brain morphology, includ-

ing abnormally enlarged anterior cerebrum, decreasedvolume of the posterior cerebrum and cerebellum,and decreased volume of the left temporal lobe.These morphologic findings were further correlatedto cognitive dysfunction in the study group. Thisstudy highlights the close association between devel-opmental defects of the face and central nervoussystem.

In a later study Nopoulous and others161 com-pared the morphology of the frontal lobe regionrelated to social function in men with and without

NSCL/P. There were significant morphologicalabnormalities in the cleft group and a direct correla-tion with social dysfunction. The authors suggestthat the abnormal social behavior which has beenfrequently associated with NSCL/P in the literaturemay be due in part to aberrant brain developmentand not just difficult psychosocial adaptation.

Retinoic acid receptor alpha (RAR-a) on 17q12,muscle segment homeobox (MSX1) on 4p16, trans-forming growth factor alpha (TGFA) on 2p13, trans-forming growth factor beta (TGFB3) on 14q12, proto-oncogene BCL3 on 19q13, and a susceptibility locus

on the X chromosome have all been linked to NSCLPin certain families, supporting the hypothesis thatseveral interacting genes participate in the etiology ofNSCLP.31,162166

Breakthroughs in the detection of genetic defectsassociated with cleft syndromes have helped to iden-tify new candidate genes associated with nonsyn-dromic clefts, although no specific disease-causinggene mutation has been detected for nonsyndromicclefts to date (Table 6).

Mutations in the interferon regulatory factor-6(IRF6) gene (1q32) has been isolated as the causeof van der Woude syndrome, and the poliovirusreceptor related-1 (PVRL1) gene is responsible forthe autosomal recessive CLP-ectodermal dysplasiasyndrome (CLPED-1).147 Common sequence vari-ants of several genes associated with clefting syn-dromes, including IRF6, PVRL1, MSX1, TBX22,MID1, PTCH1 and P63, show a significant asso-ciation with nonsyndromic clefts.147,167170 Manyof these genes play important roles in craniofacial

development.Zucchero and colleagues169 performed complexgenetic analysis of 1968 familes from 10 ethnicallydiverse populations, and determined that the risk ofnonsyndromic CL/P is associated with genetic varia-tion in IRF6. Variation at IRF6 was responsible for12% of the genetic contribution to CL/P and tripledthe risk of recurrence in families that already hadone affected child.

Jezewski et al171analyzed a large, ethnically diversecohort of patients with CL/P and found that up to2% had mutations in the coding and regulatory ele-

ments of MSX1. MSX1 is a homeobox transcriptionfactor activated by BMP signaling to stimulate thegrowth of branchial arch mesenchyme. MSX1 wasinitally associated with a syndrome of CL/P and oli-

TABLE 6Chromosomal Regions and Candidate Genes Implicated by Linkage and Association Studies

in Non-syndromal Cleft Palate

(Reprinted with permission from Cox TC: Taking it to the max: the genetic and developmental mechanisms coordinating midfacialmorphogenesis and dysmorphology. Clin Genet 65:163, 2004.)


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godontia but is now implicated in the etiology ofnonsyndromic clefts.167

An oligogenic model of several interacting locihas been proposed for both NSCLP and CP basedon familial aggregation studies. The mode ofinheritance of CP may be more consistent with a

recessive single major gene model with low pen-etrance. The suspected gene maps to chromo-some region 2q13/TGFA.172 Recent research sug-gests that nonsyndromic CP might consist of twoetiologically different subtypes, CP affecting thesoft palate only and CP affecting both the hardand soft palate.118,120,172

Facial Dimensions

Embryonic face shape predisposes to cleft lip in

mice.173

Increased transverse facial dimension maybe a risk factor for palatal clefts due to the longerdistance between palatal shelves that must be over-come for fusion. Embryonic face shape as a predis-posing factor in orofacial clefting may help explainethnic and gender differences in cleft incidence. Forexample, Asians typically have wider faces that maycontribute to the more frequent failure of palatalshelf fusion in this ethnic group.

Parental transverse craniofacial form and dimen-sion have been investigated as etiologic factors asso-ciated with the development of orofacial clefts. Suzuki

and others174compared the dento-craniofacial mor-phology of parents of children with CL/P with that ofparents of children without clefts. The parents ofCL/P children showed a distinct craniofacial mor-phology consisting of increased interorbital andintercoronoid process distance, wider nasal cavity,and increased length of the anterior cranial base andtotal cranial base.

Yoon and colleagues175 compared transverseform in Costa Rican families with NSCLP. Theyfound that the unaffected parents of children with

NSCLP had transverse facial features that weresignificantly different from the general populations.Significant findings included a disproportionatelyincreased facial width relative to facial height,increased interorbital width and increased nasalwidth in the NSCLP families, implicating transversecraniofacial form as an etiologic factor in orofacialclefting. There was a significant correlation in trans-verse facial measurements of mothers with theiraffected sons and of fathers with their affected

daughters, a pattern that suggests an X-linked modeof transmission.

The same investigators176 also analyzed theassociation of distinct craniofacial features amongthese same Costa Rican families based on lateralcephalometric measurements. They hypothesized

that the NSCLP phenotype is a combination ofdistinct craniofacial features that uniquely segre-gate in affected families and are present in affectedand unaffected members to varying degrees. Fivedistinct craniofacial features were identified in theaffected members. Unaffected members hadfewer distinct features that were different from thenormative values.

In a separate study of the same Costa Rican popu-lation, Yoon and colleagues177 found that parentaltransverse nasal asymmetry was ipsilateral to the

side of the cleft in affected children to a significantdegree. A child with a left-sided cleft was 3 timesmore likely to have a parent with increased leftnasal width.

McIntyre and colleagues178 compared PA cepha-lometric studies of parents with and without childrenborn with oral clefts in Scotland. The parents ofchildren with oral clefts had significantly largersuperolateral faces, smaller maxillary widths, andsmaller central midfaces. The authors concludedthat parental craniofacial morphology is one of therisk indicators for oral clefts among offspring.

Facial dimensions that are common traits withinracial groups may contribute to the difference in CL/P incidence among different racial groups. Delineat-ing the parental craniofacial morphology in oral cleftdisorders may help in the identification of oral cleftmorphogenes. It would also be useful in the detec-tion and counseling of parents at risk of having chil-dren with oral clefts.

Environmental Factors

Many environmental factors have been examinedin epidemiologic studies of risk factors for oral clefts.Implicated risk factors include exposure to medica-tions during pregnancy, maternal smoking, maternalalcohol consumption, dietary and vitamin deficien-cies, maternal metabolic factors, exposure to envi-ronmental toxins, altitude, birth order, season of con-ception, socioeconomic status, and parental age. Formany of these factors no conclusive trend in cleftincidence has been demonstrated across populations.


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Although CL/P and CP alone may represent onefeature of a number of recognized patterns of mal-formations attributable to environmenta

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