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The Spectrum of Orofacial CleftingBarry L. Eppley, M.D., D.M.D., John A. van Aalst, M.D., Ashley Robey, M.D.,Robert J. Havlik, M.D., and A. Michael Sadove, M.D.Indianapolis, Ind.

Learning Objectives: After studying this article, the participant should be able to: 1. Describe the differing types ofcongenital clefting defects that extend outward from the perioral region. 2. Define the sites of anatomical disruption anddeformities that these types of facial clefts cause. 3. Describe the cause and incidence, if known, of orofacial clefts andtheir inheritance/transmission risks.

Background: Clefts of the orofacial regionare among the most common congenitalfacial defects. The clinical presentation isusually that of a lateral cleft of the lipthrough the philtrum with or without ex-tension through the palatal shelves. How-ever, atypical forms of clefts with lip involve-ment also occur in a variety of patterns,some of which are embryologically predict-able; others are not.Methods: An overview of the embryology,cause, and incidence of this diverse andinteresting group of congenital orofacialclefts is presented.Results: Clefts involving the lateral upperlip; median upper lip; and oblique facial,lateral facial, and median mandibular re-gions are reviewed.Conclusions: This review of orofacial mal-formations describes clefting anomaliesthat emanate from the mouth and lips. Asthe causes of orofacial clefts are better un-derstood, it is becoming clear that a com-plex interplay between genetic and envi-ronmental variables causes these clefts.Future study of orofacial clefts will requireincreasingly sophisticated methods of elu-cidating these subtle interactions. (Plast.Reconstr. Surg. 115: 101e, 2005.)

Orofacial clefting is a failure in developingembryonic facial and palatal processes to ei-

ther completely merge or fuse, which results ina predictable series of postnatal deformities.What is frequently not appreciated is that thesecongenital anomalies show a wide variety ofanatomical disruptions extending outwardfrom the oral cavity with varying frequenciesand association with other congenital malfor-mations. As such, the term cleft lip– cleft palateshould be restricted to those clefts involvingthe embryonic primary and secondary palate.The variability of expression and decreased fre-quency of the more unusual orofacial cleftsrepresent a set of more complex and etiologi-cally distinct developmental problems.

CLASSIFICATION

A universally accepted classification schemethat fully encompasses, accurately describes,and integrates all the various types of orofacialand craniofacial clefts does not exist. Van derMeulen’s classification has an embryologic ba-sis1 and Tessier’s classification has an anatom-ical basis (Fig. 1).2 Tessier’s classification sys-tem is commonly used by surgeons because it ispurely descriptive and makes no pretense atcausation and developmental relationships.There is also an ease of correlation betweenthe anatomical defect and the required recon-structive surgery. The Tessier classification in-cludes numbered clefts from 0 (midline cleft ofthe lip and nose) to 30 (a mandibular cleft).Cleft nos. 1, 2, and 3 are through the lateralmargin of Cupid’s bow (corresponding with

From the Division of Plastic Surgery, Indiana University School of Medicine. Received for publication February 12, 2003; revised April 29,2004.

DOI: 10.1097/01.PRS.0000164494.45986.91

101e

the more commonly seen cleft lip–cleft palatedeformities). Tessier cleft nos. 4, 5, and 6 areoro-ocular clefts; however, cleft no. 6 does notemanate from the oral cavity. Cleft nos. 7, 8,and 9 are lateral facial clefts; among theseclefts, only cleft no. 7 emanates from the oralcavity. The remaining clefts are above the pal-pebral fissure (Figs. 2 and 3). Although thisclassification system is of value for most cranio-facial clefting problems, it is inadequate for thecommonly seen cleft lip–cleft palate deformity(the typical cleft lip corresponds in part toTessier cleft nos. 1, 2, and 3).

A purely descriptive classification scheme isused for this review of orofacial clefts and in-cludes only those clefts that have an oral com-ponent. In circumoral fashion, these clefts in-

clude the median cleft lip (Tessier cleft no. 0),unilateral and bilateral cleft lip (primary pal-ate; Tessier cleft nos. 1, 2, and 3), oblique facialcleft (Tessier cleft nos. 4 and 5), lateral facialcleft (Tessier cleft no. 7), and the median man-dibular cleft (Tessier cleft no. 30).

INCIDENCE

According to recent studies, the frequency oforofacial clefting is on the rise.3,4 In a study ofclefting frequency in spontaneously abortedand stillborn fetuses, the incidence of facial

FIG. 2. Variability in presentation of the more commoncleft lip–cleft palate deformities. (Above) Microform cleft lip;(center) incomplete unilateral cleft lip; (below) complete uni-lateral cleft lip–cleft palate.

FIG. 1. Craniomaxillofacial clefting classification byTessier. Using the orbit, and specifically the palpebral fis-sures, as central craniofacial landmarks, clefts are marked bytheir lines of hard- and soft-tissue cleavage. The orofacialclefts, nos. 0 through 7 and 30 (solid lines), occur primarilyinferior to the palpebral fissure. Craniofacial cleft nos. 9through 14 (dashed lines) occur superior to the palpebrallevel. (Adapted from Kawamoto, H. K., Jr. Rare craniofacialclefts. In J. C. McCarthy (Ed.), Plastic Surgery, Vol. 4. Phila-delphia: Saunders, 1990.)

102e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005

malformations was 4.25 percent.5 With the re-markable improvements in perinatal care andprenatal medical technology, it seems likelythat more of these fetuses will survive to termand require treatment. In a recent population-based sample from California, the birth preva-lence of all orofacial clefts was 0.17 percent,with isolated clefting constituting roughly two-thirds of these patients; the remainder were amixture of sequences, chromosomal aberra-tions, associations, and unknown causes.6 Anincreased awareness and understanding ofthese unique facial clefting anomalies is partic-ularly pertinent to the plastic surgeon.

EMBRYOLOGY

Virtually all cases of cleft lip–cleft palate areattributable to the failure of the medial nasalprocess to either contact or maintain contactwith the lateral nasal and maxillary processes.7The embryologic pattern of neural crest cellmigration and subsequent merging is now ap-preciated to be a complex interplay of move-ments initiated when the inferior edge of themedial nasal process joins the maxillary pro-cess at approximately day 30 in the humanembryo. A significant morphogenetic move-ment of the nasal placode (rotation and ad-vancement) then permits its lateral nasal pro-cess to sweep over the maxillary process a fewdays later to join with the medial nasal processto collectively form the upper lip-nasal unit.8 A

cellular deficiency or failure of contact main-tenance in one or several components of thissix-piece midfacial convergence results in thevariations in clinical presentations that arecommonly seen (Figs. 2 and 3). Simonart’sband, which can be seen at the posterosuperioraspect of some lip clefts (Fig. 4, left), may wellillustrate a rupture of contact (lack of contactmaintenance) rather than failure to make con-tact between the processes and may be theprimary developmental problem in manyclefts.7 This residual fibrous band is found inthe approximate location of the embryonicunion of the maxillary and median nasal pro-cesses that constitute the primary palate and isoften associated with a narrower cleft defectthan those clefts in which it is not found. Var-ious other webs or synechiae can occasionallybe seen attached to the cleft, indicating inad-vertent adhesion of structures from surround-ing facial processes (Fig. 4, right).

In addition to the importance of mergingand fusion, the size of the facial processes af-fects facial morphology and cleft susceptibility.An inherently smaller median nasal process, aswould be suspected in Asians because of theirsmaller midfaces, tendency for class III occlusalrelationships, and flatter nasal structures, maypartially account for their relatively high ratesof clefting. Conversely, some African Ameri-cans have broad, larger noses, increased facialwidths, and a tendency for maxillary dentoal-veolar protrusion, all of which indicate the

FIG. 3. (Right) Incomplete bilateral cleft lip and (left) complete bilateral cleft lip–cleft palate.

Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 103e

presence of well-developed median nasal pro-cesses and a decreased clefting frequency.

The cause of cleft lip–cleft palate is complexand multifactorial, involving both genetic andenvironmental factors (Tables I throughIV).9,10 Transmission of the cleft phenotype in asimple mendelian fashion, as is seen in manyother hereditary disorders, rarely occurs. Thisis supported by studies of cleft monozygotictwins that show a 30 to 60 percent concordancerate.9,11 When compared with the 1.0 to 4.7percent concordance rate for dizygotic twins,these results favor an important but not exclu-sive role for genetics in the development ofcleft lip–cleft palate. In a family with a cleftlip–cleft palate child, the chance that a secondchild will be born with a similar defect is 3 to 4percent; if two children have the defect, thechance of a third child being born with the

defect is 9 percent.12 In addition to genetics,environmental factors (Table III), such assmoke exposure and use of steroids, phenyt-oin, and retinoids, have also been implicatedin the development of cleft lip–cleft palate.13–20

More recently, a complex interplay betweengenetic and environmental factors has beenunfolding.

GENETIC FACTORS

Cleft lip is a feature in 171 syndromes (15percent of cleft lip–cleft palate cases are syn-dromic)9–11,21–23 (Table I). Sixty-four are auto-somal recessive, 35 are autosomal dominant,and six are X-linked recessive.10 In a seriesexamining the association of malformationswith clefting, 13.6 percent of patients with cleftlip, 36.8 percent of patients with both cleft lipand cleft palate, and 46.7 percent of patients

FIG. 4. The importance of adhesion between developing facial processes can be seen in the fibrous bands thatare occasionally seen across or attached to the cleft. (Left) Simonart’s band serving as a residual tissue connectionbetween the medial and lateral lip processes. (Right) Band from lower lip attached to cleft.

TABLE IGenetic Links to Syndromic Orofacial Clefts*

Syndrome Location Gene

Van der Woude 1q32–41Ectrodactyly ectodermal dysplasia 3q27 P63Margarita Island ectodermal dysplasia 11q23Aicardi Xp22Craniofrontonasal dysplasia Xp22Hypertelorism-microtia-clefting 1q, 7pKallman Xp22 KAL1Gorlin 9q22–31 LMX1BVelo-cardio-facial 22q11

* Adapted from Prescott, N. J., Winter, R. M., and Malcolm, S. Nonsyn-dromic cleft lip and palate: Complex genetics and environmental effects. Ann.Hum. Genet. 65: 510, 2001.

TABLE IIGenetic Links to Nonsyndromic Orofacial Clefts*

Gene Locus

SKI/MTHFR 1p36TGFb2 1q41TGFa 2p13MSX1 4p16, 1q31, 6p23PVRL1 11q23TGFb3 14q24GABRb3 15q11RARa 17q21BCL3 19q13

* Adapted from Murray, J. C. Gene/environment causes of cleft lip and/orpalate. Clin. Genet. 61: 250, 2002.


with cleft palate alone had associatedmalformations.22

Nonsyndromic cleft lip–cleft palate is a het-erogeneous disease entity with candidate cleft-ing loci on chromosomes 1, 2, 4, 6, 11, 14, 17,and 19 (Table II). Chromosome 1 is associatedwith nonsyndromic orofacial clefting by meansof a mutation in methylenetetrahydrofolate re-ductase on 1q36.24 The short arm of chromo-some 2 has a susceptibility gene in the 2p13region found to be associated with cleft lip–cleft palate.25 Studies have disagreed aboutwhether this site involves transforming growthfactor alpha26 or not.27 MSX1 located on chro-mosome 4 (4q25) has been associated withincreased risk of cleft lip–cleft palate.28 Chro-mosome 6 contains a likely gene responsiblefor cleft lip–cleft palate at 6p23.29 Other chro-mosomes with possible clefting loci includechromosome 11, the transforming growth fac-tor beta3 locus on chromosome 14, the reti-noic acid receptor-� gene on chromosome 17,the BCL3, and the transforming growth factorbeta locus on chromosome 19.30,31

ENVIRONMENTAL FACTORS

The list of environmental factors associatedwith orofacial clefting is growing (Table III).Any maternal alcohol consumption duringpregnancy increases the incidence of orofacialclefting.32 Increased alcohol consumption re-

sults in further increases in the incidence ofdeveloping both syndromic and nonsyndromicclefts.33 An association between maternal ciga-rette smoking and orofacial clefting is well es-tablished,30 resulting in at least a doubling ofthe incidence of cleft lip–cleft palate com-pared with nonsmoking mothers. Further-more, increased maternal smoking further in-creases the odds of having a child with cleftlip–cleft palate.34 The effect of maternal smok-ing appears to be related to increased serumcarbon monoxide levels,15–17 which exert theireffect on cytochrome oxidase.7

Multiple studies have shown that folate defi-ciency is associated with cleft lip–cleft pal-ate.19,20 Prenatal folic acid supplementation hasbeen shown to decrease this risk35; high phar-macologic doses (6 mg/day) are required forthe protective effect.36 At present, folic acidsupplementation is the only empiric preventa-tive treatment shown to decrease the incidenceof facial clefting. Conversely, folic acid antago-nists increase the incidence of orofacial cleft-ing.18 These findings highlight the (as yet in-completely understood) role of poor nutritionin the development of orofacial clefts, and sug-gest the reason for a link between increasedrisk of orofacial clefting and low socioeco-nomic status and the higher incidence of un-usual orofacial clefts found in developingcountries.

Maternal corticosteroid use causes a 3.4-foldincrease in orofacial clefting.37 The increasehas been corroborated by other investigators innonsyndromic cleft lip–cleft palate.14 Anticon-vulsants, including phenytoin, oxazolidinedio-nes, and valproic acid, also cause cleft lip–cleftpalate. Phenytoin causes a nearly 10-fold in-crease in the incidence of facial clefting11 andexerts its effect by inhibiting enzymes in theNADH dehydrogenase electron transportchain.7 Other pharmacologic agents, includingretinoic acid, have also been implicated in oro-facial clefting, but the exact mechanism of ac-tion remains to be determined.18

GENETIC-ENVIRONMENTAL INTERACTIONS

Much of the literature on facial clefting hasexamined environmental and genetic factorsin isolation. More recent work indicates thatthere is a complex interplay between thetwo.10,30 Smoking, for example, is known toincrease the incidence of orofacial clefting;however, infants with the transforming growthfactor alpha genotype (also previously known

TABLE IIIEnvironmental Causes of Orofacial Clefts*

Teratogen Cleft Type Genetic Link

Alcohol Cleft lip–cleft palate MSX1,TGFb3Cigarette smoke Cleft lip–cleft palate TGFaFolic acid Cleft lip–cleft palate TGFa, MTHFRSteroids Cleft lip–cleft palate TGFbAnticonvulsants Cleft lip–cleft palate GABA receptor b3Altitude Cleft lip

TGFa/b, transforming growth factor alpha/beta.* Adapted from Carinci, F., Pezzetti, F., Scapoli, L., et al. Recent develop-

ments in orofacial cleft genetics. J. Craniofac. Surg. 14: 130, 2003.

TABLE IVGenetic Mutations in Holoprosencephaly*

GeneChromosomeMap Location Reference

SHH 7q36 60TGIF 18p11 61SIX3 2p21 62ZIC2 13q22 63PTCH 9q22 64

* Adapted from Cohen, M. M., Jr. Perspectives on craniofacial anomalies,syndromes, and other disorders. In K. Y. Lin, R. C. Ogle, and J. A. Jane (Eds.),Craniofacial Surgery: Science and Surgical Techniques. Philadelphia: Saunders, 2002.


to be associated with orofacial clefting) have asixfold increase in orofacial clefting when com-bined with maternal smoking.38 Maternal ciga-rette smoking also interacts with an allelic vari-ation of MSX1 that further increases theincidence of orofacial clefting.39 Infants withallelic variants at the MSX1 site born to moth-ers who have more than four drinks per monthalso show a higher incidence of clefting.39

Maternal folic acid deficiency has been asso-ciated with orofacial clefting.40 This findingmay be explained by a variant in the maternal5,10-methylene-tetrahydrofolate reductase en-zyme, making the enzyme less efficient.41 Addi-tional work suggests that maternal genotypemay also play a role in fetal folate status.42 Withincreased understanding about the causes ofcleft lip–cleft palate, it is becoming more ap-parent that subtle interactions between the en-vironment and genetic background make in-fants susceptible to clefting.

UNILATERAL AND BILATERAL CLEFT

LIP–CLEFT PALATE

Clefts of the embryonic primary (cleft lip)and secondary palate (cleft palate) are over-whelmingly the most frequently encounteredcongenital facial defects, constituting nearlytwo-thirds of major facial malformation andnearly 80 percent of all orofacial cleft types(Figs. 2 and 3).5,6 Differences in racial suscep-tibility are well documented and are the resultof racial variations in the timing and coordina-tion of cellular morphologic patterns, particu-

larly the development of the median nasal pro-cess. As such, the frequency may range from anincidence of one in 400 to 500 live births inAsians and American Indians to one in 1500 to2000 live births in African Americans. Cauca-sian susceptibility is intermediate at one in 750to 900 live births.6,43 The left side of the pri-mary palate, for reasons as yet unclear (fetalposition and circulatory and neural anatomyhave all been implicated), is more often cleftthan the right.

MEDIAN CLEFT LIP

In contrast to clefts of the lateral lip, medianlip clefts are relatively rare. They are found inless than one in 100 cases of cleft lip–cleftpalate, with a reported incidence of between0.43 and 0.73 percent of cleft lip–cleft palatecases.44,45 Median cleft lips occur in less than0.0001 percent of all births. Racial and sexdifferences have not been established.

Like all cleft lip processes, a graded spec-trum of deformity occurs and is the result offailure of the two medial nasal processes tomeet in the midline and fuse. However, me-dian lip clefting raises concerns about the over-lying face and brain not seen in the morecommon lateral lip clefts. An incomplete me-dian cleft (vermilion notch) may occur as anisolated entity (Fig. 5) or as part of such syn-dromes as orofacial-digital syndrome (Fig. 6),which represents a spectrum of anomalies ofthe face, head, hands, and feet (types I toVI).46–48 More complete median cleft defects

FIG. 5. Incomplete median cleft lips. (Left) Vermilion notch, presence of central maxillary skeletal diastema, anddouble frenulum; (right) wider median cleft lip extending through the alveolus to the palate.


are syndromic and present as two separate en-tities: the median cleft lip with hypotelorism(holoprosencephaly) and median cleft lip withhypertelorism (median cleft face syndrome).When medial cleft lip occurs without holo-prosencephaly, head circumference is withintwo standard deviations of the mean and nor-motelorism is usual.31

Holoprosencephaly (cyclopia-rhinencephaly)results from deficient anterior neural plate devel-opment. If the original holospheric telencepha-

lon fails to develop lateral evaginations, the cere-brum remains singular rather than hemispheric.Therefore, the prosencephalic cavity remains as amonoventricle.49 The associated median facialabnormalities occur because of the sharing ofembryologic cellular tissue (mesenchymal pri-mordium) and the prechordal mesoderm (me-soderm between the prosencephalon and stomo-deum) in conjunction with migrating neuralcrest cells.50 The frontonasal prominence of theprosencephalon then produces the mediancraniofacial skeleton (crista galli, ethmoid,vomer, nasal, and premaxillary bones) and thecartilaginous septum. The overlying soft tissues(forehead, nose, and prolabium) likewise arisefrom these embryonic tissues. Unlike lateral lipclefts, which represent a problem of merging andfusion, the holoprosencephalic median lip cleftsare caused by a failure of development. The lat-eral aspects of the face are produced separatelyby the brachial arches and, as a result, are nor-mal. Although the facies of holoprosencephalyare different and parallel that of brain develop-ment (cyclopia, type I; ethmocephaly, type II;and cebocephaly, type III),51,52 the median cleftlip with hypotelorism (type IV) is characterizedby absence of the crista galli, nasal and premax-illary bones, and nasal septum. The hypoplasticethmoids accompany but are not the cause of theorbital hypotelorism, which is primarily a braindefect (Fig. 7). It is important to note that otherforms of median cleft lip exist that appear verysimilar to holoprosencephaly but without cere-

FIG. 6. Median cleft lip in orofacial-digital syndrome,which is often associated with polylobed tongue, lingual tu-mors, and absence of central maxillary incisors.

FIG. 7. Holoprosencephalic facies with median cleft lip. (Left) Absence of entire prolabial unit;(right) absence of complete premaxilla extending up to the crista galli.


bral involvement, and that have varying degreesof vomero-septal-prolabial hypoplasia.53 An intactethmoid, nasal bone, and crista galli appear torepresent the key anatomical differences in thesepatients as compared with classic holoprosen-cephaly (Fig. 8).

A group of “syndromic”-appearing patientswho have traditionally been assigned a placeon the “normal” end of the holoprosencephalyspectrum54,55 has recently been described byMulliken et al.56 These patients have nasomax-illary hypoplasia, orbital hypotelorism, and anassociated unilateral and bilateral cleft lip–cleft palate. Because these patients have nor-mal head circumference and intelligence, theycannot belong on a continuum with holo-prosencephaly.31 To differentiate these pa-tients from those with holoprosencephaly, au-thors have historically labeled these patients as“false” or “pseudomedian” cleft lips. Other au-thors have denoted this entity as a Binderanomaly,57 which is associated with chondro-dysplasia punctata, cervical spine anomalies,and fetal exposure to warfarin. The patients inthe study by Mulliken et al. did not have any ofthese characteristic findings or exposures andtherefore cannot be classified as having Binderanomalies. Mulliken et al. prefer to refer tothese patients as binderoid.56

The median cleft face syndrome or frontona-sal dysplasia appears to be the result of incom-

plete midline merging of the facial processes,with varying degrees of lateralization of their con-tents. Forebrain morphogenesis is rarely in-volved, and subsequent brain development isusually normal.58,59 Thus, frontonasal dysplasia isstrikingly different from holoprosencephaly andpresents in its extreme with a median cleft lipand palate, bifid nose, orbital hypertelorism, in-feriorly displaced V-shaped frontal hairline, andcranium bifidum occultum (Fig. 9). Unlike ho-loprosencephaly, the premaxillary segment isusually present, although it is clefted and maxil-lary incisor eruption can be expected.

Mutations in several genes have been linkedto holoprosencephaly. These include sonichedgehog (SHH),60 TGIF,61 SIX3,62 ZIC2,63 andPTCH (Table IV).64 The only comparable ani-mal model for holoprosencephaly (cyclopia)occurs in the offspring of sheep that ingestplant alkaloid.65,66 This finding is unique becauseof the specificity and reproducibility of the defectby this teratogen. Although nonspecific craniofa-cial malformations, including median cleft lip,have been produced by numerous other agentsin animals, specific teratogenic sources for me-dian defects in humans have not been reported.Alcohol—specifically, fetal alcohol syndrome—has been associated with midline developmentaldefects, including the median facial cleft in rarecases.67

OBLIQUE FACIAL CLEFTS

The term oblique facial cleft, occurring in avariety of manifestations from the lip to theorbit, is a vague designation.1 The cleft has alsobeen described by other equally nondescriptnames, including meloschisis and vertical facialand orbitofacial clefting. It really represents agroup of lateral midfacial dysplasias that con-sist of distinct malformations involving differ-ing points of origin from the lip and superiorextensions into the orbit. These clefts corre-spond to the Tessier cleft nos. 3, 4, and 5; theuse of this nomenclature is of particular helpin this area (Figs. 2 and 3).2,43 Because of theirrarity (less than 0.25 percent among all facialclefts) and incomplete case descriptions in theliterature, the actual incidence of these cleftsas a group and individually is not known.43,45,68

All known cases are sporadic, with no syn-dromic association or sex predilection.

The oblique clefts, as indicated by Tessiercleft nos. 3 through 5, occur in slightly differ-ent regions of the lateral midface (cleft nos. 1and 2 are best described as paramedian or

FIG. 8. Vomero-septal-prolabial hypoplasia can be con-fused with holoprosencephaly, but there is no upper cranio-facial involvement.


vertical facial clefts and are excluded from thisdiscussion). The most medial variety (cleft no.3, also known as a naso-ocular or nasomaxillarycleft) extends from the philtrum of the lip, asoccurs in the more common lateral cleft of thelip, to the medial canthus of the eye, withforeshortening of this distance.69 As a result, abony cleft occurs at the lateral incisor/caninearea of the alveolus, extending through thefrontal process of the maxilla to the lacrimalgroove of the medial orbit. Soft-tissue defects,including colobomas of the nasal ala and lowereyelid and an inferiorly displaced medial can-thus and globe, are characteristic. Concurrentabsence or dysfunction of the nasolacrimal sys-tem is predictably high (Fig. 10). More later-ally, the cleft no. 4 (also known as an oro-ocular cleft) spares the nose and extendstoward a more centric orbital position.70 Thelip origin of this cleft deviates from commonlip clefts and does not violate the philtral ridge.At a point between the philtrum and commis-sure, the cleft extends superiorly through thenasolabial fold and passes into the orbit justmedial to the infraorbital foramen (Fig. 11). Assuch, the medial canthal tendon and nasolac-rimal duct are usually intact. However, amarked coloboma of the lower eyelid ispresent, and in some cases, varying degrees ofanophthalmos are present. The no. 5 cleft is

primarily distinguished from the more medi-ally positioned cleft no. 4 by passing lateral tothe infraorbital foramen (Fig. 12). This skeletalpathway difference has long been recognizedand has historically (pre-Tessier) been subdi-vided into type I (no. 4) and type II (no. 5)forms of oro-ocular clefting.71 The lateraliza-tion of this cleft is also distinctly different at thealveolar level by originating posterior to thecanine. The ocular findings, however, includ-ing a severe lower eyelid coloboma, inferiordisplacement, and partial prolapse of the or-bital contents into the sinus and anophthal-mos, are not unlike findings in a no. 4 cleft.

FIG. 10. Tessier no. 3 orofacial cleft. The lip has beenpreviously repaired.

FIG. 9. Two patients exhibiting differing degrees of expression of the median cleftface syndrome. (Left) Incomplete median lip cleft with moderate widening of theinterorbital distance and nose. (Right) Increased severity with marked lateralization oforbits and nose that has previously undergone primary lip repair.


The embryology of the oblique facial clefts isdifficult to explain by the known facial processesof merging and fusion. The no. 3 cleft occursalong the naso-optic groove, formed by the con-fluence of the lateral aspects of the olfactoryplacode and frontonasal process and the medialedge of the maxillary process, and as such theassociated abnormalities are completely predict-able. Cleft nos. 4 and 5, however, correspond tono known embryologic grooves or plane of mes-enchymally supported epithelium, and their ori-gin currently remains speculative. The cause ofthese clefts has loosely been ascribed to a primaryarrest of development, neurovascular insuffi-ciency or necrosis, or a result of tears in thedeveloping maxillary process.72,73 This embryo-logic mystery has defied explanation because anexperimental oblique cleft model has only beenproduced inconsistently by maternal hypervita-

minosis A and salicylate intoxication.52 More re-cent experimental work suggests that these mal-formations are caused by a combination ofdirectly tethered tissue migration (such as fromamniotic bands) and increased local pressurethat produces cellular ischemia.74 As a result,such clefting may occur later in fetal develop-ment rather than during primary facialmorphogenesis.

LATERAL FACIAL CLEFTS

Lateral facial clefts, or commissural clefts,are best thought of as a variable finding withinthe broader congenital condition of hemifacialmicrosomia (Tessier cleft no. 7). They are thesecond most common orofacial cleft (secondto the common cleft lip), with an incidence lessthan that of hemifacial microsomia (one in3500 to 5000 live births) because of an incon-sistent occurrence within the syndrome.75 Al-though commissure clefts are not seen in everycase of hemifacial microsomia, their occur-rence should initiate a search for involvementof the ipsilateral ear, mandible, and facialnerve and overlying facial soft-tissue deficien-cies. These clefts also occur in the oculoauricu-lovertebral spectrum (historically referred to asGoldenhar syndrome), which has the addi-tional features of epibulbar dermoids, verte-bral anomalies, and central nervous system andcardiopulmonary defects.76

The clinical findings of the lateral oral cleftvariably extend along a line from the commis-sure to the tragus. Most commonly, a 1- to3-cm-long cleft is present, with disruption ofthe orbicularis and buccinator muscles andwith the cleft edges lined by vermilion.75 Onlyrarely does a complete cleft extend posterior toor beyond the anterior border of the massetermuscle, although a groove or skin depressioncontinuing along the cleft line to the ear mayoccasionally be seen (Fig. 13). Because of theassociation between lateral oral clefts andhemifacial microsomia, underlying deformitiesof the mandible are well appreciated. Less ap-preciated but equally common, particularly insevere expressions of the syndrome, is the zy-gomatico-orbital dysplasia, marked by a disrup-tion of the zygomatic arch and inferior dis-placement of the lateral canthus caused byvariable amounts of accompanying zygomatichypoplasia and resultant orbital dystopia.

Lateral facial clefts are easy to understandembryologically, as the commissure representsthe most anterior point of mesodermal merg-

FIG. 11. Tessier no. 4 orofacial cleft.

FIG. 12. Bilateral incomplete Tessier no. 5 clefts.


ing of the maxillary and mandibular processes.Should the fusion process remain incomplete,a variable spectrum from furrowing of the tis-sues to complete anatomical separation per-sists. The pathogenesis of the lateral facial cleftappears to be heterogeneous. A vascular cause,attributable to embryonic hematoma forma-tion from disruption of the stapedial arterystem, is one proposed mechanism.77 The sever-ity of the condition subsequently depends onthe size of the hematoma and its time course ofresolution as brachial arch development oc-curs.78 The cause of this embryonic hemor-rhage has been speculated to range from vas-cular flow anomalies, such as hypertension andhypoxia, to pharmacologic agents, such as sa-licylates and anticonvulsants.79 Intrauterinecompression secondary to oligohydramnios inthe embryonic head region has also been sug-gested and may account for some cases ofhemifacial microsomia that occur with otheranomalies, such as limb reduction defects.80

MEDIAN MANDIBULAR CLEFTS

Clefting of the lower face (Tessier cleft no. 30)(Fig. 1) almost universally occurs through themidline of the lip and mandible. Although para-median lower lip/mandibular clefting has beenreported, there are fewer than 70 reported casesin the literature, appearing with less frequencythan the oblique facial clefts.11,81,82 Sex and racialpredilections remain indeterminate.

A range of inferior clefting has been reportedthat extends from mild notching of the lower lipand mandibular alveolus (Fig. 14) to completecleavage of the mandible, extending into inferiorneck structures.81–85 Tongue involvement is typi-cal though variable in expression, ranging from abifid anterior tip with ankyloglossia to the bonycleft margins, to marked lingual hypoplasia. In-ferior cervical defects (midline separation, hyp-oplasia, and agenesis) of the epiglottis, strap mus-cles, hyoid bone, thyroid cartilage, and sternummay also be present, particularly when the cuta-

FIG. 13. Tessier no. 7 (commissure) clefts. (Above, left) Left-sided hemifacial microsomia with commissural cleft.(Below, left) Right-sided hemifacial microsomia with commissural cleft extending to the anterior border of themasseter. (Right) Bilateral commissural clefts without hemifacial microsomia.


neous cleft passes caudal to the gnathion pointon the chin.

The embryologic basis of median mandibu-lar clefts lies in the failure of coaptation of thefree ends of the first visceral arches in themidline. Once the arches are formed throughneural crest cell migration, vascularization,and mesodermal myoblastic ingrowth, growthcenters are organized at their tips that are re-sponsible for closing the final gap and coalesc-ing the two sides.8 As the incisor teeth arefrequently missing along the medial mandibu-lar margins, this suggests that partial or com-plete failure of growth center differentiationand development is responsible for such de-fects rather than a simple merging and contactmaintenance. Because no animal models existfor study of the median cleft lip, the cellularbasis for this defect may remain unknown forsome time. Presumably, however, more infe-rior cervical defects would be caused by similarmechanisms in the second and third visceral

arches. The occasional association of a supe-rior midline defect (cleft palate) with a medianmandibular cleft is interesting because it sug-gests that a broader defect in epithelial mesen-chymal merging and fusion is occurring or thatthe tongue abnormality affects palatal shelf clo-sure in utero in these patients.86,87

SUMMARY

This review of orofacial malformations de-scribes clefting anomalies that emanate fromthe mouth and lips—the most common cleftstructure of the face. Some of these clefts arerelatively common, including the typical cleftlip with or without cleft palate; others are ex-tremely rare. As the causes of orofacial cleftsare better understood, it is becoming clear thata complex interplay between genetic and envi-ronmental variables causes these clefts. Futurestudy of orofacial clefts will require increas-ingly sophisticated methods of elucidatingthese subtle interactions. Orofacial clefts are ofparticular relevance to plastic surgeons, whoset the world’s standard for care and recon-struction of such facial congenital deformities.

Barry L. Eppley, M.D., D.M.D.Division of Plastic SurgeryCranioFacial ProgramIndiana University School of Medicine702 Barnhill Drive, Suite 3540Indianapolis, Ind. [email protected]

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