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CME The Spectrum of Orofacial Clefting Barry 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 of congenital clefting defects that extend outward from the perioral region. 2. Define the sites of anatomical disruption and deformities that these types of facial clefts cause. 3. Describe the cause and incidence, if known, of orofacial clefts and their inheritance/transmission risks. Background: Clefts of the orofacial region are among the most common congenital facial defects. The clinical presentation is usually that of a lateral cleft of the lip through 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 and interesting group of congenital orofacial clefts is presented. Results: Clefts involving the lateral upper lip; median upper lip; and oblique facial, lateral facial, and median mandibular re- gions are reviewed. Conclusions: This review of orofacial mal- formations describes clefting anomalies that emanate from the mouth and lips. As the 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 require increasingly sophisticated methods of elu- cidating these subtle interactions. (Plast. Reconstr. Surg. 115: 101e, 2005.) Orofacial clefting is a failure in developing embryonic facial and palatal processes to ei- ther completely merge or fuse, which results in a predictable series of postnatal deformities. What is frequently not appreciated is that these congenital anomalies show a wide variety of anatomical disruptions extending outward from the oral cavity with varying frequencies and association with other congenital malfor- mations. As such, the term cleft lip– cleft palate should be restricted to those clefts involving the embryonic primary and secondary palate. The variability of expression and decreased fre- quency of the more unusual orofacial clefts represent a set of more complex and etiologi- cally distinct developmental problems. CLASSIFICATION A universally accepted classification scheme that fully encompasses, accurately describes, and integrates all the various types of orofacial and craniofacial clefts does not exist. Van der Meulen’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 is purely descriptive and makes no pretense at causation and developmental relationships. There is also an ease of correlation between the anatomical defect and the required recon- structive surgery. The Tessier classification in- cludes numbered clefts from 0 (midline cleft of the lip and nose) to 30 (a mandibular cleft). Cleft nos. 1, 2, and 3 are through the lateral margin 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 palate deformities). Tessier cleft nos. 4, 5, and 6 are oro-ocular clefts; however, cleft no. 6 does not emanate from the oral cavity. Cleft nos. 7, 8, and 9 are lateral facial clefts; among these clefts, only cleft no. 7 emanates from the oral cavity. The remaining clefts are above the pal- pebral fissure (Figs. 2 and 3). Although this classification system is of value for most cranio- facial clefting problems, it is inadequate for the commonly seen cleft lip–cleft palate deformity (the typical cleft lip corresponds in part to Tessier cleft nos. 1, 2, and 3). A purely descriptive classification scheme is used 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 facial cleft (Tessier cleft nos. 4 and 5), lateral facial cleft (Tessier cleft no. 7), and the median man- dibular cleft (Tessier cleft no. 30). INCIDENCE According to recent studies, the frequency of orofacial clefting is on the rise.3,4 In a study of clefting frequency in spontaneously aborted and stillborn fetuses, the incidence of facial FIG. 2. Variability in presentation of the more common cleft 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 by Tessier. Using the orbit, and specifically the palpebral fis- sures, as central craniofacial landmarks, clefts are marked by their lines of hard- and soft-tissue cleavage. The orofacial clefts, nos. 0 through 7 and 30 (solid lines), occur primarily inferior to the palpebral fissure. Craniofacial cleft nos. 9 through 14 (dashed lines) occur superior to the palpebral level. (Adapted from Kawamoto, H. K., Jr. Rare craniofacial clefts. 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 and prenatal medical technology, it seems likely that more of these fetuses will survive to term and 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 a mixture of sequences, chromosomal aberra- tions, associations, and unknown causes.6 An increased awareness and understanding of these unique facial clefting anomalies is partic- ularly pertinent to the plastic surgeon. EMBRYOLOGY Virtually all cases of cleft lip–cleft palate are attributable to the failure of the medial nasal process to either contact or maintain contact with the lateral nasal and maxillary processes.7 The embryologic pattern of neural crest cell migration and subsequent merging is now ap- preciated to be a complex interplay of move- ments initiated when the inferior edge of the medial nasal process joins the maxillary pro- cess at approximately day 30 in the human embryo. 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 few days later to join with the medial nasal process to collectively form the upper lip-nasal unit.8 A cellular deficiency or failure of contact main- tenance in one or several components of this six-piece midfacial convergence results in the variations in clinical presentations that are commonly seen (Figs. 2 and 3). Simonart’s band, which can be seen at the posterosuperior aspect of some lip clefts (Fig. 4, left), may well illustrate a rupture of contact (lack of contact maintenance) rather than failure to make con- tact between the processes and may be the primary developmental problem in many clefts.7 This residual fibrous band is found in the approximate location of the embryonic union of the maxillary and median nasal pro- cesses that constitute the primary palate and is often associated with a narrower cleft defect than 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 merging and fusion, the size of the facial processes af- fects facial morphology and cleft susceptibility. An inherently smaller median nasal process, as would be suspected in Asians because of their smaller midfaces, tendency for class III occlusal relationships, and flatter nasal structures, may partially account for their relatively high rates of clefting. Conversely, some African Ameri- cans have broad, larger noses, increased facial widths, 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 complex and multifactorial, involving both genetic and environmental factors (Tables I through IV).9,10 Transmission of the cleft phenotype in a simple mendelian fashion, as is seen in many other hereditary disorders, rarely occurs. This is supported by studies of cleft monozygotic twins that show a 30 to 60 percent concordance rate.9,11 When compared with the 1.0 to 4.7 percent concordance rate for dizygotic twins, these results favor an important but not exclu- sive role for genetics in the development of cleft lip–cleft palate. In a family with a cleft lip–cleft palate child, the chance that a second child will be born with a similar defect is 3 to 4 percent; if two children have the defect, the chance of a third child being born with the defect is 9 percent.12 In addition to genetics, environmental factors (Table III), such as smoke exposure and use of steroids, phenyt- oin, and retinoids, have also been implicated in the development of cleft lip–cleft palate.13–20 More recently, a complex interplay between genetic and environmental factors has been unfolding. GENETIC FACTORS Cleft lip is a feature in 171 syndromes (15 percent 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 series examining the association of malformations with clefting, 13.6 percent of patients with cleft lip, 36.8 percent of patients with both cleft lip and 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 that are occasionally seen across or attached to the cleft. (Left) Simonart’s band serving as a residual tissue connection between the medial and lateral lip processes. (Right) Band from lower lip attached to cleft. TABLE I Genetic Links to Syndromic Orofacial Clefts* Syndrome Location Gene Van der Woude 1q32–41 Ectrodactyly ectodermal dysplasia 3q27 P63 Margarita Island ectodermal dysplasia 11q23 Aicardi Xp22 Craniofrontonasal dysplasia Xp22 Hypertelorism-microtia-clefting 1q, 7p Kallman Xp22 KAL1 Gorlin 9q22–31 LMX1B Velo-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 II Genetic Links to Nonsyndromic Orofacial Clefts* Gene Locus SKI/MTHFR 1p36 TGFb2 1q41 TGFa 2p13 MSX1 4p16, 1q31, 6p23 PVRL1 11q23 TGFb3 14q24 GABRb3 15q11 RARa 17q21 BCL3 19q13 * Adapted from Murray, J. C. Gene/environment causes of cleft lip and/or palate. Clin. Genet. 61: 250, 2002. 104e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005 with cleft palate alone had associated malformations.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 associated with nonsyndromic orofacial clefting by means of a mutation in methylenetetrahydrofolate re- ductase on 1q36.24 The short arm of chromo- some 2 has a susceptibility gene in the 2p13 region found to be associated with cleft lip– cleft palate.25 Studies have disagreed about whether this site involves transforming growth factor alpha26 or not.27 MSX1 located on chro- mosome 4 (4q25) has been associated with increased risk of cleft lip–cleft palate.28 Chro- mosome 6 contains a likely gene responsible for cleft lip–cleft palate at 6p23.29 Other chro- mosomes with possible clefting loci include chromosome 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 factor beta locus on chromosome 19.30,31 ENVIRONMENTAL FACTORS The list of environmental factors associated with orofacial clefting is growing (Table III). Any maternal alcohol consumption during pregnancy increases the incidence of orofacial clefting.32 Increased alcohol consumption re- sults in further increases in the incidence of developing both syndromic and nonsyndromic clefts.33 An association between maternal ciga- rette smoking and orofacial clefting is well es- tablished,30 resulting in at least a doubling of the 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 cleft lip–cleft palate.34 The effect of maternal smok- ing appears to be related to increased serum carbon monoxide levels,15–17 which exert their effect 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 has been shown to decrease this risk35; high phar- macologic doses (6 mg/day) are required for the protective effect.36 At present, folic acid supplementation is the only empiric preventa- tive treatment shown to decrease the incidence of 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 nutrition in the development of orofacial clefts, and sug- gest the reason for a link between increased risk of orofacial clefting and low socioeco- nomic status and the higher incidence of un- usual orofacial clefts found in developing countries. Maternal corticosteroid use causes a 3.4-fold increase in orofacial clefting.37 The increase has been corroborated by other investigators in nonsyndromic cleft lip–cleft palate.14 Anticon- vulsants, including phenytoin, oxazolidinedio- nes, and valproic acid, also cause cleft lip–cleft palate. Phenytoin causes a nearly 10-fold in- crease in the incidence of facial clefting11 and exerts its effect by inhibiting enzymes in the NADH dehydrogenase electron transport chain.7 Other pharmacologic agents, including retinoic 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 has examined environmental and genetic factors in isolation. More recent work indicates that there is a complex interplay between the two.10,30 Smoking, for example, is known to increase the incidence of orofacial clefting; however, infants with the transforming growth factor alpha genotype (also previously known TABLE III Environmental Causes of Orofacial Clefts* Teratogen Cleft Type Genetic Link Alcohol Cleft lip–cleft palate MSX1,TGFb3 Cigarette smoke Cleft lip–cleft palate TGFa Folic acid Cleft lip–cleft palate TGFa, MTHFR Steroids Cleft lip–cleft palate TGFb Anticonvulsants Cleft lip–cleft palate GABA receptor b3 Altitude Cleft lip TGFa/b, transforming growth factor alpha/beta. * Adapted fromCarinci, F., Pezzetti, F., Scapoli, L., et al. Recent develop- ments in orofacial cleft genetics. J. Craniofac. Surg. 14: 130, 2003. TABLE IV Genetic Mutations in Holoprosencephaly* Gene Chromosome Map Location Reference SHH 7q36 60 TGIF 18p11 61 SIX3 2p21 62 ZIC2 13q22 63 PTCH 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. Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 105e to be associated with orofacial clefting) have a sixfold 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 the incidence of orofacial clefting.39 Infants with allelic variants at the MSX1 site born to moth- ers who have more than four drinks per month also show a higher incidence of clefting.39 Maternal folic acid deficiency has been asso- ciated with orofacial clefting.40 This finding may be explained by a variant in the maternal 5,10-methylene-tetrahydrofolate reductase en- zyme, making the enzyme less efficient.41 Addi- tional work suggests that maternal genotype may also play a role in fetal folate status.42 With increased understanding about the causes of cleft 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 encountered congenital facial defects, constituting nearly two-thirds of major facial malformation and nearly 80 percent of all orofacial cleft types (Figs. 2 and 3).5,6 Differences in racial suscep- tibility are well documented and are the result of 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 an incidence of one in 400 to 500 live births in Asians and American Indians to one in 1500 to 2000 live births in African Americans. Cauca- sian susceptibility is intermediate at one in 750 to 900 live births.6,43 The left side of the pri- mary palate, for reasons as yet unclear (fetal position and circulatory and neural anatomy have all been implicated), is more often cleft than the right. MEDIAN CLEFT LIP In contrast to clefts of the lateral lip, median lip clefts are relatively rare. They are found in less than one in 100 cases of cleft lip–cleft palate, with a reported incidence of between 0.43 and 0.73 percent of cleft lip–cleft palate cases.44,45 Median cleft lips occur in less than 0.0001 percent of all births. Racial and sex differences have not been established. Like all cleft lip processes, a graded spec- trum of deformity occurs and is the result of failure of the two medial nasal processes to meet in the midline and fuse. However, me- dian lip clefting raises concerns about the over- lying face and brain not seen in the more common lateral lip clefts. An incomplete me- dian cleft (vermilion notch) may occur as an isolated entity (Fig. 5) or as part of such syn- dromes as orofacial-digital syndrome (Fig. 6), which represents a spectrum of anomalies of the face, head, hands, and feet (types I to VI).46–48 More complete median cleft defects FIG. 5. Incomplete median cleft lips. (Left) Vermilion notch, presence of central maxillary skeletal diastema, and double frenulum; (right) wider median cleft lip extending through the alveolus to the palate. 106e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005 are syndromic and present as two separate en- tities: the median cleft lip with hypotelorism (holoprosencephaly) and median cleft lip with hypertelorism (median cleft face syndrome). When medial cleft lip occurs without holo- prosencephaly, head circumference is within two 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 a monoventricle.49 The associated median facial abnormalities occur because of the sharing of embryologic cellular tissue (mesenchymal pri- mordium) and the prechordal mesoderm (me- soderm between the prosencephalon and stomo- deum) in conjunction with migrating neural crest cells.50 The frontonasal prominence of the prosencephalon then produces the median craniofacial skeleton (crista galli, ethmoid, vomer, nasal, and premaxillary bones) and the cartilaginous septum. The overlying soft tissues (forehead, nose, and prolabium) likewise arise from these embryonic tissues. Unlike lateral lip clefts, which represent a problem ofmerging and fusion, the holoprosencephalic median lip clefts are caused by a failure of development. The lat- eral aspects of the face are produced separately by the brachial arches and, as a result, are nor- mal. Although the facies of holoprosencephaly are different and parallel that of brain develop- ment (cyclopia, type I; ethmocephaly, type II; and cebocephaly, type III),51,52 the median cleft lip with hypotelorism (type IV) is characterized by absence of the crista galli, nasal and premax- illary bones, and nasal septum. The hypoplastic ethmoids accompany but are not the cause of the orbital hypotelorism, which is primarily a brain defect (Fig. 7). It is important to note that other forms of median cleft lip exist that appear very similar 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. Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 107e bral involvement, and that have varying degrees of vomero-septal-prolabial hypoplasia.53 An intact ethmoid, nasal bone, and crista galli appear to represent the key anatomical differences in these patients as compared with classic holoprosen- cephaly (Fig. 8). A group of “syndromic”-appearing patients who have traditionally been assigned a place on the “normal” end of the holoprosencephaly spectrum54,55 has recently been described by Mulliken et al.56 These patients have nasomax- illary hypoplasia, orbital hypotelorism, and an associated unilateral and bilateral cleft lip– cleft palate. Because these patients have nor- mal head circumference and intelligence, they cannot 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 Binder anomaly,57 which is associated with chondro- dysplasia punctata, cervical spine anomalies, and fetal exposure to warfarin. The patients in the study by Mulliken et al. did not have any of these characteristic findings or exposures and therefore cannot be classified as having Binder anomalies. Mulliken et al. prefer to refer to these 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 developmentis usually normal.58,59 Thus, frontonasal dysplasia is strikingly different from holoprosencephaly and presents in its extreme with a median cleft lip and palate, bifid nose, orbital hypertelorism, in- feriorly displaced V-shaped frontal hairline, and cranium bifidum occultum (Fig. 9). Unlike ho- loprosencephaly, the premaxillary segment is usually present, although it is clefted and maxil- lary incisor eruption can be expected. Mutations in several genes have been linked to holoprosencephaly. These include sonic hedgehog (SHH),60 TGIF,61 SIX3,62 ZIC2,63 and PTCH (Table IV).64 The only comparable ani- mal model for holoprosencephaly (cyclopia) occurs in the offspring of sheep that ingest plant alkaloid.65,66 This finding is unique because of the specificity and reproducibility of the defect by this teratogen. Although nonspecific craniofa- cial malformations, including median cleft lip, have been produced by numerous other agents in animals, specific teratogenic sources for me- dian defects in humans have not been reported. Alcohol—specifically, fetal alcohol syndrome— has been associated with midline developmental defects, including the median facial cleft in rare cases.67 OBLIQUE FACIAL CLEFTS The term oblique facial cleft, occurring in a variety of manifestations from the lip to the orbit, is a vague designation.1 The cleft has also been described by other equally nondescript names, including meloschisis and vertical facial and orbitofacial clefting. It really represents a group of lateral midfacial dysplasias that con- sist of distinct malformations involving differ- ing points of origin from the lip and superior extensions into the orbit. These clefts corre- spond to the Tessier cleft nos. 3, 4, and 5; the use of this nomenclature is of particular help in this area (Figs. 2 and 3).2,43 Because of their rarity (less than 0.25 percent among all facial clefts) and incomplete case descriptions in the literature, the actual incidence of these clefts as 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 Tessier cleft nos. 3 through 5, occur in slightly differ- ent regions of the lateral midface (cleft nos. 1 and 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. 108e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005 vertical facial clefts and are excluded from this discussion). The most medial variety (cleft no. 3, also known as a naso-ocular or nasomaxillary cleft) extends from the philtrum of the lip, as occurs in the more common lateral cleft of the lip, to the medial canthus of the eye, with foreshortening of this distance.69 As a result, a bony cleft occurs at the lateral incisor/canine area of the alveolus, extending through the frontal process of the maxilla to the lacrimal groove of the medial orbit. Soft-tissue defects, including colobomas of the nasal ala and lower eyelid and an inferiorly displaced medial can- thus and globe, are characteristic. Concurrent absence 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 extends toward a more centric orbital position.70 The lip origin of this cleft deviates from common lip clefts and does not violate the philtral ridge. At a point between the philtrum and commis- sure, the cleft extends superiorly through the nasolabial fold and passes into the orbit just medial to the infraorbital foramen (Fig. 11). As such, the medial canthal tendon and nasolac- rimal duct are usually intact. However, a marked coloboma of the lower eyelid is present, and in some cases, varying degrees of anophthalmos are present. The no. 5 cleft is primarily distinguished from the more medi- ally positioned cleft no. 4 by passing lateral to the infraorbital foramen (Fig. 12). This skeletal pathway difference has long been recognized and 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 the alveolar level by originating posterior to the canine. The ocular findings, however, includ- ing a severe lower eyelid coloboma, inferior displacement, 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 been previously repaired. FIG. 9. Two patients exhibiting differing degrees of expression of the median cleft face syndrome. (Left) Incomplete median lip cleft with moderate widening of the interorbital distance and nose. (Right) Increased severity with marked lateralization of orbits and nose that has previously undergone primary lip repair. Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 109e The embryology of the oblique facial clefts is difficult to explain by the known facial processes of merging and fusion. The no. 3 cleft occurs along the naso-optic groove, formed by the con- fluence of the lateral aspects of the olfactory placode and frontonasal process and the medial edge of the maxillary process, and as such the associated abnormalities are completely predict- able. Cleft nos. 4 and 5, however, correspond to no known embryologic grooves or plane of mes- enchymally supported epithelium, and their ori- gin currently remains speculative. The cause of these clefts has loosely been ascribed to a primary arrest of development, neurovascular insuffi- ciency or necrosis, or a result of tears in the developing maxillary process.72,73 This embryo- logic mystery has defied explanation because an experimental oblique cleft model has only been produced 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 of directly tethered tissue migration (such as from amniotic bands) and increased local pressure that produces cellular ischemia.74 As a result, such clefting may occur later in fetal develop- ment rather than during primary facial morphogenesis. LATERAL FACIAL CLEFTS Lateral facial clefts, or commissural clefts, are best thought of as a variable finding within the broader congenital condition of hemifacial microsomia (Tessier cleft no. 7). They are the second most common orofacial cleft (second to the common cleft lip), with an incidence less than that of hemifacial microsomia (one in 3500 to 5000 live births) because of an incon- sistent occurrence within the syndrome.75 Al- though commissure clefts are not seen in every case of hemifacial microsomia, their occur- rence should initiate a search for involvement of the ipsilateral ear, mandible, and facial nerve and overlying facial soft-tissue deficien- cies. These clefts also occur in the oculoauricu- lovertebral spectrum (historically referred to as Goldenhar syndrome), which has the addi- tional features of epibulbar dermoids, verte- bral anomalies, and central nervous system and cardiopulmonary defects.76 The clinical findings of the lateral oral cleft variably extend along a line from the commis- sure to the tragus. Most commonly, a 1- to 3-cm-long cleft is present, with disruption of the orbicularis and buccinator muscles and with the cleft edges lined by vermilion.75 Only rarely does a complete cleft extend posterior to or beyond the anterior border of the masseter muscle, although a groove or skin depression continuing along the cleft line to the ear may occasionally be seen (Fig. 13). Because of the association between lateral oral clefts and hemifacial microsomia, underlying deformities of the mandibleare well appreciated. Less ap- preciated but equally common, particularly in severe 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 by variable amounts of accompanying zygomatic hypoplasia and resultant orbital dystopia. Lateral facial clefts are easy to understand embryologically, as the commissure represents the most anterior point of mesodermal merg- FIG. 11. Tessier no. 4 orofacial cleft. FIG. 12. Bilateral incomplete Tessier no. 5 clefts. 110e PLASTIC AND RECONSTRUCTIVE SURGERY, June 2005 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 cleft appears to be heterogeneous. A vascular cause, attributable to embryonic hematoma forma- tion from disruption of the stapedial artery stem, is one proposed mechanism.77 The sever- ity of the condition subsequently depends on the size of the hematoma and its time course of resolution 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 and hypoxia, to pharmacologic agents, such as sa- licylates and anticonvulsants.79 Intrauterine compression secondary to oligohydramnios in the embryonic head region has also been sug- gested and may account for some cases of hemifacial microsomia that occur with other anomalies, such as limb reduction defects.80 MEDIAN MANDIBULAR CLEFTS Clefting of the lower face (Tessier cleft no. 30) (Fig. 1) almost universally occurs through the midline of the lip and mandible. Although para- median lower lip/mandibular clefting has been reported, there are fewer than 70 reported cases in the literature, appearing with less frequency than the oblique facial clefts.11,81,82 Sex and racial predilections remain indeterminate. A range of inferior clefting has been reported that extends from mild notching of the lower lip and mandibular alveolus (Fig. 14) to complete cleavage of themandible, extending into inferior neck structures.81–85 Tongue involvement is typi- cal though variable in expression, ranging from a bifid anterior tip with ankyloglossia to the bony cleft margins, to marked lingual hypoplasia. In- ferior cervical defects (midline separation, hyp- oplasia, and agenesis) of the epiglottis, strapmus- cles, hyoid bone, thyroid cartilage, and sternum may 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 the masseter. (Right) Bilateral commissural clefts without hemifacial microsomia. Vol. 115, No. 7 / THE SPECTRUM OF OROFACIAL CLEFTING 111e neous cleft passes caudal to the gnathion point on the chin. The embryologic basis of median mandibu- lar clefts lies in the failure of coaptation of the free ends of the first visceral arches in the midline. Once the arches are formed through neural crest cell migration, vascularization, and mesodermal myoblastic ingrowth, growth centers 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 are frequently missing along the medial mandibu- lar margins, this suggests that partial or com- plete failure of growth center differentiation and development is responsible for such de- fects rather than a simple merging and contact maintenance. Because no animal models exist for study of the median cleft lip, the cellular basis for this defect may remain unknown for some time. Presumably, however, more infe- rior cervical defects would be caused by similar mechanisms in the second and third visceral arches. The occasional association of a supe- rior midline defect (cleft palate) with a median mandibular cleft is interesting because it sug- gests that a broader defect in epithelial mesen- chymal merging and fusion is occurring or that the 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 from the mouth and lips—the most common cleft structure of the face. Some of these clefts are relatively common, including the typical cleft lip with or without cleft palate; others are ex- tremely rare. As the causes of orofacial clefts are better understood, it is becoming clear that a complex interplay between genetic and envi- ronmental variables causes these clefts. Future study of orofacial clefts will require increas- ingly sophisticated methods of elucidating these subtle interactions. Orofacial clefts are of particular relevance to plastic surgeons, who set 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 Surgery CranioFacial Program Indiana University School of Medicine 702 Barnhill Drive, Suite 3540 Indianapolis, Ind. 46202 beppley@iupui.edu REFERENCES 1. van der Meulen, J. C., Mazzola, R., Vermey-Keers, C., Stricker, M., and Raphael, B. A morphogenetic clas- sification of craniofacial malformations. Plast. Recon- str. Surg. 71: 560, 1983. 2. Tessier, P. Anatomical classification of facial, craniofacial, and latero-facial clefts. J. Maxillofac. Surg. 4: 69, 1976. 3. Jones, K. L. 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