which mesenchyme could signal epithelial differentiation 1 is characterized by cellular condensation,is either through extracellular matrix molecules (i.e. fragmentation, phagocytosis and finally lysosomalcollagen molecules), through soluble factors (i.e. growth degradation. Type 2 is characterized primarily by thefactors), direct cell-to cell contact, or combinations of all appearance of large lysosomes which initiate cellularthe above. The actual period of fusion of the degradation. Type 3 occurs without the involvement ofmesenchymal shelves may be just a matter of minutes, lysosomes and without apparent phagocytosis.but complications in events leading up to and during The sites of cell death vary depending upon the teratogenfusion will result in a palatal clefting of varying severity. (or genetic insult) and the exposure time (i.e. Also seam disruption occurs by migration of a large developmental stage of the embryo). There seems to benumber of epithelial seam cells (perhaps 50%) into the a selective sensitivity of cells; tissues with highpalatal mesenchyme (rev by Ferguson, 1988). These proliferative activity are more likely to show cell deathfragments very quickly become undistinguishable from than tissues that proliferate more slowly. Other factorsother palatal mesenchyme cells. The epithelia on the may also been involved i.e. state of cellularnasal aspect of the palate differentiate into differentiation, differential drug distribution or otherpseudostratified ciliated columnar cells while on the oral specific cellular characteristics. Both the disappearanceaspect of the palate differentiate into stratified squamous and expansion of areas of PCD may have a role innonkeratinized cells. Osteogenic blastemata for the teratogenesis (rev by Sulik, 1988).palatal processes of the maxillary and palatine bones Pathogenesis is probably caused by one of the followingdifferentiate in the mesenchyme of the hard palate while mechanisms:several myogenic blastemata develop in the soft palate. 1) Anatomic obstruction i.e. the tongue obstruction During the period of shelf elevation, there is almost no hypothesis-only when associated with mandibulargrowth in head width but constant growth in head height. underdevelopment (Melnick, 1986). In the cases whereThis establishes a conductive orofacial environment that the chin is compressed against the sternum, the tonguepermits the expanding palatal shelves to occupy a may interpose in the space between the ascendingposition above the dorsum of the tongue. shelves. The resultant palatal deficiency is U-shaped not In human embryos palatal shelves elevate V-shaped and it is considered to be a deformation ofsimultaneously on day 43 (22-24 mm CRL), and the tissues with a normal growth potential rather than apalate is closed by 55 days (33-37 mm CRL). The malformation of tissues that may have been affected bymesenchymal fusion is complete by 60 days (45-46 mm disturbances of ectomesenchyme or other phenomena atCRL)-12. cellular level (Poswillo, 1968). 2) Interference with cell differentiation or migration, either through hormonal defect, biochemical defect, orPathogenesis of CL and CP extrinsic biochemical interference. Numerous studies have substantiated the association between teratogensIn studying different types of orofacial malformation, and clefting. Such teratogens may be individuallyanimal specimens have been proved to be especially operative in a subgroup of individuals that is geneticallyhelpful because they permit observation of embryological and biologically susceptible. Conversely, several differentand fetal stages that lead to malformations found at birth. teratogens may act together on a single mechanism The majority of congenital craniofacial malformation controlled by only a few genes. At present our knowledgeoccurs during the 5-12 weeks of development (Moore et of the teratogens that are associated with clefting is veryal., 1988). The embryonic period (from 3-9 weeks) is the limited. Only a few substances such as retinoic acidmost sensitive period during which teratogens can be (used in the treatment of acne and psoriasis), have beenparticular damaging. This is especially true for midline confirmed as teratogens with direct effect on facialmorphologic disorders such as cleft lip and palate. They morphogenesis.considered to be a palygenic multifactorial problem in Several other factors that may influence geneticwhich genetic susceptibility is influenced by multiple and behavior and early morphogenesis have receivedprobably cumulative environmental factors, interacting attention in investigation of the etiology of CL and CP (revaltogether to shift the complex process of morphogenesis by Amaratunga, 1989).of the primary and secondary palates, toward a threshold Seasonal variation in the incidence of the CLP hasof abnormality at which clefting may occur been reported by several authors while others have(multifactorial/threshold model). Both the genetic and the reported the opposite. This phenomenon has not beenenvironmental factors have not been established yet. satisfactorily explained. One possible reason is viral Cell death is a normal phenomenon seen in the infection, which may have a seasonal trend. However, adeveloping embryo (PCD). It is also a common feature correlation between clefts and viral infections has notseen in embryos after exposure to a variety of clearly been established.teratogenes that induce craniofacial malformations. There Also some authors report that CLP is higher in theare three distinct types of PCD (rev by Sulik, 1988). Type earlier born children while others conclude the opposite.
When birth rank is raised, maternal age also could be so that opportunities for palatal fusion are lost (rev byraised. Mutations of genes can occur with advanced Poswillo, 1988).parental age. The sequence of lip and palate formation extends over Monozygous twins discordant for clefting are 15 days in man. Therefore in many syndromes cleft lipinteresting. Examinations of the developing fetus by and palate may accompany anomalies of other parts ofultrasound have shown that there are altered rates of the body. Many developing systems can be disturbedfetal growth, both of the whole body and of its parts, so simultaneously by teratogenic influences which operatethat at any of one time twins may exhibit different stages over a long period of morphodifferentiation. But despiteof development. Therefore the variable expression of the fact that there are over 150 recognized disorders inclefting could result from the same factor acting on both which CL, CP or both may represent one feature, it istwins at the same time, but at relatively different stages of widely believed that the majority of affected individualstheir early growth. are otherwise structurally normal (rev by Jones,1988). With regards to lip clefting, it seems that the critical Recent studies (Shprintzen et al., 1985) havestage of lip formation is when the medial and lateral nasal emphasized the fact that a significant portion of childrenprocesses contact each other and fuse. with clefts have the cleft as one feature of a broader Anatomical variations (differences in the size, shape or pattern of malformation. It is important to recognize thatposition of the facial processes), based possibly on ethnic structural defects are not, for the most part, randomlyor other factors, may predispose to the problem of lip associated. The presence of other major and minorformation. Where the size of the facial processes is malformations in association with a cleft implies that areduced and they are not in tight apposition there is an single etiologic factor - genetic, chromosomal orincreased possibility of cleft lip. Experimental support of teratogenic - produced the pattern as a whole.the previous is found in the work of Trasler, 1968 and Although CL is frequently associated with CP, CL withBrown, Hetzel, Harne and Long, 1985 reviewed by or without CP and CP alone are distinctly different inPoswillo, 1988, where the spontaneous development of aetiology. Subsequent studies have consistentlycleft lip and palate in A strain mice is attributable to the confirmed that these two conditions indeed differ inpointed facial processes that prevent wide areas of etiology and also in incidence, sex predisposition andcontact. On the other hand in the C57 black strain of their relationship to associated birth defects. CL resultsmouse the larger facial processes facilitate wider contact from the nonfusion of the upper lip and the anterior partof the processes and therefore clefting doesnt develop. of the maxilla during weeks 5-7 and occurs at an While anatomical variation is one potential predisposing incidence of approximately 1/1000 births (Thompson andfactor in the development of cleft lip and palate, there are Thompson, Provide year). CP alone results from failure ofalso other factors. It is well established that at the time of the mesenchymal masses of the palatine processes toconsolidation of the facial processes there is a concurrent fuse during weeks 7-12 and has an average incidence ofprogram of spontaneous cell death (PCD) involved in the 0.7/1000 births. The incidence of CL with or without CPremoval of the epithelial debris from the developing nasal varies from 2.1/1000 in Japan to 0.4/1000 Nigeria (rev byplacode. When this PCD is more extensive than Moore, 1988), with the geographical variation being lessnecessary and repair of mesenchyme is disturbed, a important than ethnic differences. In contrast theweakness develops in the forming lip and alveolus. The incidence of the CP alone shows little variation incontinued action of growth traction forces may further different racial groups. This may mean that CP alone willdisrupt the association of the facial processes with the lip not fit the purely multifactorial model which includes bothmargins being pulled apart. Resultant clefts of the lip may polygenic origin and undefined environmental factors thatvary from a simple groove in the muscle to a complete would increase the variation in incidence bothcleft into the nasal floor (Poswillo, 1988). geographically and to some extend racially. Generally CL In regards with the submucous cleft palate and bifid with or without CP are more frequent in males, whereasuvula, both can be considered as microforms of isolated CP alone is more frequent in females. Therefore due topalatal clefting and are probably the result of both genetic and environmental evidence it seems thatdisturbances in the local mesenchyme at the time of CL with or without CP and CP alone are separateossification of the palatal bridge and merging of the entities.margins of the soft palate. These phenomena occur latein morphogenesis, between 7-10 weeks of humandevelopment (Poswillo, 1974). Genetic Factors There is a frequent association between clefts of the lipand cleft palate. Animal studies suggest that following the Polygenic inheritance refers to conditions determinedfailure of lip closure there is an overgrowth of the exclusively by a large number of genes, each with a smallprolabial tissues which then divert the tongue into the effect, acting addictively (i.e. hair color) (Bjornsson et al.,nasal cavity. The mesenchymal obstruction of the tongue 1989).can delay the movement of one or both palatal shelves, Multifactorial inheritance refers to conditions
determined by a combination of factors each with a minor families, found no support for a MF/T model butbut additive effect (i.e. blood pressure) (Thompson and suggested the possibility of a major gene. Also MarazitaThompson, Provide year) and has been developed to et al., 1986 have reported an analysis of ten Englishdescribe the observed non-Mendelian recurrences of multigenerational CL/P families collected by Carter,common birth defects. It includes both polygenic origin 1982). They were able to reject an MF/T model andand undefined environmental factors that will increase the demonstrated that major locus acting on a multifactorialvariation in incidence both geographically and to some background (mixed-model) gave a reasonable fit. Chung,extend racially. The multifactorial inheritance is more 1986, analyzed a series of Danish and Japanese CL/Pdifficult to analyze than other types of inheritance but it is families and concluded that the best fitting modelthought to account for much of the normal variation in predicted recessive major gene acting on a multifactorialfamilies, as well as for many common disorders, including background (mixed-model). Chung et al., 1989, analyzedcongenital malformations. Hawaiian families from several racial groups and found The normal rate of development can be thought as a that the data were consistent with a major-continuous distribution that if it is disturbed a serious gene/multifactorial model (mixed model). Ardinger, 1988,malformation may result, dividing the continuous have provided additional evidence for an associationdistribution into a normal and abnormal class separated between the locus for transforming growth factor alphaby a threshold. This has been described as the (TGFA) and CL/P locus. TGFA is believed to be themultifactorial/threshold model and several human embryonic form of epidermal growth factor, which iscongenital malformations show family patterns that fit this believed to regulate the proliferation and differentiation ofmodel. CL with or without CP and CP alone are included palatal epithelial cells both in vitro and in vivo. Hecht etin this category. al., 1991, analyzed midwestern U.S. Caukasian families CL with or without CP shows both geographical and and showed consistency with a major-locus model. Heracial variations which means that it could be explained found that the dominant or codommant models withby the multifactorial/threshold model. In contrast CP decreased penetrance fitted the best. Both the MF/Talone shows little variation in different racial groups. This model and the mixed model with a dominant major genemay mean that CP alone will not fit the purely effect were found to provide an explanation of familiarmultifactorial model. clustering pattern. Marazita et al., 1992, analyzed almost To date, there have been three pedigrees reported in 2000 Shangai families found that the best fitting modelwhich CP is clearly inherited as a single-gene X-linked was that of an autosomal recessive major locus.disorder (Moore et al., 1987; Moore et al., 1990; Melnick Farrall and Holder (Sulik et al., 1989) in their ownet al., 1980). analysis have shown that the extensive published One of these pedigrees is described to in a large recurrence risk data, which have been interpreted to beIcelandic family (293 individuals) that shows Mendelian consistent with an MF/T pattern of inheritance, areinheritance of X-linked secondary cleft palate and equally compatible with an oligogenic model with perhapsankyloglossia (Melnick et al., 1980). Family analysis as few as four genes.showed that the frequency of CP among all those In conclusion, the extensive recurrence risk data, whichrelatives was much higher among the male than among have been widely interpreted as providing evidence of athe female CP probands. There was no incidence of male polygenic multifactorial trait, are now thought to beto male transmission in this large family. The X-linked consistent with a model with a major-gene effectmode of inheritance of CP is indicated by the family contributing to about 1/3 of CL/P and acting on adistribution. Also the large size of this family together with multifactorial background. For CL/P, the observed declinethe availability of many well localized X-chromosome in risk with decreasing relatedness to the proband isprobes has made it possible to localize the defect incompatible with any generalized single-major-locussubchromosomally (using RFLP-restriction fragment (gSML) model of inheritance and is suggestive oflength polymorphism studies for linkage) to the q13-q21.1 multilocus inheritance.region of the X chromosome (Farrall and Holder, 1992).Finer mapping and the use of cell lines from patients withdeletions of the X chromosome have further localized the Teratogenesdefect to Xq21.31-q21.33 (Lammar et al., 1985). In the case of CL with or without CP, Melnick et al., Palatal shelf elevation and fusion depends on fetal1980 (Powsillo and Roy, 1965) reviewed worldwide CL/P neuromuscular activity, growth of the cranial base andrecurrence risk data and found that both a multifactorial- mandible, production of extracellular matrix andthreshold model and a monogenic with random contractile elements in the palatal shelves, shelfenvironment component model fitted poorly. adhesion, PCD of the midline epithelial seam and fusion Farrall and Holder, 1992 (Sulik et al., 1989) refer to the of the ectomesenchyme between one shelf and another.work of several investigators. According to their report: All these phenomena must act in perfect harmony over aMarazita, 1984 in his analysis of a subset of Danish CL/P short period of time in order to produce normal
palatogenesis. Factors that interfere with any of these with many cellular functions. For example, blebbing ofevents could lead to a cleft. neural crest cells membrane was noticed following retinoic exposure. This may interfere with the migratory ability of these cells. Recovery follows removal of theVitamin A retinoic acid in vitro. In vivo, recovery from a brief interference with cell migration might also be expectedBy introducing into the maternal diet of strain mice human but sufficient recovery probably does not follow theteratogenic agents such as of excess vitamin A, the excessive cell death of progenitor cells.malformation threshold in the developing embryos may Treatment of female C57B1/6J with 13-cis-retinoic acidbe shifted to the extent that 100% offspring are born with at early stage of pregnancy (8d14h to 9d0hr) has thethe expected deformity (Poswillo, 1988). Renewed more severe effect on the secondary palate (Fraser,interest in retinoic teratogenicity has followed the 1976). 12 hours after the 8d14hr treatment time, embryosintroduction of 13-cis-retinoic acid as an effective have 13 to 20 somites. Extensive expansion of cell deathtreatment for severe cystic acne. Inadvertent use of 13- at this time would be expected to have a major effect oncis-retinoic acid during the first trimester of human almost the entire secondary palatal shelf complex,pregnancy has been reported to result in a spectrum of thereby resulting in severe hypoplasia and clefting. Minormalformations termed retinoic acid embryopathy (RAE) effects would be expected to involve only the posterior(Sulik and Dehart, 1988) and includes microtia or anotia, portion of the maxillary prominences, thereby resulting inmicrognathia and in some cases CP. Induction of CP deficiency in the posterior aspect of the secondary palate.following administration of excess vitamin A to pregnant 12 hours after the 9h6hr treatment time (latelaboratory animals is well documented (Schendel et al., treatment), embryos have approximately 30 to 341989). Most of the early animal studies involved exposure somites. Expansion of cell death in embryos of this stageto forms of vitamin A that are stored in the maternal liver of development results primarily in foreshortening of theand that, therefore, have a relatively long half-life; also secondary palate, which occurs at the expense of itsinvolved multiple administrations of the drug or examined posterior portion. Major effects on the entire palatalthe developmental end-point only, thereby excluding shelves would not be expected at this treatment time.study of the developmental changes that lead to CP. Later treatment times are mostly associated with The study of Kochhar and Johnson, 1965 reviewed by induction of limb malformations (Lowry, 1970).Sulik, 1989, describes palatal clefts for which the shelveswere very small or entirely absent; these resulted frominsufficient maxillary prominence mesenchyme. These Phenytoininvestigators also found that size reduction of the palatalshelves occurred only posteriorly in the most cases. Also, under the influence of teratogenic doses of The use of all-trans-retinoic acid, which is of short half- phenytoin, the lateral nasal process fails to expand to thelife, has shown the incidence of cleft palate peaks at size necessary for tight tissue contact with the medialmore than one developmental stage in both hamsters nasal process (rev by Poswillo, 1988). Abnormaland mice (Kochhar, 1973 rev by Sulik, 1989). differentiation of the cellular processes of the The changing incidence and severity of secondary ectomesenchymal cells is probably associated with thispalatal malformations that may be induced within a condition, where the failure of union at the point ofnarrow window of time (over a 16 hour period) appear to connection which establishes the lip and primary palate.be related to a corresponding change in the pattern ofPCD in the first visceral arch. It has been shown that 13-cis-retinoic acid increases the amount of cell death in Ethanolregions of PCD in C57B1/6J mice, a strain which isparticularly prone to spontaneous craniofacial Ethanol (alcohol) is an important human teratogen. IT ismalformations. (Sulik et al., 1988; Fraser, 1976). The estimated to affect severely 1.1/1000 live births and havedistribution of excessive cell death in regions of PCD lesser effects in 3-4/1000 children born. Its abuse duringprovides a bases for understanding the composition of pregnancy results in fetal alcohol syndrome (FAS) whichsyndromes in which malformation appears to be involves a wide variety of malformations in many organs.unrelated by tissue type or location (Fraser, 1976). Abnormalities that are not diagnostic of FAS, but are It has been described a vitamin A cell necrosis as being associated with maternal ethanol abuse are termed fetalconsistent with type-2 cell death (rev by Sulik, 1988). On alcohol effects (FAE) (rev by Sulik, 1988). Treatment ofthe other hand it has been noted that lysosomal C57BL/6J female pregnant mice with ethanol when themembranes of all cells do not lyse. Only those embryos have approximately 7-10 somites results in amembranes that are at a particular stage of differentiation pattern of malformation that is consistent with theor which have been perturbed in some other way lyse. DiGeorge sequence (midline clefts in the nose and cleftMembrane destabilizasion by the retinoids may interfere palate are features of this sequence. The DiGeorge
sequence has been described in the offspring of alcoholic irradiation results in altered permeability of intracellularmothers. structures and enzyme release, i.e. rupture of lysosomal Among the cellular effects of ethanol are the increased membranes, and suggest that this results from lipidperoxidase activity, interference with cytoskeletal peroxide formation.components, diminished DNA synthesis and suppressedrates of cell division, direct effect on membranes resultingin excessive fluidity (reviewed by Sulik, 1988). Recent Hypoxiainvestigations illustrate excessive cell death within 12hrfollowing maternal treatment. The rates of cell death are Of particular interest is the hypoxia-induced cleft lip.similar to the normal rates of cell death seen in PCD, but Hypoxia in the human embryo may result from cigarettethe areas of cell death are expanded. The reason for this smoking, reduced atmospheric oxygen levels and alsoexcessive cell death is not yet clear. One possible placental insufficiency. Previous studies had shown sizeexplanation is that exposure to ethanol results in lipid reduction and abnormal apposition of the facialperoxidase/formation that leads to rupture of lysosomal prominences as possible pathogenetic mechanisms. Themembranes and release of hydrolytic enzymes (type 2 presence of cellular debris resulting from cell death in thecell deaths). deepest aspects of the invaginating nasal placodes, as well as overall growth retardation of the facial prominences, leads to inability of the facial prominencesHyperthermia to contact and fuse (rev by Sulik, 1988). There are suggested also direct effects of oxygen deficiency on theHyperthermia has teratogenic effects and the facial cells which lead to glycolysis followed by acidification ofmalformations induced include, among others, cleft lip intercapillary spaces and subsequent necrosis resultingand/or cleft palate. CNS is particularly sensitive to from intra and extracellular leakage of lysosomalhyperthermia. Facial abnormalities have been associated enzymes. It is interesting to note that chemicals thatwith human maternal hyperthermia at 4-7 weeks (rev by interfere with oxidative enzymes such as phenytoinSulik, 1988). The type and extent of damage depend on induce cleft lip in the mice.the duration of temperature elevation and the extend ofelevation. Also low sustained temperature elevationsappear to be as damaging as repeated spikes of higher Antimetaboliteselevation. Elevations of 1.5-2.5 degrees of Celsius abovenormal body temperatures represent the threshold for Methotrxate and aminopterin are two uncommonteratogenesis in human. Such elevations can result with antimetabolites that can induce cranial dysplasia and cleftexcessive exercise, the use of hot bath and saunas and palate in human. Their action is inhibitory of DNAfebrile episodes. synthesis through competitive folic acid antagonism. The Again in the case of heat-induced teratogenesis, cell pathogenesis of methotexate involves fluid imbalance,death is considered to play a major role, with the mitotic resulting perhaps from interference with osmoregulatorycells being the most susceptible. The pathogenesis of cells in extraembryonic capillary beds, which is partiallyheat-induced malformations in areas other than the CNS responsible for the malformation.has not been studied yet. It has been suggested thoughthat hyperthermia could result in intra and extracellularleakage of lysosomal enzymes which could lead in type-2 Metabolic disorderscell death. An interesting finding associated with lip clefting was that of mitochondrial myopathy of cleft muscles (Rushton,Ionizing radiation 1979). Facial muscle specimens from the cleft site were characterized by disorganized fibers, going in manyIonizing radiation acts as a direct insult to the embryo. different directions. The number of fibers appeared to beThe malformations induced are similar to those noted decreased and there is more connective tissue betweenfollowing exposure to ethanol, retinoic acid or the muscle fibers. The fiber diameters were also found tohyperthermia. The cellular mechanism,s of radiation be much smaller. NADH stain and electron microscopyinduced teratogenesis are not completed understood. revealed large accumulation of mitochondria at theThey vary from sublethal injuries affecting differentiation central portion of the fiber, giving a star shapedand cellular interactions, to effects on rates of appearance to the fiber. The mitochondria are moreproliferation and cell death (rev by Sulik, 1988). variable in shape than normal, and the cristae are moreResponse of the cells to the radiation is depended on cell densely packed than expected.cycle. Also in some instances cell death is linked to These abnormalities in mitochondrial size, location,chromosomal damages. Some studies have shown that cristae and number suggest a form of metabolic defect
that could underlie cleft lip deformities. The suggested Bjornsson A, Arnason A, Tippet P (1989). X-linked cleft palate and ankyloglossia in an Icelandic family. Cleft Palate J. 26:3-8.explanation is that a defect in energy production could Farrall M, Holder S (1992). Familiar recurrence-pattern analysis of cleftresult in insufficient cellular migration and proliferation lip with or without cleft palate. Am. J. Hum. Gen. 50: 270- 277.and thus be the pathophysiologic basis for cleft lip. As Ferguson MW (1988). Palate development. Development 103: 41-57mentioned, in addition to the mitochondria the cleft lip Fraser FC (1976). The multifactorial/threshold concept-uses andmuscles were found to be abnormal. However, no signs misuses. Teratology 14: 267-280,. Jones M (1988). Etiology of facial clefts: Prospective evaluation of 428of group denervation or reinnervation were found and the patients. Cleft Palate J. 25: 16-20.motor end plate structure appeared normal. These Lammar EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT,findings argue against denervation or abnormal Curry CJ, Fernhoff PM, Grix AW, Lott IT, Richard JM, Sun SC (1985). Retinoic acid embryopathy. N. Eng. J. Med. 313: 837-841.innervation as a cause of the abnormalities. Since the Lowry RB (1970). Sex-linked cleft palate in a British Columbian Indianinnervation was normal, the muscle atrophy was family. Pediatrics 46: 123-128.attributed to an inability of these muscles to function Melnick H, Bixler D, Fogh-Andersen P, Conneally PM (1980). Cleft lip ±properly, which was furthermore attributed to the cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968. Am. J. Med. Gen. 6: 83-97.mitochondrial energy production abnormality or to the Melnick J (1986). Cleft lip with or without cleft palate: Etiology andlack of normal fiber orientation. If the causative factor is pathogenesis. CDAJ 14: 92-98.the fiber orientation, one would expect this to improve Moore G, Ivens A, Chambers J, Bjornsson A, Arnason A, Jensson O,following adequate surgical reconstruction of the muscle Williamson R (1988) The application of molecular genetics toat the time of lip repair. On the other hand changes detection of craniofacial abnormality. Development 103: 233-239. Moore GE, Ivens A, Chambers J, Farrall M, Williamson R, Page DC,secondary to cellular energy problems would not be Bjorsson A, Arnason A, Jensson O (1987). Linkage of an Xexpected to improve following surgery. chromosome cleft palate gene. Nature, Lond. 326: 91-92. In general, common targets for some teratogenes (i.e. Moore GE, Ivens A, Newton R, Balacs MA, Henderson DJ, Jensson Ο (1990). X chromosome genes involved in the regulation of facialcells in regions of PCD that represent a developmental clefting and spina bifida. Cleft Palate J. 27: 131-135.weak point) provide reason to expect interactive effects. Poswillo D (1968). The etiology and surgery of cleft palate withRepeated exposure of teratogenes in subthreshold doses micrognathia. A R Coll Surg. Eng. 43: 61-68.of more than one agent could result in potentiation. Poswillo D (1974). The pathogenesis of submucous cleft palate. ScandPotentiation indeed occurs after repeated exposures to J. Plast Reconstr Surg. 8: 34-41. Poswillo D (1988). The etiology and pathogenesis of craniofacialvitamin A and hyperthermia. deformity. Development 103: 207-212. Powsillo D, Roy LJ (1965). The pathogenesis of cleft palate: an animal study. Br. J. Surg. 52: 902-912.CONCLUSION Rushton AR (1979). Sex-linked inheritance of cleft palate. Hum. Gen 48: 179-181. Schendel SA, Pearl RM, De’ Armond SJ (1989). Pathophysiology ofAt present our knowledge of the teratogenes that are cleft lip muscle. Plast Rec. Surg. 83: 777-784.associated with clefts is not very extended. Some of Shprintzen RJ, Siegel-Sadewitz VL, Amato J, Goldberg RB (1985). Anomalies associated with cleft lip, cleft palate, or both. Am. J.these substances (such as retinoic acid) have been Med. Gen. 20: 585-595.confirmed to have direct effects on facial morphogenesis Sulik K, Cook CS, Webster WS (1988). Teratogenes and craniofacialbut many more await identification. malformations: relationships to cell death. Development 103: 213- Metabolic disorders inherited or not, may play a role in 232the pathogenesis of clefting. Sulik KK, Dehart DB (1988). Retinoic acid-induced limb malformation resulting from apical ectodermal ridge cell death. Teratology Our knowledge of cell biology increases rapidly and 37:527-537.may eventually lead to the understanding and possibly Sulik KK, Smiley SJ, Turney TA, Speight HS, Johnston MC (1989).prevention of clefts of the lip and palate. This can Pathogenesis of cleft palate in Treacher Collins, Nager, and Miller Syndromes. Cleft Palate J. 26: 209-216.particularly apply in cases with monogenic etiology and in Thompson JS, Thompson MW (Provide year). Multifactorial inheritance.chromosomal disorders. In Genetics in Medicine, 4th edn, pp. 210-225. Philadelphia: WB Saunders.REFERENCEAmaratunga NA (1989). A study of etiologic factors for cleft lip and palate in Sri Lanka. J. Oral Maxillofac Surg. 47: 7-10.