cleft lip and palate

REVIEW Cleft Lip and Palate: Etiological Factors, A Review Abu - Hussein Muhamad1 Quick Response Code ABSTRACT: Congenital cleft-Lip and cleft palate have been the subject of many genetic studies, but until recently there has been no consensus as to their modes of inheritance. Infact, claims have been made for just about every genetic mechanism one can thinkdoi: ........................... of. Recently, however, evidence has been accumulating that favors a multifactorial basis for these malformations.1 DDS, MScD, MSc, DPDLimited to Pediatric Dentistry123 Argus Street The purpose of the present paper is to present the etiology of10441 Athens cleft lip and cleft palate both the genetic and the environmentalGreece factors. It is suggested that genetic basis for divers kinds of common or uncommon congenital malformations may very wellArticle Info: be homogeneous, while, at the same, the environmental basisReceived: April 12, 2012; is heterogeneous.Review Completed: May, 11, 2012;Accepted: June 12, 2012Published Online: August, 2012 (www. nacd. in)© NAD, 2012 - All rights reserved Key words: clef lip, cleft palate, etiology, genetic, multifactorial.Email for correspondence: muham001@otenet.grINTRODUCTION A short review of the normal embryonic development of the facial primordia is necessary before reviewingthe factors that may interfere with this development leading to clefts of the lip and the palate. In the developing embryo migration of cell masses, fusion of facial processes and the differentiation oftissues are three important events that lead eventually to an adult appearance. The pattern of development,but cells also response to environmental signals. Since both factors are present and interact, it is difficult toascertain the exact role of each of them. The facial primordia (a series of small buds of tissue that forms around the primitive mouth) are madeup mainly of neural crest cells that originate from the cranial crest (Ferguson, 1988). Neural crest cellsmigrate to the primitive oral cavity where, in association with ectodermal cells, form the maxillary processes.Palatal shelves from these processes alive at embryonic day 45 in human. An intrinsic force, mainly producedby the accumulation and hydration of hyaluronic acid-1, is progressively generated within the palatal shelvesand reaches a threshold level which exceeds the force of resistance factors (e.g. tongue). Synthesis andhydration of hyaluronic acid by palatal mesenchyme is stimulated by epidermal growth factor andtransforming growth factor beta. The erectile shelf elevating force is partly directed by bundles of type I INDIAN JOURNAL OF DENTAL ADVANCEMENTS J o u r n a l h o m e p a g e : w w w. n a c d . i nIndian J Dent Adv 2012; 4(2) 830

Cleft Lip and Palate Abu - Hussein Muhamadcolagen which run down the center of the vertical palatal processes of the maxillary and palatine bonesshelf from its base to its tip. Moreover the epithelial differentiate in the mesenchyme of the hard palatecovering and associated basement membrane of the while several myogenic blastemata develop in thepalatal shelf exhibit differential traction, which soft palate.serve to constrain and direct the swelling osmotic During the period of shelf elevation, there isforce. Also the palatal mesenchymal cells are almost no growth in head width but constant growththemselves contractile and secrete various in head height. This establish a conductive orofacialneurotransmitter that effect both mesenchymal cell environment that permits the expanding palatalcontractility and glycosaminoglycan dehydration shelves to occupy a position above the dorsum ofand therefore play a role in palate morphogenesis.1 the tongue. At this precise developmental stage the shelves In human embryos palatal shelves elevaterapidly elevate to a horizontal position above the simultaneously on day 43 (22-24 mm CRL), and thedorsum of the tongue. Self elevation probably occurs palate is closed by 55 days (33-37 mm CRL). Thewithin minutes or hours. The medial edge epithelia mesenchymal fusion is complete by 60 days (45-46of the approximating palatal shelves fuse with each mm CRL)-12.other developing cell adhesion molecules and PATHOGENESIS OF CL AND CPdesmosomes to form a midline epithelial seam. Theepithelial seam starts to thin by expansion in palatal In studying different types of orofacialheight and epithelial cell migration onto the oral malformation, animal specimens have been provedand nasal aspects of the palate 1 and then to be especially helpful because they permitdegenerates establishing mesenchyme continuity observation of embryological and fetal stages thatacross the intact horizontal palate. Medial edge lead to malformations found at birth.epithelial cells cease DNA synthesis 24-36 hrs prior The majority of congenital craniofacialto shelf contact and this is referred to as malformation occur during the 5-12 weeks ofprogrammed cell death (PCD). The basement development. 2 The embryonic period (from 3-9membrane on each side of the epithelial seam weeks) is the most sensitive period during whichremains intact even when it has completely thinned. teratogens can be particular damaging. This isEpithelial-mesenchymal recombination experiments especially true for midline morphologic disordershave demonstrated that epithelial differentiation is such as cleft lip and palate. They considered to be aspecified by the mesenchyme and that medial edge palygenic multifactorial problem in which geneticepithelial cell death is rather a “murder” by the susceptibility is influenced by multiple and probablyunderlying mesenchyme than an intrinsic epithelial cumulative environmental factors, interactingsuicide Ferguson, 1988). The ways in which altogether to shift the complex process ofmesenchyme could signal epithelial differentiation morphogenesis of the primary and secondaryis either through extracellular matrix molecules (i.e. palates, toward a threshold of abnormality at whichcollagen molecules), through soluble factors (i.e. clefting may occur (multifactorial/threshold model).growth factors), direct cell-to cell contact, or Both the genetic and the environmental factors havecombinations of all the above. The actual period of not been established yet.fusion of the mesenchymal shelves may be just a Cell death is a normal phenomenon seen in thematter of minutes, but complications in events developing embryo (PCD). It is also a commonleading up to and during fusion will result in a feature seen in embryos after exposure to a varietypalatal clefting of varying severity. of teratogenes that induce craniofacial Also seam disruption occurs by migration of a malformations. There are three distinct types oflarge number of epithelial seam cells (perhaps 50%) PCD (rev by Sulik, 1988). Type 1 is characterizedinto the palatal mesenchyme (rev by Ferguson, by cellular condensation, fragmentation,1988). These fragments very quickly become phagocytosis and finally lysosomal degradation.undistinguishable from other palatal mesenchyme Type 2 is characterized primarily by the appearancecells. The epithelia on the nasal aspect of the palate of large lysosomes which initiate cellulardifferentiate into pseudostratified ciliated columnar degradation. Type 3 occurs without the involvementcells while on the oral aspect of the palate of lysosomes and without apparent phagocytosis.differentiate into stratified squamous The sites of cell death vary depending upon thenonkeratinized cells. Osteogenic blastemata for the teratogen (or genetic insult) and the exposure time Indian J Dent Adv 2012; 4(2) 831

Cleft Lip and Palate Abu - Hussein Muhamad(i.e. developmental stage of the embryo). There Also some authors report that CLP is higher inseems to be a selective sensitivity of cells; tissues the earlier born children while others conclude thewith high proliferative activity are more likely to opposite. When birth rank is raised, maternal ageshow cell death than tissues that proliferate more also could be raised. Mutations of genes can occurslower. Other factors may also been involved i.e. with advanced parental age.state of cellular differentiation, differential drug Monozygous twins discordant for clefting aredistribution or other specific cellular characteristics. interesting. Examinations of the developing fetusBoth the disappearance and expansion of areas of by ultrasound have shown that there are alteredPCD may have a role in teratogenesis (Sulik,1988). rates of fetal growth, both of the whole body and ofPathogenesis is probably caused by one of the its parts, so that at any of one time twins may exhibitfollowing mechanisms: different stages of development. Therefore the variable expression of clefting could result from the 1) anatomic obstruction i.e. the tongue same factor acting on both twins at the same time,obstruction hypothesis-only when associated with but at relatively different stages of their earlymandibular underdevelopment.4 In the cases where growth.the chin is compressed against the sternum, thetongue may interpose in the space between the With regards to lip clefting, it seems that theascending shelves. The resultant palatal deficiency critical stage of lip formation is when the medialis U-shaped not V-shaped and it is considered to be and lateral nasal processes contact each other anda deformation of tissues with a normal growth fuse.potential rather than a malformation of tissues that Anatomical variations (differences in the size,may have been affected by disturbances of shape or position of the facial processes), basedectomesenchyme or other phenomena at cellular possibly on ethnic or other factors, may predisposelevel.5 to the problem of lip formation. Where the size of 2) interference with cell differentiation or the facial processes is reduced and they are not inmigration, either through hormonal defect, tight apposition there is an increased possibility of cleft lip. Experimental support of the previous isbiochemical defect, or extrinsic biochemical found in the work of Trasler, 1968 and Brown,interference. Numerous studies have substantiated Hetzel, Harne & Long, 1985 reviewed by Poswillo,the association between teratogens and clefting. 1988, where the spontaneous development of cleftSuch teratogens may be individually operative in a lip and palate in A strain mice is attributable to thesubgroup of individuals that is genetically and pointed facial processes that prevent wide areas ofbiologically susceptible. Conversely, several contact. On the other hand in the C57 black straindifferent teratogens may act together on a single of mouse the larger facial processes facilitate widermechanism controlled by only a few genes. At contact of the processes and therefore clefting doesn’tpresent our knowledge of the teratogens that are develop.associated with clefting is very limited. Only a fewsubstances such as retinoic acid (used in the While anatomical variation is one potentialtreatment of acne and psoriasis), have been predisposing factor in the development of cleft lipconfirmed as teratogens with direct effect on facial and palate, there are also other factors. It is wellmorphogenesis. established that at the time of consolidation of the facial processes there is a concurrent program of Several other factors that may influence genetic spontaneous cell death (PCD) involved in thebehavior and early morphogenesis have received removal of the epithelial debris from the developingattention in investigation of the etiology of CL and nasal placode. When this PCD is more extensiveCP (rev by Amaratunga,1989). than necessary and repair of mesenchyme is Seasonal variation in the incidence of the CLP disturbed, a weakness develops in the forming liphas been reported by several authors while others and alveolus. The continued action of growthhave reported the opposite. This phenomenon has traction forces may further disrupt the associationnot been satisfactorily explained. One possible of the facial processes with the lip margins beingreason is viral infection, which may have a seasonal pulled apart. Resultant clefts of the lip may varytrend. However, a correlation between clefts and from a simple groove in the muscle to a completeviral infections has not clearly been established. cleft into the nasal floor.7Indian J Dent Adv 2012; 4(2) 832

Cleft Lip and Palate Abu - Hussein Muhamad In regards with the submucous cleft palate and the geographical variation being less important thanbifid uvula, both can be considered as microforms ethnic differences. In contrast the incidence of theof isolated palatal clefting and are probably the CP alone shows little variation in different racialresult of disturbances in the local mesenchyme at groups. This may mean that CP alone will not fitthe time of ossification of the palatal bridge and the purely multifactorial model which include bothmerging of the margins of the soft palate. These polygenic origin and undefined environmentalphenomena occur late in morphogenesis, between factors that would increase the variation in incidence7-10 weeks of human development.8 both geographically and to some extend racially. There is a frequent association between clefts Generally CL with or without CP are more frequentof the lip and cleft palate. Animal studies suggest in males, whereas CP alone is more frequent inthat following the failure of lip closure there is an females. Therefore due to both genetic andovergrowth of the prolabial tissues which then divert environmental evidence it seems that CL with orthe tongue into the nasal cavity. The mesenchymal without CP and CP alone are separate entities.obstruction of the tongue can delay the movement GENETIC FACTORSof one or both palatal shelves, so that opportunities Polygenic inheritance refers to conditionsfor palatal fusion are lost (rev by Poswillo, 1988). determined exclusively by a large number of genes, The sequence of lip and palate formation each with a small effect, acting addictively (i.e. hairextends over 15 days in man. Therefore in many color) (12).syndromes cleft lip and palate may accompany Multifactorial inheritance refers to conditionsanomalies of other parts of the body. Many determined by a combination of factors each with adeveloping systems can be disturbed simultaneously minor but additive effect (i.e. blood pressure)11 andby teratogenic influences which operate over a long has been developed to describe the observed non-period of morphodifferentiation. But despite the fact Mendelian recurrences of common birth defects. Itthat there are over 150 recognized disorders in which includes both polygenic origin and undefinedCL, CP or both may represent one feature, it is environmental factors that will increase thewidely believed that the majority of affected variation in incidence both geographically and toindividuals are otherwise structurally normal (rev some extend racially. The multifactorial inheritanceby Jones,1988). Recent studies.10 have emphasize is more difficult to analyze than other types ofthe fact that a significant portion of children with inheritance but it is thought to account for much ofclefts have the cleft as one feature of a broader the normal variation in families, as well as for manypattern of malformation. It is important to recognize common disorders, including congenitalthat structural defects are not, for the most part, malformations.randomly associated. The presence of other majorand minor malformations in association with a cleft The normal rate of development can be thoughtimplies that a single etiologic factor - genetic, as a continuous distribution that if it is disturbed achromosomal or teratogenic - produced the pattern serious malformation may result, dividing theas a whole. continuous distribution into a normal and abnormal class separated by a threshold. This has been Although CL is frequently associated with CP, described as the multifactorial/threshold model andCL with or without CP and CP alone are distinctly several human congenital malformations showdifferent in aetiology. Subsequent studies have family patterns that fit this model. CL with orconsistently confirmed that these two conditions without CP and CP alone are included in thisindeed differ in etiology and also in incidence, sex category.predisposition and their relationship to associatedbirth defects. CL results from the nonfusion of the CL with or without CP shows both geographicalupper lip and the anterior part of the maxilla during and racial variations which means that it could beweeks 5-7 and occurs at an incidence of explained by the multifactorial/threshold model. Inapproximately 1/1000 births.11 CP alone results from contrast CP alone shows little variation in differentfailure of the mesenchymal masses of the palatine racial groups. This may mean that CP alone willprocesses to fuse during weeks 7-12 and has an not fit the purely multifactorial model.average incidence of 0.7/1000 births. The incidence To date, there have been three pedigreesof CL with or without CP varies from 2.1/1000 in reported in which CP is clearly inherited as a single-Japan to 0.4/1000 Nigeria (rev by Moore, 1988), with gene X-linked disorder.13, 14, 15 Indian J Dent Adv 2012; 4(2) 833

Cleft Lip and Palate Abu - Hussein Muhamad One of these pedigrees is described to in a large decreased penetrance fitted the best. Both the MF/Icelandic family (293 individuals) that shows T model and the mixed model with a dominant majorMendelian inheritance of X-linked secondary cleft gene effect were found to provide an explanation ofpalate and ankyloglossia.15 Family analysis showed familiar clustering pattern. Marazita et al, 1992,that the frequency of CP among all those relatives analyzed almost 2000 Shangai families found thatwas much higher among the male than among the the best fitting model was that of an autosomalfemale CP probands. There was no incidence of male recessive major locus.to male transmission in this large family. The X- Farrall and Holder19 in their own analysis havelinked mode of inheritance of CP is indicated by the shown that the extensive published recurrence riskfamily distribution. Also the large size of this family data, which have been interpreted to be consistenttogether with the availability of many well localized with an MF/T pattern of inheritance, are equallyX-chromosome probes has made it possible to compatible with an oligogenic model with perhapslocalize the defect subchromosomally (using RFLP- as few as four genes.restriction fragment length polymorphism studiesfor linkage) to the q13-q21.1 region of the X In conclusion, the extensive recurrence risk data, which have been widely interpreted aschromosome (16). Finer mapping and the use of cell providing evidence of a polygenic multifactoriallines from patients with deletions of the X trait, are now thought to be consistent with a modelchromosome have further localized the defect to with a major-gene effect contributing to about 1/3Xq21.31-q21.3317 of CL/P and acting on a multifactorial background. In the case of CL with or without CP, Melnick For CL/P, the observed decline in risk withet al, 198018 reviewed worldwide CL/P recurrence decreasing relatedness to the proband isrisk data and found that both a multifactorial- incompatible with any generalized single-major-threshold model and a monogenic with random locus (gSML) model of inheritance and is suggestiveenvironment component model fitted poorly. of multilocus inheritance. Farrall and Holder, 199219 refer to the work of TERATOGENESseveral investigators. According to their report: Palatal shelf elevation and fusion depends onMarazita 1984 in his analysis of a subset of Danish fetal neuromuscular activity, growth of the cranialCL/P families, found no support for a MF/T model base and mandible, production of extracellularbut suggested the possibility of a major gene. Also matrix and contractile elements in the palatalMarazita et al 1986 have reported an analysis of shelves, shelf adhesion, PCD of the midlineten English multigenerational CL/P families epithelial seam and fusion of the ectomesenchymecollected by Carter, 1982). They were able to reject between one shelf and another. All these phenomenaan MF/T model and demonstrated that a major locus must act in perfect harmony over a short period ofacting on a multifactorial background (mixed-model) time in order to produce normal palatogenesis.gave a reasonable fit. Chung 1986, analyzed a series Factors that interfere with any of these events couldof Danish and Japanese CL/P families and concluded lead to a cleft.that the best fitting model predicted a recessivemajor gene acting on a multifactorial background Vitamin A(mixed-model). Chung et al 1989, analyzed By introducing into the maternal diet of A strainHawaiian families from several racial groups and mice human teratogenic agents such as of excessfound that the data were consistent with a major- vitamin A, the malformation threshold in thegene/multifactorial model (mixed model). Ardinger developing embryos may be shifted to the extend1988, have provided additional evidence for an that 100% offspring are born with the expectedassociation between the locus for transforming deformity (7). Renewed interest in retinoicgrowth factor alpha (TGFA) and CL/P locus. TGFA teratogenicity has followed the introduction of 13-is believed to be the embryonic form of epidermal cis-retinoic acid as an effective treatment for severegrowth factor, which is believed to regulate the cystic acne. Inadvertent use of 13-cis-retinoic acidproliferation and differentiation of palatal epithelial during the first trimester of human pregnancy hascells both in vitro and in vivo. Hecht et al, 1991, been reported to result in a spectrum ofanalyzed midwestern U.S. Caukasian families and malformations termed retinoic acid embryopathyshowed consistency with a major-locus model. He (RAE) (20) and includes microtia or anotia,found that the dominant or codommant models with micrognathia and in some cases CP. Induction ofIndian J Dent Adv 2012; 4(2) 834

Cleft Lip and Palate Abu - Hussein MuhamadCP following administration of excess vitamin A to Treatment of female C57B1/6J with 13-cis-pregnant laboratory animals is well documented retinoic acid at early stage of pregnancy (8d14h to(21). Most of the early animal studies involved 9d0hr) has the more severe effect on the secondaryexposure to forms of vitamin A that are stored in palate (22). 12 hours after the 8d14hr treatmentthe maternal liver and that, therefore, have a time, embryos have 13 to 20 somites. Extensiverelatively long half-life; also involved multiple expansion of cell death at this time would beadministrations of the drug or examined the expected to have a major effect on almost the entiredevelopmental end-point only, thereby excluding secondary palatal shelf complex, thereby resultingstudy of the developmental changes that lead to CP. in severe hypoplasia and clefting. Minor effects would be expected to involve only the posterior The study of Kochhar and Johnson, 1965 portion of the maxillary prominences, therebyreviewed by Sulik, 1989, describes palatal clefts for resulting in deficiency in the posterior aspect of thewhich the shelves were very small or entirely absent; secondary palate.these resulted from insufficient maxillaryprominence mesenchyme. These investigators also 12 hours after the 9h6hr treatment time (latefound that size reduction of the palatal shelves treatment), embryos have approximately 30 to 34occurred only posteriorly in the most cases. somites. Expansion of cell death in embryos of this stage of development results primarily in The use of all-trans-retinoic acid, which is of foreshortening of the secondary palate, which occursshort half-life, has shown the incidence of cleft palate at the expense of its posterior portion. Major effectspeaks at more than one developmental stage in both on the entire palatal shelves would not be expectedhamsters and mice (Kochhar, 1973 rev by Sulik, at this treatment time. Later treatment times are1989). mostly associated with induction of limb The changing incidence and severity of malformations.23secondary palatal malformations that may be Phenytoininduced within a narrow window of time (over a 16hour period) appear to be related to a corresponding Also, under the influence of teratogenic doseschange in the pattern of PCD in the first visceral of phenytoin, the lateral nasal process fails to expandarch. It has been shown that 13-cis-retinoic acid to the size necessary for tight tissue contact withincreases the amount of cell death in regions of PCD the medial nasal process (rev by Poswillo, 1988).in C57B1/6J mice, a strain which is particularly Abnormal differentiation of the cellular processesprone to spontaneous craniofacial malformations. (3, of the ectomesenchymal cells is probably associated22). The distribution of excessive cell death in with this condition, where the failure of union atregions of PCD provides a bases for understanding the point of connection which establishes the lip andthe composition of syndromes in which malformation primary palate.appears to be unrelated by tissue type or location Ethanol(22). Ethanol (alcohol) is an important human It has been described a vitamin A cell necrosis teratogen. IT is estimated to affect severely 1.1/1000as being consistent with type-2 cell death (rev by live births and have lesser effects in 3-4/1000Sulik, 1988). On the other hand it has been noted children born. Its abuse during pregnancy resultsthat lysosomal membranes of all cells do not lyse. in fetal alcohol syndrome (FAS) which involves aOnly those membranes that are at a particular stage wide variety of malformations in many organs.of differentiation or which have been perturbed in Abnormalities that are not diagnostic of FAS, butsome other way lyse. Membrane destabilizasion by are associated with maternal ethanol abuse arethe retinoids may interfere with many cellular termed fetal alcohol effects (FAE) (rev by Sulik,functions. For example, blebbing of neural crest cells 1988). Treatment of C57BL/6J female pregnant micemembrane was noticed following retinoic exposure. with ethanol when the embryos have approximatelyThis may interfere with the migratory ability of 7-10 somites results in a pattern of malformationthese cells. Recovery follows removal of the retinoic that is consistent with the DiGeorge sequenceacid in vitro. In vivo, recovery from a brief (midline clefts in the nose and cleft palate areinterference with cell migration might also be features of this sequence. The DiGeorge sequenceexpected but sufficient recovery probably does not has been described in the offspring of alcoholicfollow the excessive cell death of progenitor cells. mothers. Indian J Dent Adv 2012; 4(2) 835

Cleft Lip and Palate Abu - Hussein Muhamad Among the cellular effects of ethanol are the altered permeability of intracellular structures andincreased peroxidase activity, interference with enzyme release, i.e. rupture of lysosomalcytoskeletal components, diminished DNA synthesis membranes, and suggest that this results from lipidand suppressed rates of cell division, direct effect peroxide formation.on membranes resulting in excessive fluidity Hypoxia(reviewed by Sulik, 1988). Recent investigationsillustrate excessive cell death within 12hr following Of particular interest is the hypoxia-inducedmaternal treatment. The rates of cell death are cleft lip. Hypoxia in the human embryo may resultsimilar to the normal rates of cell death seen in PCD, from cigarette smoking, reduced atmospheric oxygenbut the areas of cell death are expanded. The reason levels and also placental insufficiency. Previousfor this excessive cell death is not yet clear. One studies had shown size reduction and abnormalpossible explanation is that exposure to ethanol apposition of the facial prominences as possibleresults in lipid peroxidase/formation that leads to pathogenetic mechanisms. The presence of cellularrupture of lysosomal membranes and release of debris resulting from cell death in the deepesthydrolytic enzymes (type 2 cell death). aspects of the invaginating nasal placodes, as wellHyperthermia as overall growth retardation of the facial prominences, leads to inability of the facial Hyperthermia has teratogenic effects and the prominences to contact and fuse (rev by Sulik, 1988).facial malformations induced include, among others,cleft lip and/or cleft palate. CNS is particularly There are suggested also direct effects of oxygensensitive to hyperthermia. Facial abnormalities deficiency on the cells which lead to glycolysishave been associated with human maternal followed by acidification of intercapillary spaces andhyperthermia at 4-7 weeks (rev by Sulik, 1988). The subsequent necrosis resulting from intra andtype and extent of damage depend on the duration extracellular leakage of lysosomal enzymes. It isof temperature elevation and the extend of elevation. interesting to note that chemicals that interfere withAlso low sustained temperature elevations appear oxidative enzymes such as phenytoin induce cleftto be as damaging as repeated spikes of higher lip in the mice.elevation. Elevations of 1.5-2.5 degrees of Celsius Antimetabolitesabove normal body temperatures represent the Methotrxate and aminopterin are twothreshold for teratogenesis in human. Such uncommon antimetabolites that can induce cranialelevations can result with excessive exercise, the useof hot bath and saunas and febrile episodes. dysplasia and cleft palate in human. Their action is inhibitory of DNA synthesis through competitive Again in the case of heat-induced teratogenesis, folic acid antagonism. The pathogenesis ofcell death is considered to play a major role, with methotexate involves fluid imbalance, resultingthe mitotic cells being the most susceptible. The perhaps from interference with osmoregulatory cellspathogenesis of heat-induced malformations in areas in extraembryonic capillary beds, which is partiallyother than the CNS have not been studied yet. It responsible for the malformation.has been suggested though that hyperthermia couldresult in intra and extracellular leakage of lysosomal Metabolic disordersenzymes which could lead in type-2 cell death. An interesting finding associated with lipIonizing radiation clefting was that of mitochondrial myopathy of cleft Ionizing radiation acts as a direct insult to the muscles.24 Facial muscle specimens from the cleftembryo. The malformations induced are similar to site were characterized by disorganized fibers, goingthose noted following exposure to ethanol, retinoic in many different directions. The number of fibersacid or hyperthermia. The cellular mechanism,s of appeared to be decreased and there is moreradiation induced teratogenesis are not completed connective tissue between the muscle fibers. Theunderstood. They vary from sublethal injuries fiber diameters were also found to be much smaller.affecting differentiation and cellular interactions, NADH stain and electron microscopy revealed largeto effects on rates of proliferation and cell death (rev accumulation of mitochondria at the central portionby Sulik, 1988). Response of the cells to the radiation of the fiber, giving a star shaped appearance to theis depended on cell cycle. Also in some instances cell fiber. The mitochondria are more variable in shapedeath is linked to chromosomal damages. Some than normal, and the cristae are more denselystudies have shown that irradiation results in packed than expected.Indian J Dent Adv 2012; 4(2) 836

Cleft Lip and Palate Abu - Hussein Muhamad These abnormalities in mitochondrial size, 3. Sulik K, Cook C S, Webster W S: (1988). Teratogenes andlocation, cristae and number suggest a form of craniofacial malformations: relationships to cell death. Development 1988; 103: 213-232.metabolic defect that could underlie cleft lip 4. Melnick J: Cleft lip with or without cleft palate: Etiologydeformities. The suggested explanation is that a and pathogenesis. CDAJ 1986; 14: 92-98.defect in energy production could result in 5. Poswillo D: The etiology and surgery of cleft palate withinsufficient cellular migration and proliferation and micrognathia. A R Coll Surg Engl 1968; 43: 61-68.thus be the pathophysiologic basis for cleft lip. As 6. Amaratunga N A: A study of etiologic factors for cleft lip andmentioned, in addition to the mitochondria the cleft palate in Sri Lanka. J Oral Maxillofac Surg 1989; 47: 7-10.lip muscles were found to be abnormal. However, 7. Poswillo D: The etiology and pathogenesis of craniofacialno signs of group denervation or reinnervation were deformity. Development 1988; 103: 207-212.found and the motor end plate structure appeared 8. Poswillo D: The pathogenesis of submucous cleft palate.normal. These findings argue against denervation Scand J Plast Reconstr Surg 1974; 8: 34-41.or abnormal innervation as a cause of the 9. Jones M: Etiology of facial clefts: Prospective evaluation ofabnormalities. Since the innervation was normal, 428 patients. Cleft Palate J 1988; 25: 16-20.the muscle atrophy was attributed to an inability of 10. Shprintzen RJ, Siegel-Sadewitz VL, Amato J, Goldberg RB:these muscles to function properly, which was Anomalies associated with cleft lip, cleft palate, or both.furthermore attributed to the mitochondrial energy Am J Med Gen 1985; 20: 585-595.production abnormality or to the lack of normal fiber 11. Thompson JS and Thompson MW: Multifactorialorientation. If the causative factor is the fiber inheritance. In Genetics In Medicine, Philadelphia: WB Saunders; 4: 210-225.orientation, one would expect this to improve 12. Bjornsson A, Arnason A, Tippet P: X-linked cleft palatefollowing adequate surgical reconstruction of the and ankyloglossia in an Icelandic family. Cleft Palate Jmuscle at the time of lip repair. On the other hand 1989; 26:3-8.changes secondary to cellular energy problems 13. Moore GE, Ivens A, Chambers J, Farrall M, Williamson R,would not be expected to improve following surgery. Page DC, Bjorsson A, Arnason A, Jensson O: Linkage of In general a common target for some an X chromosome cleft palate gene. Nature, Lond 1987; 326: 91-92.teratogenes (i.e. cells in regions of PCD that 14. Moore GE, Ivens A, Newton R, Balacs MA, Henderson DJ,represent a developmental weak point) provide Jensson Ï: X chromosome genes involved in the regulationreason to expect interactive effects. Repeated of facial clefting and spina bifida. Cleft Palate J 1990; 27:exposure of teratogenes in subthreshold doses of 131-135,more than one agent could result in potentiation. 15. Melnick H, Bixler D, Fogh-Andersen P, Conneally PM: CleftPotentiation indeed occurs after repeated exposures lip ± cleft palate: an overview of the literature and anto vitamin A and hyperthermia. analysis of Danish cases born between 1941 and 1968. Am J Med Genet 1980; 6: 83-97.CONCLUSION 16. Farrall M, Holder S: Familiar recurrence-pattern analysis of cleft lip with or without cleft palate. Am J Hum Genet At present our knowledge of the teratogenes 1992; 50: 270- 277.that are associated with clefts is not very extended. 17. Lammar EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ,Some of these substances (such as retinoic acid) have Braun JT, Curry CJ, Fernhoff PM, Grix AW, Lott IT,been confirmed to have direct effects on facial Richard JM, Sun SC: Retinoic acid embryopathy. N Engl Jmorphogenesis but many more await identification. Med 1985; 313: 837-841. 18. Powsillo D, Roy LJ: The pathogenesis of cleft palate: an Metabolic disorders, inherited or not, may play animal study. Br J Surg 1965; 52: 902-912.a role in the pathogenesis of clefting. 19. Sulik KK, Smiley SJ, Turney TA, Speight HS, Johnston Our knowledge of cell biology increases rapidly MC: Pathogenesis of cleft palate in Treacher Collins, Nager,and may eventually lead to the understanding and and Miller Syndromes. Cleft Palate J 1989; 26: 209-216.possibly prevention of clefts of the lip and palate. 20. Sulik KK, Dehart DB: Retinoic acid-induced limbThis can particularly apply in cases with monogenic malformation resulting from apical ectodermal ridge cell death. Teratology 1988; 37:527-537.etiology and in chromosomal disorders. 21. Schendel SA, Pearl RM, De’ Armond SJ: PathophysiologyBIBLIOGRAPHY of cleft lip muscle. Plast Rec Surg 1989; 83: 777-784.1. Ferguson M. W.: Palate development. Development 1988; 22. Fraser FC: The multifactorial/threshold concept-uses and 103: 41-57. misuses. Teratology 1976; 14: 267-280.2. Moore G, Ivens A, Chambers J, Bjornsson A, Arnason A, 23. Lowry RB: Sex-linked cleft palate in a British Columbian Jensson O, Williamson R: The application of molecular Indian family. Pediatrics 1970; 46: 123-128. genetics to detection of craniofacial abnormality. 24. Rushton AR: Sex-linked inheritance of cleft palate. Hum Development 1988; 103: 233-239. Gen 1979; 48: 179-181. Indian J Dent Adv 2012; 4(2) 837

cleft lip and palate

by Abu-Hussein Muhamad on Aug 11, 2012

Accessibility

Categories

Upload Details

Usage Rights

Statistics

cleft lip and palate Document Transcript