150 M. Abu-Husseinso the palatal mesenchymal cells are themselves In human embryos, palatal shelves elevate simul-contractile and secrete various neurotransmit- taneously on day 43 (22–24 mm CRL), and the palateters that effect both mesenchymal cell contractili- is closed by day 55 (33–37 mm CRL). Mesenchymalty and glycosaminoglycan dehydration and there- fusion is complete by day 60 (45–46 mm CRL).fore play a role in palate morphogenesis . At this precise developmental stage, the shelvesrapidly elevate to a horizontal position above the Pathogenesis of CL and CPdorsum of the tongue. Self elevation probably oc-curs within minutes or hours. The medial edge In studying different types of orofacial mal-epithelia of the approximating palatal shelves fuse formation, animal specimens have been proved towith each other, developing cell adhesion mole- be especially helpful because they permit observa-cules and desmosomes to form a midline epithelial tion of embryological and fetal stages that lead toseam. The epithelial seam starts to thin by expan- malformations found at birth.sion in palatal height and epithelial cell migration The majority of congenital craniofacial mal-onto the oral and nasal aspects of the palate  and formations occur during the first 5–12 weeksthen degenerates, establishing mesenchyme conti- of fetal development . The embryonic periodnuity across the intact horizontal palate. Medial (from 3–9 weeks) is the most sensitive period dur-edge epithelial cells cease DNA synthesis 24–36 hrs ing which teratogens can be particularly damag-prior to shelf contact and this is referred to as pro- ing. This is especially true for midline morpholog-grammed cell death (PCD). The basement mem- ic disorders such as cleft lip and palate. They arebrane on each side of the epithelial seam remains considered to be a polygenic multifactorial prob-intact even when it has completely thinned. Epi- lem in which genetic susceptibility is influencedthelial-mesenchymal recombination experiments by multiple and probably cumulative environmen-have demonstrated that epithelial differentiation tal factors, interacting altogether to shift the com-is specified by the mesenchyme and that medial plex process of morphogenesis of the primary andedge epithelial cell death is rather a “murder” by secondary palates, toward a threshold of abnor-the underlying mesenchyme than an intrinsic ep- mality at which clefting may occur (multifactori-ithelial suicide (rev by Ferguson, 1988). The ways al/threshold model). Both the genetic and the en-in which mesenchyme could signal epithelial dif- vironmental factors have not yet been established.ferentiation is either through extracellular matrix Cell death is a normal phenomenon seen inmolecules (i.e. collagen molecules), through solu- the developing embryo (PCD). It is also a commonble factors (i.e. growth factors), direct cell-to cell feature seen in embryos after exposure to a varietycontact, or a combinations of all the above. The ac- of teratogens that induce craniofacial malforma-tual period of fusion of the mesenchymal shelves tions. There are three distinct types of PCD (revmay be just a matter of minutes, but complications by Sulik, 1988). Type 1 is characterized by cellu-in events leading up to and during fusion will re- lar condensation, fragmentation, phagocytosissult in a palatal clefting of varying severity. and finally lysosomal degradation. Type 2 is char- Also, seam disruption occurs by migration of acterized primarily by the appearance of large ly-a large number of epithelial seam cells (perhaps sosomes which initiate cellular degradation. Type50%) into the palatal mesenchyme (rev by Fergu- 3 occurs without the involvement of lysosomesson, 1988). These fragments very quickly become and without apparent phagocytosis.undistinguishable from other palatal mesenchyme The sites of cell death vary depending up-cells. The epithelia on the nasal aspect of the pal- on the teratogen (or genetic insult) and the expo-ate differentiate into pseudo-stratified ciliated co- sure time (i.e. developmental stage of the embryo).lumnar cells while on the oral aspect of the palate There seems to be a selective sensitivity of cells;they differentiate into stratified squamous non-ke- tissues with high proliferative activity are moreratinized cells. Osteogenic blastemata for the pala- likely to show cell death than tissues that prolif-tal processes of the maxillary and palatine bones erate more slowly. Other factors may also been in-differentiate in the mesenchyme of the hard pal- volved, i.e. the state of cellular differentiation, dif-ate while several myogenic blastemata develop in ferential drug distribution or other specific cel-the soft palate. lular characteristics. Both the disappearance and During the period of shelf elevation, there expansion of areas of PCD may have a role in tera-is almost no growth in head width but constant togenesis (rev by Sulik, 1988).growth in head height. This establishes a conduc- Pathogenesis is probably caused by one of thetive orofacial environment that permits the ex- following mechanisms:panding palatal shelves to occupy a position above 1) Anatomic obstruction, i.e. the tongue ob-the dorsum of the tongue. struction hypothesis – only when associated with
Cleft Lip and Palate 151mandibular underdevelopment . In cases where an embryo to the disturbance of lip formation.the chin is compressed against the sternum, the Where the size of the facial processes is reducedtongue may interpose in the space between the as- and they are not in tight apposition, there is an in-cending shelves. The resultant palatal deficiency is creased probability of cleft lip. Experimental sup-U-shaped not V-shaped by disturbance in growth port of the previous is found in the work of Trasler,potential not tissues that may have been affected 1968 and Brown, Hetzel, Harne & Long, 1985, re-by disturbances of ecto-mesenchyme or other phe- viewed by Poswillo, 1988, where the spontaneousnomena at the cellular level ; development of cleft lip and palate in A strain mice 2) Interference with cell differentiation or mi- is attributable to the pointed facial processes thatgration, either through hormonal defect, biochem- prevent wide areas of contact. On the other hand,ical defect, or extrinsic biochemical interference. in the C57 black strain of mouse, the larger facialNumerous studies have substantiated the associa- processes facilitate wider contact of the processestion between teratogens and clefting. Such terato- and therefore clefting doesn’t develop.gens may be individually operative in a subgroup While anatomical variation is one potentialof individuals that is genetically and biologically predisposing factor in the development of cleft lipsusceptible. Conversely, several different terato- and palate, other factors also exist. It is well es-gens may act together on a single mechanism con- tablished that at the time of consolidation of thetrolled by only a few genes. At present our knowl- facial processes, there is a concurrent program ofedge of the teratogens that are associated with spontaneous cell death (PCD). It is involved in theclefting is very limited. Only a few substances such removal of the epithelial debris from the devel-as retinoic acid (used in the treatment of acne and oping nasal placode. When this PCD is more ex-psoriasis), have been confirmed as teratogens with tensive than necessary and repair of mesenchymedirect effect on facial morphogenesis. is disturbed, a weakness develops in the forming Several other factors that may influence genet- lip and alveolus. The continued action of growthic behavior and early morphogenesis have received traction forces may further disrupt the associationattention in the investigation of the etiology of CL of the facial processes with the lip margins beingand CP (rev by Amaratunga, 1989). pulled apart. Resultant clefts of the lip may vary A seasonal variation in the incidence of CLP from a simple groove in the muscle to a completehas been reported by several authors while oth- cleft that includes the nasal floor .ers have reported the opposite. This phenomenon In regards to submucous cleft palate and bi-has not been satisfactorily explained. One possible fid uvula, both can be considered microforms ofreason is viral infection, which may have a season- isolated palatal clefting. Probably, the disturbanc-al trend. However, a correlation between clefts and es in the local mesenchyme occurred at the timeviral infections has not clearly been established. of the ossification of the palatal bridge and merg- Also, some authors report that the instance of ing of the margins of the soft palate. These phe-CLP is higher in earlier born children (in terms nomena occur between 7–10 weeks of human de-of birth order) while others conclude the opposite. velopment .When birth rank is raised, maternal age could also An association between clefts of the lip andbe raised. Mutations of genes can occur with ad- cleft palate has been observed. Animal stud-vanced parental age. ies suggest that “following the failure of lip clo- Monozygous twins discordant for clefting are sure there is an overgrowth of the prolabial tissuesinteresting. Examinations of the developing fe- which then divert the tongue into the nasal cavity.tus using ultrasound have shown that there are al- The mesenchymal obstruction of the tongue cantered rates of fetal growth, both of the whole body delay the movement of one or both palatal shelves,and of its parts, so that at any one time, twins may so that opportunities for palatal fusion are lost”exhibit different stages of development. There- (rev by Poswillo, 1988).fore the variable expression of clefting could re- Lip and palate formation lasts over 15 days insult from the same factor acting on both twins at humans. Therefore in many syndromes, cleft lipthe same time, but at relatively different stages of and palate may be accompanied by anomalies oftheir early growth. different parts of the body. Many developing sys- With regards to lip clefting, it seems that the tems can be disturbed simultaneously by terato-crucial stage of lip formation is the moment when genic influences which operate over a long periodmedial and lateral nasal processes contact each of morphodifferentiation. But despite the fact thatother and fuse. there are over 150 recognized disorders in which Anatomical variations (differences in the size, CL, CP or both may represent one feature, it isshape or position of the facial processes), possibly widely believed that the majority of affected indi-based on ethnic or other factors, may predispose viduals are otherwise structurally normal (rev by
152 M. Abu-HusseinJones, 1988). Recent studies  have emphasized well as for many common disorders, e.g. congeni-the fact that a significant portion of children with tal malformations.clefts have the cleft as one feature of a broader pat- The normal rate of development can betern of malformation. It is important to recognize thought of as a continuous distribution in which,that structural defects are not, for the most part, if it is disturbed, a serious malformation may oc-randomly associated. The presence of other ma- cur. This has been described as the multifactori-jor and minor malformations in association with al/threshold model and several human congenitala cleft implies that a single etiologic factor – ge- malformations reveal family patterns that fit thisnetic, chromosomal or teratogenic – produced the model. CL with or without CP and CP alone arepattern as a whole. included in this category. Although CL is frequently associated with CP, CL with or without CP shows both geographi-CL with or without CP and CP alone are distinctly cal and racial variations which means that it coulddifferent in etiology. Subsequent studies have con- be explained by the multifactorial/threshold mod-sistently confirmed that these two conditions indeed el. In contrast CP alone shows little variation indiffer in etiology and also in incidence, sex predis- different racial groups. This may mean that isolat-position and their relationship to associated birth ed CP will not fit the purely multifactorial model.defects. CL results from the non-fusion of the up- To date, there have been three pedigrees re-per lip and the anterior part of the maxilla at the ported in which CP is clearly inherited as a single-5–7 week of gestation and is observed in approxi- gene X-linked disorder [13–15].mately 1/1000 births . Isolated CP results from One of these pedigrees is described to a largea failure of the mesenchymal masses of the palatine Icelandic family (293 individuals) that shows Men-processes to fuse during weeks 7–12 and has an av- delian inheritance of X-linked secondary cleft palateerage incidence of 0.7/1000 births. The incidence of and ankyloglossia . Family analysis has shownCL with or without CP varies from 2.1/1000 in Ja- that the frequency of CP among all the members ofpan to 0.4/1000 in Nigeria (rev by Moore, 1988), with this family was much higher among the male thanthe geographical variation being less important than among the female CP probands. There was no in-ethnic differences. In contrast, the incidence of CP cidence of male to male transmission in this largealone shows little variation in different racial groups. family. The X-linked mode of inheritance of CP isThis may mean that CP alone will not fit the purely indicated by the family distribution. Also the largemultifactorial model which includes genetic and en- number of members of this family together withvironmental factors that would increase the varia- the availability of many X-chromosome probes hastion in incidence both geographically and to some made it possible to localize the defect subchromo-extent racially. Generally CL with or without CP is somally (using RFLP-restriction fragment lengthmore frequent in males, whereas CP alone is more polymorphism studies for linkage) to the q13-q21.1frequent in females. Therefore, due to both genetic region of the X chromosome . Finer mappingand environmental evidence, it seems that CL with and the use of cell lines from patients with dele-or without CP and CP alone are separate entities. tions of the X chromosome have further localized the defect to Xq21.31-q21.33 . In the case of CL with or without CP, Melnick Genetic Factors et al, 1980  reviewed worldwide CL/P recur- rence risk data and found that both a multifactori- Polygenic inheritance refers to conditions de- al-threshold model and a monogenic with randomtermined by a large number of genes. Each of them environment component model fitted poorly.has a small effect, but they act additively (i.e. hair Farrall and Holder, 1992  refer to the workcolor) . of several investigators. According to their report: Multifactorial inheritance refers to conditions Marazita, 1984, in his analysis of a subset of Dan-determined by a combination of factors each with ish CL/P families, found no support for a MF/Ta minor but additive effect (i.e. blood pressure)  model but suggested the possibility of a major gene.and has been developed to describe the observed Also Marazita et al, 1986, have reported an anal-non-Mendelian recurrences of common birth de- ysis of ten English multigenerational CL/P fami-fects. It includes both polygenic origin and un- lies collected by Carter, 1982. They were able to re-defined environmental factors that will increase ject an MF/T model and demonstrated that a ma-the variation in incidence depending on race and jor locus acting on a multifactorial backgroundgeographic region. The multifactorial inheritance (mixed-model) gave a reasonable fit. Chung, 1986,pattern is more difficult to analyze than any oth- analyzed a series of Danish and Japanese CL/Per type of inheritance but it is thought to account families and concluded that the best fitting modelfor much of the normal variation in families, as predicted a recessive major gene acting on a multi-
Cleft Lip and Palate 153factorial background (mixed-model). Chung et al, Vitamin A1989, analyzed Hawaiian families from several ra-cial groups and found that the data was consistent By introducing human teratogenic agents (e.g.with a major-gene/multifactorial model (mixed excess vitamin A) into the maternal diet of A strainmodel). Ardinger, 1988, has provided additional mice, it has been observed that 100% of offspringevidence for an association between the locus for are born with the expected deformity . Renewedtransforming growth factor alpha (TGFA) and the interest in retinoic teratogenicity has followed theCL/P locus. TGFA is believed to be the embryon- introduction of 13-cis-retinoic acid as an effectiveic form of epidermal growth factor, which is be- treatment for severe cystic acne. Inadvertent uselieved to regulate the proliferation and differenti- of 13-cis-retinoic acid during the first trimester ofation of palatal epithelial cells both in vitro and human pregnancy has been reported to result inin vivo. Hecht et al, 1991, analyzed mid-western a spectrum of malformations termed retinoic ac-U.S. Caucasian families and showed consisten- id embryopathy (RAE)  and includes microtiacy with a major-locus model. He found that the or anotia, micrognathia and in some cases CP. Thedominant or codommant models with decreased induction of CP following administration of excesspenetrance fitted the best. Both the MF/T mod- vitamin A to pregnant laboratory animals is wellel and the mixed model with a dominant major documented . Most of the early animal stud-gene effect were found to provide an explanation ies involved exposure to forms of vitamin A thatfor the familiar clustering pattern. Marazita et al, are stored in the maternal liver and that, therefore,1992, analyzed almost 2000 Shanghai families and have a relatively long half-life; they also involvedfound that the best fitting model was that of an au- multiple administrations of the drug or examinedtosomal recessive major locus. the developmental end-point only, thereby exclud- Farrall and Holder , in their own analysis, ing study of the developmental changes that leadhave shown that “the extensive published recur- to CP.rence risk data, which have been interpreted to be A study by Kochhar and Johnson, 1965, re-consistent with an MF/T pattern of inheritance, viewed by Sulik, 1989, describes palatal clefts forare equally compatible with an oligogenic model which the shelves were very small or entirely ab-with perhaps as few as four genes.” sent; these resulted from insufficient maxillary In conclusion, the extensive recurrence risk prominence mesenchyme. These investigators al-data, which has been widely interpreted as pro- so found that size reduction of the palatal shelvesviding evidence of a polygenic multifactorial trait, occurred only posteriorly in most cases.are now thought to be consistent with a mod- The use of all-trans-retinoic acid, which is ofel with a major-gene effect contributing to about short half-life, has shown that incidence of cleft1/3 of CL/P and acting on a multifactorial back- palate peaks at more than one developmental stageground. For CL/P, the observed decline in risk in both hamsters and mice (Kochhar, 1973, rev bywith decreasing relatedness to the proband is in- Sulik, 1989).compatible with any generalized single-major-lo- The changing incidence and severity of sec-cus (gSML) model of inheritance and is suggestive ondary palatal malformations that may be in-of multilocus inheritance. duced within a narrow window of time (over a 16 hour period) appear to be related to a cor- responding change in the pattern of PCD in the Teratogenes first visceral arch. It has been shown that 13-cis- -retinoic acid increases the amount of cell death in Palatal shelf elevation and fusion depends on regions of PCD in C57B1/6J mice, a strain whichfetal neuromuscular activity, growth of the crani- is particularly prone to spontaneous craniofacialal base and mandible, production of extracellu- malformations [3, 22]. The distribution of exces-lar matrix and contractile elements in the palatal sive cell death in regions of PCD provides a basisshelves, shelf adhesion, PCD of the midline epithe- for understanding the composition of syndromeslial seam and fusion of the ectomesenchyme be- in which malformation appears to be unrelated bytween one shelf and another. All these phenomena tissue type or location .must act in perfect harmony over a short period What has been described as vitamin A cell ne-of time in order to produce normal palatogene- crosis is consistent with type-2 cell death (rev bysis. Factors that interfere with any of these events Sulik, 1988). On the other hand, it has been not-could lead to a cleft. ed that not all lysosomal membranes of all cells lyse. Only those membranes that are at a particu- lar stage of differentiation or which have been per- turbed in some other way lyse. Membrane destabi-
154 M. Abu-Husseinlization by the retinoids may interfere with many ethanol when the embryos have approximate-cellular functions. For example, blebbing of the ly 7–10 somites results in a pattern of malforma-neural crest cell membrane was noticed follow- tion that is consistent with the DiGeorge sequenceing retinoic exposure. This may interfere with the (midline clefts in the nose and cleft palate are fea-migratory ability of these cells. Recovery follows tures of this sequence. The DiGeorge sequence hasremoval of the retinoic acid in vitro. In vivo, re- been described in the offspring of alcoholic moth-covery from a brief interference with cell migra- ers.tion might also be expected but sufficient recovery Among the cellular effects of ethanol are in-probably does not follow the excessive cell death of creased peroxidase activity, interference with cy-progenitor cells. toskeletal components, diminished DNA synthe- Treatment of female C57B1/6J with 13-cis-ret- sis and suppressed rates of cell division, direct ef-inoic acid at the early stage of pregnancy (8d14hr fects on membranes resulting in excessive fluidityto 9d0hr) has a more severe effect on the second- (reviewed by Sulik, 1988). Recent investigations il-ary palate . 12 hours after the 8d14hr treatment lustrate excessive cell death within 12hr follow-time, embryos have 13 to 20 somites. Extensive ex- ing maternal treatment. The rates of cell death arepansion of cell death at this time would be expect- similar to the normal rates of cell death seen ined to have a major effect on almost the entire sec- PCD, but the areas of cell death are expanded. Theondary palatal shelf complex, thereby resulting reason for this excessive cell death is not yet clear.in severe hypoplasia and clefting. Minor effects One possible explanation is that exposure to etha-would be expected to involve only the posterior nol results in lipid peroxidase/formation that leadsportion of the maxillary prominences, thereby re- to rupture of lysosomal membranes and release ofsulting in deficiency in the posterior aspect of the hydrolytic enzymes (type-2 cell death).secondary palate. 12 hours after the 9d6hr treatment time (latetreatment), embryos have approximately 30 to Hyperthermia34 somites. Expansion of cell death in embryos Hyperthermia has teratogenic effects and theat this stage of development results primarily in facial malformations induced include, among oth-foreshortening of the secondary palate, which oc- ers, cleft lip and/or cleft palate. CNS is particular-curs at the expense of its posterior portion. Ma- ly sensitive to hyperthermia. Facial abnormalitiesjor effects on the entire palatal shelves would not have been associated with human maternal hyper-be expected at this treatment time. Later treatment thermia at 4–7 weeks (rev by Sulik, 1988). The typetimes are mostly associated with induction of limb and extent of damage depend on the duration ofmalformations . temperature elevation and the extent of elevation. Also, low sustained temperature elevations appear to be as damaging as repeated spikes of higher ele- Phenytoin vation. Elevations of 1.5–2.5 degrees Celsius above Also, “under the influence of teratogenic dos- normal body temperatures represent the thresholdes of phenytoin, the lateral nasal process fails to for teratogenesis in humans. Such elevations canexpand to the size necessary for tight tissue con- result from excessive exercise, the use of hot bathstact with the medial nasal process” (rev by Poswil- and saunas and febrile episodes.lo, 1988). Abnormal differentiation of the cellular Again in the case of heat-induced teratogen-processes of the ectomesenchymal cells is probably esis, cell death is considered to play a major role,associated with this condition, where the lip and with the mitotic cells being the most susceptible.primary palate form. The pathogenesis of heat-induced malformations in areas other than the CNS have not been studied yet. It has been suggested though that hyperther- Ethanol mia could result in intra and extracellular leakage Ethanol (alcohol) is an important human te- of lysosomal enzymes which could lead to type-2ratogen. IT is estimated to severely affect 1.1/1000 cell death.live births and have lesser effects in 3–4/1000 chil-dren born. Its abuse during pregnancy results in fe-tal alcohol syndrome (FAS) which involves a wide Ionizing Radiationvariety of malformations in many organs. Abnor- Ionizing radiation acts as a direct insult to themalities that are not diagnostic of FAS, but are as- embryo. The malformations induced are similar tosociated with maternal ethanol abuse are termed those noted following exposure to ethanol, retino-fetal alcohol effects (FAE) (rev by Sulik, 1988). ic acid or hyperthermia. The cellular mechanismsTreatment of C57BL/6J female pregnant mice with of radiation-induced teratogenesis are not com-
Cleft Lip and Palate 155pleted understood. They vary from sublethal in- The fiber diameters were also found to be muchjuries affecting differentiation and cellular inter- smaller. NADH stain and electron microscopy re-actions, to effects on rates of proliferation and cell vealed a large accumulation of mitochondria at thedeath (rev by Sulik, 1988). Response of the cells to central portion of the fiber, giving a star shapedthe radiation is dependant on cell cycle. Also, in appearance to the fiber. The mitochondria aresome instances cell death is linked to chromosom- more variable in shape than normal, and the cris-al damage. Some studies have shown that irradia- tae are more densely packed than expected.tion results in altered permeability of intracellular These abnormalities in mitochondrial size, lo-structures and enzyme release, i.e. rupture of ly- cation, cristae and number suggest a form of met-sosomal membranes, and suggest that this results abolic defect that could underlie cleft lip deformi-from lipid peroxide formation. ties. The suggested explanation is that a defect in energy production could result in insufficient cel- lular migration and proliferation and thus be the Hypoxia pathophysiological basis for cleft lip. As mentioned, Of particular interest is hypoxia-induced cleft in addition to the mitochondria, the cleft lip mus-lip. Hypoxia in the human embryo may result cles were found to be abnormal. However, no signsfrom cigarette smoking, reduced atmospheric ox- of group denervation or reinnervation were foundygen levels and also placental insufficiency. Pre- and the motor end plate structure appeared nor-vious studies had shown size reduction and ab- mal. These findings argue against denervation ornormal apposition of the facial prominences as abnormal innervation as a cause of the abnormal-possible pathogenetic mechanisms. The presence ities. Since the innervation was normal, the mus-of cellular debris resulting from cell death in the cle atrophy was attributed to an inability of thesedeepest aspects of the invaginating nasal placodes, muscles to function properly, which was further-as well as overall growth retardation of the facial more attributed to the mitochondrial energy pro-prominences, leads to inability of the facial prom- duction abnormality or to the lack of normal fiberinences to contact and fuse (rev by Sulik, 1988). orientation. If the causative factor is the fiber ori-There are also direct effects suggested of oxygen entation, one would expect this to improve follow-deficiency on the cells which lead to glycolysis fol- ing adequate surgical reconstruction of the musclelowed by acidification of intercapillary spaces and at the time of lip repair. On the other hand, chang-subsequent necrosis resulting from intra and ex- es secondary to cellular energy problems wouldtracellular leakage of lysosomal enzymes. It is in- not be expected to improve following surgery.teresting to note that chemicals that interfere with In general, a common target for some terato-oxidative enzymes such as phenytoin induce cleft genes (i.e. cells in regions of PCD that representlip in mice. a developmental weak point) provides reason to expect interactive effects. Repeated exposure of teratogenes in subthreshold doses of more than Antimetabolites one agent could result in potentiation. Potentia- Methotrexate and aminopterin are two un- tion indeed occurs after repeated exposures to vi-common antimetabolites that can induce crani- tamin A and hyperthermia.al dysplasia and cleft palate in humans. Their ac-tion is inhibitory of DNA synthesis through com-petitive folic acid antagonism. The pathogenesis Conclusionsof methotexate involves fluid imbalance, result-ing perhaps from interference with osmoregulato- At present, our knowledge of the teratogenesry cells in extraembryonic capillary beds, which is that are associated with clefts is not very exten-partially responsible for the malformation. sive. Some of these substances (such as retinoic ac- id) have been confirmed to have direct effects on facial morphogenesis but many more await iden- Metabolic Disorders tification. Metabolic disorders, inherited or not, may An interesting finding associated with lip play a role in the pathogenesis of clefting.clefting was that of mitochondrial myopathy of Our knowledge of cell biology is increasingcleft muscles . Facial muscle specimens from rapidly and may eventually lead to the under-the cleft site were characterized by disorganized fi- standing and possibly prevention of clefts of thebers, going in many different directions. The num- lip and palate. This can particularly apply in cas-ber of fibers appeared to be decreased and there is es with monogenic etiology and in chromosom-more connective tissue between the muscle fibers. al disorders.
156 M. Abu-Hussein References  Ferguson M.W.: Palate development. Development 1988, 103, 41–57.  Moore G., Ivens A., Chambers J., Bjornsson A., Arnason A., Jensson O., Williamson R.: The application of molecular genetics to detection of craniofacial abnormality. Development 1988, 103, 233–239.  Sulik K., Cook C.S., Webster W.S.: Teratogens and craniofacial malformations: relationships to cell death. Development 1988, 103, 213–232.  Melnick J.: Cleft lip with or without cleft palate: Etiology and pathogenesis. CDAJ 1986, 14, 92–98.  Poswillo D.: The etiology and surgery of cleft palate with micrognathia. A. R. Coll. Surg. Engl. 1968, 43, 61–68.  Amaratunga N.A.: A study of etiologic factors for cleft lip and palate in Sri Lanka. J. Oral Maxillofac. Surg. 1989, 47, 7–10.  Poswillo D.: The etiology and pathogenesis of craniofacial deformity. Development 1988, 103, 207–212.  Poswillo D.: The pathogenesis of submucous cleft palate. Scand. J. Plast. Reconstr. Surg. 1974, 8, 34–41.  Jones M: Etiology of facial clefts: Prospective evaluation of 428 patients. Cleft Palate J. 1988, 25, 16–20. Shprintzen R.J., Siegel-Sadewitz V.L., Amato J., Goldberg R.B.: Anomalies associated with cleft lip, cleft pal- ate, or both. Am. J. Med. Gen. 1985, 20, 585–595. Thompson J.S., Thompson M.W.: Multifactorial inheritance. In Genetics in Medicine. Ed.: W.B. Saunders, Phila- delphia 1986, 4th ed., 210–225. Bjornsson A., Arnason A., Tippet P.: X-linked cleft palate and ankyloglossia in an Icelandic family. Cleft Palate J. 1989, 26, 3–8. Moore G.E., Ivens A., Chambers J., Farrall M., Williamson R., Page D.C., Bjorsson A., Arnason A., Jens- son O.: Linkage of an X chromosome cleft palate gene. Nature, Lond 1987, 326, 91–92. Moore G.E., Ivens A., Newton R., Balacs M.A., Henderson D.J., Jensson Ο.: X chromosome genes involved in the regulation of facial clefting and spina bifida. Cleft Palate J. 1990, 27, 131–135. Melnick H., Bixler D., Fogh-Andersen P., Conneally P.M.: Cleft lip ± cleft palate: an overview of the litera- ture and an analysis of Danish cases born between 1941 and 1968. Am. J. Med. Gen. 1980, 6, 83–97. Farrall M., Holder S.: Familiar recurrence-pattern analysis of cleft lip with or without cleft palate. Am. J. Hum. Gen. 1992, 50, 270–277. Lammar E.J., Chen D.T., Hoar R.M., Agnish N.D., Benke P.J., Braun J.T., Curry C.J., Fernhoff P.M., Grix A.W., Lott I.T., Richard J.M., Sun S.C.: Retinoic acid embryopathy. N. Engl. J. Med. 1985, 313, 837–841. Powsillo D., Roy L.J.: The pathogenesis of cleft palate: an animal study. Br. J. Surg. 1965, 52, 902–912. Sulik K.K., Smiley S.J., Turney T.A., Speight H.S., Johnston M.C.: Pathogenesis of cleft palate in Treacher Col- lins, Nager, and Miller Syndromes. Cleft Palate J. 1989, 26, 209–216. Sulik K.K., Dehart D.B.: Retinoic acid-induced limb malformation resulting from apical ectodermal ridge cell death. Teratology 1988, 37, 527–537. Schendel S.A., Pearl R.M., De’Armond S.J.: Pathophysiology of cleft lip muscle. Plast. Rec. Surg. 1989, 83, 777–784. Fraser F.C.: The multifactorial/threshold concept – uses and misuses. Teratology 1976, 14, 267–280. Lowry R.B.: Sex-linked cleft palate in a British Columbian Indian family. Pediatrics 1970, 46, 123–128. Rushton A.R.: Sex-linked inheritance of cleft palate. Hum. Gen. 1979, 48, 179–181. Address for correspondence:Muhamad Abu-HusseinPediatric Dentistry123 Argus Street10441 AthensGreeceE-mail: email@example.comReceived: 23.03.2012Accepted: 16.04.2012Praca wpłynęła do Redakcji: 23.03.2012 r.Zaakceptowano do druku: 16.04.2012 r.