2. Cleft Lip and Palate Abu - Hussein Muhamad
colagen which run down the center of the vertical palatal processes of the maxillary and palatine bones
shelf from its base to its tip. Moreover the epithelial differentiate in the mesenchyme of the hard palate
covering and associated basement membrane of the while several myogenic blastemata develop in the
palatal shelf exhibit differential traction, which soft palate.
serve to constrain and direct the swelling osmotic During the period of shelf elevation, there is
force. Also the palatal mesenchymal cells are almost no growth in head width but constant growth
themselves contractile and secrete various in head height. This establish a conductive orofacial
neurotransmitter that effect both mesenchymal cell environment that permits the expanding palatal
contractility and glycosaminoglycan dehydration shelves to occupy a position above the dorsum of
and therefore play a role in palate morphogenesis.1 the tongue.
At this precise developmental stage the shelves In human embryos palatal shelves elevate
rapidly elevate to a horizontal position above the simultaneously on day 43 (22-24 mm CRL), and the
dorsum of the tongue. Self elevation probably occurs palate is closed by 55 days (33-37 mm CRL). The
within minutes or hours. The medial edge epithelia mesenchymal fusion is complete by 60 days (45-46
of the approximating palatal shelves fuse with each mm CRL)-12.
other developing cell adhesion molecules and
PATHOGENESIS OF CL AND CP
desmosomes to form a midline epithelial seam. The
epithelial seam starts to thin by expansion in palatal In studying different types of orofacial
height and epithelial cell migration onto the oral malformation, animal specimens have been proved
and nasal aspects of the palate 1 and then to be especially helpful because they permit
degenerates establishing mesenchyme continuity observation of embryological and fetal stages that
across 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 craniofacial
to shelf contact and this is referred to as malformation occur during the 5-12 weeks of
programmed cell death (PCD). The basement development. 2 The embryonic period (from 3-9
membrane on each side of the epithelial seam weeks) is the most sensitive period during which
remains intact even when it has completely thinned. teratogens can be particular damaging. This is
Epithelial-mesenchymal recombination experiments especially true for midline morphologic disorders
have demonstrated that epithelial differentiation is such as cleft lip and palate. They considered to be a
specified by the mesenchyme and that medial edge palygenic multifactorial problem in which genetic
epithelial cell death is rather a “murder” by the susceptibility is influenced by multiple and probably
underlying mesenchyme than an intrinsic epithelial cumulative environmental factors, interacting
suicide Ferguson, 1988). The ways in which altogether to shift the complex process of
mesenchyme could signal epithelial differentiation morphogenesis of the primary and secondary
is either through extracellular matrix molecules (i.e. palates, toward a threshold of abnormality at which
collagen 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 have
combinations 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 the
matter of minutes, but complications in events developing embryo (PCD). It is also a common
leading up to and during fusion will result in a feature seen in embryos after exposure to a variety
palatal clefting of varying severity. of teratogenes that induce craniofacial
Also seam disruption occurs by migration of a malformations. There are three distinct types of
large number of epithelial seam cells (perhaps 50%) PCD (rev by Sulik, 1988). Type 1 is characterized
into 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 appearance
cells. The epithelia on the nasal aspect of the palate of large lysosomes which initiate cellular
differentiate into pseudostratified ciliated columnar degradation. Type 3 occurs without the involvement
cells 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 the
nonkeratinized cells. Osteogenic blastemata for the teratogen (or genetic insult) and the exposure time
Indian J Dent Adv 2012; 4(2) 831
3. Cleft Lip and Palate Abu - Hussein Muhamad
(i.e. developmental stage of the embryo). There Also some authors report that CLP is higher in
seems to be a selective sensitivity of cells; tissues the earlier born children while others conclude the
with high proliferative activity are more likely to opposite. When birth rank is raised, maternal age
show cell death than tissues that proliferate more also could be raised. Mutations of genes can occur
slower. Other factors may also been involved i.e. with advanced parental age.
state of cellular differentiation, differential drug Monozygous twins discordant for clefting are
distribution or other specific cellular characteristics. interesting. Examinations of the developing fetus
Both the disappearance and expansion of areas of by ultrasound have shown that there are altered
PCD may have a role in teratogenesis (Sulik,1988). rates of fetal growth, both of the whole body and of
Pathogenesis is probably caused by one of the its parts, so that at any of one time twins may exhibit
following 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 early
mandibular underdevelopment.4 In the cases where growth.
the chin is compressed against the sternum, the
tongue may interpose in the space between the With regards to lip clefting, it seems that the
ascending shelves. The resultant palatal deficiency critical stage of lip formation is when the medial
is U-shaped not V-shaped and it is considered to be and lateral nasal processes contact each other and
a 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), based
ectomesenchyme or other phenomena at cellular possibly on ethnic or other factors, may predispose
level.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 in
migration, either through hormonal defect, tight apposition there is an increased possibility of
cleft lip. Experimental support of the previous is
biochemical 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 cleft
Such teratogens may be individually operative in a
lip and palate in A strain mice is attributable to the
subgroup of individuals that is genetically and
pointed facial processes that prevent wide areas of
biologically susceptible. Conversely, several
contact. On the other hand in the C57 black strain
different teratogens may act together on a single
of mouse the larger facial processes facilitate wider
mechanism controlled by only a few genes. At
contact of the processes and therefore clefting doesn’t
present our knowledge of the teratogens that are
develop.
associated with clefting is very limited. Only a few
substances such as retinoic acid (used in the While anatomical variation is one potential
treatment of acne and psoriasis), have been predisposing factor in the development of cleft lip
confirmed as teratogens with direct effect on facial and palate, there are also other factors. It is well
morphogenesis. 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 the
behavior and early morphogenesis have received
removal of the epithelial debris from the developing
attention in investigation of the etiology of CL and
nasal placode. When this PCD is more extensive
CP (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 lip
has been reported by several authors while others and alveolus. The continued action of growth
have reported the opposite. This phenomenon has traction forces may further disrupt the association
not been satisfactorily explained. One possible of the facial processes with the lip margins being
reason is viral infection, which may have a seasonal pulled apart. Resultant clefts of the lip may vary
trend. However, a correlation between clefts and from a simple groove in the muscle to a complete
viral infections has not clearly been established. cleft into the nasal floor.7
Indian J Dent Adv 2012; 4(2) 832
4. Cleft Lip and Palate Abu - Hussein Muhamad
In regards with the submucous cleft palate and the geographical variation being less important than
bifid uvula, both can be considered as microforms ethnic differences. In contrast the incidence of the
of isolated palatal clefting and are probably the CP alone shows little variation in different racial
result of disturbances in the local mesenchyme at groups. This may mean that CP alone will not fit
the time of ossification of the palatal bridge and the purely multifactorial model which include both
merging of the margins of the soft palate. These polygenic origin and undefined environmental
phenomena occur late in morphogenesis, between factors that would increase the variation in incidence
7-10 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 frequent
of the lip and cleft palate. Animal studies suggest in males, whereas CP alone is more frequent in
that following the failure of lip closure there is an females. Therefore due to both genetic and
overgrowth of the prolabial tissues which then divert environmental evidence it seems that CL with or
the tongue into the nasal cavity. The mesenchymal without CP and CP alone are separate entities.
obstruction of the tongue can delay the movement GENETIC FACTORS
of one or both palatal shelves, so that opportunities Polygenic inheritance refers to conditions
for 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. hair
extends over 15 days in man. Therefore in many color) (12).
syndromes cleft lip and palate may accompany Multifactorial inheritance refers to conditions
anomalies of other parts of the body. Many determined by a combination of factors each with a
developing systems can be disturbed simultaneously minor but additive effect (i.e. blood pressure)11 and
by 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. It
that there are over 150 recognized disorders in which includes both polygenic origin and undefined
CL, CP or both may represent one feature, it is environmental factors that will increase the
widely believed that the majority of affected variation in incidence both geographically and to
individuals are otherwise structurally normal (rev some extend racially. The multifactorial inheritance
by Jones,1988). Recent studies.10 have emphasize is more difficult to analyze than other types of
the fact that a significant portion of children with inheritance but it is thought to account for much of
clefts have the cleft as one feature of a broader the normal variation in families, as well as for many
pattern of malformation. It is important to recognize common disorders, including congenital
that structural defects are not, for the most part, malformations.
randomly associated. The presence of other major
and minor malformations in association with a cleft The normal rate of development can be thought
implies that a single etiologic factor - genetic, as a continuous distribution that if it is disturbed a
chromosomal or teratogenic - produced the pattern serious malformation may result, dividing the
as 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 and
CL with or without CP and CP alone are distinctly several human congenital malformations show
different in aetiology. Subsequent studies have family patterns that fit this model. CL with or
consistently confirmed that these two conditions without CP and CP alone are included in this
indeed differ in etiology and also in incidence, sex category.
predisposition and their relationship to associated
birth defects. CL results from the nonfusion of the CL with or without CP shows both geographical
upper lip and the anterior part of the maxilla during and racial variations which means that it could be
weeks 5-7 and occurs at an incidence of explained by the multifactorial/threshold model. In
approximately 1/1000 births.11 CP alone results from contrast CP alone shows little variation in different
failure of the mesenchymal masses of the palatine racial groups. This may mean that CP alone will
processes 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 pedigrees
of 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
5. 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 major
Mendelian inheritance of X-linked secondary cleft gene effect were found to provide an explanation of
palate 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 that
was much higher among the male than among the the best fitting model was that of an autosomal
female 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 have
linked mode of inheritance of CP is indicated by the shown that the extensive published recurrence risk
family distribution. Also the large size of this family data, which have been interpreted to be consistent
together with the availability of many well localized with an MF/T pattern of inheritance, are equally
X-chromosome probes has made it possible to compatible with an oligogenic model with perhaps
localize the defect subchromosomally (using RFLP- as few as four genes.
restriction fragment length polymorphism studies
for linkage) to the q13-q21.1 region of the X In conclusion, the extensive recurrence risk
data, which have been widely interpreted as
chromosome (16). Finer mapping and the use of cell
providing evidence of a polygenic multifactorial
lines from patients with deletions of the X
trait, are now thought to be consistent with a model
chromosome have further localized the defect to
with a major-gene effect contributing to about 1/3
Xq21.31-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 with
et al, 198018 reviewed worldwide CL/P recurrence decreasing relatedness to the proband is
risk 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 suggestive
environment component model fitted poorly. of multilocus inheritance.
Farrall and Holder, 199219 refer to the work of TERATOGENES
several investigators. According to their report:
Palatal shelf elevation and fusion depends on
Marazita 1984 in his analysis of a subset of Danish
fetal neuromuscular activity, growth of the cranial
CL/P families, found no support for a MF/T model
base and mandible, production of extracellular
but suggested the possibility of a major gene. Also
matrix and contractile elements in the palatal
Marazita et al 1986 have reported an analysis of
shelves, shelf adhesion, PCD of the midline
ten English multigenerational CL/P families
epithelial seam and fusion of the ectomesenchyme
collected by Carter, 1982). They were able to reject
between one shelf and another. All these phenomena
an MF/T model and demonstrated that a major locus
must act in perfect harmony over a short period of
acting 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 could
of Danish and Japanese CL/P families and concluded
lead to a cleft.
that the best fitting model predicted a recessive
major gene acting on a multifactorial background Vitamin A
(mixed-model). Chung et al 1989, analyzed By introducing into the maternal diet of A strain
Hawaiian families from several racial groups and mice human teratogenic agents such as of excess
found that the data were consistent with a major- vitamin A, the malformation threshold in the
gene/multifactorial model (mixed model). Ardinger developing embryos may be shifted to the extend
1988, have provided additional evidence for an that 100% offspring are born with the expected
association between the locus for transforming deformity (7). Renewed interest in retinoic
growth 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 severe
growth factor, which is believed to regulate the cystic acne. Inadvertent use of 13-cis-retinoic acid
proliferation and differentiation of palatal epithelial during the first trimester of human pregnancy has
cells both in vitro and in vivo. Hecht et al, 1991, been reported to result in a spectrum of
analyzed midwestern U.S. Caukasian families and malformations termed retinoic acid embryopathy
showed 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 of
Indian J Dent Adv 2012; 4(2) 834
6. Cleft Lip and Palate Abu - Hussein Muhamad
CP 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 secondary
exposure to forms of vitamin A that are stored in palate (22). 12 hours after the 8d14hr treatment
the maternal liver and that, therefore, have a time, embryos have 13 to 20 somites. Extensive
relatively long half-life; also involved multiple expansion of cell death at this time would be
administrations of the drug or examined the expected to have a major effect on almost the entire
developmental end-point only, thereby excluding secondary palatal shelf complex, thereby resulting
study 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, thereby
reviewed by Sulik, 1989, describes palatal clefts for
resulting in deficiency in the posterior aspect of the
which the shelves were very small or entirely absent;
secondary palate.
these resulted from insufficient maxillary
prominence mesenchyme. These investigators also 12 hours after the 9h6hr treatment time (late
found that size reduction of the palatal shelves treatment), embryos have approximately 30 to 34
occurred 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 occurs
short half-life, has shown the incidence of cleft palate
at the expense of its posterior portion. Major effects
peaks at more than one developmental stage in both
on the entire palatal shelves would not be expected
hamsters and mice (Kochhar, 1973 rev by Sulik,
at this treatment time. Later treatment times are
1989).
mostly associated with induction of limb
The changing incidence and severity of malformations.23
secondary palatal malformations that may be
Phenytoin
induced within a narrow window of time (over a 16
hour period) appear to be related to a corresponding Also, under the influence of teratogenic doses
change in the pattern of PCD in the first visceral of phenytoin, the lateral nasal process fails to expand
arch. It has been shown that 13-cis-retinoic acid to the size necessary for tight tissue contact with
increases 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 processes
prone to spontaneous craniofacial malformations. (3, of the ectomesenchymal cells is probably associated
22). The distribution of excessive cell death in with this condition, where the failure of union at
regions of PCD provides a bases for understanding the point of connection which establishes the lip and
the 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 1.1/1000
as being consistent with type-2 cell death (rev by live births and have lesser effects in 3-4/1000
Sulik, 1988). On the other hand it has been noted children born. Its abuse during pregnancy results
that lysosomal membranes of all cells do not lyse. in fetal alcohol syndrome (FAS) which involves a
Only 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, but
some other way lyse. Membrane destabilizasion by are associated with maternal ethanol abuse are
the 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 mice
membrane was noticed following retinoic exposure. with ethanol when the embryos have approximately
This may interfere with the migratory ability of 7-10 somites results in a pattern of malformation
these cells. Recovery follows removal of the retinoic that is consistent with the DiGeorge sequence
acid in vitro. In vivo, recovery from a brief (midline clefts in the nose and cleft palate are
interference with cell migration might also be features of this sequence. The DiGeorge sequence
expected but sufficient recovery probably does not has been described in the offspring of alcoholic
follow the excessive cell death of progenitor cells. mothers.
Indian J Dent Adv 2012; 4(2) 835
7. Cleft Lip and Palate Abu - Hussein Muhamad
Among the cellular effects of ethanol are the altered permeability of intracellular structures and
increased peroxidase activity, interference with enzyme release, i.e. rupture of lysosomal
cytoskeletal components, diminished DNA synthesis membranes, and suggest that this results from lipid
and suppressed rates of cell division, direct effect peroxide formation.
on membranes resulting in excessive fluidity
Hypoxia
(reviewed by Sulik, 1988). Recent investigations
illustrate excessive cell death within 12hr following Of particular interest is the hypoxia-induced
maternal treatment. The rates of cell death are cleft lip. Hypoxia in the human embryo may result
similar to the normal rates of cell death seen in PCD, from cigarette smoking, reduced atmospheric oxygen
but the areas of cell death are expanded. The reason levels and also placental insufficiency. Previous
for this excessive cell death is not yet clear. One studies had shown size reduction and abnormal
possible explanation is that exposure to ethanol apposition of the facial prominences as possible
results in lipid peroxidase/formation that leads to pathogenetic mechanisms. The presence of cellular
rupture of lysosomal membranes and release of debris resulting from cell death in the deepest
hydrolytic enzymes (type 2 cell death). aspects of the invaginating nasal placodes, as well
Hyperthermia 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 oxygen
sensitive to hyperthermia. Facial abnormalities deficiency on the cells which lead to glycolysis
have been associated with human maternal followed by acidification of intercapillary spaces and
hyperthermia at 4-7 weeks (rev by Sulik, 1988). The subsequent necrosis resulting from intra and
type and extent of damage depend on the duration extracellular leakage of lysosomal enzymes. It is
of temperature elevation and the extend of elevation. interesting to note that chemicals that interfere with
Also low sustained temperature elevations appear oxidative enzymes such as phenytoin induce cleft
to be as damaging as repeated spikes of higher lip in the mice.
elevation. Elevations of 1.5-2.5 degrees of Celsius Antimetabolites
above normal body temperatures represent the
Methotrxate and aminopterin are two
threshold for teratogenesis in human. Such
uncommon antimetabolites that can induce cranial
elevations can result with excessive exercise, the use
of 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 of
cell death is considered to play a major role, with methotexate involves fluid imbalance, resulting
the mitotic cells being the most susceptible. The perhaps from interference with osmoregulatory cells
pathogenesis of heat-induced malformations in areas in extraembryonic capillary beds, which is partially
other than the CNS have not been studied yet. It
responsible for the malformation.
has been suggested though that hyperthermia could
result in intra and extracellular leakage of lysosomal Metabolic disorders
enzymes which could lead in type-2 cell death. An interesting finding associated with lip
Ionizing 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 cleft
embryo. The malformations induced are similar to site were characterized by disorganized fibers, going
those noted following exposure to ethanol, retinoic in many different directions. The number of fibers
acid or hyperthermia. The cellular mechanism,s of appeared to be decreased and there is more
radiation induced teratogenesis are not completed connective tissue between the muscle fibers. The
understood. 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 large
to effects on rates of proliferation and cell death (rev accumulation of mitochondria at the central portion
by Sulik, 1988). Response of the cells to the radiation of the fiber, giving a star shaped appearance to the
is depended on cell cycle. Also in some instances cell fiber. The mitochondria are more variable in shape
death is linked to chromosomal damages. Some than normal, and the cristae are more densely
studies have shown that irradiation results in packed than expected.
Indian J Dent Adv 2012; 4(2) 836
8. Cleft Lip and Palate Abu - Hussein Muhamad
These abnormalities in mitochondrial size, 3. Sulik K, Cook C S, Webster W S: (1988). Teratogenes and
location, 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: Etiology
deformities. 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 with
insufficient 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 and
mentioned, 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 craniofacial
no 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 of
abnormalities. 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: Multifactorial
orientation. 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 palate
following adequate surgical reconstruction of the
and ankyloglossia in an Icelandic family. Cleft Palate J
muscle 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 regulation
reason 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: Cleft
Potentiation indeed occurs after repeated exposures lip ± cleft palate: an overview of the literature and an
to 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 J
morphogenesis 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 limb
This 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: Pathophysiology
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