Download Pre-natal Orofacial Development - Causes of Cleft Lip and Cleft Palate

Cleft Lip (CL) or cleft palate (CP), are genetic syndromes that cause a fissure in the roof
of the mouth, or in the upper lip during the pre-natal period (Murray, JC. 2002). The clefts of
the palate can refer to either (or both) the hard palate, which is of the palatine bone itself, or
the tissue that grows over the bones. Tissues that grow further back of the mouth, closer to the
throat, is referred to as the soft palate. Cleft palate conditions affect approximately 2,650
babies yearly in the United States and 4,440 are born with cleft lips, with or without a cleft
palate, making CL/P one of the most common congenital conditions (Centre for Disease Control,
CDC. 2014). Often, cleft lip and cleft palate (CL/P) are referenced together, because the two
syndromes can occur together. According to Dr. John G. Meara and Dr. John B. Mulliken of
Boston Childrens’ hospital, CL/P can be unilateral, (occurring on one side of the face) or
bilateral (both sides), more common in boys than girls, and affect more children of Asian, Latin
descent, and Native American descent. Although when left untreated, the syndrome is usually
not fatal. However, understandably, such orofacial clefts usually results in self-esteem issues
later in life. Studies of genetic and/or teratogenic causes of CL/P during the pre-natal period can
benefit the public health of many people, due to the prevalence of its occurrence.
Pre-natal Orofacial Development
One may speculate, based on the complexities of general human development that
craniofacial development also falls under a similar category; requiring multitudes of interacting
genes. As a result, it is difficult to ascertain a single gene for a single cause (Murray, JC. 2002).
There can also be a varying degree of phenotypic expression of the syndromes, ranging from
phenotypically normal heterozygotes to fully of cleft lip and/or palates of homozygotes (Murray,
JC 2002). In addition, genes affecting CL/P can be either autosomal recessive (50%), autosomal
dominant (40%), or sex linked (10%) (Schutte and Murray. 1999). Pre-natal development of the
craniofacial tissue begins at four weeks into the gestation period. It is also a period that is highly
sensitive to disruptions due to the cells beginning to differentiate (Ward, Richard. BPK 375.
2014). Prominent developmental changes tend to occur if the gene expression is altered or
disrupted at this stage. As the cranium and face begin to develop, the maxilla (frontal cheek
bones) begin to exhibit prominences that start growing downward vertically then eventually
grows horizontally (approximately 6 weeks post conception). There have been much
speculation of what causes the horizontal shift in maxillary prominence growth, but the exact
mechanisms are unclear. Normally, the end result is that the maxillary prominences, flanking
both sides of the tongue, come together and fused to form the primordial palate shelves
(Stanier and Moore. 2004). However, in babies born with cleft palates, the primordial palatine
bone (bone of roof of the mouth) that forms the palatal shelves do not come together and fuse.
This disruption of the palatal shelving could also cause the soft palate of the mesenchymal cells
to not fuse as well. Palatogenesis is usually complete by week twelve. Some classes of genes
involved in craniofacial development are: Polarizing signals, growth factors and receptors,
transcription factors, cell adhesion molecules, and extracellular matrices (Stanier and Moore.
2004). These genes (there are presumably more than what is known) interact to result in the
development of the head and face makes it difficult to isolate a single gene for a single
particular function (For specific names of each class of genes, please refer to Table 1, pg. 4 of
research article by Stanier and Moore, 2004).
Genetic Causes
Of the numerous genes indicated in craniofacial development, Dr. JC Murray notes that
there are four genes that have prominent results in terms of causing clefts when expressions
are disrupted; those genes are: Msx1, Tfgb3, Tfap2a, Gabrb3, and their knock outs and
transgenic insertions result in CL/P in mice. Studies in mice and chicks have also revealed
several syndromic genes involved in major etiology of non-syndromic clefting (Stanier and
Moore, 2014). Therefore, Stanier and Moore propose that better understanding of these genes
may further reveal a more clear pathology to human clefting. One gene, Tbx22, has been
particularly studied because of its sex linked nature. Also, its disruption (missense, nonsense,
splice site, and frameshift) can result in palatal shelf malformation, which leads to syndromic
and nonsyndromic CL/P. It is thought that Tbx22 belongs to a family of transcription factor
genes that have an essential role in particular mesoderm formation (Stanier and Moore, 2014).
As a result, Tbx22 disruption results in CL/P and is often associated with phenotypic deviations
such as ankyloglossia, and absent/diminished uvula. Such associative disruptions with CL/P are
referred to as syndromic CL/P, where along with CL/P there are other disrupted phenotypes.
Even though high familial aggregation rates, and concordance rates in monozygotic vs.
dizyogotic twins suggest a highly genetically involved component to CL/P, the correlation is still
not 100%. Therefore, it is thought that the genetics, and the interaction with the environment
in utero can result in differing degrees of gene expression (Stanier and Moore 2004). Ultimately,
genetic abnormalities are generally thought to be the main causes of CL/P during the pre-natal
period compared to teratogens (external agents).
Teratogens
Aside from genetic causes of CL/P, teratogens, can also cause CL/P, although the
mechanisms and details are much less understood. Some known teratogens are cigarette
smoke, certain drugs, alcohol, Vitamin A and its congeners, faulty folate metabolizing enzymes
as well as a folate deficiency. However, the evidence for dietary influences are more
contentious than cigarette smoke and alcohol (Murray, JC. 2002). Considering what researchers
have discovered about cigarette smoke and its potential healthy detriments, this result is not
surprising. According to a meta-analysis study of maternal cigarette smoke during pregnancy,
Julian et el. (2004) found that there is statistically significant association between maternal
cigarette use and CL/P. The same findings were resonated by the 2014 Surgeon Generals’
Report, indicating that orofacial clefts caused by smoking in early pregnancy attributes to
approximately 6.1% (CDC. 2014). One reason that the mechanisms for smoking related CL/P
causes are poorly understood could be that there are a vast number of detrimental chemicals in
cigarette smoke. Therefore, like genetic influences of CL/P, it would be difficult to ascertain the
exact effects of a single substance for a single known cause in a precise manner.
Management and Treatment
As expected, developmental deformities such as CL/P produce complications. The main
problem being that babies may have difficulties fully sealing their lips around a nipple to
produce the vacuum required to breastfeed properly. A cleft in the palate also contributes to
this problem and is usually fixed through surgery (palatoplasty) by cutting the edges of the soft
palate into layers and reforming the inner layer of the nasal passage, as well as sewing together
the edges to form fused palates. (University of Michigan. 2014). Like CP, surgery for cleft lips
requires re-sectioning the layers of the upper lip and sewing the edges of the cleft together.
Other than CP, the other frequently observed phenotypic effect is ankyloglossia (tongue tie),
which is the condition where the tongue is anchored to the floor of the mouth at the tip. This
causes the tongue to be much shorter than normal, and can result in speech impediments as
well a general difficulty using the tongue for swallowing and maneuver. Other complications of
cleft palate include hearing deficits/infections, problems with teeth growth, and speech
impediments. Surgery for cleft lips usually occurs within 12 months, and surgery for cleft
palates usually occurs within 8 months (CDC.2014). These are periods prior to babies acquiring
the ability to speak and therefore, there may be speech impediment issues if delayed too long.
In addition, there may be psychological issues such as low self-esteem later on in life, which
likely is a of result of discrimination due to their facial deformities (CDC.2014). While pre-natal
diagnosis of CL is fairly straight forward using ultrasound, diagnosis of cleft palate usually occurs
after birth.
Looking Ahead
Aforementioned, it may be greatly beneficial to study the development of CL/P because
of their pervasiveness. Undoubtedly, it would also be beneficial to further unravel the
complexities of orofacial development such as those indicated in CL/P deformations, and
perhaps it would shed light on other genetic aspects of orofacial malformations. Since it is
known that genes potentially responsible for syndromic CL/P can also exhibit penetrance for
non-syndromic CL/P, this could be a concept that warrants specific attention. Understanding
genes such as Tbx22 could potentially lead to understanding the mechanisms for penetrance
and perhaps the roles of genes responsible for CL/P in other areas of orofacial development. As
always, advances in technology such as gene targeting will allow for more concise genetic knock
outs and other disruptions that can potentially isolate specific factors in CL/P development in
the pre-natal period (Stanier and Moore. 2004).