reviews
Luca Dalla Libera¹, Kintan Patel², Millaray santana²
The Environmental Factors Influencing Cleft
– Literature Review
Czynniki środowiskowe wpływające na powstawanie rozszczepu
– przegląd piśmiennictwa
¹ student of Padova Medical University, italy
² student’s scientific society of Dentofacial Anomalies, wroclaw Medical University, Poland
Abstract
This paper presents a review on clefts to understand etiology and environmental influences towards this anomaly. Clefts are the most common craniofacial abnormalities resulting from the incomplete development of the lip and/ or palate in the first trimester of pregnancy (4th to 12th week of pregnancy). The etiology is multifactoral, with a
very strong genetic component. The family occurrence of clefts have been proved. The fusion between the lateral palatine processes is very complicated and correlated process. Fetal development may be disturbed by many envi-ronmental factors and the exposure of the pregnant woman to them. The crucial ones are: drinking alcohol, smok-ing, radiation, diseases of mother, working in harmful environment, use of drugs and medicaments. Clefts have been growing in numbers because of advanced age of pregnant women and increased exposure to environmental risk factors. As fusion of the cleft occurs early in the pregnancy, the prevalence is very difficult, since most women are unaware of pregnancy in its early stage (Dent. Med. Probl. 2011, 48, 2, 261–266).
Key words: clefts, etiology.
Streszczenie
Praca zawiera wiadomości dotyczące rozszczepów, ma na celu zrozumienie ich etiologii i wpływu środowiska na powstawanie tej wady rozwojowej. rozszczepy są najczęściej występującą anomalią rozwojową w obrębie twarzy, wynikającą z niedokończonego rozwoju wargi i/lub podniebienia w pierwszym trymestrze ciąży (4–12 tygodnia ciąży). etiologia rozszczepów jest wieloczynnikowa, z silnie zaznaczoną komponentą genetyczną. Udowodniono rodzinne występowanie rozszczepów. Połączenie się dwóch wyrostków podniebiennych jest bardzo skompliko-wanym i złożonym procesem. rozwój płodu może być zaburzony z powodu wielu czynników środowiskowych i narażenia na nie kobiety w ciąży. Najważniejsze z nich to: spożywanie alkoholu, palenie papierosów, narażenie na promieniowanie rentgenowskie, choroby ciężarnej, praca w szkodliwych warunkach, używanie narkotyków i leków. Coraz częstsze występowanie wady rozwojowej może wynikać z późnego wieku matek i zwiększonego narażenia na szkodliwe czynniki środowiskowe. Ponieważ rozszczepy powstają na wczesnych etapach życia płodo-wego, przeciwdziałanie ich powstawaniu jest niezwykle trudne, gdyż większość kobiet nie jest świadoma ciąży w jej początkowej fazie (Dent. Med. Probl. 2011, 48, 2, 261–266).
Słowa kluczowe: rozszczepy, etiologia.
Dent. Med. Probl. 2011, 48, 2, 261–266
issN 1644-387X © Copyright by wroclaw Medical University and Polish Dental society
Clefts are the most common craniofacial ab-normalities resulting from the incomplete devel-opment of the lip and/or palate in the first trimes-ter of pregnancy. There are many factors involved in the formation of the clefts, in this article the authors discuss the etiology, epidemiology and causes concerning clefts.
Etiology of Clefts
in the early weeks of pregnancy the face is being formed, starting from the top and the two lateral sides of the maxillary bone. They develop at the same time and grow towards each other, fi-nally fusing in the middle [1].
Palate formation begins at the end of the fi-fth week of gestation. At the beginning, the palate consists of two parts, one is the anterior (primary) palate and the second one is the posterior (secon-dary) palate. The intermaxillary segment is for-med by the for-medial nasal prominences, and it is composed by the primary palate and incisors. The primary palate continues posteriorly to the incisi-ve foramen [2].
The secondary palate is formed by the late-ral palatal processes. it begins at the incisive fo-ramen and encloses two sections, one bony and one muscular. The lateral palatine processes arise at about the sixth week of development and they are composed of the deep portions of the maxil-lary prominence that form two horizontal struc-tures or palatal shelves. These two strucstruc-tures are derivatives of the first branchial arch and they are originally on either side of the tongue. when the tongue starts to move downward during the seventh week of pregnancy, the lateral processes grow medially. The fusion in the hard palate in-itiates anteriorly and persists posteriorly during the eighth week of gestation.
The fusion between the lateral palatine pro-cesses is very complicated and correlated with se-veral different procedures. Programmed cell death at the free borders and production of an adhesive layer of glycoproteins and desmosomes determi-ne an ideal bonding surface interface. The left si-de has the tensi-dency to lag behind the right sisi-de, causing a bigger percentage of the left-sided clefts. The nasal septum is concluded between the 9th and 12th weeks of gestation consequently of the growth downward into the newly formed palate.
The bone originates from the anterior palate thereafter spreads out posteriorly. The soft palate and the uvula, which compose the posterior seg-ment of the secondary palate, evolve during the eighth week of gestation. The tensor veli palatini advance, followed by the musculus uvula, indu-cing the formation around the seventeenth week of gestation [2].
The etiology of clefts is thought to be multifac-torial, with both major and minor genetic influen-ces with variable interactions from environmental factors. in recent years, a number of advancement have occurred with respect to the genetics of these conditions, in particular, characterization of the underlying gene defects correlated with various relevant clefting syndromes. The most important identification of mutations a rein the interferon regulatory factor-6 (irF6) gene as the cause of van der woude syndrome and the poliovirus receptor related-1 (PvrL1) gene as being responsible for an autosomal recessive ectodermal dysplasia syndro-me correlated with clefting. while non-specific
disease-causing gene mutations have been asso-ciated in non-syndromic clefting, a number of candidate genes have been isolated through both linkage and connected research [3, 4].
Other situations, possibly due to microde-letions or isodisomy, were also found and could contribute to clefts as well. The analysis of the ge-nes involved has indicated that point mutations in
FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of
iso-lated cleft lip with or without cleft palate, and the linkage disequilibrium data support a bigger and unspecified part for variants in or near MSX2,
JAG2, and SKI [4, 5].
Environmental Causes
Genes take an important role in facial deve-lopment, but the role of environmental influence on modulating genetic effects is just as critical. At least four major classes of environmental triggers have been studied. One of these is maternal smo-king. it is known that smoking is harmful for both mother and fetus. it gives variety of problems in fetus, from breathing problems to causing cleft. smoking cigarettes has been recognized as an im-portant covariate in clefting [6]. Drugs taken dur-ing pregnancy should also be considered as a fac-tor associated with clefts. During the first trime-ster, analgesic, chemotherapeutic and antineurotic drugs had all been more often used by the mothers of children with clefts, than by the control gro-up. it has also been proved that drugs taken by mothers of children with cleft lip, with or without palate was more frequent than the same drugs ta-ken by the mothers of children with isolated cleft palate [7]. in the group of these drugs, there are: anti-seizure/anticonvulsant medications, acne medications containing Accutane, and methotre-xate – a drug commonly used for treating cancer, arthritis, and psoriasis [8, 9].
smoking and alcohol are also involved. First- -trimester of pregnancy smoking is clearly asso-ciated with risk of cleft lip. This effect modifies variants of genes related to detoxification of com-pounds of cigarette smoke. Maternal alcohol abu-se during early pregnancy increaabu-ses the risk of oral clefts, but little is known about how genetic variation in alcohol metabolism affects this asso-ciation [6, 10].
Other factors that increase the risk of cleft lip and palate through maternal ingestion include pharmaceuticals. The problem with drugs is that they spread in body instead of just going where we want. it is that unintended spread that gives us the unwanted effect. some drugs have been
cor-related to give cleft problems, such as the antico-nvulsant phenytoin and benzodiazepines, or pe-sticides, such as dioxin [11]. Then both nutrients and cholesterol metabolism are also increasingly seen as being important in influencing embryonic development. Human body needs both vitamin, minerals, amino acid and fat to build cells, and if any of these is in low concentration or missing then the cells can form abnormally. Cells that are abnormal will also have altered role and function, which can lead to different problems. There are 4 main nutrients that play an immense role in clo-sing of the lip and palate in fetus. it is crucial to have them in normal concentration in mothers body at early stages of pregnancy so that fetus can develop in a normal way. Folic acid in particular is recognized as playing an important role in neu-ral tube formation. The identification of folic acid supplementation can decline the risk of neural tu-be defects has lead to prevention of many potential clefts [12]. edison and Muenke [13] provided data that suggested that early embryonic introduction to the cholesterol-lowering statin drugs might ha-ve presented a risk for a wide range of birth defects of the midline, including clefts of the lip and pa-late. it is important to underline the fact that not only a low level of some nutrient can affect clefts but also excessive amount of them can contribute to cleft problem. Also minimal dietary intake of B-complex vitamins, in addition to exposure to deficient or excessive amounts of vitamin A, has been linked to raise the risk of clefts development [14, 15]. excessive alcohol consumption during pregnancy has also been connected with
malfor-mations in humans, called fetal alcohol syndrome [16, 17]. it is suggested that alcohol might exert some of its embryopathic effects by destructively affecting cranial neural crest cell activities [18, 19]. A causal relation between extreme alcohol intake and fetal alcohol syndrome is generally acknow-ledged, but there is a minor epidemiologic confir-mation that alcohol causes other major malforma-tions [20]. There have even been some studies that link high altitude with cleft problems [21]. There are many more environmental causes that have not yet been discovered.
Epidemiology
Cleft lip and/or palate (CLP) make up for nearly one-third of all congenital malformations, thus making the most frequent incidence of this anomaly as 1.6 per 1000 live births. roberts, Ka-llen and Harris [23] gather the data of five birth registries from California, sweden and France to study the prevalence of CLP anomaly. Five million newborn were examined for craniofacial deformi-ties and epidemiological characteristics and they found that a total of 8315 children were affected by this anomaly amongst the sample studied. They calculated the incidence of CPL 1.57/1000, although the numbers are different in different countries. Despite the frequency of this abnor-mally the exact etiology of cleft lip and palate is vague because of its heterogeneous presentation. There are many factors contributing for CLP, some cases are sporadic while others are familiar.
Table 1. Factors disturbing the formation of the palate Tabela 1. Czynniki wpływające na powstawanie podniebień
No.
(Nr) Name(Nazwa) Affect cleft palate(Dotyczy rozszczepu podniebienia)
which gene it might affect (Którego genu mógłby dotyczyć)
1 smoking yes TDFA /MSX1 /TGFB3 /RARA /P450 /GST /EPHX1**
2 alcohol yes TGFA /MSX1 /TGFB3**
3 phenytoin yes *
4 benzodiazepines yes * 5 valproic acid yes *
6 thalidomide yes *
7 folic acid yes *
8 vitamin A yes *
9 vitamin B yes TGFA /MTHFR**
10 dioxin yes *
* studies not done yet. ** [22].
Many children born with cleft lip and palate with-out any positive family history would have genetic predisposition, which may have been exacerbated in a phenotype cleft.
The inheritance pattern in CLP is higher in children where there is a positive family history of CLP. if either parent or siblings have CLP the risk of developing cleft lip and palate is approximately 0.1%. The risk of CLP passed on to the next gen-eration differs depending on whether parent or sibling is affected. One could state that one par-ent or sibling with CLP would result in approxi-mately 4% of recurrence, while one parent and one sibling with CLP showed 10% of recurrence. However, two siblings with CLP will give rise to 14% of recurrence. One parent and two siblings with CLP would double the recurrence with 25%; further investigation showed that if both parents and minimum one sibling gave numbers like 50% recurrence [24, 25].
Among the environmental causes, anti-abor-tificant drugs, anti-emetic, phenytoin, excessive alcohol and smoking have been linked to congeni-tal defects including cleft lip and plate. Maternal alcohol abuse during early pregnancy increases the risk of oral clefts. The relationship between mater-nal tobacco and alcohol consumption during the first trimester of pregnancy and oral clefts was ob-served by analysing 161 infants with oral clefts and 1134 control infants. several analyses also showed a higher risk of cleft lip with or without cleft palate associated with smoking (odds ratio [Or] = 1.79, 95% confidence interval [Ci] = 1.07, 3.04) and an increased risk of cleft palate connected with alco-hol consumption (Or= 2.28, 95% Ci = 1.02, 5.09). The risk increased with the number of cigarettes smoked [26]. Passive smoking is also a very accurate subject to bring up in this matter. Maternal passive smoking and the risk of CLP among non-smoking women were examined in China. The odds ratio for exposure levels of 1–6 times per week and more than 6 times per week (at least 1 cigarette each time) were 1.6 (0.9–2.9) and 2.8 (1.5–5.2), respectively. The research concluded that maternal passive smoking during pregnancy was associated with an increased risk for CLP in offspring [27].
Nutrition seems to play a significant role as
well. The role of folic acid used in prevention of CLP in high dose (3–9 mg/d) suggests a positive benefit to reduce occurrence of CLP abnormality [28, 29].
it is known that older age in mothers is clearly associated with CLP. Among the 1,489,014 live births in Denmark for 23 years (1973–1996), there were 1920 children with non-syndromic cleft lip with or without cleft palate and 956 children with non-syndromic cleft palate. The connection be-tween mother and father's age was included in this analysis. results showed that older age was con-nected with increased risk of both cleft lip with or without cleft palate and cleft palate only. Both ma-ternal and pama-ternal ages were associated with the risk of CLP, but the contribution of each was de-pendent on the age of the other parent. Both high maternal age and high paternal age were linked with CLP. Higher paternal age but not maternal age showed an increased in the risk of cleft pal-ate only [30]. However, some studies showed the contrary about paternal age association with CLP. A study carried out in Brazil showed no increased risk connected with paternal age [31].
Conclusions
Clefts occur during the early weeks of preg-nancy because of disturbance in the fusion proc-ess of the lateral palatine procproc-esses. This formation is easily disturbed by many different factors. it is hard to predict when a cleft will appear in a child, but we are aware of the risks of this abnormality. some of the risks are linked with genetics, other are connected with environmental factors which could be avoided. since this formation occurs so early in the embryonic development, the mother might not know that she is pregnant, and embryo can be ex-posed to risk factors such as tobacco smoking, al-cohol and some categories of drugs. The number of clefts is increasing, due to the postponing pregnan-cy, the raised ratio of female smokers, the escalation in the use of drugs and the changes in our environ-ment. Today more research is needed about how to detect and avoid CLP as early as possible.
Acknowledgements. special thanks to Janina szeląg M.D., Ph.D. and Anna Paradowska D.M.D. for helping in this research.
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Address for correspondence:
Kintan Patelstudent’s scientific society of Dentofacial Anomalies Department of Dentofacial Anomalies
Krakowska 26 50-425 wrocław Poland e-mail: kintan_patel@hotmail.com received: 1.04.2011 revised: 30.05.2011 Accepted: 17.06.2011
Praca wpłynęła do redakcji: 1.04.2011 r. Po recenzji: 30.05.2011 r.
