Role of environmental factors in onset of non-syndromic orofacial cleft in Italian population

Introduction Non-syndromic cleft lip with or without cleft palate is the most common craniofacial anomaly affecting around 1 in 700 live births worldwide. Clefts of the human face can be classified anatomically as cleft palate only, cleft lip only, cleft lip and palate or a combined group of cleft lip with or without cleft palate, based on the differences in embryologic development. These malformations have a genetic origin, in fact several association studies have been performed to obtain important information about the candidate genes; but more important are gene–environment interactions that play an increasing role in its aetiology. In this review we analyse the role of environmental and genetic factors related to onset of cleft. Conclusion Epidemiological studies have shown how environmental factors (alcohol, smoking and drugs), as well as possible gene–environment interactions, play an important role in the onset of the malformation. On the contrary, folic acid intake seems to have a protective effect. Introduction Orofacial clefting (OFC) is the most common craniofacial anomaly affecting around 1 in 700 live births worldwide1. Clefts of the human face can be classified anatomically as cleft palate only (CPO), cleft lip only , cleft lip and palate (CLP) or a combined group of cleft lip with or without cleft palate (CL/P), based on differences in embryologic development2. Several association studies have been performed to obtain important information about the candidate genes involved in malformation3. The higher incidence of CPO and CL ± P observed in monozygotic twins (36%) compared with dizygotic twins (4.7%) further supports the hypothesis of a genetic component4,5. Epidemiological studies have highlighted the importance of gene–environment interactions as factors that play an increasing role in its etiology6,7. The most studied environmental factors are smoking, alcohol, drugs and folic acid. In this review we analyse the well-known environmental and genetic factors related to the onset of cleft. Discussion The authors have referenced some of their own studies in this review. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committee related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in these studies. Environmental factors Alcohol Materno–foetal intoxication with ethanol during pregnancy causes a well-known syndrome–the so-called foetal alcohol syndrome–characterised by pre/postnatal growth retardation and facial dysmorphism; but the association between alcohol and non-syndromic (NS) CL/P is inconsistent. In fact, during the past two decades, a series of epidemiologic studies have also revealed the role of alcohol in determining NS OFC. One study8 showed that alcohol increases the risk of NS CL ± P, whereas no significant association was found between alcohol and CPO, or in syndromic clefts. In 1999, other authors observed that the risk of delivering infants with OFC phenotypes for mothers who take alcohol during pregnancy is dose related9. In the same year, other authors examined the allelic variants of three genes– transforming growth factor alpha (TGF-A), TGF-B3 and MSX1–and their interaction with two exposures during pregnancy (cigarette smoking and alcohol consumption)10. They demonstrated that the development of CL ± P and CPO may be influenced by these risk factors, especially when they interact with specific allelic variants. The risk estimated for maternal smoking was significantly elevated in the case of CPO, and was higher among infants with allelic variants at the TGF-B3 or MSX1 sites. In contrast, the risk estimated for maternal alcohol consumption was significantly more elevated in the case of CL ± P, and was higher among infants with allelic variants at the MSX1 site. Drugs There are drugs whose effects on chronic pain syndrome (CPS) development are demonstrated. Diazepam assumption has an important effect in developing CPS during * Corresponding author Email: [email protected] 1 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy 2 Department of Translational Surgery and Medicine, Bicocca University, Milan, Italy 3 Department of Experimental, Diagnostic and Specialty Medicine, University di Bologna, Bologna, Italy