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Nonsyndromic cleft lip and/or palate (or orofacial cleft, OFC) is a malformation characterized by an incomplete separation between nasal and oral cavities without any associated anomalies. The last point defines the distinction between syndromic and nonsyndromic OFC. Nonsyndromic OFC is one of the most common malformations among live births and is composed of two separate entities: cleft lip with or without cleft palate (CL+/-P) and cleft palate isolated (CPI). Because of the complex etiology of nonsyndromic OFC, which is due to the differences between CL+/-P and CPI, and the heterogeneity of each group, caused by the number of genes involved, the type of inheritance, and the interaction with environmental factors, we reviewed those genes and available loci in the literature whose involvement in the onset of nonsyndromic OFC has more sound scientific evidence. Genetic studies on human populations have demonstrated that CL+/-P and CPI have distinct genetic backgrounds and, therefore, environmental factors probably disclose only these malformations. In CL+/-P several loci, OFC from 1 to 10 have been identified. The first locus, OFC1, has been mapped to chromosome 6p24. Other CL+/-P loci have been mapped to 2p13 (OFC2), 19q13.2 (OFC3) and 4q (OFC4). OFC5-8 are identified by mutations in the MSX1, IRF6, PVRL1, and TP73L gene, respectively. OFC9 maps to 13q33.1-q34, whereas OFC10 is associated with haploinsufficiency of the SUMO1 gene. In addition, MTHFR, TGF-beta3, and RARalpha play a role in cleft onset. In CPI one gene has been identified (TBX22) at present, but others are probably involved. Greater efforts are necessary in order to have a complete picture of the main factors involved in lip and palate formation. These elements will permit us to better understand and better treat patients affected by OFC.

Background: Genetic studies have demonstrated that non-syndromic cleft is composed of two separate entities - cleft palate only (CPO) and cleft of lip, alveolus with or without cleft palate (CL+/-P) -, both have a heterogeneous genetic background and environmental factors contribute to the onset of these malformations. Previous studies have shown that TGFbeta3 could be involved in these diseases, but no conclusive results have been reached., Purpose: In order to detect if TGFbeta3 has a role in cleft diseases, a series of non-syndromic cleft patients and controls are analyzed for TGFbeta3 protein expression., Material and Methods: Forty-three non-syndromic cleft patients and 21 unaffected subjects were involved in this study. Paraffin-embedded specimens were matched with the TGFbeta3 antibody and then scanned with a computerized image analyzer. TGFbeta3 was found to be absent (less than 10%), moderate (from 10% to 30%) and highly expressed (higher than 30%) in epithelium (EP), minor palatal salivary gland (GL) and fibres of elevator palati muscle (MU). Data was statistically analyzed with a Kruskal-Wallis test., Results: Only GL and EP have a statistically significant lower expression in non-syndromic cleft compared to unaffected subjects. A subsequent comparison between CL+/-P and CPO groups demonstrates a statistically significant difference only for GL, with a lower expression in GL of CPO patients., Conclusions: TGFbeta3 is decreasingly expressed in GL of unaffected CL+/-P and CPO patients and thus further strength is given to a pathogenetic role of TGFbeta3 in the onset of clefts.