Most clefts are polygenic and multifactorial in origin with many genetic and environmental factors contributing. Genetic factors cause clefts in 20% to 50% of the cases and the remaining clefts are attributable to either environmental factors (such as teratogens) or gene-environment interactions. The polygenic/multifactorial inheritance model predicts that most individuals will be born without clefts; however with a number of genetic or environmental factors, it can result in cleft formation. The development of the face is coordinated by complex morphogenetic events and rapid proliferative expansion, and is thus highly susceptible to environmental and genetic factors, rationalising the high incidence of facial malformations. During the first six to eight weeks of pregnancy, the shape of the embryo's head is formed. Five primitive tissue lobes grow: If these tissues fail to meet, a gap appears where the tissues should have joined (fused). This may happen in any single joining site, or simultaneously in several or all of them. The resulting birth defect reflects the locations and severity of individual fusion failures (e.g., from a small<unk>  or<unk>  fissure up to a completely malformed face). The upper<unk>  is formed earlier than the<unk> , from the first three lobes named a to c above. Formation of the<unk>  is the last step in joining the five embryonic facial lobes, and involves the back portions of the lobes b and c. These back portions are called<unk> l shelves, which grow towards each other until they fuse in the middle. This process is very vulnerable to multiple toxic substances, environmental pollutants, and nutritional imbalance. The biologic mechanisms of mutual recognition of the two cabinets, and the way they are glued together, are quite complex and obscure despite intensive scientific research. Orofacial clefts may be associated with a syndrome (syndromic) or may not be associated with a syndrome (nonsyndromic). Syndromic clefts are part of syndromes that are caused by a variety of factors such as environment and genetics or an unknown cause. Nonsyndromic clefts, which are not as common as syndromic clefts, also have a genetic cause. Genetics Genetic factors contributing to<unk>  formation have been identified for some syndromic cases. Many clefts run in families, even though in some cases there does not seem to be an identifiable syndrome present. A number of genes are involved including cleft<unk>  and<unk>  transmembrane protein 1 and GAD1, One study found an association between mutations in the HYAL2 gene and<unk>  formation. Syndromes * The Van der Woude syndrome is caused by a specific variation in the gene IRF6 that increases the occurrence of these deformities threefold. Mutations in interferon regulatory factor 6 (IRF6) that cause cleft<unk><unk>  are also implicated in neural tube defects such as spina bifida. * Another syndrome, Siderius X-linked intellectual disability, is caused by mutations in the PHF8 gene (); in addition to cleft<unk>  or<unk> , symptoms include facial dysmorphism and mild mental retardation. In some cases, cleft<unk>  is caused by syndromes that also cause other problems: * Stickler syndrome can cause cleft<unk>  and<unk> , joint pain, and myopia. * Loeys–Dietz syndrome can cause cleft<unk>  or bifid uvula, hypertelorism, and aortic aneurysm. * Hardikar syndrome can cause cleft<unk>  and<unk> , Hydronephrosis, Intestinal obstruction and other symptoms. * Cleft<unk><unk>  may be present in many different chromosome disorders including Patau syndrome (trisomy 13). * Malpuech facial clefting syndrome * Hearing loss with craniofacial syndromes * Popliteal pterygium syndrome * Cornelia de Lange syndrome * Treacher Collins syndrome *Pierre Robin syndrome Specific genes Type OMIM Gene Locus OFC1 ? 6p24 OFC2 ? 2p13 OFC3 ? 19q13 OFC4 ? 4q OFC5 MSX1 4p16.1 OFC6 ? 1q OFC7 PVRL1 11q OFC8 TP63 3q27 OFC9 ? 13q33.1-q34 OFC10 SUMO1 2q32.2-q33 OFC11 BMP4 14q22 OFC12 ? 8q24.3 Many genes associated with syndromic cases of cleft<unk><unk>  (see above) have been identified to contribute to the incidence of isolated cases of cleft<unk><unk> . This includes in particular sequence variants in the genes IRF6, PVRL1 and MSX1. The understanding of the genetic complexities involved in the morphogenesis of the midface, including molecular and cellular processes, has been greatly aided by research on animal models, including of the genes BMP4, SHH, SHOX2, FGF10 and MSX1. Environmental factors Environmental influences may also cause, or interact with genetics to produce, orofacial clefts. An example of the link between environmental factors and genetics comes from a research on mutations in the gene PHF8. The research found that PHF8 encodes for a histone lysine demethylase, and is involved in epigenetic regulation. The catalytic activity of PHF8 depends on molecular oxygen, a factor considered important from reports on increased incidence of cleft<unk><unk>  in mice that have been exposed to hypoxia early during pregnancy. Cleft<unk>  and other congenital abnormalities have also been linked to maternal hypoxia caused by maternal smoking, with the estimated attributable fraction of orofacial clefts due to smoking in early pregnancy being 6.1%. Orofacial clefts occur very early in pregnancy and so smoking cessation right after recognition of pregnancy is unlikely to reduce the exposure during the critical time period. Maternal alcohol use has also been linked to cleft<unk>  and<unk>  due to the effects on the cranial neural crest cells. The degree of the effect, however, is unknown and requires further research. Some forms of maternal hypertension treatment have been linked to cleft<unk>  and<unk> . Other environmental factors that have been studied include seasonal causes (such as pesticide exposure); maternal diet and vitamin intake; retinoids (members of the vitamin A family); anticonvulsant drugs; nitrate compounds; organic solvents; parental exposure to lead; alcohol; cigarette use; and a number of other psychoactive drugs (e.g. cocaine, crack cocaine, heroin). Current research continues to investigate the extent to which folic acid can reduce the incidence of clefting. Folic acid alone or in combination with vitamins and minerals prevents neural tube defects but does not have a clear effect on cleft<unk><unk>  incidence. The mechanism behind beneficial folate supplementation is due to folate playing a pivotal role in DNA synthesis and methylation and contributes to both development and gene expression.
Cleft lip and cleft palate
Malpuech facial clefting syndrome
Hemifacial microsomia
Anodontia
Acephaly
Hand and foot deformity with flat facies
Nager acrofacial dysostosis
Microcephaly