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 lip or palate fissure up to a completely malformed face). the upper lip is formed earlier than the palate, from the first three lobes named a to c above. formation of the palate 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 palatal 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 cleft lip and cleft palate 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 lip and palate transmembrane protein 1 and gad1, one study found an association between mutations in the hyal2 gene and cleft lip and cleft palate 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 lip palate 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 (omim: 300263); in addition to cleft lip or palate, symptoms include facial dysmorphism and mild intellectual disability. in some cases, cleft palate is caused by syndromes that also cause other problems: stickler syndrome can cause cleft lip and palate, joint pain, and myopia. loeys–dietz syndrome can cause cleft palate or bifid uvula, hypertelorism, and aortic aneurysm. hardikar syndrome can cause cleft lip and palate, hydronephrosis, intestinal obstruction and other symptoms. cleft lip/palate 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 119530 ? 6p24 ofc2 602966 ? 2p13 ofc3 600757 ? 19q13 ofc4 608371 ? 4q ofc5 608874 msx1 4p16.1 ofc6 608864 ? 1q ofc7 600644) pvrl1 11q ofc8 129400 tp63 3q27 ofc9 610361 ? 13q33.1-q34 ofc10 601912 sumo1 2q32.2-q33 ofc11 600625 bmp4 14q22 ofc12 612858 ? 8q24.3 many genes associated with syndromic cases of cleft lip/palate (see above) have been identified to contribute to the incidence of isolated cases of cleft lip/palate. 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 lip/palate in mice that have been exposed to hypoxia early during pregnancy. cleft lip 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 lip and palate 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 lip and palate. 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 lip palate 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. diagnosis traditionally, the diagnosis is made at the time of birth by physical examination. recent advances in prenatal diagnosis have allowed obstetricians to diagnose facial clefts in utero with ultrasonography. clefts can also affect other parts of the face, such as the eyes, ears, nose, cheeks, and forehead. in 1976, paul tessier described fifteen lines of cleft. most of these craniofacial clefts are even rarer and are frequently described as tessier clefts using the numerical locator devised by tessier. classification cleft lip and cleft palate is an "umbrella term" for a collection of orofacial clefts. it includes clefting of the upper lip, the maxillary alveolus (dental arch), and the hard or soft palate, in various combinations. proposed anatomic combinations include: cleft lip cleft lip and alveolus cleft lip, alveolus, and palate cleft lip and palate (with an intact alveolus) cleft palate prenatal diagnosis cleft lip with or without palate is classified as the most common congenital birth defect. it has been noted that the prevalence of orofacial clefts varies by race. the highest number of cases have been recorded among asians and native americans, followed by europeans, hispanics and african-americans. the critical period for cleft development ranges from the 4th to the 12th week of intrauterine life. clefts of the primary palate develop between the 4th and 7th weeks of intrauterine life, while clefts of the secondary palate develop between the 8th and 12th embryonic weeks. accurate evaluation of craniofacial malformations is usually possible with the ultrasound scan performed during pregnancy. this is however not a routine procedure according to the american institute of ultrasound in medicine. the accuracy of ultrasonography for prenatal diagnosis of cleft lip +/- palate is dependent on the experience of the sonologist, maternal body type, foetal position, the amount of amniotic fluid and the type of cleft. prenatal diagnosis enables appropriate and timely education and discussion with parents by the cleft team. this helps improve the quality of treatment received by the child and improves quality of life. an accurate prenatal diagnosis of the clp anomaly is critical for establishing long-term treatment planning, prediction of treatment outcome, and discussion and education of the parent. although there is no intrauterine treatment for clp, both mother and child benefit from early diagnosis and education. a multidisciplinary team approach is now accepted as the standard of care in dealing with clp patients. the time period immediately after the diagnosis and the first year after the birth is most challenging for parents. a systematically planned treatment plan and support system will help assist parents. the ultimate aim is to help educate parents and create awareness so as to improve care provided for the child. treatment cleft lip and palate is very treatable; however, the kind of treatment depends on the type and severity of the cleft. most children with a form of clefting are monitored by a cleft palate team or craniofacial team through young adulthood. care can be lifelong and are looked after by craniofacial cleft teams often consist of: cleft surgeons, orthodontists, speech and language therapists, restorative dentists, psychologists, ent surgeons and audio-logical physicians. treatment procedures can vary between craniofacial teams. for example, some teams wait on jaw correction until the child is aged 10 to 12 (argument: growth is less influential as deciduous teeth are replaced by permanent teeth, thus saving the child from repeated corrective surgeries), while other teams correct the jaw earlier (argument: less speech therapy is needed than at a later age when speech therapy becomes harder). within teams, treatment can differ between individual cases depending on the type and severity of the cleft. cleft lip within the first 2–3 months after birth, surgery is performed to close the cleft lip. while surgery to repair a cleft lip can be performed soon after birth, often the preferred age is at approximately 10 weeks of age, following the "rule of 10s" coined by surgeons wilhelmmesen and musgrave in 1969 (the child is at least 10 weeks of age; weighs at least 10 pounds, and has at least 10g hemoglobin). if the cleft is bilateral and extensive, two surgeries may be required to close the cleft, one side first, and the second side a few weeks later. the most common procedure to repair a cleft lip is the millard procedure pioneered by ralph millard. millard performed the first procedure at a mobile army surgical hospital (mash) unit in korea. often an incomplete cleft lip requires the same surgery as complete cleft. this is done for two reasons. firstly the group of muscles required to purse the lips run through the upper lip. to restore the complete group a full incision must be made. secondly, to create a less obvious scar the surgeon tries to line up the scar with the natural lines in the upper lip (such as the edges of the philtrum) and tuck away stitches as far up the nose as possible. incomplete cleft gives the surgeon more tissue to work with, creating a more supple and natural-looking upper lip. the blue lines indicate incisions. movement of the flaps; flap a is moved between b and c. c is rotated slightly while b is pushed down. pre-operation post-operation, the lip is swollen from surgery and will look more natural within weeks. see photos in the section above. pre-surgical devices in some cases of a severe bilateral complete cleft, the premaxillary segment will be protruded far outside the mouth. nasoalveolar molding prior to surgery can improve long-term nasal symmetry where there is complete unilateral cleft lip–cleft palate, compared to correction by surgery alone, according to a retrospective cohort study. in this study, significant improvements in nasal symmetry were observed in multiple areas including measurements of the projected length of the nasal ala (lateral surface of the external nose), position of the superoinferior alar groove, position of the mediolateral nasal dome, and nasal bridge deviation. "the nasal ala projection length demonstrated an average ratio of 93.0 percent in the surgery-alone group and 96.5 percent in the nasoalveolar molding group," this study concluded. a systematic review found in conclusion that nasoalveolar molding had a positive effect on the primary surgery of cleft lip/or palate treatment and aesthetics. cleft palate a repaired cleft palate on a 64-year-old female often a cleft palate is temporarily covered by a palatal obturator (a prosthetic device made to fit the roof of the mouth covering the gap). this device re-positions displaced alveolar segments and helps reduce the cleft lip separation. the obturator will improve speech as there's now proper airflow and improve feeding and breathing as the gap in the hard and soft palate is closed over so cannot affect it. cleft palate can also be corrected by surgery, usually performed between 6 and 12 months. approximately 20–25% only require one palatal surgery to achieve a competent velopharyngeal valve capable of producing normal, non-hypernasal speech. however, combinations of surgical methods and repeated surgeries are often necessary as the child grows. one of the new innovations of cleft lip and cleft palate repair is