Editing Cleft lip and cleft palate (section)

==Cause==
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 [[Teratology|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.<ref name=":6" />

The development of the face is coordinated by complex [[morphogenesis|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:

{{unbulleted list|style=margin-left:1em
|'''a)''' one from the top of the head down towards the future upper lip (frontonasal prominence);
|'''b-c)''' two from the cheeks, which meet the first lobe to form the upper lip (maxillar prominence);
|'''d-e)''' and just below, two additional lobes grow from each side, which form the chin and lower lip (mandibular prominence).}}
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 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.<ref name="Palatal fusion - where do the midli">{{cite journal | vauthors = Dudas M, Li WY, Kim J, Yang A, Kaartinen V | title = Palatal fusion - where do the midline cells go? A review on cleft palate, a major human birth defect | journal = Acta Histochemica | volume = 109 | issue = 1 | pages = 1–14 | year = 2007 | pmid = 16962647 | doi = 10.1016/j.acthis.2006.05.009 }}</ref> 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.<ref name="Palatal fusion - where do the midli"/>

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.<ref name = "Meeks_2018">{{cite book | vauthors = Meeks NJ, Saenz M, Tsai AC, Elias ER | chapter = Genetics & Dysmorphology |date=2018 |url=http://accessmedicine.mhmedical.com/content.aspx?aid=1153315258 | title = Current Diagnosis & Treatment: Pediatrics | veditors = Hay WW, Levin MJ, Deterding RR, Abzug MJ |edition=24th |publisher=McGraw-Hill Education |access-date=August 6, 2019}}</ref>

===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.<ref>{{cite journal | vauthors = Beaty TH, Ruczinski I, Murray JC, Marazita ML, Munger RG, Hetmanski JB, Murray T, Redett RJ, Fallin MD, Liang KY, Wu T, Patel PJ, Jin SC, Zhang TX, Schwender H, Wu-Chou YH, Chen PK, Chong SS, Cheah F, Yeow V, Ye X, Wang H, Huang S, Jabs EW, Shi B, Wilcox AJ, Lie RT, Jee SH, Christensen K, Doheny KF, Pugh EW, Ling H, Scott AF | title = Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate | journal = Genetic Epidemiology | volume = 35 | issue = 6 | pages = 469–478 | date = September 2011 | pmid = 21618603 | pmc = 3180858 | doi = 10.1002/gepi.20595 }}</ref> A number of genes are involved including [[cleft lip and palate transmembrane protein 1]] and [[GAD1]],<ref name="Kanno2004">{{cite journal | vauthors = Kanno K, Suzuki Y, Yamada A, Aoki Y, Kure S, Matsubara Y | title = Association between nonsyndromic cleft lip with or without cleft palate and the glutamic acid decarboxylase 67 gene in the Japanese population | journal = American Journal of Medical Genetics. Part A | volume = 127A | issue = 1 | pages = 11–16 | date = May 2004 | pmid = 15103710 | doi = 10.1002/ajmg.a.20649 | s2cid = 30016360 }}
</ref> One study found an association between mutations in the [[HYAL2]] gene and cleft lip and cleft palate formation.<ref>{{Cite news|url=http://www.medicalnewstoday.com/articles/315211.php|title=Scientists find genetic mutation that causes cleft lip and palate, heart defects| vauthors = Sandoiu A |date=January 17, 2017|newspaper=Medical News Today|language=en|access-date=January 31, 2017|url-status=live|archive-url=https://web.archive.org/web/20170129210707/http://www.medicalnewstoday.com/articles/315211.php|archive-date=January 29, 2017}}</ref>

====Syndromes====
* The [[Van der Woude syndrome]] is caused by a specific variation in the gene ''[[IRF6]]'' that increases the occurrence of these deformities threefold.<ref>{{cite journal | vauthors = Dixon MJ, Marazita ML, Beaty TH, Murray JC | title = Cleft lip and palate: understanding genetic and environmental influences | journal = Nature Reviews. Genetics | volume = 12 | issue = 3 | pages = 167–178 | date = March 2011 | pmid = 21331089 | pmc = 3086810 | doi = 10.1038/nrg2933 }}</ref><ref>{{cite journal | vauthors = Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC | title = Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate | journal = The New England Journal of Medicine | volume = 351 | issue = 8 | pages = 769–780 | date = August 2004 | pmid = 15317890 | doi = 10.1056/NEJMoa032909 | s2cid = 3324418 }}</ref><ref>{{cite news |url=http://news.bbc.co.uk/1/hi/health/3577784.stm |title=Cleft palate genetic clue found |access-date=July 1, 2007 |work=BBC News |date=August 30, 2004 |url-status=live |archive-url=https://web.archive.org/web/20070208233204/http://news.bbc.co.uk/1/hi/health/3577784.stm |archive-date=February 8, 2007 }}</ref> Mutations in interferon regulatory factor 6 (IRF6) that cause cleft lip palate are also implicated in neural tube defects such as spina bifida.<ref>{{cite journal | vauthors = Kousa YA, Zhu H, Fakhouri WD, Lei Y, Kinoshita A, Roushangar RR, Patel NK, Agopian AJ, Yang W, Leslie EJ, Busch TD, Mansour TA, Li X, Smith AL, Li EB, Sharma DB, Williams TJ, Chai Y, Amendt BA, Liao EC, Mitchell LE, Bassuk AG, Gregory S, Ashley-Koch A, Shaw GM, Finnell RH, Schutte BC | title = The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation | journal = Human Molecular Genetics | volume = 28 | issue = 10 | pages = 1726–1737 | date = May 2019 | pmid = 30689861 | pmc = 6494790 | doi = 10.1093/hmg/ddz010 }}</ref>
* Another syndrome, Siderius [[X-linked intellectual disability]], is caused by mutations in the ''[[PHF8]]'' gene ({{OMIM|300263||shortlink}}); in addition to cleft lip or palate, symptoms include facial dysmorphism and mild intellectual disability.<ref>{{cite journal | vauthors = Siderius LE, Hamel BC, van Bokhoven H, de Jager F, van den Helm B, Kremer H, Heineman-de Boer JA, Ropers HH, Mariman EC | title = X-linked mental retardation associated with cleft lip/palate maps to Xp11.3-q21.3 | journal = American Journal of Medical Genetics | volume = 85 | issue = 3 | pages = 216–220 | date = July 1999 | pmid = 10398231 | doi = 10.1002/(SICI)1096-8628(19990730)85:3<216::AID-AJMG6>3.0.CO;2-X | doi-access = free }}</ref>

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]].<ref>{{cite journal | vauthors = Kronwith SD, Quinn G, McDonald DM, Cardonick E, Onyx P, LaRossa D, Borns P, Stambolian DE, Zackai EH | title = Stickler's syndrome in the Cleft Palate Clinic | journal = Journal of Pediatric Ophthalmology and Strabismus | volume = 27 | issue = 5 | pages = 265–267 | year = 1990 | pmid = 2246742 | doi = 10.3928/0191-3913-19900901-12 }}</ref><ref>{{cite journal | vauthors = Mrugacz M, Sredzińska-Kita D, Bakunowicz-Lazarczyk A, Piszcz M | title = [High myopia as a pathognomonic sign in Stickler's syndrome] | language = pl | journal = Klinika Oczna | volume = 107 | issue = 4-6 | pages = 369–371 | year = 2005 | pmid = 16118961 }}</ref>
* [[Loeys–Dietz syndrome]] can cause cleft palate or [[bifid uvula]], [[hypertelorism]], and [[aortic aneurysm]].<ref>{{cite journal | vauthors = Sousa SB, Lambot-Juhan K, Rio M, Baujat G, Topouchian V, Hanna N, Le Merrer M, Brunelle F, Munnich A, Boileau C, Cormier-Daire V | title = Expanding the skeletal phenotype of Loeys-Dietz syndrome | journal = American Journal of Medical Genetics. Part A | volume = 155A | issue = 5 | pages = 1178–1183 | date = May 2011 | pmid = 21484991 | doi = 10.1002/ajmg.a.33813 | s2cid = 27999412 }}</ref>
* [[Hardikar syndrome]] can cause cleft lip and palate, [[Hydronephrosis]], [[Intestinal obstruction]] and other symptoms.<ref>[http://www.wrongdiagnosis.com/h/hardikar_syndrome/symptoms.htm#symptom_list Hardikar syndrome symptoms]</ref>
* 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 sequence|Pierre Robin syndrome]]<ref>{{Citation| vauthors = Wall J, Albanese CT |title=Pediatric Surgery|date=2015|url=http://accessmedicine.mhmedical.com/content.aspx?aid=1105497830|work=CURRENT Diagnosis & Treatment: Surgery| veditors = Doherty GM |edition=14th|publisher=McGraw-Hill Education|access-date=August 6, 2019}}</ref><ref name = "Meeks_2018" />

====Specific genes====
{| class="wikitable" style = "float: right; margin-left:15px; text-align:center"
|-
! Type
! [[OMIM]]
! Gene
! Locus
|-
| OFC1
| {{OMIM|119530||none}}
| ?
| 6p24
|-
| OFC2
| {{OMIM|602966||none}}
| ?
| 2p13
|-
| OFC3
| {{OMIM|600757||none}}
| ?
| 19q13
|-
| OFC4
| {{OMIM|608371||none}}
| ?
| 4q
|-
| OFC5
| {{OMIM|608874||none}}
| ''[[MSX1]]''
| 4p16.1
|-
| OFC6
| {{OMIM|608864||none}}
| ?
| 1q
|-
| OFC7
| {{OMIM|600644)||none}}
| ''[[PVRL1]]''
| 11q
|-
| OFC8
| {{OMIM|129400||none}}
| ''[[TP63]]''
| 3q27
|-
| OFC9
| {{OMIM|610361||none}}
| ?
| 13q33.1-q34
|-
| OFC10
| {{OMIM|601912||none}}
| ''[[SUMO1]]''
| 2q32.2-q33
|-
| OFC11
| {{OMIM|600625||none}}
| ''[[BMP4]]''
| 14q22
|-
| OFC12
| {{OMIM|612858||none}}
| ?
| 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]]''.<ref name="pmid14756664">{{cite journal | vauthors = Cox TC | title = Taking it to the max: the genetic and developmental mechanisms coordinating midfacial morphogenesis and dysmorphology | journal = Clinical Genetics | volume = 65 | issue = 3 | pages = 163–176 | date = March 2004 | pmid = 14756664 | doi = 10.1111/j.0009-9163.2004.00225.x | s2cid = 22472334 }}</ref> 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]]''.<ref name="pmid14756664" />

===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,<ref name= "PMID19843542">{{cite journal | vauthors = Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CD, Klose RJ, Ratcliffe PJ, Schofield CJ | title = PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase | journal = Human Molecular Genetics | volume = 19 | issue = 2 | pages = 217–222 | date = January 2010 | pmid = 19843542 | pmc = 4673897 | doi = 10.1093/hmg/ddp480 | author-link8 = Christopher J. Schofield }}</ref> and is involved in [[epigenetic regulation]]. The catalytic activity of ''PHF8'' depends on molecular [[oxygen]],<ref name= "PMID19843542" /> a factor considered important from reports on increased incidence of cleft lip/palate in mice that have been exposed to [[Hypoxia (medical)|hypoxia]] early during pregnancy.<ref>{{cite journal | vauthors = Millicovsky G, Johnston MC | title = Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL/Fr mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 9 | pages = 5722–5723 | date = September 1981 | pmid = 6946511 | pmc = 348841 | doi = 10.1073/pnas.78.9.5722 | doi-access = free | bibcode = 1981PNAS...78.5722M }}</ref>

Cleft lip and other [[congenital abnormalities]] have also been linked to maternal hypoxia caused by [[Smoking and pregnancy|maternal smoking]],<ref>{{cite journal | vauthors = Shi M, Wehby GL, Murray JC | title = Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects | journal = Birth Defects Research. Part C, Embryo Today | volume = 84 | issue = 1 | pages = 16–29 | date = March 2008 | pmid = 18383123 | pmc = 2570345 | doi = 10.1002/bdrc.20117 }}</ref> 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.<ref>{{cite journal | vauthors = Honein MA, Devine O, Grosse SD, Reefhuis J | title = Prevention of orofacial clefts caused by smoking: implications of the Surgeon General's report | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 100 | issue = 11 | pages = 822–825 | date = November 2014 | pmid = 25045059 | pmc = 4559232 | doi = 10.1002/bdra.23274 }}</ref>

Maternal [[Alcohol use disorder|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.<ref>{{cite journal | vauthors = Bell JC, Raynes-Greenow C, Turner RM, Bower C, Nassar N, O'Leary CM | title = Maternal alcohol consumption during pregnancy and the risk of orofacial clefts in infants: a systematic review and meta-analysis | journal = Paediatric and Perinatal Epidemiology | volume = 28 | issue = 4 | pages = 322–332 | date = July 2014 | pmid = 24800624 | doi = 10.1111/ppe.12131 }}</ref> Some forms of maternal [[hypertension]] treatment have been linked to cleft lip and palate.<ref name="pmid8574428">{{cite journal | vauthors = Hurst JA, Houlston RS, Roberts A, Gould SJ, Tingey WG | title = Transverse limb deficiency, facial clefting and hypoxic renal damage: an association with treatment of maternal hypertension? | journal = Clinical Dysmorphology | volume = 4 | issue = 4 | pages = 359–363 | date = October 1995 | pmid = 8574428 | doi = 10.1097/00019605-199510000-00013 | s2cid = 6330050 }}</ref> Other environmental factors that have been studied include seasonal causes (such as pesticide exposure); maternal diet and vitamin intake; [[retinoid]]s (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.<ref>{{cite journal | vauthors = Boyles AL, Wilcox AJ, Taylor JA, Meyer K, Fredriksen A, Ueland PM, Drevon CA, Vollset SE, Lie RT | title = Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts | journal = American Journal of Medical Genetics. Part A | volume = 146A | issue = 4 | pages = 440–449 | date = February 2008 | pmid = 18203168 | pmc = 2366099 | doi = 10.1002/ajmg.a.32162 }}</ref> 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.<ref>{{cite journal | vauthors = De-Regil LM, Peña-Rosas JP, Fernández-Gaxiola AC, Rayco-Solon P | title = Effects and safety of periconceptional oral folate supplementation for preventing birth defects | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 12 | pages = CD007950 | date = December 2015 | pmid = 26662928 | pmc = 8783750 | doi = 10.1002/14651858.CD007950.pub3 }}</ref> 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.<ref>{{cite journal | vauthors = Wehby GL, Goco N, Moretti-Ferreira D, Felix T, Richieri-Costa A, Padovani C, Queiros F, Guimaraes CV, Pereira R, Litavecz S, Hartwell T, Chakraborty H, Javois L, Murray JC | title = Oral cleft prevention program (OCPP) | journal = BMC Pediatrics | volume = 12 | issue = 1 | pages = 184 | date = November 2012 | pmid = 23181832 | pmc = 3532199 | doi = 10.1186/1471-2431-12-184 | doi-access = free }}</ref>