Rozszczep wargi i podniebienia – Patofizjologia i mechanizm

Rozszczep wargi i podniebienia
Patofizjologia i mechanizm

Rozszczep wargi i podniebienia jest jedną z najczęstszych wad wrodzonych twarzoczaszki, o złożonej etiologii wieloczynnikowej, obejmującej zarówno czynniki genetyczne, jak i środowiskowe. Embriologicznie, wada wynika z nieprawidłowej fuzji wyrostków twarzowych i płytek podniebiennych w okresie 4-8 tygodnia ciąży, co prowadzi do utrzymania otwartej przestrzeni między nimi. Kluczowe szlaki molekularne zaangażowane w patogenezę to m.in. TGF-β, BMP, Sonic Hedgehog (SHH), WNT oraz czynniki transkrypcyjne takie jak Msx1, IRF6 i TBX1. Utrata funkcji receptorów, np. TgfR3, czy zaburzenia w splicingu tRNA (np. gen DDX1) wpływają na proliferację, migrację i różnicowanie komórek, co skutkuje rozszczepem. Czynniki ryzyka środowiskowe to m.in. palenie tytoniu, cukrzyca, niedobory kwasu foliowego (witamin B6 i B12), ekspozycja na teratogeny oraz alkohol w ciąży. Suplementacja kwasu foliowego przed ciążą wykazuje działanie ochronne.

Patogeneza rozszczepu wargi i podniebienia

Rozwój embriologiczny a powstawanie rozszczepu
Mechanizmy molekularne rozszczepu
Nowe odkrycia dotyczące mechanizmów molekularnych
Interakcje genetyczno-środowiskowe
Konsekwencje i znaczenie kliniczne

Podsumowanie mechanizmów patogenetycznych

Kolejne rozdziały

Patogeneza rozszczepu wargi i podniebienia

Rozszczep wargi i podniebienia (ang. cleft lip and palate) należy do najczęstszych wad wrodzonych twarzoczaszki. Etiologia tej deformacji jest złożona i wieloczynnikowa, obejmująca zarówno czynniki genetyczne, jak i środowiskowe. Wada ta może występować jako część zespołów chromosomalnych, jednogenowych zaburzeń mendlowskich, jako skutek działania czynników teratogennych lub w ramach jeszcze niescharakteryzowanych zespołów.¹ Zrozumienie molekularnych mechanizmów powstawania rozszczepu jest kluczowe dla skutecznego leczenia i profilaktyki.

Rozwój embriologiczny a powstawanie rozszczepu

Rozwój embriologiczny twarzy i podniebienia jest niezwykle złożonym procesem obejmującym migrację komórek, różnicowanie komórkowe oraz apoptozę. Pierwotne struktury twarzowe pochodzą z komórek grzebienia nerwowego we wczesnej embriogenezie. Ulegają one transformacji do komórek nabłonkowo-mezenchymalnych i migrują do obszaru przyszłej twarzoczaszki, gdzie łączą się z komórkami ektodermy i mezodermy, tworząc łuki skrzelowe i wyrostki twarzowe.¹

Proces ten rozpoczyna się w 4. tygodniu ciąży, gdy pięć wyrostków twarzowych otacza rozwijającą się jamę ustną. Niepowodzenie, zakłócenie lub przerwanie któregokolwiek z punktów fuzji może spowodować rozszczep.² Embriologicznie wyjaśnia to, dlaczego rozszczep wargi wynikający z braku połączenia wyrostka nosowego i szczękowego często współwystępuje z rozszczepem podniebienia pierwotnego.³

W przypadku rozwoju podniebienia wtórnego, proces rozpoczyna się od początkowych wypustek wyrostków szczękowych, czyli płytek podniebiennych. Struktury te są początkowo zorientowane pionowo, za podniebieniem pierwotnym i bocznie od rozwijającego się języka. W 8. tygodniu ciąży płytki te zaczynają układać się poziomo i zbliżać się do linii środkowej, zaczynając od przodu, tuż za podniebieniem pierwotnym, a fuzja w linii środkowej postępuje do tyłu w sposób „zamka błyskawicznego”. Niepowodzenie fuzji w linii środkowej prowadzi do rozszczepu podniebienia.⁴⁵

Mechanizmy molekularne rozszczepu

Istnieje znaczna heterogeniczność w szlakach molekularnych związanych z rozwojem rozszczepu wargi i podniebienia. Ponad 300 genów zostało powiązanych z fuzją podniebienia u ludzi i w modelach zwierzęcych.⁶ Najczęściej badane szlaki molekularne obejmują te związane z zewnątrzkomórkowymi czynnikami sygnałowymi, czynnikami transkrypcyjnymi i cząsteczkami adhezji komórkowej.

Szlaki związane z formowaniem wargi i podniebienia obejmują:⁷

Szlak Sonic hedgehog (geny SHH i SPRY2)
Szlak morfogenetycznych białek kości (geny BMP4 i BMP2)
Szlaki czynników wzrostu fibroblastów (geny FGF10 i FGF7)
Receptory i ligandy transformującego czynnika wzrostu beta (TGF-β)

⁸⁹¹⁰

Szlak TGF-beta i BMP

Nadrodzina transformującego czynnika wzrostu (TGF) obejmuje rodzinę TGF-beta, a także inne rodziny, w tym białka morfogenetyczne kości (BMP), czynniki wzrostu i różnicowania (GDF), aktywiny (ACT) i inhibiny (INH). Receptor TgfR3 wiąże wszystkie trzy ligandy Tgf, a także BMP2. Utrata TgfR3 powoduje zatrzymanie uniesienia i wydłużenia płytki podniebiennej oraz zakłóca ekspresję szlaków sygnałowych zarówno TGF, jak i BMP w obrębie płytek podniebiennych.¹¹

W morfogenezie twarzy, sygnalizacja TGF-β jest niezbędna do fuzji podniebienia poprzez interakcję z innymi szlakami sygnałowymi, takimi jak WNT, FGF i BMP. Szlak sygnalizacyjny BMP (białko morfogenetyczne kości) reguluje proliferację komórek, różnicowanie komórek i apoptozę, które są krytycznymi etapami morfogenezy twarzy. Dysregulacja tych procesów prowadzi do rozszczepu wargi lub podniebienia.¹²

Szlak Sonic Hedgehog

Gen Sonic hedgehog (Shh) należy do rodziny genów Hedgehog, które kodują białka ważne dla interakcji komórka-komórka i jest wymagany do rozwoju podniebienia i wyrostka czołowo-nosowego. Nabłonkowo ekspresjonowany Shh bezpośrednio sygnalizuje do mezenchymy, aby regulować rozrost podniebienia, a sygnalizacja Shh reguluje ekspresję Bmp2, Bmp4, Msx1 i Fgf10 w sąsiedniej mezenchymie podniebiennej.¹³

Szlak WNT

Badania sugerują, że szlak sygnalizacyjny WNT obejmuje kanoniczne i niekanoniczne tryby sygnalizacji i odgrywa kluczową rolę w morfogenezie twarzy, regulując kluczowe procesy rozwoju wargi i podniebienia, takie jak proliferacja komórek, migracja i różnicowanie, a także wchodzi w interakcje z innymi szlakami. Zakłócenie tego szlaku zaburza normalne ścieżki rozwojowe, prowadząc do rozwoju rozszczepu wargi i/lub podniebienia zarówno typu zespołowego, jak i niezespolowego.¹⁴

Inne czynniki transkrypcyjne i regulacyjne

Gen homeobox Msx1 jest również ekspresjonowany w zawiązkach twarzy i jest wymagany do ekspresji Bmp2 i Bmp4 w mezenchymie podniebiennej oraz Shh w nabłonku krawędzi przyśrodkowej.¹⁵

Czynnik regulacyjny interferonu 6 (IRF6) należy do rodziny dziewięciu czynników transkrypcyjnych, które wiążą się z określonymi sekwencjami DNA i regulują ekspresję genów.¹⁶ Zaburzenia funkcji IRF6 mogą prowadzić do nieprawidłowości w formowaniu podniebienia.

Płytkopochodny czynnik wzrostu (PDGF) i jego receptory PDGFR i PDGFR okazały się kluczowe dla proliferacji komórek, przeżycia i migracji.¹⁷

Czynnik transkrypcyjny Tbox (TBX1) jest mediatorem nieprawidłowości rozwojowych i wykazano, że jest niezbędny do normalnego wydłużania i unoszenia podniebienia.¹⁸

Naczyniowy śródbłonkowy czynnik wzrostu A, czynnik wzrostu zaangażowany w angiogenezę i kostnienie, również okazał się niezbędny dla rozwoju podniebienia.¹⁹

Nowe odkrycia dotyczące mechanizmów molekularnych

Najnowsze badania biologów z MIT ujawniły, jak wariant genetyczny często występujący u osób z wadami twarzowymi prowadzi do rozwoju rozszczepu wargi i podniebienia. Ich odkrycia sugerują, że wariant zmniejsza dostępność komórek do tRNA (transferowego RNA), cząsteczki, która jest krytyczna dla składania białek. Kiedy to się dzieje, embrionalne komórki twarzy nie są w stanie połączyć się, aby utworzyć wargę i podniebienie.²⁰

Gen DDX1 okazał się niezbędny do splicingu cząsteczek tRNA, które odgrywają kluczową rolę w syntezie białek. Chociaż w ludzkim genomie występuje około 400 różnych tRNA, tylko część z nich wymaga splicingu, i to właśnie te tRNA są najbardziej dotknięte utratą DDX1.²¹²²

Badacze mają nadzieję zbadać, czy czynniki środowiskowe związane z wadami twarzowymi wpływają również na funkcję tRNA. Niektóre z ich wstępnych prac wykazały, że stres oksydacyjny – nagromadzenie szkodliwych wolnych rodników – może prowadzić do fragmentacji cząsteczek tRNA.²³

Interakcje genetyczno-środowiskowe

Większość rozszczepów twarzoczaszki, podobnie jak większość powszechnych wad wrodzonych, jest spowodowana interakcją między czynnikami genetycznymi i środowiskowymi. W tych przypadkach czynniki genetyczne tworzą podatność na rozszczepy. Kiedy czynniki środowiskowe (tzw. wyzwalacze) wchodzą w interakcję z genetycznie podatnym genotypem, rozszczep rozwija się na wczesnym etapie rozwoju.²⁴

Rozszczep rozwija się, gdy embrionalne części zwane wyrostkami (które są zaprogramowane do wzrostu, ruchu i łączenia się ze sobą w celu utworzenia poszczególnych części embrionu) nie docierają do siebie na czas i otwarta przestrzeń (rozszczep) między nimi utrzymuje się. W normalnej sytuacji wyrostki wrastają w otwartą przestrzeń poprzez migrację komórkową i namnażanie, dotykają się nawzajem i łączą się razem.²⁵

Ogólnie rzecz biorąc, każdy czynnik, który mógłby uniemożliwić wyrostkom dotarcie do siebie – na przykład poprzez spowolnienie migracji lub namnażania komórek grzebienia nerwowego, zatrzymanie wzrostu i rozwoju tkanek na pewien czas lub zabicie niektórych komórek, które już znajdują się w tym miejscu – spowodowałby utrzymanie rozszczepu. Ponadto nabłonek pokrywający mezenchymę może nie ulegać zaprogramowanej śmierci komórkowej, dzięki czemu nie może dojść do fuzji wyrostków.²⁶

Czynniki środowiskowe

Czynniki ryzyka, które zwiększają prawdopodobieństwo wystąpienia rozszczepu wargi i podniebienia, obejmują:²⁷

Palenie tytoniu w czasie ciąży
Cukrzyca przed ciążą (typ 1 lub 2)
Stosowanie niektórych leków przeciwpadaczkowych w czasie ciąży
Niedobory żywieniowe, szczególnie kwasu foliowego i witamin B6 i B12
Narażenie na chemikalia w czasie ciąży
Konsumpcja alkoholu w czasie ciąży

²⁸

Badania epidemiologiczne i raporty obserwacyjne wykazały, że suplementy kwasu foliowego przyjmowane przez matkę przed ciążą mają działanie ochronne w zmniejszaniu częstości występowania rozszczepu wargi i podniebienia, podczas gdy palenie i spożywanie alkoholu przed ciążą zwiększają ryzyko powstawania rozszczepu.²⁹

Epigenetyka w rozszczepieniu wargi i podniebienia

Czynniki środowiskowe mogą wchodzić w interakcje z genami na różne sposoby, powodując ich „włączanie lub wyłączanie” w miarę rozwoju dziecka w łonie matki.³⁰ Ten proces nazywany jest „epigenetyką”.

Ze względu na stosunkowo niewielki sukces w identyfikacji przyczynowych czynników genetycznych zaangażowanych w rozszczep, mimo licznych przeprowadzonych badań asocjacyjnych, niedawno zwrócono uwagę na rolę programowania epigenetycznego, czyli modyfikacji, które nie obejmują sekwencjonowania DNA. Metylacja DNA odgrywa centralną rolę w regulowaniu tego procesu i może w przyszłości służyć jako ocena ryzyka i cele terapeutyczne dla pacjentów z rozszczepem.³¹

Istnieje obecnie rosnące zrozumienie krytycznej roli epigenetyki w rozwoju twarzoczaszki i sposobu, w jaki czynniki środowiskowe wchodzą w interakcję z podatnością genetyczną. Regulatory epigenetyczne (np. mikroRNA [miRNA]) odgrywają kluczową rolę w ontogenezie regionu twarzowo-ustnego.³²

Konsekwencje i znaczenie kliniczne

Rozszczep podniebienia tworzy trwałą komunikację między jamą ustną a nosową, co ma szkodliwy wpływ na mowę, połykanie i oddychanie, szczególnie u noworodków. Rozszczep podniebienia prowadzi do niepożądanego wycieku powietrza podczas mowy, uniemożliwiając prawidłowe tworzenie dźwięków zwartych i prowadząc do mowy hiponazalnej. Jeśli nie zostanie naprawiony, może prowadzić do dożywotnich błędów w rozwoju mowy, które mogą być trudne do przezwyciężenia za pomocą terapii mowy.³³

Zrozumienie molekularnych mechanizmów powstawania rozszczepu pomoże klinicystom przewidzieć, którzy pacjenci mogą mieć trudności z gojeniem, na przykład ci z mutacjami w Irf6, BMP4 lub rodzinie TGF, a w przyszłości, miejmy nadzieję, podejmować decyzje dotyczące leczenia chirurgicznego i medycznego w oparciu o informacje genetyczne.³⁴

Złożoność patogenezy rozszczepu wargi i podniebienia wymaga multidyscyplinarnego podejścia do leczenia. Zespół zajmujący się rozszczepem może obejmować chirurga plastycznego, chirurga szczękowego, ortodontę, otolaryngologa, okulistę, pracownika socjalnego, pielęgniarkę, audiologa, logopedę i genetyka.³⁵ Wczesna prosta naprawa chirurgiczna maksymalizuje optymalną mowę, pomaga w karmieniu, pomaga w zmniejszeniu infekcji ucha środkowego i przywraca normalne oddzielenie jamy ustnej i nosowej, minimalizując jednocześnie zaburzenia wzrostu szczęki górnej.³⁶

Podsumowanie mechanizmów patogenetycznych

Patogeneza rozszczepu wargi i podniebienia jest złożonym procesem obejmującym interakcje między czynnikami genetycznymi, epigenetycznymi i środowiskowymi. Kluczowe aspekty tego procesu obejmują:

Nieprawidłową fuzję wyrostków twarzowych podczas embriogenezy
Zaburzenia w szlakach sygnalizacyjnych (TGF-β, BMP, Sonic Hedgehog, WNT)
Dysregulację czynników transkrypcyjnych (Msx1, IRF6, TBX1)
Zaburzenia w funkcji tRNA i syntezie białek
Interakcje genetyczno-środowiskowe wpływające na ekspresję genów
Wpływ epigenetyki na rozwój twarzoczaszki

³⁷³⁸³⁹

Identyfikacja czynników przyczyniających się do etiologii rozszczepu wargi i podniebienia jest ważna dla zapobiegania ich rozwojowi i podejmowania niezbędnych środków.⁴⁰ Badania molekularne przyczynią się do wyjaśnienia funkcjonowania szlaków sygnałowych zaangażowanych w rozwój wargi i podniebienia, a tym samym do lepszego zrozumienia patogenezy rozszczepu.⁴¹

Lepsze zrozumienie embriologii i genetyki rozszczepienia twarzoczaszki ma kluczowe znaczenie dla opracowania biologicznie istotnego systemu klasyfikacji rozszczepów twarzoczaszki.⁴² Niedawna identyfikacja określonych genów zaangażowanych w rozszczepianie twarzoczaszki zespołowe i niezespołowe pokazuje korelację między obydwoma stanami z nakładającą się podstawą genetyczną.⁴³

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Materiały źródłowe

#1 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
Cleft lip and palate are common craniofacial deformities. The etiology underlying these deformities is complex and multifactorial and they can occur as part of one of many chromosomal syndromes, Mendelian single gene disorders, teratogenic effects, and as yet uncharacterized syndromes. […] The etiology of CLP is multifactorial and complex and includes both genetic and environmental factors. […] More than 300 genes have been implicated in palatal fusion in human and experimental animal models. Single gene mutations can lead to clefting. […] However, the etiology of clefting is still poorly known with multiple molecular pathways associated with cleft lip and palate. […] The most commonly studied molecular pathways include those involved with extracellular signaling factors, transcription factors, and cell adhesion molecules.
#1 Cleft Palate – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK563128/
Cleft palate arises from abnormal development of the palate or surrounding structures during gestation. Embryologic development of the palate is an extraordinarily complex sequence of events involving cell migration, cell differentiation, and apoptosis. The primordial facial structures originate from neural crest cells very early in embryogenesis. These then undergo a transformation to epithelial-mesenchymal cells and migrate to the proto-craniofacial area, where they are joined by ectodermal and mesoderm cells, combining to form the branchial arches and the facial processes. This process begins in gestational week 4, wherein the following 5 facial prominences surround the developing mouth and oral cavity: […] Failure, disruption, or interruption of any of these fusion points can result in clefting. This embryologically explains why a cleft lip resulting from the failure of fusion of the nasal and maxillary processes is also commonly associated with a cleft of the primary palate, as these structures are formed by the same stage in embryological development. A failure of other embryological fusion events can result in various atypical facial clefts. For example, the failure of lateral fusion of the maxillary and mandibular processes yields the Tessier 7 cleft. Gestational weeks 4 through 6 are crucial for craniofacial development, and teratogenic events during these weeks are more likely to result in cleft facial abnormalities.
#2 Cleft Palate – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK563128/
Cleft palate arises from abnormal development of the palate or surrounding structures during gestation. Embryologic development of the palate is an extraordinarily complex sequence of events involving cell migration, cell differentiation, and apoptosis. The primordial facial structures originate from neural crest cells very early in embryogenesis. These then undergo a transformation to epithelial-mesenchymal cells and migrate to the proto-craniofacial area, where they are joined by ectodermal and mesoderm cells, combining to form the branchial arches and the facial processes. This process begins in gestational week 4, wherein the following 5 facial prominences surround the developing mouth and oral cavity: […] Failure, disruption, or interruption of any of these fusion points can result in clefting. This embryologically explains why a cleft lip resulting from the failure of fusion of the nasal and maxillary processes is also commonly associated with a cleft of the primary palate, as these structures are formed by the same stage in embryological development. A failure of other embryological fusion events can result in various atypical facial clefts. For example, the failure of lateral fusion of the maxillary and mandibular processes yields the Tessier 7 cleft. Gestational weeks 4 through 6 are crucial for craniofacial development, and teratogenic events during these weeks are more likely to result in cleft facial abnormalities.
#3 Cleft lip and cleft palate – Wikipedia
https://en.wikipedia.org/wiki/Cleft_lip_and_cleft_palate
Cleft lip and palate are the result of tissues of the face not joining properly during development. As such, they are a type of birth defect. The cause is unknown in most cases. Risk factors include smoking during pregnancy, diabetes, obesity, an older mother, and certain medications (such as some used to treat seizures). […] 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 lip or palate fissure up to a completely malformed face).
#4 Cleft Palate – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK563128/
The secondary palate forms from initial outgrowths of the maxillary processes, the palatal shelves. These structures are initially oriented vertically, posterior to the primary palate, and lateral to the developing tongue. These shelves begin to orient themselves horizontally in gestational week 8 and progress towards midline fusion, beginning anteriorly, immediately behind the primary palate, with midline fusion progressing posteriorly in a „zipper” fashion. As the palatal shelves extend toward one another in the midline, the medial edge epithelium makes a point of contact. These then fuse into a midline epithelial seam, subsequently degenerating into mesenchymal tissue, establishing mesenchymal continuity of the full palate. Failure of midline fusion results in cleft palate. […] Significant heterogeneity exists in the molecular pathways associated with the development of CL/P and CPO. The pathways associated with the formation of the lip and palate include the sonic hedgehog pathway (SHH and SPRY2 genes), which interacts closely with the bone morphogenic pathway (BMP4 and BMP2 genes), fibroblast growth factor pathways (FGF10 and FGF7 genes), and transforming growth factor-beta (TGF) receptors and ligands. Disruption of these pathways at various stages results in varying severity, laterality, and location of clefts.
#5 Pediatric Cleft Lip and Palate: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/995535-overview
In facial morphogenesis, neural crest cells migrate into the facial region, where they form the skeletal and connective tissue and all dental tissues except the enamel. Vascular endothelium and muscle are of mesodermal origin. The upper lip is derived from medial nasal and maxillary processes. Failure of merging between the medial nasal and maxillary processes at 5 weeks’ gestation, on one or both sides, results in CL. CL usually occurs at the junction between the central and lateral parts of the upper lip on either side. The cleft may affect only the upper lip, or it may extend more deeply into the maxilla and the primary palate. (Cleft of the primary palate includes CL and cleft of the alveolus.) If the fusion of palatal shelves is impaired also, the CL is accompanied by CP, forming the CLP anomaly.
#6 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
Cleft lip and palate are common craniofacial deformities. The etiology underlying these deformities is complex and multifactorial and they can occur as part of one of many chromosomal syndromes, Mendelian single gene disorders, teratogenic effects, and as yet uncharacterized syndromes. […] The etiology of CLP is multifactorial and complex and includes both genetic and environmental factors. […] More than 300 genes have been implicated in palatal fusion in human and experimental animal models. Single gene mutations can lead to clefting. […] However, the etiology of clefting is still poorly known with multiple molecular pathways associated with cleft lip and palate. […] The most commonly studied molecular pathways include those involved with extracellular signaling factors, transcription factors, and cell adhesion molecules.
#7 Cleft Palate – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK563128/
The secondary palate forms from initial outgrowths of the maxillary processes, the palatal shelves. These structures are initially oriented vertically, posterior to the primary palate, and lateral to the developing tongue. These shelves begin to orient themselves horizontally in gestational week 8 and progress towards midline fusion, beginning anteriorly, immediately behind the primary palate, with midline fusion progressing posteriorly in a „zipper” fashion. As the palatal shelves extend toward one another in the midline, the medial edge epithelium makes a point of contact. These then fuse into a midline epithelial seam, subsequently degenerating into mesenchymal tissue, establishing mesenchymal continuity of the full palate. Failure of midline fusion results in cleft palate. […] Significant heterogeneity exists in the molecular pathways associated with the development of CL/P and CPO. The pathways associated with the formation of the lip and palate include the sonic hedgehog pathway (SHH and SPRY2 genes), which interacts closely with the bone morphogenic pathway (BMP4 and BMP2 genes), fibroblast growth factor pathways (FGF10 and FGF7 genes), and transforming growth factor-beta (TGF) receptors and ligands. Disruption of these pathways at various stages results in varying severity, laterality, and location of clefts.
#8 Orofacial Clefts: Genetics of Cleft Lip and Palate
https://www.mdpi.com/2073-4425/14/8/1603
Facial development is a complex process that includes the development of the mouth, lips, palate and nose, and it takes place between the fourth and the twelfth week of embryonic development. […] A series of cellular growth and differentiation, migration and apoptosis takes place in a highly coordinated manner, and defects in this sequence of events could result in the development of cleft lip, cleft palate or both, and, although cleft lip and palate occur together, their embryonic origin is different. […] The exact molecular pathway that results in cleft lip and palate remains a target for multiple molecular studies. […] Signaling molecules involving multiple signaling pathways such as WNT, TGF/BMP and FGF and morphogens have been studied for their involvement in the pathogenesis of cleft lip, and cleft lip and palate.
#9 Orofacial Clefts: Genetics of Cleft Lip and Palate
https://www.mdpi.com/2073-4425/14/8/1603
Studies have suggested that the WNT signaling pathway includes canonical and noncanonical modes of signaling and plays a key role in facial morphogenesis by regulating crucial and critical processes for lip and palate development, such as cell proliferation, migration and differentiation, and also cross-interact with other pathways. […] Disruption in this pathway dysregulates the normal developmental pathways leading to cleft lip and/or cleft palate development of both the syndromic and nonsyndromic type. […] Pathogenic variants in the genes involved in the WNT pathway such as the Wnt3A gene were found to be associated with nonsyndromic cleft lip/or palate and could also affect the development and morphogenesis of the neural crest, leading to the development of orofacial clefts. […] The TGF-Î² (Transforming Growth Factor-Î²) signaling pathway plays a crucial role in various biological and cellular processes regulating cell growth, immune responses, embryonic development and other processes.
#10 Orofacial Clefts: Genetics of Cleft Lip and Palate
https://www.mdpi.com/2073-4425/14/8/1603
In facial morphogenesis, TGF-Î² signaling is essential for palatal fusion through its interaction with other signaling pathways such as WNT, FGF and BMP. […] The BMP (Bone Morphogenetic Protein) signaling pathway regulates cell proliferation, cell differentiation and apoptosis, which are critical steps for facial morphogenesis. […] Dysregulation in these processes results in cleft lip or cleft palate.
#11 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
The Transforming Growth Factor (TGF) superfamily is comprised of the transforming growth factor beta family, as well as other families, including bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins (ACTs), and inhibins (INHs). […] TgfR3 binds all three Tgf ligands as well as BMP2. The loss of TgfR3 results in arrested palatal shelf elevation and elongation and interfered and also led to atypical expression of both TGF and BMP signaling pathways within the palatal shelves. […] The Sonic hedgehog (Shh) gene is part of the Hedgehog gene family, which encode proteins important for cell-cell interaction and has is required for palate and frontonasal development. […] Epithelially expressed Shh has been shown to directly signal to the mesenchyme to regular palate outgrowth, with Shh signaling regulating Bmp2, Bmp4, Msx1, and Fgf10 expression in adjacent palatal mesenchyme.
#12 Orofacial Clefts: Genetics of Cleft Lip and Palate
https://www.mdpi.com/2073-4425/14/8/1603
In facial morphogenesis, TGF-Î² signaling is essential for palatal fusion through its interaction with other signaling pathways such as WNT, FGF and BMP. […] The BMP (Bone Morphogenetic Protein) signaling pathway regulates cell proliferation, cell differentiation and apoptosis, which are critical steps for facial morphogenesis. […] Dysregulation in these processes results in cleft lip or cleft palate.
#13 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
The Transforming Growth Factor (TGF) superfamily is comprised of the transforming growth factor beta family, as well as other families, including bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins (ACTs), and inhibins (INHs). […] TgfR3 binds all three Tgf ligands as well as BMP2. The loss of TgfR3 results in arrested palatal shelf elevation and elongation and interfered and also led to atypical expression of both TGF and BMP signaling pathways within the palatal shelves. […] The Sonic hedgehog (Shh) gene is part of the Hedgehog gene family, which encode proteins important for cell-cell interaction and has is required for palate and frontonasal development. […] Epithelially expressed Shh has been shown to directly signal to the mesenchyme to regular palate outgrowth, with Shh signaling regulating Bmp2, Bmp4, Msx1, and Fgf10 expression in adjacent palatal mesenchyme.
#14 Orofacial Clefts: Genetics of Cleft Lip and Palate
https://www.mdpi.com/2073-4425/14/8/1603
Studies have suggested that the WNT signaling pathway includes canonical and noncanonical modes of signaling and plays a key role in facial morphogenesis by regulating crucial and critical processes for lip and palate development, such as cell proliferation, migration and differentiation, and also cross-interact with other pathways. […] Disruption in this pathway dysregulates the normal developmental pathways leading to cleft lip and/or cleft palate development of both the syndromic and nonsyndromic type. […] Pathogenic variants in the genes involved in the WNT pathway such as the Wnt3A gene were found to be associated with nonsyndromic cleft lip/or palate and could also affect the development and morphogenesis of the neural crest, leading to the development of orofacial clefts. […] The TGF-Î² (Transforming Growth Factor-Î²) signaling pathway plays a crucial role in various biological and cellular processes regulating cell growth, immune responses, embryonic development and other processes.
#15 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
The Msx1 homeobox gene is also expressed in the facial promorida and is required for the expression of Bmp2 and Bmp4 in palatal mesenchyme and Shh in medial edge epithelium. […] Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that bind to specific DNA sequences and regulate gene expression. […] Platelet-derived growth factor (PDGF) and its receptors PDGFR and PDGFR have been shown to be crucial for cell proliferation, survival, and migration. […] The Tbox transcription factor TBX1 is a mediator of developmental abnormalities and has been shown to be essential for normal palatal elongation and elevation. […] Vascular endothelial growth factor A, a growth factor involved in angiogenesis and ossification has also been shown to be essential for palatal development.
#16 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
The Msx1 homeobox gene is also expressed in the facial promorida and is required for the expression of Bmp2 and Bmp4 in palatal mesenchyme and Shh in medial edge epithelium. […] Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that bind to specific DNA sequences and regulate gene expression. […] Platelet-derived growth factor (PDGF) and its receptors PDGFR and PDGFR have been shown to be crucial for cell proliferation, survival, and migration. […] The Tbox transcription factor TBX1 is a mediator of developmental abnormalities and has been shown to be essential for normal palatal elongation and elevation. […] Vascular endothelial growth factor A, a growth factor involved in angiogenesis and ossification has also been shown to be essential for palatal development.
#17 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
The Msx1 homeobox gene is also expressed in the facial promorida and is required for the expression of Bmp2 and Bmp4 in palatal mesenchyme and Shh in medial edge epithelium. […] Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that bind to specific DNA sequences and regulate gene expression. […] Platelet-derived growth factor (PDGF) and its receptors PDGFR and PDGFR have been shown to be crucial for cell proliferation, survival, and migration. […] The Tbox transcription factor TBX1 is a mediator of developmental abnormalities and has been shown to be essential for normal palatal elongation and elevation. […] Vascular endothelial growth factor A, a growth factor involved in angiogenesis and ossification has also been shown to be essential for palatal development.
#18 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
The Msx1 homeobox gene is also expressed in the facial promorida and is required for the expression of Bmp2 and Bmp4 in palatal mesenchyme and Shh in medial edge epithelium. […] Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that bind to specific DNA sequences and regulate gene expression. […] Platelet-derived growth factor (PDGF) and its receptors PDGFR and PDGFR have been shown to be crucial for cell proliferation, survival, and migration. […] The Tbox transcription factor TBX1 is a mediator of developmental abnormalities and has been shown to be essential for normal palatal elongation and elevation. […] Vascular endothelial growth factor A, a growth factor involved in angiogenesis and ossification has also been shown to be essential for palatal development.
#19 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
The Msx1 homeobox gene is also expressed in the facial promorida and is required for the expression of Bmp2 and Bmp4 in palatal mesenchyme and Shh in medial edge epithelium. […] Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that bind to specific DNA sequences and regulate gene expression. […] Platelet-derived growth factor (PDGF) and its receptors PDGFR and PDGFR have been shown to be crucial for cell proliferation, survival, and migration. […] The Tbox transcription factor TBX1 is a mediator of developmental abnormalities and has been shown to be essential for normal palatal elongation and elevation. […] Vascular endothelial growth factor A, a growth factor involved in angiogenesis and ossification has also been shown to be essential for palatal development.
#20 Azthena logo with the word Azthena
https://www.news-medical.net/news/20250417/Study-unveils-genetic-pathway-leading-to-cleft-lip-and-palate-formation.aspx
Cleft lip and cleft palate are among the most common birth defects, occurring in about one in 1,050 births in the United States. These defects, which appear when the tissues that form the lip or the roof of the mouth do not join completely, are believed to be caused by a mix of genetic and environmental factors. […] In a new study, MIT biologists have discovered how a genetic variant often found in people with these facial malformations leads to the development of cleft lip and cleft palate. […] Their findings suggest that the variant diminishes cells’ supply of transfer RNA, a molecule that is critical for assembling proteins. When this happens, embryonic face cells are unable to fuse to form the lip and roof of the mouth. […] This particular gene was known to be part of the complex involved in the splicing of transfer RNA, but it wasn’t clear that it played such a crucial role for this process and for facial development. Without the gene, known as DDX1, certain transfer RNA can no longer bring amino acids to the ribosome to make new proteins.
#21 Azthena logo with the word Azthena
https://www.news-medical.net/news/20250417/Study-unveils-genetic-pathway-leading-to-cleft-lip-and-palate-formation.aspx
Cleft lip and cleft palate, also known as orofacial clefts, can be caused by genetic mutations, but in many cases, there is no known genetic cause. […] The mechanism for the development of these orofacial clefts is unclear, mostly because they are known to be impacted by both genetic and environmental factors. […] Their studies revealed that these variants are located in an enhancer region called e2p24.2. Enhancers are segments of DNA that interact with protein-coding genes, helping to activate them by binding to transcription factors that turn on gene expression. […] DDX1, it turned out, is necessary for splicing transfer RNA (tRNA) molecules, which play a critical role in protein synthesis. […] While there are about 400 different tRNAs found in the human genome, only a fraction of those tRNAs require splicing, and those are the tRNAs most affected by the loss of DDX1. […] The researchers now hope to explore whether environmental factors linked to orofacial birth defects also influence tRNA function. Some of their preliminary work has found that oxidative stress – a buildup of harmful free radicals – can lead to fragmentation of tRNA molecules.
#22 New study reveals how cleft lip and cleft palate can arise | MIT News | Massachusetts Institute of Technology
https://news.mit.edu/2025/new-study-reveals-how-cleft-lip-and-cleft-palate-can-arise-0417
MIT biologists have discovered that disruptions in transfer RNA function can lead to the development of cleft lip and cleft palate. […] Their findings suggest that the variant diminishes cells supply of transfer RNA, a molecule that is critical for assembling proteins. When this happens, embryonic face cells are unable to fuse to form the lip and roof of the mouth. […] DDX1, it turned out, is necessary for splicing transfer RNA (tRNA) molecules, which play a critical role in protein synthesis. […] While this is the first study to link tRNA to craniofacial malformations, previous studies have shown that mutations that impair ribosome formation can also lead to similar defects. […] One interesting parallel between these two is that the cells that form the face are coming from the same place as the cells that form the neurons, so it seems that these particular cells are very susceptible to tRNA defects. […] Some of their preliminary work has found that oxidative stress a buildup of harmful free radicals can lead to fragmentation of tRNA molecules.
#23 Azthena logo with the word Azthena
https://www.news-medical.net/news/20250417/Study-unveils-genetic-pathway-leading-to-cleft-lip-and-palate-formation.aspx
Cleft lip and cleft palate, also known as orofacial clefts, can be caused by genetic mutations, but in many cases, there is no known genetic cause. […] The mechanism for the development of these orofacial clefts is unclear, mostly because they are known to be impacted by both genetic and environmental factors. […] Their studies revealed that these variants are located in an enhancer region called e2p24.2. Enhancers are segments of DNA that interact with protein-coding genes, helping to activate them by binding to transcription factors that turn on gene expression. […] DDX1, it turned out, is necessary for splicing transfer RNA (tRNA) molecules, which play a critical role in protein synthesis. […] While there are about 400 different tRNAs found in the human genome, only a fraction of those tRNAs require splicing, and those are the tRNAs most affected by the loss of DDX1. […] The researchers now hope to explore whether environmental factors linked to orofacial birth defects also influence tRNA function. Some of their preliminary work has found that oxidative stress – a buildup of harmful free radicals – can lead to fragmentation of tRNA molecules.
#24 Pediatric Cleft Lip and Palate: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/877970-overview
CP is a partial or total lack of fusion of palatal shelves. It can occur in the following ways: Defective growth of palatal shelves, Failure of the shelves to attain a horizontal position, Lack of contact between shelves, Rupture after fusion of shelves. The secondary palate develops from the right and left palatal processes. Fusion of palatal shelves begins at 8 weeks’ gestation and continues usually until 12 weeks’ gestation. One hypothesis is that a threshold is noted beyond which delayed movement of palatal shelves does not allow closure to take place, and this results in a CP. […] Most orofacial clefts, like most common congenital anomalies, are caused by an interaction between genetic and environmental factors. In those instances, genetic factors create a susceptibility for clefts. When environmental factors (ie, triggers) interact with a genetically susceptible genotype, a cleft develops during an early stage of development.
#25 Pediatric Cleft Lip and Palate: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/877970-overview
A cleft develops when embryonic parts called processes (which are programmed to grow, move, and join with each other to form an individual part of the embryo) do not reach each other in time and an open space (cleft) between them persists. In the normal situation, the processes grow into an open space by means of cellular migration and multiplication, touch each other, and fuse together. […] In general, any factor that could prevent the processes from reaching each otherfor instance, by slowing down migration or multiplication of neural crest cells, by stopping tissue growth and development for a time, or by killing some cells that are already in that locationwould cause a cleft to persist. Also, the epithelium that covers the mesenchyme may not undergo programmed cell death, so that fusion of processes cannot take place.
#26 Pediatric Cleft Lip and Palate: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/877970-overview
A cleft develops when embryonic parts called processes (which are programmed to grow, move, and join with each other to form an individual part of the embryo) do not reach each other in time and an open space (cleft) between them persists. In the normal situation, the processes grow into an open space by means of cellular migration and multiplication, touch each other, and fuse together. […] In general, any factor that could prevent the processes from reaching each otherfor instance, by slowing down migration or multiplication of neural crest cells, by stopping tissue growth and development for a time, or by killing some cells that are already in that locationwould cause a cleft to persist. Also, the epithelium that covers the mesenchyme may not undergo programmed cell death, so that fusion of processes cannot take place.
#27 Cleft Lip/Cleft Palate | Birth Defects | CDC
https://www.cdc.gov/birth-defects/about/cleft-lip-cleft-palate.html
Cleft lip and cleft palate are birth defects that occur when a baby’s lip or mouth don’t form properly. […] The causes of orofacial clefts among most infants are unknown. Cleft lip and cleft palate are thought to be caused by a combination of genes and other factors. […] CDC research has found some factors that increase the risk of having a baby with an orofacial cleft: Smoking during pregnancy, Having diabetes before pregnancy (type 1 or 2), Use of certain epilepsy medications during pregnancy. […] Surgical repair can help restore function to the lips and mouth. It may help improve breathing, hearing, and speech and language development.
#28 Cleft lip and palate: Epidemiology and etiology
https://www.oatext.com/cleft-lip-and-palate-epidemiology-and-etiology.php
Cleft lip and palate are considered as one of the most common birth defects that result in medical, psychological, and social problems in affected individuals and their families. They have a complex etiology in which both genetic and environmental factors play a role. Risk factors such as vitamin deficiency, especially folic acid deficiency, and maternal smoking, alcohol consumption, drug use, and chemical exposure have been associated with cleft lip and palate development. […] The multifactorial inheritance model, which involves the interaction of genetic and environmental factors, is a good example for the epidemiological findings of nsCL/P. […] Cleft lip and palate is a multifactorial disease; it is caused by the interaction of genetic factors and environmental factors such as maternal smoking, alcohol consumption, inadequate nutritional intake of folic acid and vitamins B6 and B12, and chemical exposure during pregnancy.
#29 Cleft lip and palate: Epidemiology and etiology
https://www.oatext.com/cleft-lip-and-palate-epidemiology-and-etiology.php
Cleft lip and palate are considered as one of the most common birth defects that result in medical, psychological, and social problems in affected individuals and their families. It has a complex etiology in which both genetic and environmental factors play a role. Risk factors such as vitamin deficiency, especially folic acid deficiency, and maternal smoking, alcohol consumption, drug use, and chemical exposure have been associated with cleft lip and palate development. […] Identifying the factors contributing to cleft lip and palate etiology is important for preventing their development and for taking necessary measures. […] Cleft lip and palate are hereditary diseases in which environmental and genetic factors together play a role, leading to different clinical outcomes. […] Epidemiological studies and observational reports have shown that folic acid supplements taken by the mother before pregnancy have a protective effect in reducing the incidence of cleft lip and palate, whereas smoking and alcohol consumption before pregnancy increase the risk of cleft lip and palate formation.
#30 Cleft Lip & Palate Association
https://www.clapa.com/what-is-cleft-lip-palate/what-causes-a-cleft/
These environmental factors can interact with genes in different ways, causing them to âswitch on or offâ as a baby develops in the womb. […] While some conditions can point to a single genetic factor as a cause, there have been a number of different genes identified as increasing the risk of having a child with a cleft. […] It may also be a matter of certain environmental factors switching genes on or off as a baby is developing in the womb. This is called âepigeneticsâ. […] Sometimes a cleft is caused by part of a âsyndromeâ, which is when lots of different symptoms happen together. […] Estimates can vary widely, but based on UK statistics, around 15-30% of clefts happen as part of a syndrome or condition. […] The causes of cleft lip and palate are much more complicated and vary greatly from case to case, so even if both parents have a cleft it can be very difficult to accurately predict how, if at all, their children will be affected. […] It is important to remember that a cleft may be caused by another condition or syndrome which has not been diagnosed, in which case the chances of inheriting the cleft will be very different.
#31 Epidemiology of Cleft Lip and Palate | IntechOpen
https://www.intechopen.com/chapters/53918
Disturbance of this closely controlled cascade can result in a facial cleft where these facial primordia ultimately fail to meet and fuse or form the proper structures. […] Both genetic and environmental factors have been shown to influence the risk of CL/P and CPO. […] In contrast, nonsyndromic CL/P is complex and multifactorial in origin. […] Furthermore, there is evidence that the presence of environmental factorsâin particular, maternal smokingâmodulates the risk conferred by genetic factors and vice-versa, complicating the genetic analysis of nonsyndromic forms of CLP. […] Due to the relative lack of success in identifying causal genetic factors involved in OFC despite the numerous association studies that have been performed, recent attention has been directed toward the role of epigenetic programming, or modifications that do not involve DNA sequencing. […] DNA methylation plays a central role in regulating this process, and may perhaps serve as future risk assessment and therapeutic targets for patients with OFC.
#32 Pediatric Cleft Lip and Palate: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/877970-overview
Advances in modern molecular biology, developments in methods of genome manipulation, and availability of complete genome sequences led to an understanding of the roles of particular genes that are associated with embryonic development of the orofacial complex. […] The first candidate gene was transforming growth factor- (TGFA), which showed an association with nonsyndromic CLP in a White population. […] Other candidate genes that were described as being associated with nonsyndromic CLP included D4S192, RARA, MTHFR, RFC1, GABRB3, PVRL1, and IRF6. […] The identification of factors that contribute to the etiology of nonsyndromic CL/P is important for prevention, treatment planning, and education. With an increasing number of couples who seek genetic counseling as a part of their family planning, the knowledge of how specific genes contribute to formation of nonsyndromic CL/P has gained an increased importance. […] There is now a growing understanding of the critical role of epigenetics in craniofacial development and the ways in which environmental factors interact with genetic susceptibility. Epigenetic regulators (eg, microRNAs [miRNAs]) play vital roles in the ontogeny of the orofacial region.
#33 Cleft Palate – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK563128/
A cleft palate creates a persistent communication between these 2 spaces, with deleterious effects on speech, swallowing, and breathing, particularly in neonates. A cleft palate leads to unwanted air escape during speech, preventing the proper formation of plosive sounds and leading to hyponasal speech. If unrepaired, this can lead to lifelong errors in speech development that can be challenging to overcome with speech therapy.
#34 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
Understanding the molecular mechanisms of cleft formation will help the clinician anticipate which patients may have difficulties healing, such as those with mutations in Irf6, BMP4, or the TGF family, and in the future hopefully make surgical and medical treatment decisions based on genetic information.
#35 Cleft Lip +/- Cleft Palate Â« Charge Syndrome Foundation
https://www.chargesyndrome.org/cleft-lip-cleft-palate/
Orofacial clefting can interfere with feeding in any individual. […] Children with CHARGE often have additional feeding problems due to neurologically-based velopharyngeal incompetency and/or reflux. […] Children with CHARGE typically have more ear infections and require PE tubes more often and for a longer period of time than other children with clefts. […] An undiagnosed submucous cleft palate can interfere with speech development, already complicated in these children due to hearing loss and facial palsy. […] The cleft team may include a plastic surgeon, oral surgeon, orthodontist, otolaryngologist, ophthalmologist, social worker, nurse, audiologist, speech pathologist, and geneticist. […] Early simple surgical repair maximizes optimal speech, aids in feeding, assists in reducing middle ear infections, and re-establishes normal separation of the oral and nasal cavity while minimizing growth disturbances of the upper jaw.
#36 Cleft Lip +/- Cleft Palate Â« Charge Syndrome Foundation
https://www.chargesyndrome.org/cleft-lip-cleft-palate/
Orofacial clefting can interfere with feeding in any individual. […] Children with CHARGE often have additional feeding problems due to neurologically-based velopharyngeal incompetency and/or reflux. […] Children with CHARGE typically have more ear infections and require PE tubes more often and for a longer period of time than other children with clefts. […] An undiagnosed submucous cleft palate can interfere with speech development, already complicated in these children due to hearing loss and facial palsy. […] The cleft team may include a plastic surgeon, oral surgeon, orthodontist, otolaryngologist, ophthalmologist, social worker, nurse, audiologist, speech pathologist, and geneticist. […] Early simple surgical repair maximizes optimal speech, aids in feeding, assists in reducing middle ear infections, and re-establishes normal separation of the oral and nasal cavity while minimizing growth disturbances of the upper jaw.
#37 Cellular and molecular mechanisms of cleft palate development
https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/
Cleft lip and palate are common craniofacial deformities. The etiology underlying these deformities is complex and multifactorial and they can occur as part of one of many chromosomal syndromes, Mendelian single gene disorders, teratogenic effects, and as yet uncharacterized syndromes. […] The etiology of CLP is multifactorial and complex and includes both genetic and environmental factors. […] More than 300 genes have been implicated in palatal fusion in human and experimental animal models. Single gene mutations can lead to clefting. […] However, the etiology of clefting is still poorly known with multiple molecular pathways associated with cleft lip and palate. […] The most commonly studied molecular pathways include those involved with extracellular signaling factors, transcription factors, and cell adhesion molecules.
#38 Orofacial Clefts: Genetics of Cleft Lip and Palate
https://www.mdpi.com/2073-4425/14/8/1603
Facial development is a complex process that includes the development of the mouth, lips, palate and nose, and it takes place between the fourth and the twelfth week of embryonic development. […] A series of cellular growth and differentiation, migration and apoptosis takes place in a highly coordinated manner, and defects in this sequence of events could result in the development of cleft lip, cleft palate or both, and, although cleft lip and palate occur together, their embryonic origin is different. […] The exact molecular pathway that results in cleft lip and palate remains a target for multiple molecular studies. […] Signaling molecules involving multiple signaling pathways such as WNT, TGF/BMP and FGF and morphogens have been studied for their involvement in the pathogenesis of cleft lip, and cleft lip and palate.
#39 Azthena logo with the word Azthena
https://www.news-medical.net/news/20250417/Study-unveils-genetic-pathway-leading-to-cleft-lip-and-palate-formation.aspx
Cleft lip and cleft palate are among the most common birth defects, occurring in about one in 1,050 births in the United States. These defects, which appear when the tissues that form the lip or the roof of the mouth do not join completely, are believed to be caused by a mix of genetic and environmental factors. […] In a new study, MIT biologists have discovered how a genetic variant often found in people with these facial malformations leads to the development of cleft lip and cleft palate. […] Their findings suggest that the variant diminishes cells’ supply of transfer RNA, a molecule that is critical for assembling proteins. When this happens, embryonic face cells are unable to fuse to form the lip and roof of the mouth. […] This particular gene was known to be part of the complex involved in the splicing of transfer RNA, but it wasn’t clear that it played such a crucial role for this process and for facial development. Without the gene, known as DDX1, certain transfer RNA can no longer bring amino acids to the ribosome to make new proteins.
#40 Cleft lip and palate: Epidemiology and etiology
https://www.oatext.com/cleft-lip-and-palate-epidemiology-and-etiology.php
Cleft lip and palate are considered as one of the most common birth defects that result in medical, psychological, and social problems in affected individuals and their families. It has a complex etiology in which both genetic and environmental factors play a role. Risk factors such as vitamin deficiency, especially folic acid deficiency, and maternal smoking, alcohol consumption, drug use, and chemical exposure have been associated with cleft lip and palate development. […] Identifying the factors contributing to cleft lip and palate etiology is important for preventing their development and for taking necessary measures. […] Cleft lip and palate are hereditary diseases in which environmental and genetic factors together play a role, leading to different clinical outcomes. […] Epidemiological studies and observational reports have shown that folic acid supplements taken by the mother before pregnancy have a protective effect in reducing the incidence of cleft lip and palate, whereas smoking and alcohol consumption before pregnancy increase the risk of cleft lip and palate formation.
#41 Cleft lip and palate: Epidemiology and etiology
https://www.oatext.com/cleft-lip-and-palate-epidemiology-and-etiology.php
Many candidate genes have been and are still being investigated to elucidate the underlying genetic mechanism of cleft lip and palate. […] Molecular studies will contribute to the clarification of the functioning of signaling pathways involved in lip and palate development and thus to a better understanding of cleft lip and palate pathogenesis.
#42 Cleft Lip and Cleft Palate: A Comprehensive Understanding of Etiology, Pathogenesis and an Oral Physicianâs Role in Comprehensive Care, Science Journal of Clinical Medicine, Science Publishing Group
https://www.sciencepublishinggroup.com/article/10.11648/j.sjcm.s.2016050401.13
Cleft lip with or without cleft palate (CL/CP) is one of the most common structural birth defects, with treatment in multiple surgeries, speech therapy, and orthodontic treatments over first 18 years of life. […] Better understanding of the embryology and genetics of orofacial clefting is crucial for development of a biologically relevant orofacial cleft classification system. […] The recent identification of specific genes involved in syndromic and non-syndromic orofacial clefting shows a correlation between both conditions with an overlapping genetic basis. […] However, it has limited application with screening of specific candidates, association studies and genome-wide scans in revealing the molecular basis of human clefting.
#43 Cleft Lip and Cleft Palate: A Comprehensive Understanding of Etiology, Pathogenesis and an Oral Physicianâs Role in Comprehensive Care, Science Journal of Clinical Medicine, Science Publishing Group
https://www.sciencepublishinggroup.com/article/10.11648/j.sjcm.s.2016050401.13
Cleft lip with or without cleft palate (CL/CP) is one of the most common structural birth defects, with treatment in multiple surgeries, speech therapy, and orthodontic treatments over first 18 years of life. […] Better understanding of the embryology and genetics of orofacial clefting is crucial for development of a biologically relevant orofacial cleft classification system. […] The recent identification of specific genes involved in syndromic and non-syndromic orofacial clefting shows a correlation between both conditions with an overlapping genetic basis. […] However, it has limited application with screening of specific candidates, association studies and genome-wide scans in revealing the molecular basis of human clefting.