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. Orofacial clefting can be classified as nonsyndromic, or found as an isolated defect, which occurs in about 85% of cleft lip with or without cleft palate and about 45% of cleft palate alone. […] 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.

• #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: Frontonasal prominence in the median, Bilateral maxillary prominences laterally, Bilateral mandibular prominences laterally and inferiorly. By week 5 of embryogenesis, the frontonasal prominence develops into medial and lateral nasal processes via a cleavage. These medial and lateral nasal processes then fuse with the maxillary process to form the upper lip. The medial nasal processes then fuse in the midline to form the intermaxillary segment, which forms the philtrum of the upper lip and the primary palate (ie, the portion of the palate anterior to the incisive foramen) in gestational week 6. The lateral nasal processes will go on to form the nasal alae. The mandibular processes fuse in the midline to form the lower lip and mandible, while the lateral fusion of the mandibular and maxillary processes forms the oral commissures. Failure, disruption, or interruption of any of these fusion points can result in clefting.

• #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: Frontonasal prominence in the median, Bilateral maxillary prominences laterally, Bilateral mandibular prominences laterally and inferiorly. By week 5 of embryogenesis, the frontonasal prominence develops into medial and lateral nasal processes via a cleavage. These medial and lateral nasal processes then fuse with the maxillary process to form the upper lip. The medial nasal processes then fuse in the midline to form the intermaxillary segment, which forms the philtrum of the upper lip and the primary palate (ie, the portion of the palate anterior to the incisive foramen) in gestational week 6. The lateral nasal processes will go on to form the nasal alae. The mandibular processes fuse in the midline to form the lower lip and mandible, while the lateral fusion of the mandibular and maxillary processes forms the oral commissures. Failure, disruption, or interruption of any of these fusion points can result in clefting.

• #2 Cleft Palate – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563128/

  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. 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.

• #2 Cellular and molecular mechanisms of cleft palate development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/

  The most commonly studied molecular pathways include those involved with extracellular signaling factors, transcription factors, and cell adhesion molecules. […] 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.

• #3 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.

• #3 Cellular and molecular mechanisms of cleft palate development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/

  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. […] 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.

• #3 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.

• #3 Cleft Palate – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563128/

  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. […] 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. In the immediate postpartum period, neonates are obligate nasal breathers. The abnormal communication between the mouth and nose can lead to the tongue protruding into the nasal cavity and interrupting normal nasal breathing. In addition to hampering the ability of the infant to latch onto a nipple, a cleft palate can interfere with primary feeding and the suck-swallow-breathe coordination necessary for maintaining nutrition. Long-term effects can also include dental malposition, abnormal facial growth, and catastrophic psychosocial effects due to stigmata associated with cleft speech and nasal regurgitation of food.

• #4 Pediatric Cleft Lip and Palate: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/877970-overview

  There has been considerable interest in identifying genes that contribute to the etiology of orofacial clefting. 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. […] Gene-gene interactions have also been examined. A complex interplay of several genes, each making a small contribution to the overall risk, may lead to formation of clefts. […] The identification of factors that contribute to the etiology of nonsyndromic CL/P is important for prevention, treatment planning, and education.

• #4 Cellular and molecular mechanisms of cleft palate development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6383315/

  Vascular endothelial growth factor A, a growth factor involved in angiogenesis and ossification has also been shown to be essential for palatal development. […] 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.

• #5 Orofacial Clefts: Genetics of Cleft Lip and Palate

  https://www.mdpi.com/2073-4425/14/8/1603

  The TGF-β (Transforming Growth Factor-β) signaling pathway plays a crucial role in various biological and cellular processes regulating cell growth, immune responses, embryonic development and other processes. […] In facial morphogenesis, TGF-β 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.

• #5 Orofacial Clefts: Genetics of Cleft Lip and Palate

  https://www.mdpi.com/2073-4425/14/8/1603

  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. […] 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.

• #5 Orofacial Clefts: Genetics of Cleft Lip and Palate

  https://www.mdpi.com/2073-4425/14/8/1603

  The rapid growth of the neural cells results in the expansion of the cranial region and elongation and folding of the neural tube in week 4 of embryonic development, and the development of the face from five primordia or facial prominences. […] 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.

• #6 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). […] 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.

• #7 Genetic etiology of cleft lip and cleft palate

  https://www.aimspress.com/article/10.3934/molsci.2020016

  Genetic studies in humans have demonstrated that Cleft lip with or without cleft palate (CL/P) have a diverse genetic background and probably environmental factors influencing these malformations. CL/P is one of the most common congenital birth defects in the craniofacial region with complex etiology involving multiple genetic factors, environmental factors and gene-environment interaction. […] The article describes the brief introduction of CL/P, epidemiology and general concepts, etiological factors, and the genes implicated in the etiology of nonsyndromic CL/P (NSCL/P) as suggested by different human genetic studies, animal models, and other expression studies.

• #8 29: Cleft Lip and Palate: An Overview | Pocket Dentistry

  https://pocketdentistry.com/29-cleft-lip-and-palate-an-overview/

  Cleft lip with or without palate (CL/P) is the most common craniofacial birth defect with an estimated quarter of a million affected babies born each year in the world. […] Non-syndromic CL/P is a complex trait with multifactorial etiology, resulting from gene-gene and gene-environmental interactions. […] The most recent estimates suggest that anywhere from 3 to 14 genes contribute to cleft lip and palate. […] Aberrant transforming growth factor beta-3 (TGF-3) signaling plays a role in the pathogenesis of cleft palate. […] Environmental factors that contribute to the etiology of facial clefting disorders include cigarette smoking, folic acid deficiency during the periconceptional period, and maternal exposure to alcohol and teratogenic medications such as retinoids, corticosteroids, and anticonvulsants (phenytoin and valproic acid).

• #9 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 ‘switch on or off’ 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 ‘epigenetics’. […] Sometimes a cleft is caused by part of a ‘syndrome’, 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.

• #10 Cleft Lip & Cleft Palate: Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/10947-cleft-lip-cleft-palate

  Cleft lip and cleft palate are separations in the upper lip and mouth that occur while a fetus develops in the uterus. […] Cleft lip and cleft palate are openings in a baby’s upper lip or roof of their mouth (palate). They’re congenital abnormalities (birth defects) that form while a fetus develops in the uterus. Cleft lips and cleft palates happen when tissues of the upper lip and roof of the mouth don’t join together properly during fetal development. […] In most cases, there’s no known cause of cleft lip or cleft palate, and parents can’t prevent it. Most scientists believe a combination of genetic (inherited) and environmental (related to the natural world) factors cause clefts. […] Some studies suggest cleft lips and cleft palates have a genetic component. If you or your partner were born with a cleft lip or palate, your chance of having a baby with a cleft is around 2% to 8%.

• #10 Cleft Lip & Cleft Palate: Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/10947-cleft-lip-cleft-palate

  Treatment for cleft lip and cleft palate begins at birth. Surgical treatment begins as early as 3 months and can last until the teen years. […] Surgery treats cleft lip and/or cleft palate. The exact details of treatment depend on the extent of the cleft, your child’s age and other special needs or health conditions. […] Possible risks of surgery include bleeding, infection and damage to nerves, tissues or other structures. Cleft lip and cleft palate surgery is usually successful, and risks are low. […] Children often need treatment beyond surgery for cleft lip or palate. Some other treatments their healthcare providers may recommend are speech therapy and orthodontic treatment. […] Problems with eating, hearing and speech are common in children with clefts. Children may also have issues with their teeth or self-esteem.

• #11

  https://step1.medbullets.com/embryology/103022/cleft-lip-and-palate

  causes are multifactorial […] concordance rate for monozygotic twins is approximately 40-60% […] suggests that genetics does not act alone […] cleft lip occurs in 1 in 1,000 […] occurs more often in males […] cleft palate occurs in 1 in 2,000 […] occurs more often in females […] of the known 200 syndromes associated with cleft lip and palate, van der Woude syndrome is the most common […] due to mutations on chromosome 1 […] characterized by facial deformities, most commonly lip pits […] can diagnose facial deformities as early as 18 weeks […] upon diagnosis infant and family are immediately referred to a craniofacial center for management […] Primary treatment is surgical correction […] Children with cleft palate often have difficulty sucking due to air leakage between the nose and mouth

• #12 Cleft Lip and Cleft Palate: Incidence, Etiology and Development | IntechOpen

  https://www.intechopen.com/chapters/89204

  Cleft lip and palate are birth defects or congenital in nature occurring during development. The cause is unknown but risk factors attributing to this facial anomaly are smoking, diabetes, obesity, increased age of mother and certain drugs used during pregnancy. Cleft lip and palate are considered to be polygenic and multifactorial in origin with involvement of many genetic and environmental factors. Literature reports that the cleft lip and palate are due to involvement of genetic factors in 20 to 50% of cases and in rest of the cases, these facial anomalies are reported to be caused by environmental factors or a combination of gene and environmental factors. […] Environmental factors in isolation or interacting with genetic factors produce cleft lip and cleft palate. Example of environmental factors along with genetic factors causing the cleft lip and cleft palate is mutation in the gene PHF8. Investigators found that PHF8 encodes for a histone lysine demethylase and this gene regulates epigeneticity and is catalytic in action. But catalytic activity of PHF8 gene depends on the level of oxygen, i.e. less is oxygen more is catalytic activity. Increased incidence of cleft lip and palate has been observed in mice exposed to hypoxia (less of oxygen) during early pregnancy. So, it can be interpreted that environmental factors (hypoxia) in conjunction with genetic factors (PHF8 gene) cause cleft lip and cleft palate.

• #13 Cleft Lip and/or Palate – myFace

  https://www.myface.org/craniofacial-conditions/cleft-lip-and-or-palate/

  There are also many environmental factors that have been associated with increased risk of cleft lip and palate, including: Exposure to various drugs (anti-seizure medications, ondansetron, diazepam, nitrofurantoin, corticosteroids, methotrexate) during pregnancy, Maternal tobacco or alcohol use, Maternal folate deficiency during pregnancy. […] Clefts can vary a great deal in their severity; for example, a mild form of cleft lip may present as a slight notch in the upper lip, while the most severe forms can present as a complete separation of the upper lip that extends into the nose. […] A child with a cleft lip/palate may require a variety of treatments and services depending on the severity of the cleft especially if it is associated with a syndrome or other congenital anomaly. The goals of treatment for the cleft(s) are to ensure normal breathing, feeding, hearing, speech and language development, and maxillofacial growth while preventing long-term complications. […] Even after surgery, children living with clefts can continue to face challenges depending on the type and severity of the cleft. These complications may require additional treatments and support services.

• #14 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. A cleft lip happens if the tissue making up the upper lip doesn’t join completely before birth, leaving an opening. A cleft palate happens if the tissue that makes up the palate doesn’t join together completely. Cleft palate can occur with or without cleft lip. 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.

• #15 Cleft lip and palate: Epidemiology and etiology

  https://www.oatext.com/cleft-lip-and-palate-epidemiology-and-etiology.php

  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. […] 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.

• #16

  https://www.nhs.uk/conditions/cleft-lip-and-palate/

  A cleft lip or palate happens when the structures that form the upper lip or palate fail to join together when a baby is developing in the womb. […] The exact reason why this happens to some babies is often unclear. It’s very unlikely to have been caused by anything you did or did not do during pregnancy. […] In a few cases, cleft lip and palate is associated with: the genes a child inherits from their parents (although most cases are a one-off), smoking in pregnancy or drinking alcohol while pregnant, obesity during pregnancy, a lack of folic acid during pregnancy, taking certain medicines in early pregnancy, such as some anti-seizure medicines. […] In some cases, a cleft lip or palate can occur as part of a condition that causes a wider range of birth defects, such as 22q11 deletion syndrome (sometimes called DiGeorge or velocardiofacial syndrome) and Pierre Robin sequence.

• #17 Cleft Lip and Palate: Causes, Symptoms, Diagnosis, Treatment

  https://www.webmd.com/oral-health/cleft-lip-cleft-palate

  Another potential cause may be related to a medication a mother may have taken during pregnancy. Some drugs that may cause cleft lip and cleft palate include anti-seizure/anticonvulsant drugs, acne drugs containing Accutane, and methotrexate, a drug commonly used for treating cancer, arthritis, and psoriasis. […] Cleft lip and cleft palate may also occur as a result of exposure to viruses or chemicals while the fetus is developing in the womb.

• #18 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. […] The researchers now hope to explore whether environmental factors linked to orofacial birth defects also influence tRNA function.

• #19 Susceptibility to DNA Damage as a Molecular Mechanism for Non-Syndromic Cleft Lip and Palate | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065677

  Non-syndromic cleft lip/palate (NSCL/P) is a complex, frequent congenital malformation, determined by the interplay between genetic and environmental factors during embryonic development. […] Here, using a combination of transcriptomic profiling and functional approaches, we report that NSCL/P dental pulp stem cells exhibit dysregulation of a co-expressed gene network mainly associated with DNA double-strand break repair and cell cycle control (p=2.881025.02109). […] In conclusion, we show for the first time that cellular defences against DNA damage may take part in determining the susceptibility to NSCL/P. […] The interplay between genetic and environmental factors during embryonic development is thought to be determinant in the aetiology of NSCL/P. […] Therefore, if disease susceptibility is shaped by transcriptional anomalies, which in turn are driven by the individuals genetic constitution, a feasible approach to investigate the aetiology of NSCL/P is the gene expression analysis of cells from affected individuals.

• #19 Susceptibility to DNA Damage as a Molecular Mechanism for Non-Syndromic Cleft Lip and Palate | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065677

  Taken together, the results indicated that NSCL/P cells feature transcriptional dysregulation of genes involved in cell cycle control and DNA damage repair mediated by BRCA1. […] We observed that a significantly greater proportion of NSCL/P cells were positively stained for -H2AX (-H2AX+ cells; quantitated in relation to untreated cells for each individual) after 6 and 24 hours of H2O2 treatment, when compared to controls (p0.05; Fig. 3A, smaller graph). […] Therefore, we propose that the concurrent accumulation of G1/early S cells and elevated DSB signals at 24 hours, observed in NSCL/P subgroup II, reflects the inability of these cells to undergo homology-directed DSB repair. […] We showed that transcriptional dysregulation of BRCA1 and its co-operators is associated with an accumulation of DSBs in NSCL/P cells, compared to controls.

• #20 Susceptibility to DNA Damage as a Molecular Mechanism for Non-Syndromic Cleft Lip and Palate | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065677

  The finding that CDC45L fails to undergo up-regulation in NSCL/P cells exposed to H2O2 further suggests that deficiency in this type of DNA repair could play a role in the manifestation of the observed NSCL/P cellular phenotypes, as this DEG is involved in new DNA synthesis during homologous recombination repair. […] Therefore, the combined effects of transcriptional dysregulation and of environmental factors must be critical in a tissue-and time-specific manner, which can explain why orofacial clefts have not been observed in knockout animal models for pivotal DNA repair genes, including E2F1. […] In conclusion, we report here that gene networks governing cellular defences against DNA damage may play a role in the aetiology of NSCL/P, in accordance with the idea that orofacial clefts and cancer may have overlapping aetiologies.

• #21 Cleft Lip and Palate

  https://www.asha.org/practice-portal/clinical-topics/cleft-lip-and-palate/?srsltid=AfmBOoqTMYJhUaoj1tfleJcRjZE1oU_HLvcYVe9m5B9b5Ul_pCxaAoMa

  Velopharyngeal dysfunction (VPD) is a general term that does not indicate causality. Velopharyngeal insufficiency (VPI) is due to a structural abnormality (cleft palate, post adenoidectomy). Velopharyngeal incompetence is due to a neurogenic cause (head trauma, stroke, cerebral palsy, neurologic disease). […] There are a number of causes of VPD, the most common of which is cleft palate or submucous cleft palate. Other common causes include a short palate, deep pharynx, and weak or uncoordinated palatal muscle function caused by neurological disorders. […] Surgical intervention or other physical management is needed to manage speech disorders resulting from VPD (e.g., hypernasality). […] Surgical procedures can include repair of cleft lip and repair of cleft palate.

• #22 Pathophysiology of the Cleft Palate | SpringerLink

  https://link.springer.com/10.1007/978-981-15-8124-3_5

  Having understood the structure and functioning of the palate, it becomes easier to recognize its implicit defects and dysfunctions which manifest as a disorder of feeding, swallowing and impairment in the speech of individuals with a cleft palate. The degree and severity of disordered functioning is directly proportional to the size and type of defect in the palate. […] A disorder of eating, drinking, and swallowing challenges the nutritional intake, affecting the physical and mental health as well as social well-being of the child. […] Disorder of speech is evident through hypernasality, hyponasality, or mixed nasality, and inappropriate or displaced resonance accompanied by misarticulation of speech sounds. […] It may be said here that a cleft palate causes more concern than the cleft lip, as the latter poses a bigger cosmetic problem, than the one pertaining to malfunctioning of the speech mechanism.

• #23 Cleft Lip and Palate Types

  https://www.verywellhealth.com/what-is-a-cleft-lip-2709800

  The cause of cleft lip is not well understood. During fetal development, nasal and lip elements do not come together properly. Researchers believe some cleft lips may have genetic causes. Others could happen because of something in the environment or a medication taken during pregnancy. For example, people who smoke during pregnancy are more likely to have a baby with a cleft lip. […] The orbicularis oris muscle is not in continuity in a complete cleft lip. Instead of encircling the mouth, the muscle inserts into the base of the nose on both sides of the cleft. This disruption creates difficulty speaking, eating and drinking. […] The lack of continuity in the muscle makes clear speech difficult for these individuals. Feeding can be more difficult.

• #24

  https://childrens.wvumedicine.org/cleft-lip-and-cleft-palate

  A cleft is an opening or split in the roof of the mouth or the upper lip. It occurs when these body parts dont fuse properly during development in the womb. […] While nobody knows the exact cause of a cleft, children with mothers who had infections, nutritional deficiencies and/or smoked during pregnancy may be at a higher risk. However, many clefts are from healthy pregnancies and is rather common. […] A cleft lip and cleft palate can be repaired with surgery. However, there can be complications caused by the cleft that need to be addressed by experts. […] The most common complications of a cleft include: […] Muscles involved with speech may not work well. This can lead to a delay in speech or speech impairments. Your child will see speech therapists before and after each reconstructive surgery.

• #24

  https://childrens.wvumedicine.org/cleft-lip-and-cleft-palate

  Treatment usually beings with some form of nonsurgical molding. This is either nasoalveolar molding (NAM) or lip taping in the first few weeks after birth. This treatment uses tape or a dental plate to reduce the size of the cleft by bringing together the two sections of skin and muscle. […] If the pharynx (tissue at back of mouth) does not close properly, a child may continue having speech problems after palate repair. Another speech surgery may be needed. A palatal lengthening, pharyngoplasty or a pharyngeal flap procedure is a procedure that can improve the function of the pharynx. […] Children born with cleft palate will sometimes develop a misaligned jaw where the lower jaw protrudes out further than the upper jaw (called an underbite). The team may recommend a surgery to help re-align the jaw.

• #25 Cleft lip and palate Information | Mount Sinai – New York

  https://www.mountsinai.org/health-library/diseases-conditions/cleft-lip-and-palate

  Hearing problems are common in children with cleft lip or palate. Your child should have a hearing test at an early age, and it should be repeated over time. […] Your child may still have problems with speech after the surgery. This is caused by muscle problems in the palate. Speech therapy will help your child.

• #26

  https://cleftpalatejournal.pitt.edu/ojs/cleftpalate/article/view/256

  Unilateral conditions of cleft lip and palate consistently show an associated skeletal deformity of which maxillary displacement, pre-maxillary distortion and malformation of the nose are prominent features. […] It is thought that the cleft condition, embryologically, represents a relatively minor failure of development and that the skeletal deformity is not part of the original affliction, but rather that it is superimposed upon the facial structure during subsequent development. […] While a clear understanding of the pathogenesis of the skeletal deformity is apparently essential in the interests of treatment, present day opinion is divided about its cause and little is known of its mode of development. […] A detailed histological investigation of the problem was therefore carried out on human specimens of different ages having the unilateral cleft condition. […] As well as inquiring into possible causes, attention was given to the related problems of the time of onset and rate of development of the skeletal deformity.

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