Cleft lip and palate

Cleft lip and palate

Child with cleft lip and palate.
Classification and external resources
Specialty Otorhinolaryngology, pediatrics
ICD-10 Q35-Q37
ICD-9-CM 749
DiseasesDB 29604 29414
MedlinePlus 001051
eMedicine ped/2679

Cleft lip and cleft palate, also known as orofacial cleft and cleft lip and palate, is a group of conditions that includes cleft lip (CL), cleft palate (CP), and both together (CLP).[1][2] A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate is when the roof of the mouth contains an opening into the nose. These disorders can result in feeding problems, speech problems, hearing problems, and frequent ear infections. Less than half the time the condition is associated with other disorders.[1]

Cleft lip and palate is due to tissues of the face not properly joining together during development. They are a type of birth defect. The cause in most cases is unknown.[1] Risk factors include smoking during pregnancy, diabetes, an older mother, obesity, and certain medications such as some used to treat seizures.[1][2] They can often be diagnosed during an ultrasound done during pregnancy.[1]

A cleft lip or palate can be successfully treated with surgery. This is often done in the first few months of life for cleft lip and before eighteen months for cleft palate. Speech therapy and dental care may also be needed. With appropriate treatment outcomes are good.[1]

Cleft lip and palate occurs in about 1 to 2 per 1000 births in the developed world.[2] CL is about twice as common in males as females, while CP without CL is more common in females.[2] In 2013 it resulted in about 3,300 deaths globally down from 7,600 deaths in 1990.[3] The condition was previously known as a hare-lip due to similarity to a rabbit, but that term is now generally considered to be offensive.[4]

Signs and symptoms

If the cleft does not affect the palate structure of the mouth it is referred to as cleft lip. Cleft lip is formed in the top of the lip as either a small gap or an indentation in the lip (partial or incomplete cleft) or it continues into the nose (complete cleft). Lip cleft can occur as a one sided (unilateral) or two sided (bilateral). It is due to the failure of fusion of the maxillary and medial nasal processes (formation of the primary palate).

A mild form of a cleft lip is a microform cleft.[5] A microform cleft can appear as small as a little dent in the red part of the lip or look like a scar from the lip up to the nostril.[6] In some cases muscle tissue in the lip underneath the scar is affected and might require reconstructive surgery.[7] It is advised to have newborn infants with a microform cleft checked with a craniofacial team as soon as possible to determine the severity of the cleft.[8]

Cleft palate

Cleft palate is a condition in which the two plates of the skull that form the hard palate (roof of the mouth) are not completely joined. The soft palate is in these cases cleft as well. In most cases, cleft lip is also present. Cleft palate occurs in about one in 700 live births worldwide.[9]

Palate cleft can occur as complete (soft and hard palate, possibly including a gap in the jaw) or incomplete (a 'hole' in the roof of the mouth, usually as a cleft soft palate). When cleft palate occurs, the uvula is usually split. It occurs due to the failure of fusion of the lateral palatine processes, the nasal septum, and/or the median palatine processes (formation of the secondary palate).

The hole in the roof of the mouth caused by a cleft connects the mouth directly to the inside of the nose.

Note: the next images show the roof of the mouth. The top shows the nose, the lips are colored pink. For clarity the images depict a toothless infant.

A result of an open connection between the mouth and inside the nose is called velopharyngeal inadequacy (VPI). Because of the gap, air leaks into the nasal cavity resulting in a hypernasal voice resonance and nasal emissions while talking.[10] Secondary effects of VPI include speech articulation errors (e.g., distortions, substitutions, and omissions) and compensatory misarticulations and mispronunciations (e.g., glottal stops and posterior nasal fricatives).[11] Possible treatment options include speech therapy, prosthetics, augmentation of the posterior pharyngeal wall, lengthening of the palate, and surgical procedures.[10]

Submucous cleft palate (SMCP) can also occur, which is a cleft of the soft palate with a classic clinical triad of a bifid, or split, uvula which is found dangling in the back of the throat, a furrow along the midline of the soft palate, and a notch in the back margin of the hard palate.[12]

Psychosocial

Most children who have their clefts repaired early enough are able to have a happy youth and social life. Having a cleft palate/lip does not inevitably lead to a psychosocial problem. However, adolescents with cleft palate/lip are at an elevated risk for developing psychosocial problems especially those relating to self-concept, peer relationships and appearance. Adolescents may face psychosocial challenges but can find professional help if problems arise. A cleft palate/lip may impact an individual’s self-esteem, social skills and behavior. There is research dedicated to the psychosocial development of individuals with cleft palate. Self-concept may be adversely affected by the presence of a cleft lip and/or cleft palate, particularly among girls.[13]

Research has shown that during the early preschool years (ages 3–5), children with cleft lip and/or cleft palate tend to have a self-concept that is similar to their peers without a cleft. However, as they grow older and their social interactions increase, children with clefts tend to report more dissatisfaction with peer relationships and higher levels of social anxiety. Experts conclude that this is probably due to the associated stigma of visible deformities and possible speech impediments. Children who are judged as attractive tend to be perceived as more intelligent, exhibit more positive social behaviors, and are treated more positively than children with cleft lip and/or cleft palate.[14] Children with clefts tend to report feelings of anger, sadness, fear, and alienation from their peers, but these children were similar to their peers in regard to "how well they liked themselves."

The relationship between parental attitudes and a child’s self-concept is crucial during the preschool years. It has been reported that elevated stress levels in mothers correlated with reduced social skills in their children.[15] Strong parent support networks may help to prevent the development of negative self-concept in children with cleft palate.[16] In the later preschool and early elementary years, the development of social skills is no longer only impacted by parental attitudes but is beginning to be shaped by their peers. A cleft lip and/or cleft palate may affect the behavior of preschoolers. Experts suggest that parents discuss with their children ways to handle negative social situations related to their cleft lip and/or cleft palate. A child who is entering school should learn the proper (and age-appropriate) terms related to the cleft. The ability to confidently explain the condition to others may limit feelings of awkwardness and embarrassment and reduce negative social experiences.[17]

As children reach adolescence, the period of time between age 13 and 19, the dynamics of the parent-child relationship change as peer groups are now the focus of attention. An adolescent with cleft lip and/or cleft palate will deal with the typical challenges faced by most of their peers including issues related to self-esteem, dating and social acceptance.[18][19][20] Adolescents, however, view appearance as the most important characteristic above intelligence and humor.[21] This being the case, adolescents are susceptible to additional problems because they cannot hide their facial differences from their peers. Adolescent boys typically deal with issues relating to withdrawal, attention, thought, and internalizing problems and may possibly develop anxiousness-depression and aggressive behaviors.[20] Adolescent girls are more likely to develop problems relating to self-concept and appearance. Individuals with cleft lip and/or cleft palate often deal with threats to their quality of life for multiple reasons including: unsuccessful social relationships, deviance in social appearance and multiple surgeries.

Complications

A baby being fed using a customized bottle. The upright sitting position allows gravity to help the baby swallow the milk more easily

Cleft may cause problems with feeding, ear disease, speech and socialization.

Due to lack of suction, an infant with a cleft may have trouble feeding. An infant with a cleft palate will have greater success feeding in a more upright position. Gravity will help prevent milk from coming through the baby's nose if he/she has cleft palate. Gravity feeding can be accomplished by using specialized equipment, such as the Haberman Feeder, or by using a combination of nipples and bottle inserts like the one shown, is commonly used with other infants. A large hole, crosscut, or slit in the nipple, a protruding nipple and rhythmically squeezing the bottle insert can result in controllable flow to the infant without the stigma caused by specialized equipment.

Individuals with cleft also face many middle ear infections which may eventually lead to hearing loss. The Eustachian tubes and external ear canals may be angled or tortuous, leading to food or other contamination of a part of the body that is normally self-cleaning. Hearing is related to learning to speak. Babies with palatal clefts may have compromised hearing and therefore, if the baby cannot hear, it cannot try to mimic the sounds of speech. Thus, even before expressive language acquisition, the baby with the cleft palate is at risk for receptive language acquisition. Because the lips and palate are both used in pronunciation, individuals with cleft usually need the aid of a speech therapist.

Cause

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:

a) one from the top of the head down towards the future upper lip; (Frontonasal Prominence)
b-c) two from the cheeks, which meet the first lobe to form the upper lip; (Maxillar Prominence)
d-e) and just below, two additional lobes grow from each side, which form the chin and lower lip; (Mandibular Prominence)

If these tissues fail to meet, a gap appears where the tissues should have joined (fused). This may happen in any single joining site, or simultaneously in several or all of them. The resulting birth defect reflects the locations and severity of individual fusion failures (e.g., from a small lip or palate fissure up to a completely malformed face).

The upper lip is formed earlier than the palate, from the first three lobes named a to c above. Formation of the palate is the last step in joining the five embryonic facial lobes, and involves the back portions of the lobes b and c. These back portions are called palatal shelves, which grow towards each other until they fuse in the middle.[22] This process is very vulnerable to multiple toxic substances, environmental pollutants, and nutritional imbalance. The biologic mechanisms of mutual recognition of the two cabinets, and the way they are glued together, are quite complex and obscure despite intensive scientific research.[23]

Genetics

Genetic factors contributing to cleft lip and cleft palate formation have been identified for some syndromic cases, but knowledge about genetic factors that contribute to the more common isolated cases of cleft lip/palate is still patchy.

Many clefts run in families, even though in some cases there does not seem to be an identifiable syndrome present,[24] possibly because of the current incomplete genetic understanding of midfacial development.

A number of genes are involved including cleft lip and palate transmembrane protein 1 and GAD1,[25] one of the glutamate decarboxylases. Many genes are known to play a role in craniofacial development and are being studied through the FaceBase initiative for their part in clefting. These genes are AXIN2, BMP4, FGFR1, FGFR2, FOXE1, IRF6, MAFB (gene), MMP3, MSX1, MSX2 (Msh homeobox 2), MSX3, PAX7, PDGFC, PTCH1, SATB2, SOX9, SUMO1 (Small ubiquitin-related modifier 1), TBX22, TCOF (Treacle protein), TFAP2A, VAX1, TP63, ARHGAP29, NOG, NTN1, WNT genes, and locus 8q24.[26]

Syndromes

In some cases, cleft palate is caused by syndromes which also cause other problems.

Specific genes

Type OMIM Gene Locus
OFC1 119530 ? 6p24
OFC2 602966 ? 2p13
OFC3 600757 ? 19q13
OFC4 608371 ? 4q
OFC5 608874 MSX1 4p16.1
OFC6 608864 ? 1q
OFC7 600644) PVRL1 11q
OFC8 129400 TP63 3q27
OFC9 610361 ? 13q33.1-q34
OFC10 601912 SUMO1 2q32.2-q33
OFC11 600625 BMP4 14q22
OFC12 612858 ? 8q24.3

Many genes associated with syndromic cases of cleft lip/palate (see above) have been identified to contribute to the incidence of isolated cases of cleft lip/palate. This includes in particular sequence variants in the genes IRF6, PVRL1 and MSX1.[35] The understanding of the genetic complexities involved in the morphogenesis of the midface, including molecular and cellular processes, has been greatly aided by research on animal models, including of the genes BMP4, SHH, SHOX2, FGF10 and MSX1.[35]

Environment

Environmental influences may also cause, or interact with genetics to produce, orofacial clefting. An example for how environmental factors might be linked to genetics comes from research on mutations in the gene PHF8 that cause cleft lip/palate (see above). It was found that PHF8 encodes for a histone lysine demethylase,[36] and is involved in epigenetic regulation. The catalytic activity of PHF8 depends on molecular oxygen,[36] a fact considered important with respect to reports on increased incidence of cleft lip/palate in mice that have been exposed to hypoxia early during pregnancy.[37] In humans, fetal cleft lip and other congenital abnormalities have also been linked to maternal hypoxia, as caused by e.g. maternal smoking,[38] maternal alcohol abuse or some forms of maternal hypertension treatment.[39] Other environmental factors that have been studied include: seasonal causes (such as pesticide exposure); maternal diet and vitamin intake; retinoids — which are members of the vitamin A family; anticonvulsant drugs; alcohol; cigarette use; nitrate compounds; organic solvents; parental exposure to lead; and illegal drugs (cocaine, crack cocaine, heroin, etc.).

Current research continues to investigate the extent to which folic acid can reduce the incidence of clefting.[40]

Diagnosis

Traditionally, the diagnosis is made at the time of birth by physical examination. Recent advances in prenatal diagnosis have allowed obstetricians to diagnose facial clefts in utero.[41]

Clefts can also affect other parts of the face, such as the eyes, ears, nose, cheeks, and forehead. In 1976, Paul Tessier described fifteen lines of cleft. Most of these craniofacial clefts are even rarer and are frequently described as Tessier clefts using the numerical locator devised by Tessier.[42]

Treatment

Cleft lip and palate is very treatable; however, the kind of treatment depends on the type and severity of the cleft.

Most children with a form of clefting are monitored by a cleft palate team or craniofacial team through young adulthood.[43] Care can be lifelong. Treatment procedures can vary between craniofacial teams. For example, some teams wait on jaw correction until the child is aged 10 to 12 (argument: growth is less influential as deciduous teeth are replaced by permanent teeth, thus saving the child from repeated corrective surgeries), while other teams correct the jaw earlier (argument: less speech therapy is needed than at a later age when speech therapy becomes harder). Within teams, treatment can differ between individual cases depending on the type and severity of the cleft.

Cleft lip

Within the first 2–3 months after birth, surgery is performed to close the cleft lip. While surgery to repair a cleft lip can be performed soon after birth, often the preferred age is at approximately 10 weeks of age, following the "rule of 10s" coined by surgeons Wilhelmmesen and Musgrave in 1969 (the child is at least 10 weeks of age; weighs at least 10 pounds, and has at least 10g hemoglobin).[44] If the cleft is bilateral and extensive, two surgeries may be required to close the cleft, one side first, and the second side a few weeks later. The most common procedure to repair a cleft lip is the Millard procedure pioneered by Ralph Millard. Millard performed the first procedure at a Mobile Army Surgical Hospital (MASH) unit in Korea.[45]

Often an incomplete cleft lip requires the same surgery as complete cleft. This is done for two reasons. Firstly the group of muscles required to purse the lips run through the upper lip. In order to restore the complete group a full incision must be made. Secondly, to create a less obvious scar the surgeon tries to line up the scar with the natural lines in the upper lip (such as the edges of the philtrum) and tuck away stitches as far up the nose as possible. Incomplete cleft gives the surgeon more tissue to work with, creating a more supple and natural-looking upper lip.

Pre-surgical devices

In some cases of a severe bi-lateral complete cleft, the premaxillary segment will be protruded far outside the mouth.

Nasoalveolar molding prior to surgery can improve long-term nasal symmetry among patients with complete unilateral cleft lip-cleft palate patients compared to correction by surgery alone, according to a retrospective cohort study.[46] In this study, significant improvements in nasal symmetry were observed in multiple areas including measurements of the projected length of the nasal ala (lateral surface of the external nose), position of the superoinferior alar groove, position of the mediolateral nasal dome, and nasal bridge deviation. "The nasal ala projection length demonstrated an average ratio of 93.0 percent in the surgery-alone group and 96.5 percent in the nasoalveolar molding group" this study concluded.

Cleft palate

A repaired cleft palate on a 64-year-old female.

Often a cleft palate is temporarily covered by a palatal obturator (a prosthetic device made to fit the roof of the mouth covering the gap).

Cleft palate can also be corrected by surgery, usually performed between 6 and 12 months. Approximately 20–25% only require one palatal surgery to achieve a competent velopharyngeal valve capable of producing normal, non-hypernasal speech. However, combinations of surgical methods and repeated surgeries are often necessary as the child grows. One of the new innovations of cleft lip and cleft palate repair is the Latham appliance.[47] The Latham is surgically inserted by use of pins during the child's 4th or 5th month. After it is in place, the doctor, or parents, turn a screw daily to bring the cleft together to assist with future lip and/or palate repair.

If the cleft extends into the maxillary alveolar ridge, the gap is usually corrected by filling the gap with bone tissue. The bone tissue can be acquired from the patients own chin, rib or hip.

Speech and hearing

A tympanostomy tube is often inserted into the eardrum to aerate the middle ear.[48] This is often beneficial for the hearing ability of the child.

Children with cleft palate typically have a variety of speech problems. Some speech problems result directly from anatomical differences such as velopharyngeal inadequacy. Velopharyngeal inadequacy refers to the inability of the soft palate to close the opening from the throat to the nasal cavity, which is necessary for many speech sounds, such as /p/, /b/, /t/, /d/, /s/, /z/, etc.[49] This type of errors typically resolve after palate repair.[50]

However, sometimes children with cleft palate also have speech errors which develop as the result of an attempt to compensate for the inability to produce the target phoneme. These are known as compensatory articulations. Compensatory articulations are usually sounds that are non-existent in normal English phonology, often do not resolve automatically after palatal repair, and make a child’s speech even more difficult to understand.[50][51][52]

Speech-language pathology can be very beneficial to help resolve speech problems associated with cleft palate. In addition, research has indicated that children who receive early language intervention are less likely to develop compensatory error patterns later.[53]

Hearing loss

Hearing impairment is particularly prevalent in children with cleft palate. The tensor muscle fibres that open the eustachian tubes lack an anchor to function effectively. In this situation, when the air in the middle ear is absorbed by the mucous membrane, the negative pressure is not compensated, which results in the secretion of fluid into the middle ear space from the mucous membrane.[54] Children with this problem typically have a conductive hearing loss primarily caused by this middle ear effusion.[55]

Sample treatment schedule

Note that each individual patient's schedule is treated on a case-by-case basis and can vary per hospital. The table below shows a common sample treatment schedule. The colored squares indicate the average timeframe in which the indicated procedure occurs. In some cases this is usually one procedure (for example lip repair) in other cases this is an ongoing therapy (for example speech therapy).

Age
0m
3m
6m
9m
1y
2y
3y
4y
5y
6y
7y
8y
9y
10y
11y
12y
13y
14y
15y
16y
17y
18y
Palatal obturator                                            
Repair cleft lip                                            
Repair soft palate                                            
Repair hard palate                                            
Tympanostomy tube                                            
Speech therapy/pharyngoplasty                                            
Bone grafting jaw                                            
Orthodontics                                            
Further cosmetic corrections (Including jawbone surgery)                                            

Craniofacial team

Main article: Craniofacial team

A craniofacial team is routinely used to treat this condition. The majority of hospitals still use craniofacial teams; yet others are making a shift towards dedicated cleft lip and palate programs. While craniofacial teams are widely knowledgeable about all aspects of craniofacial conditions, dedicated cleft lip and palate teams are able to dedicate many of their efforts to being on the cutting edge of new advances in cleft lip and palate care.

Many of the top pediatric hospitals are developing their own CLP clinics in order to provide patients with comprehensive multi-disciplinary care from birth through adolescence. Allowing an entire team to care for a child throughout their cleft lip and palate treatment (which is ongoing) allows for the best outcomes in every aspect of a child's care. While the individual approach can yield significant results, current trends indicate that team based care leads to better outcomes for CLP patients. .[56]

Epidemiology

Cleft lip and palate occurs in about 1 to 2 per 1000 births in the developed world.[2]

Rates for cleft lip with or without cleft palate and cleft palate alone varies within different ethnic groups.

The highest prevalence rates for (CL ± P) are reported for Native Americans and Asians. Africans have the lowest prevalence rates.[57]

Rate of occurrence of CPO is similar for Caucasians, Africans, North American natives, Japanese and Chinese. The trait is dominant.

It caused about 4,000 deaths globally in 2010 down from 8,400 in 1990.[58]

Prevalence of "cleft uvula" has varied from .02% to 18.8% with the highest numbers found among Chippewa and Navajo and the lowest generally in Africans.[59][60]

Society and culture

Names

Cleft lip may be technically known as cheiloschisis and cleft palate as palatoschisis.

Controversy

In some countries, cleft lip or palate deformities are considered reasons (either generally tolerated or officially sanctioned) to perform abortion beyond the legal fetal age limit, even though the fetus is not in jeopardy of life or limb. Some human rights activists contend this practice of "cosmetic murder" amounts to eugenics.

Notable cases

Name Comments
John Henry "Doc" Holliday American dentist, gambler and gunfighter of the American Old West, who is usually remembered for his friendship with Wyatt Earp and the Gunfight at the O.K. Corral [61]
Tutankhamen Egyptian pharaoh who may have had a slightly cleft palate according to diagnostic imaging [62]
Thorgils Skarthi Thorgils 'the hare-lipped'—a 10th-century Viking warrior and founder of Scarborough, England. [63]
Tad Lincoln Fourth and youngest son of President Abraham Lincoln [64]
Carmit Bachar American dancer and singer [65][66]
Jürgen Habermas German philosopher and sociologist [67]
Ljubo Milicevic Australian professional footballer [68]
Stacy Keach American actor and narrator [69]
Cheech Marin American actor and comedian [70]
Chin-Chin American magician and stage illusionist [71]
Owen Schmitt American football fullback [72]
Tim Lott English author and journalist [73]
Richard Hawley English musician [73]
Dario Šarić Croatian professional basketball player [74]
Antoinette Bourignon Flemish mystic [75]

Works of fiction

The eponymous hero of J.M. Coetzee's 1983 novel Life & Times of Michael K has a cleft lip. However, the cleft lip is more frequently portrayed negatively in popular culture. Examples include Oddjob, the secondary villain of the James Bond novel Goldfinger by Ian Fleming (the film adaptation does not mention this but leaves it implied); the fanciful portrayal of Roman Emperor Commodus in the 2000 film Gladiator,;[76] and serial killer Francis Dolarhyde in the film Red Dragon.[77]

Compassion for those with cleft palates has been used as the theme of young adult novels such as Words in the Dust by Trent Reedy and Whisper by Christina Struyk-Bonn.

Other animals

Cleft lips and palates are occasionally seen in cattle and dogs, and rarely in sheep, cats, horses, pandas and ferrets. Most commonly, the defect involves the lip, rhinarium, and premaxilla. Clefts of the hard and soft palate are sometimes seen with a cleft lip. The cause is usually hereditary. Brachycephalic dogs such as Boxers and Boston Terriers are most commonly affected.[78] An inherited disorder with incomplete penetrance has also been suggested in Shih tzus, Swiss Sheepdogs, Bulldogs, and Pointers.[79] In horses, it is a rare condition usually involving the caudal soft palate.[80] In Charolais cattle, clefts are seen in combination with arthrogryposis, which is inherited as an autosomal recessive trait. It is also inherited as an autosomal recessive trait in Texel sheep. Other contributing factors may include maternal nutritional deficiencies, exposure in utero to viral infections, trauma, drugs, or chemicals, or ingestion of toxins by the mother, such as certain lupines by cattle during the second or third month of gestation.[81] The use of corticosteroids during pregnancy in dogs and the ingestion of Veratrum californicum by pregnant sheep have also been associated with cleft formation.[82]

Difficulty with nursing is the most common problem associated with clefts, but aspiration pneumonia, regurgitation, and malnutrition are often seen with cleft palate and is a common cause of death. Providing nutrition through a feeding tube is often necessary, but corrective surgery in dogs can be done by the age of twelve weeks.[78] For cleft palate, there is a high rate of surgical failure resulting in repeated surgeries.[83] Surgical techniques for cleft palate in dogs include prosthesis, mucosal flaps, and microvascular free flaps.[84] Affected animals should not be bred due to the hereditary nature of this condition.

See also

References

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  2. 1 2 3 4 5 Watkins, SE; Meyer, RE; Strauss, RP; Aylsworth, AS (April 2014). "Classification, epidemiology, and genetics of orofacial clefts.". Clinics in plastic surgery 41 (2): 149–63. doi:10.1016/j.cps.2013.12.003. PMID 24607185.
  3. ↑ GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.". Lancet 385: 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442.
  4. ↑ Boklage, Charles E. (2010). How new humans are made cells and embryos, twins and chimeras, left and right, mind/selfsoul, sex, and schizophrenia. Singapore: World Scientific. p. 283. ISBN 9789812835147.
  5. ↑ Kim EK, Khang SK, Lee TJ, Kim TG (May 2010). "Clinical features of the microform cleft lip and the ultrastructural characteristics of the orbicularis oris muscle". Cleft Palate Craniofac. J. 47 (3): 297–302. doi:10.5555/08-270.1. PMID 19860522.
  6. ↑ Yuzuriha S, Mulliken JB (November 2008). "Minor-form, microform, and mini-microform cleft lip: anatomical features, operative techniques, and revisions". Plast. Reconstr. Surg. 122 (5): 1485–93. doi:10.1097/PRS.0b013e31818820bc. PMID 18971733.
  7. ↑ Tosun Z, Hoşnuter M, Sentürk S, Savaci N (2003). "Reconstruction of microform cleft lip". Scand J Plast Reconstr Surg Hand Surg 37 (4): 232–5. doi:10.1080/02844310310016412. PMID 14582757.
  8. ↑ Tollefson TT, Humphrey CD, Larrabee WF, Adelson RT, Karimi K, Kriet JD (2011). "The spectrum of isolated congenital nasal deformities resembling the cleft lip nasal morphology". Arch Facial Plast Surg 13 (3): 152–60. doi:10.1001/archfacial.2011.26. PMID 21576661.
  9. ↑ "Statistics by country for cleft palate". WrongDiagnosis.com. Retrieved 2007-04-24.
  10. 1 2 Sloan GM (2000). "Posterior pharyngeal flap and sphincter pharyngoplasty: the state of the art". Cleft Palate Craniofac. J. 37 (2): 112–22. doi:10.1597/1545-1569(2000)037<0112:PPFASP>2.3.CO;2. PMID 10749049.
  11. ↑ Hill JS (2001). "Velopharyngeal insufficiency: An update on diagnostic and surgical techniques". Current Opinion in Otolaryngology & Head and Neck Surgery 9 (6): 365–8. doi:10.1097/00020840-200112000-00005.
  12. ↑ Kaplan EN (1975). "The Occult and Submucous Cleft Palate". Cleft Palate Journal 12: 356–68. PMID 1058746.
  13. ↑ Leonard BJ, Brust JD (1991). "Self-concept of children and adolescents with cleft lip and/or palate". Cleft Palate Craniofac. J. 28 (4): 347–353. doi:10.1597/1545-1569(1991)028<0347:SCOCAA>2.3.CO;2. PMID 1742302.
  14. ↑ Tobiasen JM (July 1984). "Psychosocial correlates of congenital facial clefts: a conceptualization and model". Cleft Palate J 21 (3): 131–9. PMID 6592056.
  15. ↑ Pope AW, Ward J (1997). "Self-perceived facial appearance and psychosocial adjustment in preadolescents with craniofacial anomalies". Cleft Palate Craniofac. J. 34 (5): 396–401. doi:10.1597/1545-1569(1997)034<0396:SPFAAP>2.3.CO;2. PMID 9345606.
  16. ↑ Bristow & Bristow 2007, pp. 82–92
  17. ↑ "Cleft Palate Foundation". Retrieved 2007-07-01.
  18. ↑ Snyder HT, Bilboul MJ, Pope AW (2005). "Psychosocial adjustment in adolescents with craniofacial anomalies: a comparison of parent and self-reports". Cleft Palate Craniofac. J. 42 (5): 548–55. doi:10.1597/04-078R.1. PMID 16149838.
  19. ↑ Endriga MC, Kapp-Simon KA (1999). "Psychological issues in craniofacial care: state of the art". Cleft Palate Craniofac. J. 36 (1): 3–11. doi:10.1597/1545-1569(1999)036<0001:PIICCS>2.3.CO;2. PMID 10067755.
  20. 1 2 Pope AW, Snyder HT (July 2005). "Psychosocial adjustment in children and adolescents with a craniofacial anomaly: age and sex patterns". Cleft Palate Craniofac. J. 42 (4): 349–54. doi:10.1597/04-043R.1. PMID 16001914.
  21. ↑ Prokhorov AV, Perry CL, Kelder SH, Klepp KI (1993). "Lifestyle values of adolescents: results from Minnesota Heart Health Youth Program". Adolescence 28 (111): 637–47. PMID 8237549.
  22. ↑ Dudas M, Li WY, Kim J, Yang A, Kaartinen V (2007). "Palatal fusion — where do the midline cells go? A review on cleft palate, a major human birth defect". Acta Histochem. 109 (1): 1–14. doi:10.1016/j.acthis.2006.05.009. PMID 16962647.
  23. ↑ Dudas M, Li WY, Kim J, Yang A, Kaartinen V (2007). "Palatal fusion — where do the midline cells go? A review on cleft palate, a major human birth defect". Acta Histochem. 109 (1): 1–14. doi:10.1016/j.acthis.2006.05.009. PMID 16962647.
  24. ↑ Beaty TH, Ruczinski I, Murray JC; et al. (May 2011). "Evidence for gene-environment interaction in a genome wide study of isolated, non-syndromic cleft palate". Genet Epidemiol 35 (6): 469–78. doi:10.1002/gepi.20595. PMC 3180858. PMID 21618603.
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  26. ↑ FaceBase. (2012). Gene Wiki. Retrieved from https://www.facebase.org/resources/gene-wiki.
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  34. ↑ Hardikar syndrome symptoms
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  37. ↑ Millicovsky, G.; Johnston, M.C. (1981). "Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL/Fr mice". Proc. Natl. Acad. Sci. U.S.A. 78 (9): 5722–5723. doi:10.1073/pnas.78.9.5722. PMC 348841. PMID 6946511.
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  39. ↑ Hurst, J. A.; Houlston, R.S.; Roberts, A.; Gould, S.J.; Tingey, W.G. (1995). "Transverse limb deficiency, facial clefting and hypoxic renal damage: an association with treatment of maternal hypertension?". Clin. Dysmorphol. 4 (4): 359–363. doi:10.1097/00019605-199510000-00013. PMID 8574428.
  40. ↑ Boyles AL, Wilcox AJ, Taylor JA; et al. (February 2008). "Folate and One-Carbon Metabolism Gene Polymorphisms and Their Associations With Oral Facial Clefts". American Journal of Medical Genetics 146A (4): 440–9. doi:10.1002/ajmg.a.32162. PMC 2366099. PMID 18203168.
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  42. ↑ Tessier P (June 1976). "Anatomical classification facial, cranio-facial and latero-facial clefts". J Maxillofac Surg 4 (2): 69–92. doi:10.1016/S0301-0503(76)80013-6. PMID 820824.
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  44. ↑ Lydiatt DD, Yonkers AJ, Schall DG (November 1989). "The management of the cleft lip and palate patient". Nebr Med J 74 (11): 325–8; discussion 328–9. PMID 2586685.
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