|Year : 2019 | Volume
| Issue : 2 | Page : 73-83
A comprehensive review of orofacial cleft patients at a university hospital genetic department in the UK
Rajshree Jayarajan1, Pradeep Vasudevan2
1 Department of Plastic Surgery , University Hospitals of Leicester, Leicester, UK
2 Department of Genetics, University Hospitals of Leicester, Leicester, UK
|Date of Web Publication||7-Aug-2019|
Dr. Rajshree Jayarajan
Department of Plastic Surgery, University Hospitals of Leicester, Leicester
Source of Support: None, Conflict of Interest: None
Background: Cleft lip and palate or isolated cleft palate is one of the most common congenital anomalies with a general prevalence of 1 in 700 live births. The aetiology is considered to be a combination of genetic and environmental factors. Clinical genetics service provides information, diagnosis, counselling, management and support to patients and families with genetic disorders. Materials and Methods: Data collection was carried out retrospectively from the Genetics department database. The details regarding referrals, assessment, genetic tests and outcomes were analyzed. Results: There were 33 cases from 2012 to 2016. The majority of cases (61%) were White British. Others included Caribbean, Chinese, Indian, Other Asian, and other mixed categories. 67% of patients had associated other anomalies ranging from being part of a syndrome to separate entities. 36% had family history of clefts and 24% of family members had anomalies other than cleft. Genetic analysis showed abnormality only in 4 of the cases (12%) and 2 had results of unknown significance. Conclusions: Genetic counselling should be built into the plan of cleft care in a structured manner and made available to both patients and parents. There should be a global approach to improve identification and analysis of functional elements controlling gene expression. Integration of genetics and environmental risk using epigenetics is warranted so that aetiology can be better defined and eventual outcome would be more effective clinical care and prevention.
Keywords: Chromosomal microarray, cleft lip, cleft palate, genetic counseling, genetics
|How to cite this article:|
Jayarajan R, Vasudevan P. A comprehensive review of orofacial cleft patients at a university hospital genetic department in the UK. J Cleft Lip Palate Craniofac Anomal 2019;6:73-83
|How to cite this URL:|
Jayarajan R, Vasudevan P. A comprehensive review of orofacial cleft patients at a university hospital genetic department in the UK. J Cleft Lip Palate Craniofac Anomal [serial online] 2019 [cited 2020 Jan 19];6:73-83. Available from: http://www.jclpca.org/text.asp?2019/6/2/73/264098
| Introduction|| |
Orofacial cleft is one of the most common congenital anomalies with a general prevalence of 1 in 700 live births. The incidence is highest in Asians and North American Indians (1 in 500) and lowest in Africans (1 in 2500). Syndromic clefts are associated with other malformations and are usually due to a single gene. There are 2027 entries in Online Mendelian Inheritance in Man when searched under “cleft lip and palate.” Majority of orofacial clefts are nonsyndromic –70% of cleft lip/palate cases and 50% of cleft palate cases Nonsyndromic cleft lip/palate (NSCL/P). The classification into syndromic or nonsyndromic is based on the presence or absence of other congenital anomalies in addition to the cleft. Syndromic clefts are caused primarily by chromosomal anomalies.
The etiology of NSCL/P is considered to be a combination of genetic and environmental factors. The variations in prevalence across the continents and various socioeconomic classes point to a likelihood of environmental influences. Some of the environmental factors implicated are medications during pregnancy, maternal alcohol consumption and smoking, dietary and vitamin deficiencies, diabetes, antiepileptic drugs, environmental toxins, altitude, birth order, socioeconomic status, and parental age.,,,,
A multitude of genetic approaches, such as genome-wide and candidate gene association studies, linkage analysis, whole-exome sequencing, and whole-genome sequencing, have been undertaken to identify pathogenic genetic variants. These results suggest etiologic heterogeneity among populations and the presence of multiple genes involved in the etiology of cleft lip with or without cleft palate (CL/P).
Orofacial cleft is a condition which can only be managed by a multidisciplinary team approach – the team consisting of pediatrician; cleft surgeon; ear, nose, and throat surgeon; speech therapist; orthodontist; maxillofacial surgeon; psychologist; and geneticist.
A proper understanding of the etiology of clefts is required for prevention and treatment and to determine the prediction of prognosis for individuals affected by the disorder.
Genetic assessment and chromosomal analysis forms part of the care pathway for cleft patients. “All patients (and their parents) will be offered a referral to the clinical genetic team when appropriate and at discharge from the cleft team” as per the core standard service specification of NHS England.
| Methodology|| |
Data collection was done from 2012 to 2016 from the genetic department database.
All patients were seen and reviewed by a clinical geneticist. The patients underwent a comprehensive assessment of family history, detailed examination, and investigations as required, to identify if there is a likely genetic cause for cleft.
A retrospective review of mode of cleft referrals and characteristics of the referred patients to the Department of Genetics of University Hospitals of Leicester over a period of 5 years was done [Table 1]. A detailed analysis of the results was carried out to provide insight into:
- Population-based prevalence of cleft referrals obtained in this area of multiethnic groups
- Ethnic variations
- Association of the clefts with other anomalies if any
- Results of genetic analysis
- Frequency of family history of the same condition
- Presence of other anomalies in family members.
| Results|| |
The Department of Genetics in University Hospitals of Leicester, UK, is contracted to see genetic cases in Leicester, Leicestershire, and Rutland, a population of over 1.1 million with an annual birth rate of approximately 10,000. The data in this study are from the genetic database here and not a cleft center.
The data collection was done retrospectively for a period of 5 years from 2012 to 2016. All patients seen in the genetic department from 2012 to 2016 have been included. Duplicates from the previous year's carryover were eliminated. This resulted in a total of 33 new referrals. Details of family history and associated anomalies are from the records when seen in the department as well as referral letters and other clinical records available in the system.
[Figure 1] shows the distribution over the 5 years.
From the analysis of the cases presented here, there has been a predominance in cleft in the White British to as much as 61% [Figure 2] out of all the references to genetics. Distribution of clefts by about 40% in other ethnic groups reflects the multiethnic nature of Leicester.
As expected, the majority of patients referred to genetics have been having the finding of several associated anomalies [Figure 3] in the cleft children, even though all of them could not be included in any of the syndromic categories. These included tracheo-oesophageal fistula, atrial septal defect, inguinal/umbilical hernia, coloboma, pectus excavatum, dysplastic kidney and other renal anomalies, strabismus, seizures, behavioral problems, and learning difficulties.
A family history of clefts was seen in 36% (about a third) of the total patients [Figure 4]. Out of the 12 patients with family history positive, 11 were either the parent or a sibling.
An interesting feature is that approximately one-fourth (24%) of the patients [Figure 5] had a family history of anomalies other than cleft. The anomalies in the siblings of the cleft children included tracheo-oesophageal fistula in the sibling of a cleft child with TOF and another sibling of the same child having laryngomalacia. Other anomalies noted in family members were dyslexia, cardiac anomalies, and learning difficulties.
Genetic analysis of the cleft patients yielded definitive positive results only in 4 of the 33 cases tested [Figure 6]. An extra chromosome in short arm 2p11.2 was detected in one case, and a patient with Pierre Robin sequence showed microarray 1–2 Mb deletion within band 13q12.2 and 0.19 Mb deletion within band 16p11.2. MLL2 gene change was detected in one indicating Kabuki syndrome. BCORc3809G. Ap.(Tr-p1270Ter) was confirmed in a child with oculofaciocardiodental syndrome.
Two other patients yielded results which are of uncertain significance. They were recruited to Deciphering Developmental Disorder study. No reports are available for four cases seen initially in the clinic.
| Discussion|| |
Widely clefts can be classified as cleft lip (CL), cleft lip and palate (CLP), or cleft palate alone (CP). Primary and secondary palates have a distinct developmental origin, but CL and CLP share a defect of the primary palate and therefore the inclusion in a common group CL/P.
In addition, there are subclinical phenotypes – microform cleft of lip which could present as a scar on body of lip or a notch in the vermillion and submucous cleft of palate which may manifest as a bifid uvula, a blue line in the midline of soft palate (indicating the absence of muscle in the midline), or a notch in the hard palate. These may represent incomplete penetration or lack of Mendelian inheritance patterns.
Embryology of cleft lip and palate
The normal developmental process of the face requires the coordination of a series of events which includes cell growth, migration, and differentiation. A complex mechanism is involved in the embryogenesis at a molecular level.
The face develops during the 4th week of intrauterine life when neural crest cells migrate to form five facial primordia – the frontonasal prominence, paired maxillary and mandibular processes. The maxillary process derived from the proximal half of the first arch grows to meet and fuse with the nasal processes (medial and lateral). Failure in growth or fusion at this stage results in cleft involving the upper lip, alveolus and/or primary palate. The mesodermal reinforcement along the line of fusion is impaired in cleft cases resulting in breakdown. The secondary palate arises from two palatal shelves which are initially vertical due to the interposition of the tongue at this stage. The proposed theory for palatal formation is, with mandibular development and tongue dropping downward by the 7th week, the palatal shelves swing into a horizontal position and fuse.
Isolated cleft lip and palate
The etiology of isolated clefts, when syndromes and dominant families have been excluded, is a combination of genetic and environmental factors. A number of candidate genes have been identified some of which play a major role in cleft development. Schliekelman and Slatkin estimate that 3–6 major genetic loci may contribute to clefts. IRF6 plays a substantial role with an attributable risk of 12% [Table 2].
|Table 2: Recurrence rate of isolated cleft lip with or without cleft palate|
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Isolated cleft palate
Infants with CP are more likely to have associated malformations and syndromes than those with CL/P. Examination and required investigations are done to exclude these prior to counseling. Recurrence risk is shown in [Table 3].
Older studies give a 5%–15% risk for offspring of an affected parent. This may not truly represent isolated CP as some affected individuals may have a dominant condition or del 22q11 that would now be detected and a lower risk is likely.
Several molecules have been implicated in signaling facial primordial identity, epithelial differentiation, and shelf remodeling – Extra cellular matrix (ECM) molecules, growth factors such as sonic hedgehog, bone morphogenetic protein, fibroblast growth factors, and members of the transforming growth factor-beta (TGF-beta)., Elevation of palatal shelves and fusion is accelerated by TGF-beta. Other growth factors such as epidermal growth factor and transforming growth factor-alpha (TGF-alpha) also play an important role in the biosynthesis of ECM in the palatal shelves.
The first gene to be associated with CL/P is TGF-alpha, 2p13. There are a multitude of genes linked to clefts and the numbers keep changing rapidly. Description of these is beyond the purpose of this article.
Leicester is one of the most multiethnic areas in the United Kingdom. Even though 89% of the population in Leicestershire is White British, in Leicester city White British constitutes only 45% of the population as evidenced from the 2011 census [Figure 7].
|Figure 7: Ethnic diversity 1991–2011 (local dynamics of diversity: evidence from 2011 Census. With permission from Centre on Dynamics of Ethnicity)|
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In our 5-year data, 61% of patients were White British, 6% Indian, 6% Caribbean, and 3% each – Chinese, other Asian, and other mixed. In 18% of patients, the ethnicity was not recorded. We have not looked into area-specific referrals.
Prenatal detection of CL is possible using ultrasound at 20 weeks of gestation. It may not be detected on routine obstetric scans, and a small cleft may be missed even with expert scanning. CP is difficult to detect in Ultra sound scan (USS) in pregnancy. The small jaw of Pierre Robin sequence may be visualized with specialist training.
According to the Cleft Registry and Audit Network analysis of children born in 2016, the majority of all babies with a cleft diagnosed in 2016 were antenatal (42.9%) or at birth (42.9%). The proportion of children diagnosed antenatal varies according to cleft type (P < 0.001), with only 1.3% of CP patients diagnosed antenatally in 2016 compared to rates of 67%, 82.4%, and 88.3% for CL, bilateral CLP, and unilateral CLP (UCLP), respectively.
In our series, there were 9 cases of cleft which had been detected by ultrasound antenatally, of which four were bilateral, three UCLP, and one CL. Type of cleft in one of these is unavailable. None of those detected by USS were cases of isolated CP.
No history of exposure to teratogens has been noted in any of the cases.
Prenatal chromosomal microarray (CMA), which provides higher resolution compared to standard karyotype used earlier, can be offered as an option when there is a strong family history of clefts or when a cleft is detected in routine USS.
Association with other anomalies
Orofacial clefts in conjunction with other defects are considered syndromic clefts. These have a strong genetic etiology. Even though not part of a named syndrome, there are various anomalies involving different systems of the body that can be associated with clefts.
In our series, 67% of the total number had other anomalies in addition to the cleft, most of which could not be placed under a named syndrome.
It is considered that loss-of-function coding mutations could result in a syndrome with a cleft, while downregulation of expression through a tissue-specific regulator could manifest just as an isolated cleft. In a study of patients with NSCL/P, 3.2% demonstrated malformations of the central nervous system such as dysgenesis of the corpus callosum and holoprosencephaly (HPE). One pathway that is known to play a critical role in cranial anomalies is the hedgehog signaling pathway, which has an important association with complex abnormalities, particularly HPE, hypotelorism, and CL/P. Conductive hearing loss is a common complication in CP due either to mechanical disruption or to otitis media caused by the connection of the Eustachian tube to the cleft-exposed oral cavity. Apart from this, a link between hearing loss and brain abnormalities in orofacial clefts seems to be substantial and the key could be due to abnormality in the superior temporal plane. Association between NSCL/P and cancer has also been found in various studies.,, The association was most frequent for breast cancer but also found in colorectal, gastric, prostate, and uterine cancers.
A study of orofacial clefts by Hadadi et al. including 196 orofacial clefts showed syndromic cases to be 19% and other congenital anomalies as high as 21% with congenital heart anomaly being the commonest (58.5%). A 31-year study in Portugal between 1981 and 2012 with 701 orofacial clefts had 219 cases (31.2%) with associated congenital malformations. In their series, the most common were head and neck malformations (60.3%), followed by cardiovascular (28.3%).
Association of major congenital anomalies with orofacial clefts has been reported to be about 20% of liveborn infants and it is assumed that the figure is much higher among stillborn as per the global registry database on craniofacial anomalies. Their study based on 15 registries included infants registered with CL or CP and other defects from 7,180,511 live births, stillbirths, and terminated pregnancies. A detailed breakup of the types has shown 11.4% of CL/P infants and 8.4% of CP infants with multiple malformation. The most frequent association was congenital heart defects (28.6%).
Family history of clefts
The risk of having a child with cleft based on the incidence in the other members of the family is shown in [Table 2] and [Table 3].
Analysis of the patients referred to the genetic department over 5 years showed that 36% of the total cases had a member in the family affected by cleft. The high values could be explained by the fact that the referrals to genetics are usually the severe ones and ones with family history. It is also worth noting that 24% of the cases had a family member with an anomaly other than cleft. No history of consanguinity has been found in any of the cases.
Genes and environmental factors
A very interesting finding in the study of susceptibility genes for CL/P is the attempt to correlate specific gene variants with specific environmental risk factors. It has been suggested that some genetic variants could represent a background risk which is accentuated on exposure to some environmental agents [Table 4]. In many cases, these variants were not detected in the affected child but the mother. This represents an important step in the prevention of NSCL/P where it is possible to identify the genetic component and the specific environmental agent and avoid exposure to the agent.
|Table 4: Gene-environment interactions in the pathogenesis of cleft lip with or without cleft palate|
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During the study period, genetic analysis was done with G banding in the department. Since 2017, CMA has been in use. As this has high sensitivity for submicroscopic aberrations, we will be conducting another study in the next 5 years where we expect to be able to pick up the subtler aberrations.
The relevance of genetic analysis and counseling in cleft patients
Diagnosis of a syndrome in a child is important to the treating physician as well as the parents. The management decisions depend on the extent of involvement. For example, a cleft child with trisomy 13 (Patau syndrome) has substantial involvement of various systems, many of which are not compatible with life, and the median survival is only 3 months. The child may not have a typical presentation for clinical diagnosis, and hence, it is imperative that a genetic analysis should be carried out to obtain an accurate diagnosis so that a treatment plan can be formulated [Figure 8]. The recurrence risk is low for the free trisomy 13 variant, while it is high for the partial trisomy 13 and Robertsonian variants. Hence, karyotyping of parents is essential in this situation to address the risk for future pregnancies and to carry out prenatal cytogenetic testing. With the availability of noninvasive prenatal testing now, where the mother's blood sample is used for testing the DNA of the fetus, there is no risk to either the mother or the fetus as for the earlier tests such as amniocentesis and chorionic villus sampling. Preimplantation genetic diagnosis is also available.
Trisomy 18 (Edwards' syndrome) which is also associated with clefts is another severe condition with life-threatening medical problems with only 5%–10% of children surviving past their 1st year. However, most cases are not inherited. Only partial trisomy 18 is inherited, people who carry a balanced translocation with no signs of the syndrome are at an increased risk of having children with the condition.
In less severe syndromes, once a clear-cut diagnosis has been made, accessibility to social care and special education is available for the child unlike a generic statement that the child has CP and speech problems. This also helps parents to get guidance and backing from support groups and provides eligibility to enter the child for research trials.
Recently, many centers have introduced microarray as a first line of testing. Even if this is found to be normal, if a syndrome is suspected, it would be judicious to refer to genetics for an expert analysis.
Asian countries with high incidence of cleft, especially India, where state-of-the-art cleft care is being provided in many centers, lack of registries and data collection on a national basis has resulted in a lag in terms of research and publications in this field. Building up genetic counseling as a regular part of the multidisciplinary cleft care would have a positive impact on future management. There is potential for India to be a pacesetter in this field if the wealth of material available can be utilized by setting up registries, database, and protocols at state level to begin with and then national level.
| Conclusion|| |
The inheritance pattern in clefts is confounded by gene–gene and gene–environment interactions, and studies investigating the role of epigenetic factors in cleft etiology are progressing. It would be prudent to refer cleft cases which are detected in prenatal scans and those with other congenital anomalies or syndromes and family history of clefts for genetic assessment. As our understanding of the risk factors for NSCL\P has improved and we are now armed with more sensitive diagnostic tests, we will be able to provide more accurate genetic analysis and counseling and thus providing parents with accurate information regarding the condition, and the likelihood recurrence, to enable them to make informed choices regarding pregnancy and future management. Identification of further genes in relation to CL/P and analysis through high-efficiency systems will help in investigating several risk alleles, and thus, a personalized prevention strategy can be organized for carriers.
The authors would like to thank Aiswarya Lakshmi for help with data collection and preparation of charts and Anand Raghavan for help with collection of ethnic data.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Murthy J, Bhaskar L. Current concepts in genetics of nonsyndromic clefts. Indian J Plast Surg 2009;42:68-81.
] [Full text]
Yu Y, Zuo X, He M, Gao J, Fu Y, Qin C, et al.
Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity. Nat Commun 2017;8:14364.
Vieira AR. Genetic and environmental factors in human cleft lip and palate. Front Oral Biol 2012;16:19-31.
Little J, Cardy A, Munger RG. Tobacco smoking and oral clefts: A meta-analysis. Bull World Health Organ 2004;82:213-8.
Spilson SV, Kim HJ, Chung KC. Association between maternal diabetes mellitus and newborn oral cleft. Ann Plast Surg 2001;47:477-81.
Castilla EE, Lopez-Camelo JS, Campaña H. Altitude as a risk factor for congenital anomalies. Am J Med Genet 1999;86:9-14.
Vieira AR, Orioli IM, Murray JC. Maternal age and oral clefts: A reappraisal. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:530-5.
Yang J, Carmichael SL, Canfield M, Song J, Shaw GM. National Birth Defects Prevention Study. Socioeconomic status in relation to selected birth defects in a large multicentered US case-control study. Am J Epidemiol 2008;167:145-54.
Schliekelman P, Slatkin M. Multiplex relative risk and estimation of the number of loci underlying an inherited disease. Am J Hum Genet 2002;71:1369-85.
Stanier P, Moore GE. Genetics of cleft lip and palate: Syndromic genes contribute to the incidence of non-syndromic clefts. Hum Mol Genet 2004;13:R73-81.
Ferguson MW, Honig LS. Epithelial-mesenchymal interactions during vertebrate palatogenesis. Curr Top Dev Biol 1984;19:137-64.
Dixon MJ, Carette MJ, Moser BB, Ferguson MW. Differentiation of isolated murine embryonic palatal epithelium in culture: Exogenous transforming growth factor alpha modulates matrix biosynthesis in defined experimental conditions. In Vitro
Cell Dev Biol 1993;29A:51-61.
Ardinger HH, Buetow KH, Bell GI, Bardach J, VanDemark DR, Murray JC. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet 1989;45:348-53.
Setó-Salvia N, Stanier P. Genetics of cleft lip and/or cleft palate: Association with other common anomalies. Eur J Med Genet 2014;57:381-93.
Shen EY, Huang FY. Cleft lip and palate associated with malformation of the central nervous system: A prospective neurosonographic study. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1996;37:39-44.
Belloni E, Muenke M, Roessler E, Traverso G, Siegel-Bartelt J, Frumkin A, et al.
Identification of sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet 1996;14:353-6.
Dietz A, Pedersen DA, Jacobsen R, Wehby GL, Murray JC, Christensen K. Risk of breast cancer in families with cleft lip and palate. Ann Epidemiol 2012;22:37-42.
Menezes R, Marazita ML, Goldstein McHenry T, Cooper ME, Bardi K, Brandon C, et al.
AXIS inhibition protein 2, orofacial clefts and a family history of cancer. J Am Dent Assoc 2009;140:80-4.
Lima LS, Silvério Mde O, Swerts MS, Aquino SN, Martelli DR, Martelli-Júnior H. Frequency of cancer in first-degree relatives of patients with cleft lip and/or palate in the Brazilian population. Braz Dent J 2013;24:200-3.
Hadadi AI, AlWohaibi D, Almtrok N, Aljahdali N, AIMeshal O, Badri M. Congenital anomalies associated with syndromic and non-syndromic cleft lip and palate. JPRAS Open 2017;14:5-15.
Pereira AV, Fradinho N, Carmo S, de Sousa JM, Rasteiro D, Duarte R, et al.
Associated malformations in children with orofacial clefts in portugal: A 31-year study. Plast Reconstr Surg Glob Open 2018;6:e1635.
Stuppia L, Capogreco M, Marzo G, La Rovere D, Antonucci I, Gatta V, et al.
Genetics of syndromic and nonsyndromic cleft lip and palate. J Craniofac Surg 2011;22:1722-6.
Hwang SJ, Beaty TH, Panny SR, Street NA, Joseph JM, Gordon S, et al.
Association study of transforming growth factor alpha (TGF alpha) taqI polymorphism and oral clefts: Indication of gene-environment interaction in a population-based sample of infants with birth defects. Am J Epidemiol 1995;141:629-36.
Shaw GM, Wasserman CR, Lammer EJ, O'Malley CD, Murray JC, Basart AM, et al.
Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. Am J Hum Genet 1996;58:551-61.
Shaw GM, Wasserman CR, Murray JC, Lammer EJ. Infant TGF-alpha genotype, orofacial clefts, and maternal periconceptional multivitamin use. Cleft Palate Craniofac J 1998;35:366-70.
Christensen K, Olsen J, Nørgaard-Pedersen B, Basso O, Støvring H, Milhollin-Johnson L, et al.
Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: A population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 1999;149:248-55.
Maestri NE, Beaty TH, Hetmanski J, Smith EA, McIntosh I, Wyszynski DF, et al.
Application of transmission disequilibrium tests to nonsyndromic oral clefts: Including candidate genes and environmental exposures in the models. Am J Med Genet 1997;73:337-44.
Romitti PA, Lidral AC, Munger RG, Daack-Hirsch S, Burns TL, Murray JC, et al.
Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: Evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts. Teratology 1999;59:39-50.
Beaty TH, Hetmanski JB, Zeiger JS, Fan YT, Liang KY, VanderKolk CA, et al.
Testing candidate genes for non-syndromic oral clefts using a case-parent trio design. Genet Epidemiol 2002;22:1-11.
Boyles AL, DeRoo LA, Lie RT, Taylor JA, Jugessur A, Murray JC, et al.
Maternal alcohol consumption, alcohol metabolism genes, and the risk of oral clefts: A population-based case-control study in Norway, 1996-2001. Am J Epidemiol 2010;172:924-31.
Rothman KJ, Moore LL, Singer MR, Nguyen US, Mannino S, Milunsky A, et al.
Teratogenicity of high Vitamin A intake. N
Engl J Med 1995;333:1369-73.
Little J, Gilmour M, Mossey PA, Fitzpatrick D, Cardy A, Clayton-Smith J, et al.
Folate and clefts of the lip and palate – A U.K.-Based case-control study: Part II: Biochemical and genetic analysis. Cleft Palate Craniofac J 2008;45:428-38.
Shaw GM, Todoroff K, Finnell RH, Rozen R, Lammer EJ. Maternal vitamin use, infant C677T mutation in MTHFR, and isolated cleft palate risk. Am J Med Genet 1999;85:84-5.
Jugessur A, Wilcox AJ, Lie RT, Murray JC, Taylor JA, Ulvik A, et al.
Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads. Am J Epidemiol 2003;157:1083-91.
Chevrier C, Perret C, Bahuau M, Zhu H, Nelva A, Herman C, et al.
Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts. Am J Med Genet A 2007;143A: 248-57.
Kamal M, Varghese D, Bhagde J, Singariya G, Simon AM, Singh A, et al.
Anesthesia in a child operated for cleft lip associated with Patau's syndrome. Rev Bras Anestesiol 2018;68:197-9.
Plaiasu V, Ochiana D, Motei G, Anca I, Georgescu A. Clinical relevance of cytogenetics to pediatric practice. Postnatal findings of Patau syndrome – Review of 5 cases. Maedica (Buchar) 2010;5:178-85.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4]