Deep orofacial phenotyping of population-based infants with isolated cleft lip and isolated cleft palate

AbstractIsolated orofacial clefts (OFC) are common with poorly understood aetiology. Heterogeneous phenotypes and subphenotypes confound aetiological variant findings. To improve OFC phenome understanding, population-based, consecutive, pre-treatment infants with isolated unilateral cleft lip (UCL, n = 183) and isolated cleft palate (CP, n = 83) of similar ancestry were grouped for deep phenotyping. Subphenotypes stratified by gender and cleft severity were evaluated for primary dental malformations and maturation using radiographs. We found that cleft severity and tooth agenesis were inadequate to distinguish heterogeneity in infants with UCL and CP. Both groups featured slow dental maturity, significantly slower in males and the UCL phenotype. In 32.8% of infants with UCL, supernumerary maxillary lateral incisors were present on the cleft lip side, but not in infants with CP, suggesting a cleft dental epithelium and forme fruste cleft dentoalveolus of the UCL subphenotype. The findings underscored the importance of deep phenotyping to disclose occult OFC subphenotypes.

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A Population-Based Evaluation of Antenatal Diagnosis of Orofacial Clefts

The Cleft Palate-Craniofacial Journal ◽

10.1597/06-202.1 ◽

2008 ◽

Vol 45 (2) ◽

pp. 148-153 ◽

Cited By ~ 21

Author(s):

Kathleen A. Russell ◽

Victoria M. Allen ◽

Mary E. MacDonald ◽

Kirsten Smith ◽

Linda Dodds

Keyword(s):

Nova Scotia ◽

Cleft Palate ◽

Cleft Lip ◽

Chromosomal Abnormalities ◽

Antenatal Diagnosis ◽

Population Based ◽

Orofacial Clefts ◽

Antenatal Detection ◽

Type Mode ◽

Isolated Cleft Palate

Objectives: To evaluate the changes in prevalence and antenatal detection of cleft lip with or without cleft palate and isolated cleft palate and to describe the association between anomalies and rates of antenatal diagnosis in Nova Scotia from 1992 to 2002. Design: This population-based cohort study employed the Nova Scotia Atlee Perinatal Database, the Fetal Anomaly Database, and IWK Cleft Palate Database in Halifax, Nova Scotia, Canada. Outcome Measures: Cleft type, mode of diagnosis, and associated abnormalities of orofacial clefts for liveborn infants, stillbirths, and second trimester terminations of pregnancy between 1992 and 2002 were determined. Results: There were 225 fetuses identified as having orofacial clefts. The overall prevalence of clefts was 2.1 in 1000 live births, and this prevalence did not change with time. The overall antenatal detection of cleft lip with or without cleft palate was 23%; however, there was improvement in detection of cleft lip with or without cleft palate from the years 1992 to 1996 (14%) to the years 1997 to 2002 (30%, p = .02). No isolated cleft palates were detected antenatally. Associated structural anomalies were seen in 34.2% of cases with orofacial clefts, and chromosomal abnormalities were associated with 9.8%. Conclusions: The prevalence of orofacial clefts in Nova Scotia has not changed from 1992 to 2002. The proportion of antenatally diagnosed cleft lip with or without cleft palate in Nova Scotia is consistent with rates reported in the literature and has increased from 1992 to 2002.

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Maternal Smoking during Early Pregnancy, GSTP1 and EPHX1 Variants, and Risk of Isolated Orofacial Clefts

The Cleft Palate-Craniofacial Journal ◽

10.1597/06-011.1 ◽

2007 ◽

Vol 44 (4) ◽

pp. 366-373 ◽

Cited By ~ 15

Author(s):

Dorian Ramirez ◽

Edward J. Lammer ◽

David M. Iovannisci ◽

Cecile Laurent ◽

Richard H. Finnell ◽

...

Keyword(s):

Cleft Palate ◽

Maternal Smoking ◽

Cleft Lip ◽

Detoxification Enzymes ◽

Glutathione S Transferase ◽

Orofacial Clefts ◽

Functional Polymorphisms ◽

Increased Risk ◽

Cleft Lip Palate ◽

Isolated Cleft Palate

Objective: To examine the interactions between four fetal xenobiotic metabolizing gene polymorphisms, maternal cigarette smoking, and risk for oral cleft defects. Design and Participants: California population–based case-control study of 431 infants born with isolated orofacial clefts and 299 nonmalformed controls. Main Outcome Measures: Infants were genotyped for functional polymorphisms of the detoxification enzymes microsomal epoxide hydrolase-1 (EPHX1 T→C [Tyr113His], and A→G [His139Arg]), and glutathione-S transferase Pi-1 (GSTP1 A→G [Ile105Val] and C→T [Ala114Val]), and risks for cleft outcomes were measured for gene only and gene-maternal smoking effects. Results: Although smoking was associated with an increased risk for isolated cleft lip ± palate, we found no independent associations of genotypes of EPHX1-codon 113 or GSTP1-codon 105 polymorphisms for either isolated cleft lip ± palate or isolated cleft palate. The heterozygote genotype for the EPHX1-codon 139 polymorphism was associated with an increased risk of isolated cleft palate (odds ratio = 1.6 [95% confidence interval, 1.0 to 2.6]). Infant EPHX1 and GTSP1 polymorphic variants did not appreciably alter the risks for clefts associated with maternal smoking, nor were any EPHX1 combined genotype-specific risks found. Infant genotypes of the GSTP1-codon 105 polymorphism, combined with glutathione-S-transferase-μ-1 null genotypes, did not appreciably alter the risk of orofacial clefts. Conclusions: Our results suggest that genetic variation of the detoxification enzymes EPHX1 and GSTP1 did not increase the risks of orofacial clefting, nor do they influence the risks associated with maternal smoking.

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Birth Defect Co-Occurrence Patterns Among Infants With Cleft Lip and/or Palate

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211010060 ◽

2021 ◽

pp. 105566562110100

Author(s):

Maria Luisa Navarro Sanchez ◽

Renata H. Benjamin ◽

Laura E. Mitchell ◽

Peter H. Langlois ◽

Mark A. Canfield ◽

...

Keyword(s):

Cleft Palate ◽

Birth Defects ◽

Birth Defect ◽

Cleft Lip ◽

Population Based ◽

Orofacial Clefts ◽

Developmental Mechanisms ◽

Using Data ◽

Occurrence Patterns ◽

Population Based Registry

Objective: To investigate 2- to 5-way patterns of defects co-occurring with orofacial clefts using data from a population-based registry. Design: We used data from the Texas Birth Defects Registry for deliveries between 1999 and 2014 to Texas residents, including 1884 cases with cleft palate (CP) and 5289 cases with cleft lip with or without cleft palate (CL±P) without a known syndrome. We identified patterns of defects co-occurring with CP and with CL±P observed more frequently than would be expected if these defects occurred independently. We calculated adjusted observed-to-expected ( O/ E) ratios to account for the known tendency of birth defects to cluster nonspecifically. Results: Among infants without a syndrome, 23% with CP and 21% with CL±P had at least 1 additional congenital anomaly. Several combinations of defects were observed much more often than expected. For example, the combination of CL±P, congenital hydrocephaly, anophthalmia, and other nose anomalies had an O/ E ratio of 605. For both CP and CL±P, co-occurrence patterns with the highest O/ E ratios involved craniofacial and brain abnormalities, and many included the skeletal, cardiovascular, and renal systems. Conclusions: The patterns of defects we observed co-occurring with clefts more often than expected may help improve our understanding of the relationships between multiple defects. Further work to better understand some of the top defect combinations could reveal new phenotypic subgroups and increase our knowledge of the developmental mechanisms that underlie the respective defects.

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PAX7, PAX9 and RYK Expression in Cleft Affected Tissue

Medicina ◽

10.3390/medicina57101075 ◽

2021 ◽

Vol 57 (10) ◽

pp. 1075

Author(s):

Mārtiņš Vaivads ◽

Ilze Akota ◽

Māra Pilmane

Keyword(s):

Cleft Palate ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Rank Correlation ◽

Control Group ◽

Orofacial Clefts ◽

Spearman’S Rank Correlation ◽

Morphological Studies ◽

Affected Tissue ◽

Isolated Cleft Palate

Background and Objectives: Cleft lip with or without cleft palate is one of the most common types of congenital malformations. Transcription factors paired box 7 and 9 (PAX7, PAX9) and receptor-like tyrosine kinase (RYK) have been previously associated with the formation of orofacial clefts but their exact possible involvement and interactions in the tissue of specific cleft types remains uncertain. There is a limited number of morphological studies analyzing these specific factors in cleft affected tissue due to ethical aspects and the limited amount of available tissue material. This study analyses the presence of PAX7, PAX9, and RYK immunopositive structures within different cleft affected tissue to assess their possible involvement in cleft morphopathogenesis. Materials and Methods: Cleft affected tissue was collected from non-syndromic orofacial cleft patients during cleft correcting surgery (36 patients with unilateral cleft lip, 13 patients with bilateral cleft lip, 26 patients with isolated cleft palate). Control group oral cavity tissue was obtained from 7 patients without cleft lip and palate. To evaluate the number of immunopositive structures in the cleft affected tissue and the control group, a semiquantitative counting method was used. Non-parametric statistical methods (Kruskal–Wallis H test, Mann–Whitney U test, and Spearman’s rank correlation) were used. Results: Statistically significant differences for the number of PAX7, PAX9, and RYK-positive cells were notified between the controls and the patient groups. Multiple statistically significant correlations between the factors were found in each cleft affected tissue group. Conclusions: PAX7, PAX9, and RYK have a variable involvement and interaction in postnatal morphopathogenesis of orofacial clefts. PAX7 is more associated with the formation of unilateral cleft lip, while PAX9 relates more towards the isolated cleft palate. The stable presence of RYK in all cleft types indicates its possible participation in different facial cleft formations.

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Clinical and Epidemiologic Description of Orofacial Clefts in Bogota and Cali, Colombia, 2001-2015

The Cleft Palate-Craniofacial Journal ◽

10.1177/1055665617741062 ◽

2017 ◽

Vol 55 (4) ◽

pp. 517-520 ◽

Cited By ~ 4

Author(s):

K. Sarmiento ◽

S. Valencia ◽

G. Gracia ◽

P. Hurtado-Villa ◽

I. Zarante

Keyword(s):

Cleft Palate ◽

Cleft Lip ◽

Design Method ◽

Tertiary Care ◽

Craniofacial Anomalies ◽

Orofacial Clefts ◽

Care Facilities ◽

Surveillance Programs ◽

Monitoring And Surveillance ◽

Isolated Cleft Palate

Objectives: Among congenital craniofacial anomalies, orofacial clefts (OFCs) are the most common. Global prevalence is 2 in 1000 and in Colombia, 1 in 700. Our goal was to describe cleft palate (CP) prevalence and cleft lip with or without cleft palate (CL±P) from 2001 to 2015 in Bogota and Cali, Colombia. Method: Using the ECLAMC case-control design method, information was obtained from the Congenital Anomalies Monitoring and Surveillance Programs in Bogota and Cali. We describe the prevalence of cases classified into the following groups: isolated, polymalformed, and syndromic. The proportion of cases and controls was 1:4. Data were analyzed using frequency distribution and Student t test to compare means and 95% confidence intervals (CIs). Results: We identified 529 OFC cases and 2116 controls from 448,930 births: a rate of 11.8 per 10,000 (CI = 10.80-12.83). From the total cases, 73% were identified with CL/CP compared to 27% with CP. Males had higher CL±P (59%) prevalence, whereas the highest neonatal mortality was observed among polymalformed cases (7%). The most common anomaly identified among our cases was cleft lip without isolated cleft palate (58%). We found that OFCs are linked to birthweight, size, and gestational age and higher parity with statistically significant differences in all variables compared to controls. Conclusions: OFC is a highly prevalent anomaly in Colombia, with a range of maternal and infant differences across case subgroups. The identification of important OFC subgroups that follow certain patterns of prevalence may prove useful to primary and tertiary care facilities with the goal of reducing further disability.

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Dental Subphenotypes in Infants With Orofacial Clefts—A Longitudinal Population-Based Retrospective Radiographic Study of the Primary and Secondary Dentitions

The Cleft Palate-Craniofacial Journal ◽

10.1177/1055665621990148 ◽

2021 ◽

pp. 105566562199014

Author(s):

Mimi Yow ◽

Nuno V. Hermann ◽

Yuan Wei ◽

Agneta Karsten ◽

Sven Kreiborg

Keyword(s):

Cleft Lip ◽

Population Based ◽

Dental Anomalies ◽

Orofacial Clefts ◽

Developmental Patterns ◽

Dental Maturation ◽

Northern European ◽

Maxillary Lateral Incisor ◽

Isolated Cleft Palate ◽

Historical Controls

Objectives: To determine the developmental patterns of primary and secondary dentitions in infants with orofacial clefts. Design: Retrospective, longitudinal, population-based cohort study. Materials: Longitudinal records and radiographs of 192 nonsyndromic Northern European infants with isolated unilateral cleft lip (UCL, n = 111) and isolated cleft palate (CP, n = 81). Methods: Radiographic assessments of primary and secondary dentition anomalies and dental maturation, by gender and cleft severity for comparisons between the groups and with historical controls. Results: In infants with UCL, the frequencies of dental anomalies were high in both primary (38.7%) and secondary (18.0%) dentitions. Primary and secondary dentition anomalies were not observed in infants with CP and different in the UCL group ( P = .003). Risk differences involved primary supernumerary teeth ( P = .0001) and talon cusp formation ( P = .0001), and secondary tooth agenesis ( P = .001) of the maxillary lateral incisor on the side of the cleft lip. Delayed primary and secondary dental maturation occurred in the UCL and CP groups, greater in infants with UCL ( P < .0001). Primary and secondary dental maturation featured sexual dimorphism with greater delay in males (UCL, P < .0001; CP, .0001 > P = .001). The effect of cleft severity on dental maturation was significant in infants with UCL ( P = .0361) and CP ( P = .0175) in the primary but not in the secondary dentition. Conclusions: There were different dental anomalies in the primary and secondary dentitions in operated infants with UCL and no dental anomalies in unoperated infants with CP. Dental maturation was delayed in infants with UCL and CP with greater delay in males compared to females.

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Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate

Human Genetics ◽

10.1007/s00439-016-1754-7 ◽

2017 ◽

Vol 136 (3) ◽

pp. 275-286 ◽

Cited By ~ 68

Author(s):

Elizabeth J. Leslie ◽

Jenna C. Carlson ◽

John R. Shaffer ◽

Azeez Butali ◽

Carmen J. Buxó ◽

...

Keyword(s):

Cleft Palate ◽

Cleft Lip ◽

Orofacial Clefts ◽

Genome Wide ◽

Meta Analyses ◽

Novel Associations

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Dental anomalies frequency in submucous cleft palate versus complete cleft palate

European Journal of Orthodontics ◽

10.1093/ejo/cjab003 ◽

2021 ◽

Author(s):

João Paulo Schwartz ◽

Daniela Gamba Garib

Keyword(s):

Cleft Palate ◽

Permanent Teeth ◽

Tooth Agenesis ◽

Dental Anomalies ◽

Supernumerary Teeth ◽

Chi Square ◽

Intergroup Comparison ◽

Significant Difference ◽

Submucous Cleft Palate ◽

Isolated Cleft Palate

Summary Background/Objectives This retrospective study evaluated the prevalence of dental anomalies of number in different subphenotypes of isolated cleft palate. Materials/Methods The sample comprised 26 individuals with submucous cleft palate (group S) and 68 individuals with complete cleft palate (group C) aged between 9 and 12 years from a single centre. Panoramic radiographs were evaluated regarding the presence of dental anomalies of number in permanent teeth. Intergroup comparison was performed using chi-square tests (P < 0.05). Results Tooth agenesis was found in 34.61 and 36.76 per cent of group S and group C, respectively. The most commonly missing teeth were the maxillary second premolar, maxillary lateral incisor, and mandibular second premolar. Supernumerary teeth were found in none and 1.47 per cent of the individuals with submucous and complete cleft palate, respectively. No statistically significant difference was found between groups for the frequency of tooth agenesis and supernumerary teeth. Limitations Only dental anomalies of number were evaluated. Conclusions/Implications Individuals with submucous and complete cleft palate showed similar prevalence for tooth agenesis and supernumerary teeth. Dental anomalies frequency seems not to be a discriminator for subphenotypes of cleft palate.

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Morphological Presentation of Orofacial Clefts: An Epidemiological Study of 5004 Patients in a Tertiary Care Hospital of Central India

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211057739 ◽

2021 ◽

pp. 105566562110577

Author(s):

Jaideep Singh Chauhan ◽

Sarwpriya Sharma

Keyword(s):

Cleft Palate ◽

Epidemiological Study ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Tertiary Care ◽

Central India ◽

Care Hospital ◽

Orofacial Clefts ◽

Chi Square ◽

The Right

Objective: To analyse the morphological presentation of orofacial clefts, gender, syndromes and systemic anomalies associated with them. Design: This was an epidemiological study performed in the patients who were registered for cleft lip and palate surgeries in our centre. The data was evaluated both retrospectively as well as prospectively. Patients/ Participants: The patients registered from November 2006 to April 2021 were studied. Out of 5276 patients, data of 5004 cases were analysed, rest 272 patients were excluded due to lack of information. Statistical analysis and Chi square test were applied. Results: Cleft deformities were more common in males than females. Cleft lip with palate was the commonest phenotype (52.2%). It was followed by isolated cleft lip (22.9%), isolated cleft palate (22.1%), rare clefts (1.62%) and syndromic clefts (1.18%). Unilateral variants were more frequent than bilateral. In unilateral, left side was more common than the right side. Among bilateral, most of the cases had premaxillary protrusion. In the present study, 3.46% of all the patients had associated anomalies affecting their other organs. Less common cleft phenotypes like microform cleft lip and submucous cleft palate ± bifid uvula showed frequency of 0.62% and 0.64% respectively. Conclusion: Thorough examination of cleft deformity should be done as it may appear as an isolated deformity or part of a syndrome and have associated systemic anomalies. This may help us to deliver comprehensive care to the patients and can prevent potential operative complications.

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