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Background: Orofacial clefts (OFC) are linked with several genetic and environmental factors. The aim of this study was to explore the association of potential risk factors with OFCs in India., Methods: This was a hospital-based, matched case-control (1:4 ratio; matching done for parity) study conducted in Hyderabad, Bengaluru, and Delhi-National Capital Region. Cases (nonsyndromic clefts) were recruited from treatment centers, while controls (live births) were recruited from maternity centers. Information on exposures was collected during personal interviews. Exposures of interest included folic acid supplementation during the peri-conceptional period, consanguineous marriage, exposure to drugs, infections during pregnancy, family history of OFC, and dietary factors., Results: A total of 785 participants were included in the study: 157 cases and 628 controls. A family history of cleft lip/palate (adjusted odds ratio [AOR], 15.48; 95% confidence interval [CI], 4.36-54.96; p value = 0.001), exclusive vegetarianism (AOR, 4.47; 95% CI, 1.83-10.98; p value = 0.001), and delayed first conception (AOR, 2.55, 95% CI, 1.25-5.21, p = 0.01) were found to be strongly associated with higher risk of OFCs. Supplementation with folic acid during first 3 months of pregnancy was not found to be protective against OFCs (AOR, 1.24; 95% CI, 0.59-2.58; p value = 0.56)., Conclusion: Our study confirmed the importance of family history as a risk factor for OFC. Our study did not show an association with folic acid supplementation but was underpowered to detect small effects. Our finding of higher risk among vegetarians requires replication. Birth Defects Research 109:1284-1291, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc., (© 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.)

We treated 11 cases (52.7 ± 14.9 years, all male) with varicella zoster virus (VZV) meningitis and 437 cases with adult aseptic meningitis from 2004 to 2016. The incidence rate of adult VZV meningitis in the cases with aseptic meningitis was 2.5%. Herpes zoster infections are reported to have occurred frequently in summer and autumn. VZV meningitis also occurred frequently in the similar seasons, in our patients. The diagnoses were confirmed in 9 cases with positive VZV-DNA in the cerebrospinal fluid and in 2 cases with high VZV-IgG indexes (> 2.0). For diagnosis confirmation, the former test was useful for cases within a week of disease onset, and the latter index was useful for cases after a week of disease onset. Zoster preceded the meningitis in 8 cases, while the meningitis preceded zoster in 1 case, and 2 cases did not have zoster (zoster sine herpete). Two patients were carriers of the hepatitis B virus, 1 patient was administered an influenza vaccine 4 days before the onset of meningitis, and 1 patient was orally administered prednisolone for 2 years, for treatment. Their immunological activities might have been suppressed. The neurological complications included trigeminal neuralgia, facial palsy (Ramsay Hunt syndrome), glossopharyngeal neuralgia, and Elsberg syndrome. Because the diseases in some patients can become severe, they require careful treatment.

Objectives: To perform a case-control study of maternal occupational physical activity and risk for orofacial clefts in Texas during 1999-2009., Methods: We used logistic regression to assess 14 measures of physical activity estimated from a job exposure matrix, using the maternal occupation reported on the birth certificate, among 887 children with cleft lip with or without cleft palate (CLP), 436 children with cleft palate only (CP), and 1932 controls., Results: After adjusting for several potential confounders, seven measures of physical activity (as a categorical and/or continuous variable) were significantly associated with CLP, CP, or both. Positive associations were seen for keeping balance, kneeling, standing, and walking/running (odds ratio 95% confidence interval range 1.0-1.9 for fourth versus first quartile). A significant positive trend was also seen for bending/twisting. Negative associations were seen for repetitive motion and sitting., Conclusions: Maternal occupational physical activity may be related to the etiology of orofacial clefts., (© 2017 Wiley Periodicals, Inc.)

While several studies have investigated maternal exposures as risk factors for oral clefts, few have examined paternal factors. We conducted an international multi-centered case-control study to better understand paternal risk exposures for oral clefts (cases = 392 and controls = 234). Participants were recruited from local hospitals and oral cleft repair surgical missions in Vietnam, the Philippines, Honduras, and Morocco. Questionnaires were administered to fathers and mothers separately to elicit risk factor and family history data. Associations between paternal exposures and risk of clefts were assessed using logistic regression adjusting for potential confounders. A father's personal/family history of clefts was associated with significantly increased risk (adjusted OR: 4.77; 95% CI: 2.41-9.45). No other significant associations were identified for other suspected risk factors, including education (none/primary school v. university adjusted OR: 1.29; 95% CI: 0.74-2.24), advanced paternal age (5-year adjusted OR: 0.98; 95% CI: 0.84-1.16), or pre-pregnancy tobacco use (adjusted OR: 0.96; 95% CI: 0.67-1.37). Although sample size was limited, significantly decreased risks were observed for fathers with selected occupations. Further research is needed to investigate paternal environmental exposures as cleft risk factors.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, is an autosomal genetic disease with the main features of ankyloblepharon filiforme adnatum, ectodermal defects, and cleft lip/palate. The authors report a patient with 17 months old girl with AEC syndrome having ankyloblepharon, cleft and palate, and ectrodactyly with some associated features. Etiology, clinical features, differential diagnosis, and treatment have been elaborated in this clinical report.

Orofacial clefts, specifically cleft lip and/or cleft palate (CL/P), are among the most common congenital anomalies. CL/P vary in their location and severity and comprise 3 overarching groups: cleft lip (CL), cleft lip with cleft palate (CLP), and cleft palate alone (CP). CL/P may be associated with one of many syndromes that could further complicate a child's needs. Care of patients with CL/P spans prenatal diagnosis into adulthood. The appropriate timing and order of specific cleft-related care are important factors for optimizing outcomes; however, care should be individualized to meet the specific needs of each patient and family. Children with CL/P should receive their specialty cleft-related care from a multidisciplinary cleft or craniofacial team with sufficient patient and surgical volume to promote successful outcomes. The primary care pediatrician at the child's medical home has an essential role in making a timely diagnosis and referral; providing ongoing health care maintenance, anticipatory guidance, and acute care; and functioning as an advocate for the patient and a liaison between the family and the craniofacial/cleft team. This document provides background on CL/P and multidisciplinary team care, information about typical timing and order of cleft-related care, and recommendations for cleft/craniofacial teams and primary care pediatricians in the care of children with CL/P., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

A case-control study was conducted to reveal risk factors for cleft lip and palate. The main group consisted of 41mothers of infants with orofacial clefts (cleft lip and/or palate) who were born in Tbilisi maternity houses during 2015-2016. The control group was composed of 61 mothers who have given birth to healthy babies in the same maternity houses. Information on possible risk factors was collected using a special form. In order to evaluate a role of these risk factors, bivariate analysis was conducted at the first stage of the study. Odds ratio (OR) was calculated for each factor, significance of the results was evaluated by calculating 95% confidence intervals (95% CI). At the next stage of the study the factors significantly correlated with the development of orofacial clefts were identified and multivariate analysis was performed using a multiple logistic regression model. According to the study results stressful situations in the families of pregnant women play the most significant role in the development of cleft lip and palate with standardized (adjusted) OR=7.76, 95% CI: 1.93-31.33. Other risk factors such as contracting infectious or noncommunicable diseases during the first trimester of pregnancy as well as use of medications during this period have some impact on the development of these malformations (OR=2.10, 95% CI: 0.77-5.70; OR=2.88, 95% CI: 0.83-9.97 and OR=2.22, 95% CI: 0.77-10.41, correspondingly).

Background: While there is some evidence that maternal exposure to ambient air pollution is associated with orofacial clefts in offspring, the epidemiologic studies have been largely equivocal. We evaluated whether maternal exposure to elevated county-level ambient fine particulate matter with aerodynamic diameter ≤2.5µm (PM 2.5 ) and ozone during early gestation was associated with a higher prevalence of orofacial clefts., Methods: Birth data consisting of 4.7 million births from 2001 to 2007 were obtained from National Birth Defects Prevention Network for four states - Arizona, Florida, New York (excluding New York City), and Texas. The air pollution exposure assessment for gestational weeks 5-10 was based on county-level average concentrations of PM 2.5 and ozone data generated using a Bayesian fusion model available through CDC's Environmental Public Health Tracking Network. Two outcomes were analyzed separately: cleft lip with or without cleft palate, cleft palate alone. In logistic regression analyses, we adjusted for factors that were suspected confounders or modifiers of the association between the prevalence of orofacial clefts and air pollution, i.e., infant sex, race-ethnicity, maternal education, smoking status during pregnancy, whether this was mother's first baby, maternal age., Results: Each 10µg/m 3 increase in PM 2.5 concentration was significantly associated with cleft palate alone (OR =1.43, 95% CI: 1.11-1.86). There was no significant association between PM 2.5 concentration and cleft lip with or without cleft palate. No associations were observed between ozone exposure and the two outcomes of orofacial clefts., Conclusions: Our study suggests that PM 2.5 significantly increased the risk of cleft palate alone, but did not change the incidence of cleft lip with or without palate. Ozone levels did not correlate with incidence of orofacial clefts., (Published by Elsevier Inc.)

Purpose: To examine maternal smoking and body mass index (BMI) interactions in contributing to risk of oral clefts., Methods: We studied 4935 cases and 10,557 controls from six population-based studies and estimated a pooled logistic regression of individual-level data, controlling for study fixed effects and individual-level risk factors., Results: We found a significant negative smoking-BMI interaction, with cleft risk with smoking generally declining with higher BMI. For all clefts combined, the odds ratio for smoking was 1.61 (95% confidence interval [CI]: 1.39-1.86) at BMI 17 (underweight), 1.47 (95% CI: 1.34-1.62) at BMI 22 (normal weight), 1.35 (95% CI: 1.22-1.48) at BMI 27 (overweight), 1.21 (95% CI: 1.04-1.41) at BMI 33 (obese), and 1.13 (95% CI: 0.92-1.38) at BMI 37 (very obese). A negative interaction was also observed for isolated clefts and across cleft types but was more pronounced for cleft lip only and cleft palate only., Conclusions: Our findings suggest that the risk of oral clefts associated with maternal smoking is largest among underweight mothers, although the smoking-BMI interaction is strongest for cleft lip only and cleft palate only. BMI was not protective for the effects of smoking; a clinically relevant increase in smoking-related cleft risk was still present among heavier women., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aims: Morphogenesis of the upper lip and palate is a complex process involving highly regulated interactions between epithelial and mesenchymal cells. Genetic evidence in humans and mice indicates the involvement of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) in cleft lip palate (CLP) aetiology. This study investigated whether expression of MMP-2, MMP-8, MMP-9, TIMP-2, and TIMP-4, which are essential for the upper lip and palate fusion, is dysregulated in children with CLP., Methods: Oral mucosa tissue samples were obtained from patients with complete unilateral (CU) CLP (n = 25) and complete bilateral (CB) CLP (n = 19) during corrective plastic surgery and in unaffected control subjects (n = 10). MMPs and TIMPs expression was assessed by immunohistochemistry, and the data were analyzed using the Kruskal - Wallis test with the Bonferroni correction., Results: In CLP patients, MMP-2, TIMP-2 immunoreactivity in the oral mucosa was seen to have a few to abundant structures, but the overall number of MMP-2, TIMP-2-positive structures was greater than that in controls (P < 0.01). The total number of TIMP-4, MMP-9-positive cells showed a significant decrease in the CBCLP compared with that of CUCLP (P < 0.001). MMP-8 expression trends in the CLP group were similar to those of the control group., Conclusions: The results suggest that TIMP-4 and MMP-9 are the main ECM remodeling regulatory proteins expressed in CUCLP affected tissues of the oral mucosa. The increased expression of MMP-2 and TIMP-2 in CLP tissues implicates these factors in the regulation of cell migration during ECM turnover independently of different types of clefts. Investigation of MMP and TIMP expression in tissue samples from patients with CLP appears to be a promising approach to the etiopathogenesis of CLP.

Background: A risk prediction model of non-syndromic cleft lip with or without cleft palate (NSCL/P) was established by a discriminant analysis to predict the individual risk of NSCL/P in pregnant women., Methods: A hospital-based case-control study was conducted with 113 cases of NSCL/P and 226 controls without NSCL/P. The cases and the controls were obtained from 52 birth defects' surveillance hospitals in Hunan Province, China. A questionnaire was administered in person to collect the variables relevant to NSCL/P by face to face interviews. Logistic regression models were used to analyze the influencing factors of NSCL/P, and a stepwise Fisher discriminant analysis was subsequently used to construct the prediction model., Results: In the univariate analysis, 13 influencing factors were related to NSCL/P, of which the following 8 influencing factors as predictors determined the discriminant prediction model: family income, maternal occupational hazards exposure, premarital medical examination, housing renovation, milk/soymilk intake in the first trimester of pregnancy, paternal occupational hazards exposure, paternal strong tea drinking, and family history of NSCL/P. The model had statistical significance (lambda = 0.772, chi-square = 86.044, df = 8, P < 0.001). Self-verification showed that 83.8 % of the participants were correctly predicted to be NSCL/P cases or controls with a sensitivity of 74.3 % and a specificity of 88.5 %. The area under the receiver operating characteristic curve (AUC) was 0.846., Conclusions: The prediction model that was established using the risk factors of NSCL/P can be useful for predicting the risk of NSCL/P. Further research is needed to improve the model, and confirm the validity and reliability of the model.

Animal models have shown evidence of the role of maternal methyl donor status and its metabolism (one-carbon metabolism) in normal embryonic maxillofacial development. Nevertheless, studies in humans have shown conflicting results for the association of maternal methylation status biomarkers in the aetiology of the main craniofacial birth defects: non-syndromic orofacial clefts (NSOFCs). The aim of this study was to perform a meta-analysis assessing the relationship between maternal levels of methylation status biomarkers (plasma and erythrocyte folates and plasma vitamin B12 and homocysteine) and the risk of NSOFCs. A literature search of the conventional and grey medical-scientific databases identified 12 studies considering these variables. Based on standardized differences between means among cases and controls (Cohen's d test), evidence was found of an association only with high plasma homocysteine (d=0.37; P=0.026) when single effects were pooled. In addition to its usefulness as a marker of poor methyl-donor intake and/or metabolism, homocysteine appears to have a teratogenic effect. Although the results are based on a relatively small number of reports and/or studies of small sample sizes showing between-study heterogeneity, these problems were resolved by including an additional analysis. Therefore these findings constitute a real contribution towards explaining the complex aetiology of orofacial clefts., (Copyright © 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Using individual participant data from six population-based case-control studies, we conducted pooled analyses to examine maternal alcohol consumption and the risk of clefts among >4600 infants with cleft lip only, cleft lip with cleft palate, or cleft palate only and >10,000 unaffected controls. We examined two first-trimester alcohol measures: average number of drinks/sitting and maximum number of drinks/sitting, with five studies contributing to each analysis. Study-specific odds ratios (ORs) were estimated using logistic regression and pooled to generate adjusted summary ORs. Across studies, 0.9-3.2 % of control mothers reported drinking an average of 5+ drinks/sitting, while 1.4-23.5 % reported drinking a maximum of 5+ drinks/sitting. Compared with non-drinkers, mothers who drank an average of 5+ drinks/sitting were more likely to deliver an infant with cleft lip only (pooled OR 1.48; 95 % confidence intervals 1.01, 2.18). The estimate was higher among women who drank at this level 3+ times (pooled OR 1.95; 1.23, 3.11). Ever drinking a maximum of 5+ drinks/sitting and non-binge drinking were not associated with cleft risk. Repeated heavy maternal alcohol consumption was associated with an increased risk of cleft lip only in offspring. There was little evidence of increased risk for other cleft types or alcohol measures., Competing Interests: Conflicts of Interest: None declared.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common craniofacial birth defect that has a complex etiology. Genome-wide association studies have recently identified new loci associated with NSCL/P, but these loci have not been analyzed in a Mexican Mestizo population. A complex etiology implies the presence of genetic interactions, but there is little available information regarding this in NSCL/P, and no signaling pathway has been clearly implicated in humans. Here, we analyzed the associations of 24 single nucleotide polymorphisms (SNPs) with NSCL/P in a Mexican Mestizo population (133 cases, 263 controls). The multifactorial dimensionality reduction method was used to examine gene-gene and gene-folic acid consumption interactions for the 24 SNPs analyzed in this study and for 2 additional SNPs that had previously been genotyped in the same study population. Six SNPs located in paired box 7, ventral anterior homeobox 1, sprouty RTK signaling antagonist 2, bone morphogenetic protein 4, and tropomyosin 1 genes were associated with higher risks of NSCL/P (P = 0.0001 to 0.04); 2 SNPs, 1 each in netrin 1 and V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B, were associated with a lower risk of NSCL/P (P = 0.013 to 0.03); and 2 SNPs, 1 each in ATP binding cassette subfamily A member 4 (ABCA4) and noggin, showed associations with NSCL/P that approached the threshold of significance (P = 0.056 to 0.07). In addition, 6 gene-gene interactions (P = 0.0001 to 0.001) and an ABCA4-folic acid consumption interaction (P < 0.0001) were identified. On the basis of these results, combined with those of previous association studies in the literature and biological characterizations of murine models, we propose an interaction network in which interferon regulatory factor 6 plays a central role in the etiology of NSCL/P., (© International & American Associations for Dental Research 2016.)

Background: Shanxi Province is a region in China with a high incidence of orofacial clefts (OFCs). Our objective is to investigate the effect of maternal exposure to indoor air pollution (IAP) from coal combustion and tobacco smoke on the risk of an infant being born with orofacial clefts., Methods: Data were derived from an ongoing population-based case-control study of major external structural birth defects in Shanxi Province. Subjects included 213 cases with OFCs and 1319 healthy babies born between November 2002 and December 2014 in four rural counties. Exposure information was collected by face-to-face interview with mothers within 1 week of delivery or pregnancy termination. The authors derived an exposure index by integrating a series of IAP-related characteristics concerning dwelling and lifestyle., Results: Increased odds of OFC were associated with IAP exposure from heating (adjusted odds ratio [aOR] = 2.4; 95% confidence interval [CI], 1.2-4.5) and from smoking (aOR = 1.8; 95% CI: 1.3, 2.5), but not with exposure from cooking (aOR = 0.9; 95% CI, 0.6-1.4). Compared with women without IAP exposure, the aORs of OFC for children of women with exposure indices of 1, 2, 3 and ≥ 4 were 1.1 (95% CI, 0.6-1.8), 1.4 (95% CI, 0.8-2.4), 1.8 (95% CI, 1.0-3.2), and 3.4 (95% CI, 1.6-7.4), respectively, demonstrating a clear dose-response trend (p < 0.001)., Conclusion: Periconceptional exposure to IAP from coal combustion and tobacco smoking may increase the risk of OFCs in offsprings of women in Shanxi Province. Birth Defects Research (Part A) 106:708-715, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: Nonsyndromic orofacial cleft (NSOFC) etiology is multifactorial and heterogeneous. This study aimed to identify environmental risk factors related to NSOFC in the Western Region of Saudi Arabia., Methods: A case-control study carried out in seven hospitals in two main cities (Jeddah and Maddina) over 2 years on parents of 112 infants with NSOFC (infants were also examined) and 138 infant controls, matched for age (<18 months), gender, and location, completed a questionnaire on 3-month pregestation and first trimester events., Results: There was significantly increased NSOFC risk with twin pregnancies (P = .01, odds ratio [OR] = 9.5, 95% confidence interval [CI]: 1.15 to 78.4), maternal antibiotic use (P = .021, OR = 2.71, 95% CI: 1.11 to 6.62), antiemetic medication (P = .005, OR = 2.85, 95% CI: 1.3 to 6), severe morning sickness (P = .006, OR = 3.6, 95% CI: 1.34 to 9.65), illness (P = .009, OR = 2.19, 95% CI: 1.17 to 4.08), common cold/flu (P = .003, OR = 3.32, 95% CI: 1.48 to 7.58), Jorak smoking (P = .004, OR = 14.07, 95% CI: 1.55 to 128.1), and passive smoking (P = .05, OR = 2.05, 95% CI: 1.05 to 4.01). Reduced NSOFC risk was found with calcium supplementation (P = .02, OR = 0.32, 95% CI: 0.11 to 0.88), incense use (P = .03, OR = 0.58, 95% CI: 0.34 to 0.98), and maternal drinking water, with Zamzam water (which contains a high concentration of minerals) showing a significant protective effect compared with tap water (P = .01, 95% CI: 0.06 to 0.6) and bottled water (P = .02, 95% CI: 0.03 to 0.57)., Conclusion: Twin births, maternal antibiotic use, antiemetic medication, severe morning sickness, common cold/flu, Jorak smoking, and passive smoking were associated with infants born with NSOFC. Calcium supplementation, incense use, and Zamzam water reduced the risk of NSOFC, raising the possibility of community preventive programs.

Background: One infant in 700 is born with an oral cleft. Prior studies suggest low micronutrient status is associated with an increased risk of oral clefts. Environmental factors such as passive smoke exposure or supplement use may also affect oral cleft risk. We examined nutrition and environmental related risk factors for oral clefts., Methods: We conducted a case-control study in Northeast Thailand in 2012 to 2013. We enrolled 95 cases and 95 controls. We recruited cases with a nonsyndromic cleft lip with or without a cleft palate (CL±P) less than 24 months old. Cases were matched to controls on age and place of conception. We collected survey data, a food frequency questionnaire, and measured zinc concentrations in toenail trimmings. We calculated descriptive statistics by case and control status. We used conditional logistic regression to estimate unadjusted and adjusted associations, 95% confidence intervals (CIs), and p-values., Results: Any liver intake (adjusted OR [aOR] for ≥1/week versus none), 10.58; 95%CI, 1.74-64.37, overall p = 0.02) and the presence of food insecurity (aOR, 9.62; 95% CI, 1.52-61.05; p = 0.02) in the periconceptional period increased CL±P risk. Passive smoke exposure increased the risk of CL±P (aOR, 6.52; 95% CI, 1.98-21.44; p < 0.01). Toenail zinc concentrations were not associated with CL±P risk., Conclusion: Our findings add to a growing body of knowledge of environmental risk factors for oral clefts from low- and middle-income countries. Our findings on liver are contradictory to prior results. Large multisite studies are needed to identify environmental and genetic risk factors for oral clefts. Birth Defects Research (Part A) 106:624-632, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The Tessier number 3 cleft is rare. In this paper, we report two extremely rare cases of simultaneous Tessier number 3 cleft, contralateral cleft lip, and signs of amniotic band syndrome. In the two cases, we confirmed that amniotic bands were the probable cause of the Tessier number 3 cleft, where swallowed fibrous strands of amniotic bands entangle a typical cleft lip and cause the more severe Tessier number 3 cleft. In this study, Z-plasty was performed for one case, and a straight-line method was used for the other. Postoperatively, the appearance of both patients was satisfactory, as expected. Consequently, treatment for the Tessier number 3 cleft should be designed individually based on the severity of deformity., (Copyright © 2016. Published by Elsevier Ltd.)

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Non-syndromic congenital cleft lip and jaw (CLJ) is a condition reported in several cattle breeds, but a detailed classification system does not exist for cattle. The objective of the present study was to describe the phenotypic variability of this orofacial malformation in Vorderwald × Montbéliarde cattle. For this purpose, a classification system of CLJ was developed on examination of five orofacial structures: (1) lips, (2) the processus (proc.) nasalis of the os incisivum, (3) the dental plate with adjacent segments of the hard palate, (4) the facial bones (os incisivum, os maxillare, os nasale and os palatinum) and (5) the mandibles. Each structure was given a score reflecting the degree of the lesion from absent (score 0) to severe., Results: Nine cases were included in the study and they shared absence of the abaxial rostral part of the processus (proc.) nasalis of the os incisivum, partial loss of the rugae palatinae and the dental plate. A sigmoid curvature of the rostral lower jaw as well as a lateral deviation of the face and rostral lower jaw was highly variable in their expression. These deformations were present in eight of nine cases. In addition to the complete CLJ, three animals had an incomplete CLJ on the contralateral site with variable defects of the rostral part of the proc. nasalis of the os incisivum., Conclusions: A complete CLJ is obviously accompanied by a loss of parts of the proc. nasalis of the os incisivum. Extent and localization of the missing parts of the proc. nasalis were similar in all cases. A precise classification of the various CLJ forms is necessary.

Objectives: We determined the association between maternal neighborhood socioeconomic position (SEP) and the risk of cleft lip with or without cleft palate (CL±P) or cleft palate alone (CP) in offspring., Methods: We obtained information on CL±P (n = 2555) and CP (n = 1112) cases and unaffected controls (n = 14 735) among infants delivered during 1999 to 2008 from the Texas Birth Defects Registry. Neighborhood SEP variables, drawn from the 2000 US Census, included census tract-level poverty, education, unemployment, occupation, housing, and crowding, from which we created a composite neighborhood deprivation index (NDI). We used mixed-effects logistic regression to evaluate neighborhood SEP and oral clefts., Results: Mothers with CL±P-affected offspring were more likely to live in high-NDI (adverse) areas than mothers with unaffected offspring (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.05, 1.37). This association was strongest among Hispanic mothers (OR = 1.32, 95% CI = 1.07, 1.62). No associations were observed with CP., Conclusions: Using data from one of the world's largest active surveillance birth defects registries, we found that adverse neighborhood SEP is modestly associated with CL±P, especially among Hispanics. These findings may have important implications for health disparities prevention.

The Objective: The aim of the study was evaluation of metal ions (nickel and chromium) released from orthodontic appliances in cleft lip and palate patients and the usefulness of non-invasive matrices (saliva and hair)., Materials and Methods: The material studied consisted of 100 individuals, including 59 females and 41 males of 5 to 16 years of age, which were divided into 3 groups: experimental-patients with cleft lip and palate (36 individuals, the average treatment time 5.74 years); control group-patients without cleft lip and palate, during orthodontic treatment (32 individuals, the average treatment time 1.78 years) and the control group patients without cleft lip and palate, without any orthodontic appliances (32 individuals). Samples (saliva, hair) were collected and subjects underwent a survey by questionnaire. Multi-elemental analyses of the composition of non-invasive matrices was conducted in an accredited laboratory by inductively coupled plasma spectrometry technique ICP-OES. The results were reported as mean contents of particular elements (Cd, Cr, Cu, Fe, Mn, Mo, Ni, Si) in hair and in saliva., Results: The concentration of Cr, Ni, Fe and Cu ions in saliva of cleft lip and palate patients were several times higher as compared with not treated orthodontically control groups and higher than in the group with orthodontic appliances. Among the assessed matrices, hair of cleft lip and palate patients seem to be not a meaningful biomarker., Conclusion: It was found that orthodontic appliances used in long-term treatment of cleft lip and palate patients do not release toxic levels of Cr and Ni ions.

Background: Non-syndromic orofacial clefts (NSOCs) are complex disease involving genetic triggers, environmental factors, and their interplay. Recent studies demonstrated that EYA1, a member of eye absent gene family, might contribute to NSOCs., Methods: We investigated three single nucleotide polymorphisms (SNPs) and eight environmental factors (multivitamin, folic acid and calcium supplementation history, maternal alcohol consumption, common cold history, maternal smoking and environmental tobacco smoke in the first trimester, and paternal smoking in the 3 months before pregnancy) among 294 case-parent trios and 183 individual controls in western Han Chinese to evaluate the relationship between EYA1, environmental factors, and NSOCs. To be better known the gene's role in the etiology of NSOCs, we performed statistical analysis in different aspects including the linkage disequilibrium test, transmission disequilibrium test, haplotype analysis, multiple logistic regression analysis, and conditional logistic regression analysis., Results: Allele C at rs3779748 showed an over-transmission in NSCL/P trios (P = 0.03), and genotype A/A at rs10094908 was under-transmitted among NSCL/P trios (P = 0.03), whereas over-transmitted among NSCPO trios (P = 0.02). The haplotype GC of rs10094908-rs3779748 was over-transmitted among NSCL/P trios (P = 0.05) and NSCPO trios (P = 0.05), respectively. Maternal common cold history, environmental tobacco smoke, and maternal alcohol consumption during the first trimester of pregnancy were risk factors for NSOCs, while calcium supplementation during the first trimester showed a protective effect. No evidence of interactions between EYA1 and environmental factors was found., Conclusions: These results revealed an association between EYA1, some environmental factors, and NSOCs in western Han Chinese., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Cleft lip and/or palate (CL/P) represent the most common congenital anomalies of the face., Objective: To assess the relationship between maternal smoking, gender and CL/P., Methods: This is an epidemiological cross-sectional study. We interviewed 1519 mothers divided into two groups:, Cases: mothers of children with CL/P (n=843) and, Controls: mothers of children without CL/P (n=676). All mothers were classified as smoker or non-smoker subjects during the first trimester of pregnancy. To determine an association among maternal smoking, gender, and CL/P, odds ratios were calculated and the adjustment was made by a logistic regression model., Results: An association between maternal smoking and the presence of cleft was observed. There was also a strong association between male gender and the presence of cleft (OR=3.51; 95% CI 2.83-4.37). By binary logistic regression analysis, it was demonstrated that both variables were independently associated with clefts. In a multivariate analysis, male gender and maternal smoking had a 2.5- and a 1.5-time greater chance of having a cleft, respectively., Conclusion: Our findings are consistent with a positive association between maternal smoking during pregnancy and CL/P in male gender. The results support the importance of smoking prevention and introduction of cessation programs among women with childbearing potential., (Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Introduction: Cloverleaf skull syndrome, or Kleeblattschädel syndrome, is a rare malformation in which the skull has a cloverleaf appearance. It is caused by the premature closure of several sutures, being evident before birth., Objective: To present our experience in a case of cloverleaf skull syndrome, and update the information from the literature., Clinical Case: A female infant of 5 months of age, diagnosed at birth with cleft lip and palate and hydrocephaly. A peritoneal ventricle valve was implanted at 30 days of life, and an ocular enucleation was performed due to an infectious process. The patient was followed-up in Genetics, where it confirmed a macrocephaly and craniosynostosis type cloverleaf skull. The 46XX cytogenetic study and echocardiography were normal. The brain CT scan showed multiple anomalies associated with hydrocephaly and non-specific malformations., Conclusion: Cloverleaf skull may be present in isolated form or associated with other congenital abnormalities, leading to various craniosynostosis syndromes, such as Crouzon, Pfeiffer or Carpenter. It may also be a component of the amniotic rupture sequence or to different dysplasias, such as campomelic dysplasia, thanatophoric dysplasia type 2, or the asphyxiating thoracic dystrophy of Jeune. The case presented does not fulfil all the characteristics needed to be included within a specific syndrome, and on not having a family history that suggests a hereditary pattern or chromosome abnormalities, it is concluded that it is a case of a congenital anomaly of sporadic presentation., (Copyright © 2015 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

In this study, we sought to determine the association between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) to understand the etiology of the disease. A total of 200 NSCLP cases and 327 controls were recruited at the Maternal and Child Health Hospital of Xuzhou City. We conducted face-to-face interviews with the mothers of both cases and controls. The factors increasing the risk of NSCLP were a positive family history [odds ratio (OR)=56.74], pesticide exposure (OR=8.90), and indoor decoration pollution (OR=4.32). On the other hand, the factors decreasing the risk of NSCLP were a high education level (OR=0.22) and supplementation of folic acid (OR=0.23) and multivitamins (OR=0.16). Positive family history, pesticide exposure, and indoor decoration pollution are associated with the risk of NSCLP. In contrast, high education level and folic acid and multivitamin supplementation are protective factors against NSCLP., (Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Background: Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity., Aim: To estimate holoprosencephaly prevalence at birth., Patients and Methods: All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described., Results: Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed., Conclusions: Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).

Complete tracheal ring causes congenital tracheal stenosis in neonates and infants. We have to prevent further tracheal stenosis in perioperative period. This is a case report of an infant with congenital tracheal stenosis due to complete tracheal ring who underwent primary cleft lip closure under general anesthesia. An 8 month-old boy was scheduled for bilateral cleft lip closure. His first operation at two months was canceled because of unsuccessful intubation in previous hospital. He came to our hospital to seek a second opinion. His CT scan showed long segment stenosis of the trachea below glottis. The tracheobronchial endoscopy showed complete tracheal rings 1.5 cm below glottis to the bifurcation. Considering his aspiration episode, we decided to do the cleft lip closure promptly after examinations. We chose an ID 3.0 mm RAE tracheal tube, which is commercially narrowest We intubated 2 cm below glottis, and confirmed that the tip did not touch narrowed trachea with endoscope. This tube was fixed in the center of the mandible and packed with gauze. He was discharged on 8 POD without complication. CT scan and its integrated 3 D image of the trachea were useful to understand the approximate structure. However endoscopic examination allowed more detailed structure-measurement below glottis.

We report the case of a no. 4 Tessier cleft in association with an unknown cleft of the mandible extending to the external auditory meatus. This has not been previously published in the literature and its underlying pathology remains undetermined. The nature of the cleft, possible classifications, and potential embryologic origins will be discussed. Amniotic band syndrome is the most likely cause of the cleft., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Sensory development is complex, with both morphologic and neural components. Development of the senses begins in early fetal life, initially with structures and then in-utero stimulation initiates perception. After birth, environmental stimulants accelerate each sensory organ to nearly complete maturity several months after birth. Vision and hearing are the best studied senses and the most crucial for learning. This article focuses on the cranial senses of vision, hearing, smell, and taste. Sensory function, embryogenesis, external and genetic effects, and common malformations that may affect development are discussed, and the corresponding sensory organs are examined and evaluated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Studies have found a consistent positive association between maternal smoking and non-syndromic orofacial clefts (NSOFC). However, no comprehensive assessment of the association between NSOFC and passive smoking has been undertaken. This systematic review and meta-analysis explores the relationship between maternal passive smoking and NSOFC, and compares the associations between passive and active smoking., Methods and Findings: Search strategy, inclusion / exclusion criteria, and data extraction from studies reporting maternal passive smoking and NSOFC was implemented without language restrictions. Risks of bias in the identified studies were assessed and this information was used in sensitivity analyses to explain heterogeneity. Meta-analysis and meta-regression of the extracted data were performed. Egger's test was used to test for small study effects. Fourteen eligible articles were identified. Maternal passive smoking exposure was associated with a twofold increase in risk of NSOFC (odds ratio: 2.11, 95% confidence interval: 1.54-2.89); this was apparent for both cleft lip with and without palate (OR: 2.05, 95% CI: 1.27-3.3) and cleft palate (OR: 2.11, 95% CI: 1.23-3.62). There was substantial heterogeneity between studies. In the studies that provided data enabling crude and adjusted odd ratios to be compared, adjustment for potential confounders attenuated the magnitude of association to about a 1.5-fold increase in risk., Conclusion: Overall, maternal passive smoking exposure results in a 1.5 fold increase in risk of NSOFC, similar to the magnitude of risk reported for active smoking, but there is marked heterogeneity between studies. This heterogeneity is not explained by differences in the distribution of cleft types, adjustment for covariates, broad geographic region, or study bias/quality. This thorough meta-analysis provides further evidence to minimize exposure to environmental tobacco smoke in policy making fora and in health promotion initiatives.

Previously an unexpected association of maternal angina pectoris (MAP) during pregnancy with a higher risk of orofacial clefts in their children was found. There were three objectives of this study: (i) to evaluate the validity of MAP-diagnoses in the previous study and the recent history of mothers with MAP in a follow-up study; (ii) to estimate the prevalence of other congenital abnormalities in the offspring of mothers with MAP; and (iii) to analyze the possible effect of confounders for the risk of orofacial clefts. The large dataset of population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities, 1980-1996 was evaluated including 22 843 cases with congenital abnormalities and 38 151 controls without any defect. Twenty-two cases (0.10%) and 12 controls (0.03%) were born to mothers with medically recorded MAP (odds ratio [OR] with 95% confidence interval [CI]: 3.7, 1.8-7.3). Of 22 cases, six had isolated cleft lip ± palate (OR with 95% CI: 13.3, 4.9-35.9) and two were affected with isolated cleft palate (OR with 95% CI: 10.5, 2.3-47.6). The diagnosis of MAP was confirmed in seven women visited at home in 2009-2010, two had recent myocardial infarction and five were smokers. There was no higher risk for other congenital abnormalities. In conclusion the higher risk of orofacial clefts was confirmed in the children of mothers with MAP and smoking may trigger the genetic predisposition of both MAP and orofacial clefts. However, the number of cases was limited and therefore further studies are needed to confirm or reject this theoretically and practically important observation., (© 2014 Japanese Teratology Society.)

Fetal sacrococcygeal teratomas (SCTs) occur in one to two per 20 000 pregnancies that cause high-output cardiac failure. High-output cardiac failure leads to polyhydramnios, hydrops, intrauterine fetal demise and preterm birth. Vascular disruption defects refer to those involving the interruption or destruction of some part of the fetal vasculature. We present a rare case of huge SCT causing multiple fetal disruption defects like cleft lip and palate and limb anomalies besides hydrops.

Objective: To explore the risk factors for CL/P in Hubei Province, China., Methods: A hospital-based, matched case-control study was conducted. One hundred and eight cases with CL/P were matched by age and sex with 108 normal controls. Their parents were retrospectively interviewed using a questionnaire. Univariate and multivariate analyses were used to calculate the relative risk by odds ratio and 95% confidence interval., Results: Univariate analysis identified ten factors as significantly related to CL/P (P < 0.05). Multivariate conditional logistic regression models showed that five of these factors were significantly associated with CL/P. Paternal occupational exposure (OR = 13.08, 95% CI: 2.35-72.86), first-trimester maternal illness (OR = 36.67, 95% CI: 5.37-250.36), first-trimester maternal bad mood (OR = 8.69, 95% CI: 1.35-55.84), first-trimester maternal diet of eggs or milk (≥5 meals per week, OR = 6.72, 95% CI: 1.23-36.69), and first-trimester maternal sexual activity (OR = 5.98, CI 95%:1.14-31.49) were risk factors for CL/P., Conclusions: In our study, we identified that paternal occupational exposure, first-trimester maternal illness, first-trimester maternal bad mood, first-trimester maternal diet of eggs or milk (≥5 meals per week), and first-trimester maternal sexual activities were significantly associated with increased CL/P., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction and Objectives: It is difficult to identify the environmental factors which together influence the occurrence of congenital malformations. It could be helpful to define the geographic location of the areas with an increased prevalence of such malformations. The aim of this study is to define if there are regions in Poland where the prevalence of isolated cleft lip, with or without a cleft palate (CL±P), is increased, and to present a method for searching for such areas., Materials and Methods: The analysis included the whole area of Poland monitored in 2007-2008 by the Polish Register of Congenital Malformations (PRCM). The area was divided into 3,045 census regions. The number of children with CL±P in those years was 514, and the size of the reference population (live births) was 802,372. Two methods were used for the detection of clusters with an increased prevalence of isolated CL±P: the LISA analysis and Kulldorff's scan statistic, and described in detail., Results: The prevalence of isolated CL±P and the smoothed prevalence were calculated for every community. The results of the LISA and Kulldorff's analyses were consistent. Both methods located the sites with an increased prevalence of isolated CL±P. The lack of statistical significance of clusters indicated by Kulldorff's statistic, and the significance of clusters detected with the use of the LISA method, indicated the existence of clusters with an only slightly increased prevalence of isolated CL±P., Conclusions: The study shows the usefulness of the LISA and Kulldorff's spatial analyses in epidemiological studies, including the etiology of congenital malformations. Because the two methods work in different ways, good results can be obtained when they are used together.

Median cleft lip is a midline vertical cleft through the upper lip. This is a very rare anomaly described in the literature. Median cleft lip is caused by the failure of fusion of the medial nasal prominences. In this case report, a 4-month-old boy with a median cleft associated with a mass of the upper lip is presented. The patient has no other anomalies of the nose or alveolus. The patient has normotelorism. A Z-plasty technique was used on the skin of the base of the columella. A vertical excision of the cleft with muscle approximation was performed on the white roll and the wet-dry border of either side of the defect of the upper lip. Postoperatively, the patient had a satisfactory result. The incisive scars were not visible. Cupid's bow was appropriately aligned, and the height of the upper lip was equal on both sides., (Copyright © 2014. Published by Elsevier Ltd.)

© 2014 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc., (© 2014 Wiley Periodicals, Inc.)

Background: According to the 2014 Surgeon General's Report, smoking in early pregnancy can cause orofacial clefts. We sought to examine the implications of this causal link for the potential prevention of orofacial clefts in the United States., Methods: Using published data on the strength of the association between orofacial clefts and smoking in early pregnancy and the prevalence of smoking at the start of pregnancy, we estimated the attributable fraction for smoking as a cause of orofacial clefts. We then used the prevalence of orofacial clefts in the United States to estimate the number of orofacial clefts that could be prevented in the United States each year by eliminating exposure to smoking during early pregnancy. We also estimated the financial impact of preventing orofacial clefts caused by maternal smoking based on a published estimate of attributable healthcare costs through age 10 for orofacial clefts., Results: The estimated attributable fraction of orofacial clefts caused by smoking in early pregnancy was 6.1% (95% uncertainty interval 4.4%, 7.7%). Complete elimination of smoking in early pregnancy could prevent orofacial clefts in approximately 430 infants per year in the United States, and could save an estimated $40.4 million in discounted healthcare costs through age 10 for each birth cohort., Conclusion: Understanding the magnitude of the preventable burden of orofacial clefts related to maternal smoking could help focus smoking cessation efforts on women who might become pregnant., (© 2014 Wiley Periodicals, Inc.)

Background: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common disorder with complex etiology. The Bone Morphogenetic Protein 4 gene (BMP4) has been considered a prime candidate gene with evidence accumulated from animal experimental studies, human linkage studies, as well as candidate gene association studies. The aim of the current study is to test for linkage and association between BMP4 and NSCL/P that could be missed in genome-wide association studies (GWAS) when genotypic (G) main effects alone were considered., Methodology/principal Findings: We performed the analysis considering G and interactions with multiple maternal environmental exposures using additive conditional logistic regression models in 895 Asian and 681 European complete NSCL/P trios. Single nucleotide polymorphisms (SNPs) that passed the quality control criteria among 122 genotyped and 25 imputed single nucleotide variants in and around the gene were used in analysis. Selected maternal environmental exposures during 3 months prior to and through the first trimester of pregnancy included any personal tobacco smoking, any environmental tobacco smoke in home, work place or any nearby places, any alcohol consumption and any use of multivitamin supplements. A novel significant association held for rs7156227 among Asian NSCL/P and non-syndromic cleft lip and palate (NSCLP) trios after Bonferroni correction which was not seen when G main effects alone were considered in either allelic or genotypic transmission disequilibrium tests. Odds ratios for carrying one copy of the minor allele without maternal exposure to any of the four environmental exposures were 0.58 (95%CI = 0.44, 0.75) and 0.54 (95%CI = 0.40, 0.73) for Asian NSCL/P and NSCLP trios, respectively. The Bonferroni P values corrected for the total number of 117 tested SNPs were 0.0051 (asymptotic P = 4.39*10(-5)) and 0.0065 (asymptotic P = 5.54*10(-5)), accordingly. In European trios, no significant association was seen for any SNPs after Bonferroni corrections for the total number of 120 tested SNPs., Conclusions/significance: Our findings add evidence from GWAS to support the role of BMP4 in susceptibility to NSCL/P originally identified in linkage and candidate gene association studies.

Background: The teratogenic effects of maternal alcohol consumption during pregnancy include anomalies of craniofacial structures derived from the cranial neural crest cells. The presence of specific craniofacial anomalies contributes to the diagnosis of fetal alcohol spectrum disorders. Cleft lip and palate [orofacial clefts (OFCs)], also derived from the cranial neural crest cells, are common congenital anomalies, but their relationship with prenatal alcohol consumption is unknown., Methods: To evaluate the association between maternal consumption of alcohol during pregnancy and the occurrence of OFCs in infants, we conducted a systematic review and meta-analyses of published studies. We examined the associations between any alcohol consumption, binge level drinking, and heavy and moderate levels of consumption vs. no or low levels of consumption., Results: After screening 737 publications, we identified 33 studies (23 case-control and 10 cohort studies). There was considerable heterogeneity in individual study design, quality measures and study results. Findings from random effects meta-analyses suggest no relationship between prenatal alcohol consumption and the occurrence of OFCs {pooled odds ratios for any alcohol intake and binge level drinking respectively: cleft lip with or without cleft palate 1.00 [95% confidence interval (CI) 0.86, 1.16] from 18,349 participants in 13 studies, 1.04 [95% CI 0.87, 1.24] [8763 individuals, 4 studies]; cleft palate only 1.05 [95% CI 0.92, 1.21] [21,459 individuals, 17 studies], 0.94 [95% CI 0.74, 1.21] [7730 participants, 4 studies]}., Conclusions: While we found no association between alcohol consumption during pregnancy and OFCs in infants, the influence of study design, particularly in relation to alcohol exposure measurement and OFC ascertainment cannot be ignored., (© 2014 John Wiley & Sons Ltd.)

Objectives: To estimate the influence of a short mandible on the risk of developing a cleft palate with/without a cleft lip (CP)., Setting and Sample Population: The retrospective sample consisted of 115 2-month-old Danish infants with CP, and 70 control infants with unilateral incomplete cleft lip (UICL)., Material and Methods: Cephalometric X-rays were obtained. Mandibular length (Lm ) was measured and corrected for body length (Lb ) to remove influence of varying body length in the sample. Logistic regression was applied to the corrected mandibular length (Lmc ) to calculate the risk of having a cleft palate., Results: The mean mandibular length in the group with CP was about 4 mm shorter than in the control group. Odds ratio (OR) was calculated to be 0.58 (95% confidence interval 0.48-0.68), implying that an individual's risk of cleft palate with/without a cleft lip increases about 50% per mm decrease in mandibular length., Conclusions: A special facial type including a short mandible is a possible risk factor for cleft palate, and it was found that the risk of cleft palate increases 58% per mm decreases in mandibular length., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cleft lip, which results from impaired facial process growth and fusion, is one of the most common craniofacial birth defects. Many genes are known to be involved in the etiology of this disorder; however, our understanding of cleft lip pathogenesis remains incomplete. In the present study, we uncovered a role for sonic hedgehog (SHH) signaling during lip fusion. Mice carrying compound mutations in hedgehog acyltransferase (Hhat) and patched1 (Ptch1) exhibited perturbations in the SHH gradient during frontonasal development, which led to hypoplastic nasal process outgrowth, epithelial seam persistence, and cleft lip. Further investigation revealed that enhanced SHH signaling restricts canonical WNT signaling in the lambdoidal region by promoting expression of genes encoding WNT inhibitors. Moreover, reduction of canonical WNT signaling perturbed p63/interferon regulatory factor 6 (p63/IRF6) signaling, resulting in increased proliferation and decreased cell death, which was followed by persistence of the epithelial seam and cleft lip. Consistent with our results, mutations in genes that disrupt SHH and WNT signaling have been identified in both mice and humans with cleft lip. Collectively, our data illustrate that altered SHH signaling contributes to the etiology and pathogenesis of cleft lip through antagonistic interactions with other gene regulatory networks, including the canonical WNT and p63/IRF6 signaling pathways.

Aim: Aim of the review was to provide a literature overview of the birth defects of cleft lip and/or cleft palate (CL/P)., Methods: Through the use of the PubMed database items were collected that would provide information about the condition, leading to the discussion of the following topics: epidemiology, anatomical features, genetics, environmental factors, diagnosis and treatment., Results: According to these data, the CL/P are the most common congenital malformations of the craniofacial region. There are different phenotypes and clinical features of this malformation, which differ according to the anatomical structures involved: cleft lip, cleft lip and cleft palate. The etiology is multifactorial and includes both genetic factors and environmental factors. For proper diagnosis and treatment it is important to complete a multidisciplinary approach to guide the patient from birth to the end of growth. Among the outstanding figures for the care of the anomaly are: the gynecologist, the pediatrician, the maxillofacial surgeon and orthodontist. Individuals with a cleft lip and/or cleft palate may experience problems in feeding, pronunciation, hearing and social integration, which can be corrected to a different extent by surgery, dental treatment, speech therapy and psychosocial interventions., Conclusion: Today the optimal treatment is difficult to find, because of the large variability of malformations and the subjective response of each patient to therapy.

Ankyloblepharon filiforme adnatum (AFA) is a rare congenital anomaly characterized by partial or complete adhesion of upper and lower eyelids, usually seen as an isolated finding but often associated with other anomalies or a well-defined syndrome. We report two cases of AFA who presented at a tertiary eye care center of West Bengal. Family history of consanguinity was absent. One baby had abnormal tuft of hair over the small of the back. No other congenital abnormalities were detected in any of them. The adhesions of the eyelids were divided by a number 15 blade after crushing with mosquito forceps in both cases without any anesthesia. Subsequent ocular examinations following separation and during follow-up revealed normal eyelid function, ocular motility, and fundus. In a case of AFA, timely separation of the eyelids is crucial to avoid the development of occlusion amblyopia. Cases of AFA reported in the literature are reviewed.

Background and Objective: Fever during pregnancy has been suspected to harm the developing fetus. However, until now, no systematic analysis of the available evidence has been undertaken to assess the impact of maternal fever on health outcomes in the child. The goal of this study was to systematically review evidence from epidemiologic studies on adverse health outcomes of the offspring in relation to exposure to maternal fever during pregnancy., Methods: Systematic searches in PubMed, Web of Science, and the Cochrane Library were performed by using Medical Subject Headings, Boolean operators, and truncation, and references of references were reviewed. Cohort and case-control studies addressing health outcomes of prenatal fever exposure in humans were eligible for inclusion. Studies with no direct reference to fever, studies in selected populations (eg, preterm births), and studies published before 1990 were excluded., Results: The available literature supported an increased risk of adverse offspring health in association with fever during pregnancy. The strongest evidence was available for neural tube defects, congenital heart defects, and oral clefts, in which meta-analyses suggested between a 1.5- and nearly 3-fold increased risk with fever exposure in the first trimester. We did not find strong evidence of a dose-response relationship, but there was some evidence that antipyretic medications may have a protective effect when used in relation to febrile episodes., Conclusions: We found substantial evidence to support the contention that maternal fever during pregnancy may negatively affect offspring health. The harmful effects seemed to cover both short- and longer-term health outcomes; however, for several outcomes, the evidence was insufficient to judge any association.

The aim of this study was to analyze the association of potential risk factors such as positive family cleft history, smoking, use of drugs during pregnancy, and parental age with oral clefts in offspring within the Kosovo population. We conducted a population-based case-control study of live births in Kosovo from 1996 to 2005. Using a logistic regression model, 244 oral cleft cases were compared with 488 controls. We have excluded all syndromic clefts. Heredity increases the risk of clefts in newborns [odds ratio (OR) = 8.25, 95% confidence interval (CI) 3.12-23.52]. Clefts were also associated with smoking (OR = 1.87, 95% CI 0.75-4.08), use of drugs during pregnancy (OR = 2.25, 95% CI 0.82-5.12), increasing maternal age (OR = 1.83, 95% CI 1.42-2.49), and increasing paternal age (OR = 1.3, 95% CI 1.2- 1.4). We found heredity to be the most important factor for cleft occurrence in Kosovar newborns. Another significant potential risk factor for occurrence of clefts is the parental age. We found the use of drugs and smoking during pregnancy to be less significant.