Embryologically Based Classification Specifies Gender Differences in the Prevalence of Orofacial Cleft Subphenotypes

Background: A recently published validated classification system divides all orofacial cleft (OFC) subphenotypes into groups based on underlying developmental mechanisms, that is, fusion and differentiation, and their timing, that is, early and late periods, in embryogenesis of the primary and secondary palates. Aims: The aim of our study was to define gender differences in prevalence for all subphenotypes in newborns with OFC in the Netherlands. Methods: This was a retrospective cross-sectional study on children with OFC born from 2006 to 2016. Clefts were classified in early (E-), late (L-), and early/late (EL-) embryonic periods, in primary (P-), secondary (S-), and primary/secondary (PS-) palates, and further divided into fusion (F-), differentiation (D-), and fusion/differentiation (FD-) defects, respectively. Results: A total of 2089 OFC children were analyzed (1311 males and 778 females). Orofacial cleft subphenotypes in females occurred significantly more frequent in the L-period compared to males (66% vs 55%, P = .000), whereas clefts in males occurred significantly more in the EL-periods (40% vs 27%, P = .000). Females had significantly more S-palatal clefts (42% vs 23%, P = .000), while males had significantly more PS-palatal clefts (44% vs 30%, P = .000). Furthermore, the clefts in females were significantly more frequent the result of an F-defect (60% vs 52%, P = .000). Conclusions: Orofacial cleft in females mainly occur in the L-period are mostly S-palatal clefts, and are usually the result of an F-defect. Orofacial cleft in males more commonly occur in the EL-periods, are therefore more often combined PS-palatal clefts, and are more frequent D- and FD-defects

Median cleft of the lower lip and mandible: Case reports, a new embryologic hypothesis, and subdivision

Median clefts of the lower lip and mandible are rare. In the literature so far, about 62 cases have been described. In addition, three more patients are presented here. These cases show a broad variation in the severity of this deformity, ranging from a simple notch in the vermilion to a complete cleft of the lip involving the tongue, the chin, the mandible, the supporting structures of the median of the neck, and the manubrium sterni. Several hypotheses concerning the pathogenesis of median clefts of the lip and mandible have been proposed. Most authors consider it to be a failure of fusion of the first pair of branchial arches or failure of mesodermal penetration into the midline. From our embryologic point of view, however, instead of paired branchial arches, only one first branchial arch develops during the early embryonic period (≤17 mm crown-rump length). Within this first branchial arch, two mandibular processes grow out, separated by a groove in the median. These mandibular processes do not fuse but merge during the late embryonic period (≥17 mm to ≤60 mm crown-rump length). In the same developmental period, there is formation of the lip and the alveolar process and the anlage and outgrowth of one membrane bone center in each mandibular process, resulting in the formation of the mandible with its symphysis. As a consequence of the preceding, we propose the following subdivision of the median clefts of the lip and/or mandible. Hypoplasia of the mandibular processes during the early embryonic period will lead to the severest cleft of the mandible extending into the neck. During the late embryonic period, the less severe median clefts will develop. Disturbances of the outgrowth of bone centers of the mandible, resulting in nonformation of its symphysis, cause clefting of the mandible with involvement of all related soft tissues. Defects in the merging process produce just a notch of the vermilion or a higher cleft of the lower lip with or without involvement of the alveolar process of the mandible. In conclusion, the variety of the clefts in the median of the lower lip and/or mandible as well as the low rate of incidence can be explained by the embryologic hypothesis proposed here

Nutrition and genes in the development of orofacial clefting

Clefts of the lip, alveolus, and/or palate, which are called orofacial clefts (OFC), occur in 0.5 to 3 per 1000 live and stillbirths. The pathogenesis of these congenital malformations remains largely unknown, but evidence is increasing that both nutritional and genetic factors are involved. Unlike genetic factors, nutritional causes can be corrected and may therefore contribute to the prevention of OFC. The goal of this review is to summarize the embryogenesis and genes involved in OFC, and to give an overview of the nutrients and related genes in humans. Improving our knowledge of the role of nutrition, genes, and their interactions in the pathogenesis of OFC may stimulate the development of nutritional interventions for OFC prevention in the future

Regional Variation in Prevalence of Oral Cleft Live Births in the Netherlands 1997-2007: Time-Trend Analysis of Data from Three Dutch Registries

The Eurocat registry Northern Netherlands (NNL) has been used in regional context, as well as in national/international context, to describe the epidemiology of oral clefts (OC). However, the region NNL seems to have prevalence data different fromDutch national registries and certain other European areas. Thismay be due to differences in registration methods or geographical variation. To investigate whether the prevalence of OC live births varies regionally in the Netherlands, we established time trends for NNL and the rest of the Netherlands over 1997-2007 using data from two national registries (the OC Registry and The Netherlands Perinatal Registry) and a regional registry (Eurocat NNL). We found that the overall live-birth prevalence-comprising cleft lip/alveolus +/- cleft palate and cleft palate only-was significantly higher in NNL (15.1-21.4 per 10,000) than in the rest of the Netherlands (13.2-16.1 per 10,000). None of the registries showed significant trends for NNL, whereas both national registries showed that the live-birth prevalence of cleft lip/alveolus +/- cleft palate decreased significantly in the rest of the Netherlands. Despite some differences in prevalence between the registries, they showed similar regional variation in prevalence and trends. In conclusion, the prevalence of OC live births varies significantly in the Netherlands, not only between but also within registries. This underlines that extrapolation of regional cleft data should be done with caution. To further investigate OC etiology and evaluate preventive strategies, future studies should consider geographical differencesbetween and within countries-regarding the various cleft sub-phenotypes among live births, stillbirths, and pregnancy terminations. (C) 2011 Wiley Periodicals, Inc

Seasonal Influence on the Numbers of Gender-Related Orofacial Cleft Conceptions in the Netherlands

Background: In the multifactorial etiology of orofacial clefts (OFCs), environmental factors play an important role. To trace the influence of these factors, the timing of the cell biological mechanisms that occur during embryological development of the primary and secondary palates must be taken into account. That is, the fusion process of the facial and palatal processes, respectively, followed by their differentiation into bone and musculature, which take place during the first trimester of pregnancy. During this period, harmful seasonal influences such as viral infections and vitamin deficiencies could induce OFC in the embryo. Aims: The aim of this study is to find out whether a seasonal conception period with an increased risk of OFC development exists, particularly gender related. Methods: This was a retrospective cross-sectional study on children with OFC born in the Netherlands from 2006 to 2016. Total conception rates of live births in the Netherlands were used as a control group. χ2 tests were performed to analyze monthly and seasonal differences. Males and females, positive and negative family history and subphenotype groups based on fusion and/or differentiation (F- and/or D-) defects, and their timing in embryogenesis were analyzed separately. Results: In total, 1653 children with OFC, 1041 males and 612 females, were analyzed. Only males with FD-defects showed a significant seasonal variation with an increase in conceptions during spring, most often in May. Conclusions: Males with FD-defects showed a significant seasonal variation with an increase in conceptions during spring. No other seasonal trends could be demonstrated

Decrease in Prevalence of Cleft lip, Alveolus and Palate After Nationwide Introduction of the Second-Trimester Anomaly Scan in the Netherlands

OBJECTIVE: Some studies have suggested that introducing a second-trimester anomaly scan (SAS) leads to increased rates of termination of pregnancy (TOP) in fetuses with orofacial clefts (OFCs). The aim of this study was to evaluate the impact of a nationwide introduction of SAS on the prevalence of live births with OFCs in the Netherlands. DESIGN: Retrospective cohort study. SETTING: Tertiary setting. POPULATION: Included in the study were all patients diagnosed with OFCs as recorded in the “Dutch Association for Cleft Palate Anomalies” database between 1997 and 2019. INTERVENTIONS: Patients were divided into three categories: cleft lip with or without alveolus (CL/A), cleft lip, alveolus and palate (CLAP) and cleft palate (CP) based on anatomical landmarks at the first consultation. MAIN OUTCOME MEASURES: Prevalence rates of OFCs before and after the nationwide introduction of the SAS on January 1, 2007 were compared. RESULTS: Overall, 1899 patients were diagnosed with CL/A, 2586 with CLAP and 2927 with CP. The prevalence of clefts before and after introduction of the SAS did not differ (P = 0.85). The prevalence of CL/A decreased (P = 0.04), and that of CLAP decreased (P = 0.01) and that of CP increased (P = 0.02). CONCLUSIONS: This study demonstrates a significant decrease in the prevalence of CL/A and CLAP after introduction of the SAS. However, due to an increase in CP, the prevalence of all patients born with OFCs has not changed in the Netherlands between 1997 and 2019

The role of bone centers in the pathogenesis of craniosynostosis

This paper describes the role of the displacement of bone centers, i.e., the tubers, in the pathogenesis of craniosynostosis. This displacement was studied in 54 patients with isolated or syndromic craniosynostosis in the form of CT scans as well as in two dry neonate skulls with Apert syndrome. For comparison, 49 fetal and 8 normal infant dry skulls were studied. Our investigation was restricted to the coronal and metopic sutures. The results showed a significantly more occipital localization of the frontal bone center and a more frontal localization of the parietal bone center at the side of a synostotic coronal suture in the isolated form as well as in Apert syndrome. In contrast, this was not the case in Crouzon syndrome, thus showing that these two syndromes have a different pathogenesis. For trigonocephaly, a more anteromedial localization of the frontal bone centers was found

Validation of the Dutch registry of common oral clefts: Quality of recording specific oral cleft features

Objective: Since 1997, common oral clefts in the Netherlands have been recorded in the national oral cleft registry using a unique descriptive recording system. This study validates data on the topographic-anatomical structure, morphology, and side of individual anomalies of the primary palate and secondary palate that form the oral cleft. Design: Validation study. Setting: All 15 Dutch cleft palate teams reporting presurgery oral cleft patients to the national registry. Patients: A random sample of 250 cases registered in the national database with oral clefts from 1997 through 2003; of these, 13 cases were excluded. Main Outcome Measures: By linking registry data with clinical data, we identified differential recording rates by comparing the prevalence, and we measured the degree of agreement by computing validity and reliability statistics. Results: The topographic-anatomical structures (lip, alveolus, and hard and soft palates) of the anomalies had near-perfect interdatabase agreement with a sensitivity of 88% to 99%. However, when analyzing the individual anomalies in detail (morphology and side), validity decreased and depended on morphological severity. This association was most evident for anomalies of the secondary palate. For example, sensitivity was higher for ''complete cleft hard palate'' (92%) than for ''submucous cleft hard/soft palate'' (69%). Conclusions: Overall, the validity of Dutch registry data on oral clefts is good, supporting the feasibility of this unique recording system. However, when analyzing oral cleft data in detail, the quality appears to be related to anatomical location and morphological severity. This might have implications for etiologic research based on registry data and for guidelines on neonatal examination