Birth Defects Research Research Articles

Value of sharing and networking among birth defects surveillance programs: an ICBDSR perspective.

Birth defects (BD), also known as congenital anomalies, are structural or functional abnormalities present at birth as a result of abnormal prenatal development. Their cause can be broadly categorized as genetic, environmental, or a combination of both. It is estimated that approximately 3-6% of newborn infants worldwide are affected by BD, many of which are associated with serious morbidity, mortality, and lifelong disabilities. The International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), founded in 1974, promotes worldwide birth defect surveillance, research, and prevention through the ongoing sharing of data, expertise, and training. In this review, we show value and contribution of BD surveillance systems in pursuing these aims. In the time of personalized medicine for many rare and common diseases, there are still massive gaps in our understanding of the causes and mechanisms of many birth defects, especially structural congenital anomalies. The main aim of the Sustainable Development Goals (SDGs), adopted by the United Nations in 2015, is to ensure healthy lives and promote well-being for all children. One specific goal is to end preventable deaths of newborns and children less than 5years of age by 2030. The SDGs also underscore the need to consider BD as a priority in the global child health agenda. It can be said that counting BD helps BD to count. By sharing data and expertise and joining in surveillance and research, BD surveillance programs can play a major role in increasing our understanding of the causes of BD, and promoting prevention.

Causes of Congenital Malformations.

Many different causes of malformations have been established. The surveillance of a consecutive population of births, including stillbirths and elective terminations of pregnancy because of fetal anomalies, can identify each infant with malformations and determine the frequency of the apparent etiologies. This report is a sequel to the first such analysis in the first 10 years of this Active Malformations Surveillance Program (Nelson and Holmes, ). The presence of malformations was determined among 289,365 births over 41 years (1972-2012) at the Brigham and Women's Hospital in Boston. The abnormalities were identified from the review of the examination findings of the pediatricians and consultants and diagnostic testing for the live-born infants and the autopsies of the fetuses in elective terminations and stillbirths. A total of 7020 (2.4%) infants and fetuses with one or more malformations were identified with these apparent etiologies in 26.6%: Mendelian disorders, including infants with postaxial polydactyly, type B; chromosome abnormalities; vascular disruption; complications of monozygous twinning; and environmental factors. The malformations of unknown etiology were a much larger group. While several causes of malformations have been identified, many remain unexplained. Combining the ascertainment in a future surveillance programs with genome sequencing and chromosome microarray analysis will increase significantly the number of malformations attributed to genetic mechanisms. Birth Defects Research 110:87-91, 2018.© 2018 Wiley Periodicals, Inc.

Stillborn Infants: Associated Malformations.

Stillbirth, defined as death of a fetus in utero after 20 weeks of gestation, occurs in 1 to 2% of pregnancies in the United States. Many of these stillborn infants have associated malformations, including chromosome abnormalities, neural tube defects, and malformation syndromes. Other causes are abnormalities of the placenta and maternal conditions, such as pre-eclampsia and obesity. A consecutive sample of malformed stillborn infants can establish the relative frequency and severity of the associated malformations. Stillbirths were identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital (1972-2012). The findings at autopsy, including the findings in the placenta and the results of diagnostic studies, were compiled. One hundred twenty-seven stillborn infants with malformations were identified at autopsy among 289,365 pregnancies, including trisomies 21, 18, and 13; 45,X; triploidy; anencephaly; lower urinary tract obstruction; holoprosencephaly and severe heart defects, such as hypoplastic left heart syndrome and tetralogy of Fallot with pulmonary atresia. The severity of the abnormalities in stillborn infants was more severe than the spectrum of abnormalities identified in live-born infants. An autopsy of the stillborn fetus, including chromosome microarray and an examination of the placenta, can identify the underlying causes of the stillbirth. This review of stillborn fetuses with malformations showed that several different lethal malformations and heart defects are more common than among live-born infants. These postmortem examinations can improve the counseling of the parents about risks in future pregnancies. Birth Defects Research 110:114-121, 2018.© 2018 Wiley Periodicals, Inc.

Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.

The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc.

Iniencephaly.

Iniencephaly is a severe developmental abnormality of the craniovertebral junction in which the head is retroflexed dramatically. Anatomic studies have identified striking changes in the vertebrae and skull: marked lordosis of the cervical vertebrae, duplicated cervical vertebrae, irregularly fused cervical vertebrae, a widened foramen magnum and a small posterior fossa. The affected infant appears to have no neck, as the skin of the face is continuous with the chest and the skin of the posterior scalp is continuous with the skin of the back. Iniencephaly is considered a rare neural tube defect. The frequency has been higher in geographic areas in which the rates of occurrence of anencephaly and myelomeningocele were high. Most affected fetuses are either stillborn or die soon after birth. However, one affected individual is an adult with normal intelligence. A malformations surveillance program can identify an unselected group of infants with iniencephaly. This approach can determine the prevalence rate, the frequency of associated malformations, and the occurrence of close relatives with other neural tube defects. Over 41 years, the surveillance of 289,365 births identified eight fetuses and newborn infants with iniencephaly. Five of the eight had either an additional encephalocele or a thoracic myelomeningocele. Two of the eight affected infants had a sibling or a cousin with anencephaly. These findings suggest a relationship between the occurrence of iniencephaly and the most common neural tube defects, anencephaly and myelomeningocele. Recent experience confirms that this complex neural tube defect is not always lethal. Birth Defects Research 110:128-133, 2018. © 2018 Wiley Periodicals, Inc.

Prevalence and Risk of Birth Defects Observed in a Prospective Cohort Study: The Hokkaido Study on Environment and Children's Health.

BackgroundPrevalence rates of all anomalies classified as birth defects, including those identified before the 22nd gestational week, are limited in published reports, including those from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). In our birth cohort study, we collected the data for all birth defects after 12 weeks of gestation.MethodsSubjects in this study comprised 19,244 pregnant women who visited one of 37 associated hospitals in the Hokkaido Prefecture from 2003 through 2012, and completed follow-up. All birth defects after 12 weeks of gestation, including 55 marker anomalies associated with environmental chemical exposures, were recorded. We examined parental risk factors for birth defects and the association between birth defects and risk of growth retardation.ResultsPrevalence of all birth defects was 18.9/1,000 births. The proportion of patients with birth defects delivered between 12 and 21 weeks of gestation was approximately one-tenth of all patients with birth defects. Among those with congenital malformation of the nerve system, 39% were delivered before 22 weeks of gestation. All patients with anencephaly and encephalocele were delivered before 22 weeks of gestation. We observed different patterns of parental risk factors between birth defect cases included in ISBDSR and cases not included. Cases included in ISBDSR were associated with an increased risk of preterm birth. Cases not included in ISBDSR were associated with an increased risk of being small for gestational age at term.ConclusionsData from our study complemented the data from ICBDSR. We recommend that birth defects not included in ICBDSR also be analyzed to elucidate the etiology of birth defects.

Using State Birth Defects Registries to Evaluate Regional Critical Congenital Heart Disease Newborn Screening

Most states have now passed legislation mandating pulse oximetry for all newborns, or have promulgated regulations or guidelines to encourage use of routine pulse oximetry. State-based birth defects registries may be well positioned to track and evaluate critical congenital heart disease (CCHD) screening coverage and outcomes. This purpose of this study was to determine: (1) the proportion of cases detected by screening, (2) health services use by children with CCHDs during the first year of life, and (3) mortality outcomes. Records of children born in 2012 to 2013 with any of seven CCHD lesions were identified in New England birth defects databases. Information was abstracted from each child's medical record. Descriptive statistics were used to report results. From nearly 160,000 live births, 208 CCHD diagnoses were noted in the records of 157 children. Screening was noted in 67% of records of confirmed cases of CCHDs. Data completeness varied by state; for example, information was available regarding prenatal diagnosis in 91% of records and age at first surgery in 85% among states with active surveillance compared with 35% and 75%, respectively, with passive surveillance. Documentation of screening results in medical records was inconsistent. The one year survival was 85% (77/91). Birth defects surveillance systems can provide information on outcomes for infants with CCHDs. However, information varies by surveillance method and by hospital practices. Engaging hospitals in standardizing recording procedures and enhancing training and quality control could increase the value of birth defects registries records in assessing outcomes for children identified through CCHD screening. Birth Defects Research 109:1414-1422, 2017.© 2017 Wiley Periodicals, Inc.

Proximity to Pediatric Cardiac Surgical Care among Adolescents with Congenital Heart Defects in 11 New York Counties.

Many individuals with congenital heart defects (CHDs) discontinue cardiac care in adolescence, putting them at risk of adverse health outcomes. Because geographic barriers may contribute to cessation of care, we sought to characterize geographic access to comprehensive cardiac care among adolescents with CHDs. Using a population-based, 11-county surveillance system of CHDs in New York, we characterized proximity to the nearest pediatric cardiac surgical care center among adolescents aged 11 to 19 years with CHDs. Residential addresses were extracted from surveillance records documenting 2008 to 2010 healthcare encounters. Addresses were geocoded using ArcGIS and the New York State Street and Address Maintenance Program, a statewide address point database. One-way drive and public transit time from residence to nearest center were calculated using R packages gmapsdistance and rgeos with the Google Maps Distance Matrix application programming interface. A marginal model was constructed to identify predictors associated with one-way travel time. We identified 2522 adolescents with 3058 corresponding residential addresses and 12 pediatric cardiac surgical care centers. The median drive time from residence to nearest center was 18.3 min, and drive time was 30 min or less for 2475 (80.9%) addresses. Predicted drive time was longest for rural western addresses in high poverty census tracts (68.7 min). Public transit was available for most residences in urban areas but for few in rural areas. We identified areas with geographic barriers to surgical care. Future research is needed to determine how these barriers influence continuity of care among adolescents with CHDs. Birth Defects Research 109:1494-1503, 2017.© 2017 Wiley Periodicals, Inc.

Early Gestational Hypoxia and Adverse Developmental Outcomes.

Hypoxia is a normal and essential part of embryonic development. However, this state may leave the embryo vulnerable to damage when oxygen supply is disturbed. Embryofetal response to hypoxia is dependent on duration and depth of hypoxia, as well as developmental stage. Early postimplantation rat embryos were resilient to hypoxia, with many surviving up to 1.5 hr of uterine clamping, while most mid-gestation embryos were dead after 1 hour of clamping. Survivors were small and many had a range of defects, principally terminal transverse limb reduction defects. Similar patterns of malformations occurred when embryonic hypoxia was induced by maternal hypoxia, interruption of uteroplacental flow, or perfusion and embryonic bradycardia. There is good evidence that high altitude pregnancies are associated with smaller babies and increased risk of some malformations, but these results are complicated by increased risk of pre-eclampsia. Early onset pre-eclampsia itself is associated with small for dates and increased risk of atrio-ventricular septal defects. Limb defects have clearly been associated with chorionic villus sampling, cocaine, and misoprostol use. Similar defects are also observed with increased frequency among fetuses who are homozygous for thalassemia. Drugs that block the potassium current, whether as the prime site of action or as a side effect, are highly teratogenic in experimental animals. They induce embryonic bradycardia, hypoxia, hemorrhage, and blisters, leading to transverse limb defects as well as craniofacial and cardiovascular defects. While evidence linking these drugs to birth defects in humans is not compelling, the reason may methodological rather than biological. Birth Defects Research 109:1358-1376, 2017.© 2017 Wiley Periodicals, Inc.

Manifestations of Hypoxia in the Second and Third Trimester Placenta.

The placental pathologies that develop in the context of hypoxic insults to the fetus and placenta are termed maternal vascular malperfusion (MVM). On molecular analysis, these lesions primarily show evidence of oxidative damage, suggesting that they arise in the context of hypoxia-reperfusion injury. The earliest abnormalities are likely incomplete or absent remodeling of maternal spiral arteries (decidual arteriopathy). These vascular remodeling defects then lead to subsequent damage patterns, including accelerated villous maturation, distal villous hypoplasia, increased syncytial knots, villous infarction, retroplacental hemorrhage, and placental hypoplasia. MVM may occur in a surprisingly wide array of clinical disorders, but the relation between these clinical disorders and placental MVM is complex. It seems likely that these clinical disorders represent final common pathways for multiple etiologies, only some of which result in MVM. Birth Defects Research 109:1345-1357, 2017.© 2017 Wiley Periodicals, Inc.

Association Study of Transforming Growth Factor Alpha TaqI Polymorphism and the Risk of Cleft Lip and/or Palate in an Iranian Population

The aim of this study is to evaluate the association of TGFA TaqI polymorphism with nonsyndromic cleft lip and/or palate (NSCLP) in an Iranian population. In this case-control study, 113 children with NSCLP and 209 controls were included. Genotyping of the TaqI polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism methods. A p-value of <0.05 was considered statistically significant. For the TGFA TaqI polymorphism, the distributions of genotypes in the NSCLP (p = 0.810) and control group (p = 0.422) were in Hardy-Weinberg equilibrium. There was no statistically significant difference in the genotype distribution (p = 0.059) and allele frequency (p = 0.065) of the TGFA TaqI polymorphism in the NSCLP and control groups. TGFA TaqI polymorphism was not associated with the risk of NSCLP in Iranian children. Birth Defects Research 109:1386-1389, 2017.© 2017 Wiley Periodicals, Inc.

Hypoxia and Placental Development.

Hemochorial placentation is orchestrated through highly regulated temporal and spatial decisions governing the fate of trophoblast stem/progenitor cells. Trophoblast cell acquisition of specializations facilitating invasion and uterine spiral artery remodeling is a labile process, sensitive to the environment, and represents a process that is vulnerable to dysmorphogenesis in pathologic states. Hypoxia is a signal guiding placental development, and molecular mechanisms directing cellular adaptations to low oxygen tension are integral to trophoblast cell differentiation and placentation. Hypoxia can also be used as an experimental tool to investigate regulatory processes controlling hemochorial placentation. These developmental processes are conserved in mouse, rat, and human placentation. Consequently, elements of these developmental events can be modeled and hypotheses tested in trophoblast stem cells and in genetically manipulated rodents. Hypoxia is also a consequence of a failed placenta, yielding pathologies that can adversely affect maternal adjustments to pregnancy, fetal health, and susceptibility to adult disease. The capacity of the placenta for adaptation to environmental challenges highlights the importance of its plasticity in safeguarding a healthy pregnancy. Birth Defects Research 109:1309-1329, 2017.© 2017 Wiley Periodicals, Inc.

Altered Electroencephalography Spectral Profiles in Rats with Different Patterns of Experimental Brain Dysplasia.

Malformations of cortical development, such as focal cortical dysplasia, are commonly associated with intractable epilepsy. Multiple animal models were created in attempts to recapitulate features of human malformations of cortical development. These manipulations give rise to various focal or diffuse anatomical abnormalities, accompanied by altered susceptibility to epileptic seizures. Both in humans and in models of dysplasia, the question of timing of the initiating insult is important. Here, we used a rat model of cerebral dysplasia elicited by prenatal irradiation at gestational days (E) 13, 15, 17, or 19. Previous results suggest these animals are characterized by different patterns of dysplasia as well as different reactivity to seizurogenic stimuli in several seizure models. Rats were implanted with telemetric electroencephalography (EEG) transmitters. We compared EEG data from freely moving animals with anatomical observations obtained with MRI, as well as Western blotting and immunohistochemistry. We performed spectral analyses of EEG signal, revealing differential regulation of specific bands (including delta, theta, alpha-beta, gamma) in animals with different patterns of dysplasia. Relative contribution of low-frequency activity in delta band is the lowest in E15 and the highest in E19. Conversely, higher frequency bands, corresponding to alpha/beta and gamma components, are reduced in E15 versus E19. This is accompanied by altered expression of glial markers in the E19 group. To our knowledge, this constitutes the first quantitative description of power spectral properties in this experimental model, providing insight into mechanisms underlying the anatomical and electrophysiological abnormalities associated with brain dysplasia of different types. Birth Defects Research, 110:303-316, 2018. © 2017 Wiley Periodicals, Inc.

Hypoxia: From Placental Development to Fetal Programming.

Hypoxia may influence normal and different pathological processes. Low oxygenation activates a variety of responses, many of them regulated by hypoxia-inducible factor 1 complex, which is mostly involved in cellular control of O2 consumption and delivery, inhibition of growth and development, and promotion of anaerobic metabolism. Hypoxia plays a significant physiological role in fetal development; it is involved in different embryonic processes, for example, placentation, angiogenesis, and hematopoiesis. More recently, fetal hypoxia has been associated directly or indirectly with fetal programming of heart, brain, and kidney function and metabolism in adulthood. In this review, the role of hypoxia in fetal development, placentation, and fetal programming is summarized. Hypoxia is a basic mechanism involved in different pregnancy disorders and fetal health developmental complications. Although there are scientific data showing that hypoxia mediates changes in the growth trajectory of the fetus, modulates gene expression by epigenetic mechanisms, and determines the health status later in adulthood, more mechanistic studies are needed. Furthermore, if we consider that intrauterine hypoxia is not a rare event, and can be a consequence of unavoidable exposures to air pollution, nutritional deficiencies, obesity, and other very common conditions (drug addiction and stress), the health of future generations may be damaged and the incidence of some diseases will markedly increase as a consequence of disturbed fetal programming. Birth Defects Research 109:1377-1385, 2017.© 2017 Wiley Periodicals, Inc.

Hypoxic Stress Forces Adaptive and Maladaptive Placental Stress Responses in Early Pregnancy

This review focuses on hypoxic stress and its effects on the placental lineage and the earliest differentiation events in mouse and human placental trophoblast stem cells (TSCs). Although the placenta is a decidual organ at the end of pregnancy, its earliest rapid growth and function at the start of pregnancy precedes and supports growth and function of the embryo. Earliest function requires that TSCs differentiate, however, "hypoxia" supports rapid growth, but not differentiation of TSCs. Most of the literature on earliest placental "hypoxia" studies used 2% oxygen which is normoxic for TSCs. Hypoxic stress happens when oxygen level drops below 2%. It decreases anabolism, proliferation, potency/stemness and increases differentiation, despite culture conditions that would sustain proliferation and potency. Thus, to study the pathogenesis due to TSC dysfunction, it is important to study hypoxic stress below 2%. Many studies have been performed using 0.5 to 1% oxygen in cultured mouse TSCs. From all these studies, a small number has examined human trophoblast lines and primary first trimester placental hypoxic stress responses in culture. Some other stress stimuli, aside from hypoxic stress, are used to elucidate common and unique aspects of hypoxic stress. The key outcomes produced by hypoxic stress are mitochondrial, anabolic, and proliferation arrest, and this is coupled with stemness loss and differentiation. Hypoxic stress can lead to depletion of stem cells and miscarriage, or can lead to later dysfunctions in placentation and fetal development. Birth Defects Research 109:1330-1344, 2017. © 2017 Wiley Periodicals, Inc.

Maternal Use of Weight Loss Products and the Risk of Neural Tube Defects in Offspring: A Systematic Literature Review.

Several studies have assessed potential associations between use of weight loss products in the periconceptional period and neural tube defects (NTDs). However, the individual studies are inconclusive and there has not been a systematic review of this literature. We conducted a systematic search, using Ovid MEDLINE and PubMed, to identify studies that evaluated the association between products used for weight loss and the risk of NTDs. Because many studies of birth defects only evaluate a composite birth defect outcome, we evaluated studies that defined the outcome as "any major birth defect" or as NTDs. We abstracted data on study design, exposure definition, outcome definition, covariates and effect size estimates from each article that met our inclusion criteria. For studies that evaluated a composite birth defect outcome, we also abstracted the number of NTD cases included in the composite outcome. We used a modified version of the Newcastle-Ottawa Scale to assess the quality of each article. We screened 865 citations and identified nine articles that met our inclusion criteria. The majority of studies reported positive associations between maternal use of weight loss products and birth defects (overall and NTDs). However, there were few significant associations and there was considerable heterogeneity in the specific exposures assessed across the nine studies. Our systematic review of weight loss products and NTDs indicates that the literature on this topic is sparse. Because several studies reported modest, positive associations between risk and use of weight loss products, additional studies are warranted. Birth Defects Research 110:48-55, 2018. © 2017 Wiley Periodicals, Inc.

Sickness Status and Neural Tube Defects: A Case-Control Study in a North Indian Population.

The prevalence of neural tube defects (NTDs) in India is high in comparison to other regions in the world, with the Northern part reporting the highest prevalence. To explore the risk factors for NTDs, a case-control study was carried out in Delhi from January 2008 to June 2011. Using multivariate logistic regression model analysis, 308 cases were compared with 580 controls and adjusted odds ratio (AOR) was calculated using SPSS version 17. Maternal factors that were significantly associated with increased risk of NTDs were inter-pregnancy interval (AOR = 3.175; 95% confidence interval [CI], 2.007-5.024), hyperthermia during the first trimester (AOR = 2.07; 95% CI, 1.131-3.788), maturation ill pregnancy (AOR = 1.956; 95% CI, 1.385-2.763), chronic illness (AOR = 1.648; 95% CI, 1.103-2.462), and use of antibiotics (AOR = 5.589; 95% CI, 1.789-17.455). Differences in the risk were also found between upper and lower NTD. It was observed that all of the former five variables, except for chronic illness, were associated with risk for upper NTDs (AOR = 1.532; 95% CI, 0.916-2.563). In contrast, hyperthermia before conception (and not during the first trimester) was found to be additionally associated with risk for lower NTDs (AOR = 2.782; 95% CI, 1.302-5.944). These findings highlight heterogeneity in the etiology of upper and lower NTDs. The study also highlights the risk factors that should be considered in combating the risk of NTDs. Birth Defects Research 109:1393-1399, 2017.© 2017 Wiley Periodicals, Inc.

ATP Binding Cassette Sub-family Member 2 (ABCG2) and Xenobiotic Exposure During Early Mouse Embryonic Stem Cell Differentiation.

ATP binding cassette sub-family member 2 (ABCG2) is a well-defined efflux transporter found in a variety of tissues. The role of ABCG2 during early embryonic development, however, is not established. Previous work which compared data from the ToxCast screening program with that from in-house studies suggested an association exists between exposure to xenobiotics that regulate Abcg2 transcription and differentiation of mouse embryonic stem cells (mESC), a relationship potentially related to redox homeostasis. mESC were grown for up to 9 days. Pharmacological inhibitors were used to assess transporter function with and without xenobiotic exposure. Proliferation and differentiation were evaluated using RedDot1 and quantiative reverse transcriptase-polymerase chain reaction, respectively. ABCG2 activity was assessed using a Pheophorbide a-based fluorescent assay. Protein expression was measured by capillary-based immunoassay. ABCG2 activity increased in differentiating mESC. Treatment with K0143, an inhibitor of ABCG2, had no effect on proliferation or differentiation. As expected, mitoxantrone and topotecan, two chemotherapeutics, displayed increased toxicity in the presence of K0143. Exposure to K0143 in combination with chemicals predicted by ToxCast to regulate ABCG2 expression did not alter xenobiotic-induced toxicity. Moreover, inhibition of ABCG2 did not shift the toxicity of either tert-Butyl hydroperoxide or paraquat, two oxidative stressors. As previously reported, ABCG2 serves a protective role in mESC. The role of ABCG2 in regulating redox status, however, was unclear. The hypothesis that ABCG2 plays a fundamental role during mESC differentiation or that regulation of the receptor by xenobiotics may be associated with altered mESC differentiation could not be supported. Birth Defects Research, 110:35-47, 2018. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Novel Mutation of LRP6 Identified in Chinese Han Population Links Canonical WNT Signaling to Neural Tube Defects.

Neural tube defects (NTDs), the second most frequent cause of human congenital abnormalities, are debilitating birth defects due to failure of neural tube closure. It has been shown that noncanonical WNT/planar cell polarity (PCP) signaling is required for convergent extension (CE), the initiation step of neural tube closure (NTC). But the effect of canonical WNT//β-catenin signaling during NTC is still elusive. LRP6 (low density lipoprotein receptor related proteins 6) was identified as a co-receptor for WNT/β-catenin signaling, but recent studies showed that it also can mediate WNT/PCP signaling. In this study, we screened mutations in the LRP6 gene in 343 NTDs and 215 ethnically matched normal controls of Chinese Han population. Three rare missense mutations (c.1514A>G, p.Y505C); c.2984A>G, p.D995G; and c.4280C>A, p.P1427Q) of the LRP6 gene were identified in Chinese NTD patients. The Y505C mutation is a loss-of-function mutation on both WNT/β-catenin and PCP signaling. The D995G mutation only partially lost inhibition on PCP signaling without affecting WNT/β-catenin signaling. The P1427Q mutation dramatically increased WNT/β-catenin signaling but only mildly loss of inhibition on PCP signaling. All three mutations failed to rescue CE defects caused by lrp6 morpholino oligos knockdown in zebrafish. Of interest, when overexpressed, D995G did not induce any defects, but Y505C and P1427Q caused more severe CE defects in zebrafish. Our results suggested that over-active canonical WNT signaling induced by gain-of-function mutation in LRP6 could also contribute to human NTDs, and a balanced WNT/β-catenin and PCP signaling is probably required for proper neural tube development. Birth Defects Research 110:63-71, 2018. © 2017 Wiley Periodicals, Inc.

CranFlow: An Application for Record-Taking and Management Through the Brazilian Database on Craniofacial Anomalies.

The World Health Organization has recognized the relevance of databases on craniofacial anomalies since . To date, there is no universal standard instrument/database focused on risk factors, clinical and genetic data collection, and follow-up that enables comparison between different populations and genotype-phenotype correlation. Although studies have shown that specific genes would impact outcomes, knowledge is not sufficient to subsidize cost-effectiveness strategies for diagnosis, surgical decision, and a multi-professional approach toward personalized medicine. Based on a clinical genetic approach, a Web-based application named CranFlow-Craniofacial Anomalies: Registration, Flow, and Management has been developed. It prospectively collects clinical and genetic information for the Brazilian Database on Craniofacial Anomalies (syndromic and nonsyndromic orofacial cleft, 22q11.2 deletion syndrome, and other craniofacial related disorders). A comprehensive list of CranFlow's features is provided. We present preliminary results on 1546 cases already recorded and followed, which allows recognizing 10% of diagnosis changes. The identification of risk factors, consistent genetic approach associated with clinical data and follow-up result in valuable information to develop and improve personalized treatment and studies on genotype-phenotype correlation. Adoption of CranFlow in different clinical services may support comparison between populations. This application has the potential to contribute to improvements in healthcare, quality of services, clinical and surgical outcomes, and the standard of living of individuals with craniofacial anomalies. Birth Defects Research 110:72-80, 2018. © 2017 Wiley Periodicals, Inc.