{"title":"56th Annual Teratology Society Meeting","authors":"","doi":"10.1002/bdra.23519","DOIUrl":"https://doi.org/10.1002/bdra.23519","url":null,"abstract":"","PeriodicalId":8983,"journal":{"name":"Birth defects research. Part A, Clinical and molecular teratology","volume":"106 5","pages":"309-456"},"PeriodicalIF":0.0,"publicationDate":"2016-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdra.23519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91582226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The methylenetetrahydrofolate reductase (MTHFR) polymorphism is a risk factor for neural tube defects. C677T and A1298C MTHFR polymorphisms produce an enzyme with reduced folate-related one carbon metabolism, and this has been associated with aberrant methylation modifications in DNA and protein.
Methods
A meta-analysis was conducted to assess the association between MTHFR C677T/A1298C genotypes and global genomic methylation.
Results
Eleven studies met the inclusion criteria. Of these, 10 were performed on C677T MTHFR genotypes and 6 were performed on A1298C MTHFR genotypes. Our results did not indicate any correlation between global methylation and MTHFR A1298C, C677T polymorphisms.
Na Yang, Linlin Wang, Richard H. Finnell, Zhiwen Li, Lei Jin, Le Zhang, Robert M. Cabrera, Rongwei Ye, Aiguo Ren
Background
After years of periconceptional folic acid supplementation, the prevalence of neural tube defects (NTDs) remains stable following the remarkable reduction observed immediately after the fortification practice. There is accumulating evidence that folate receptor (FR) autoimmunity may play a role in the etiology of folate-sensitive NTDs.
Methods
From 2011 to 2013, 118 NTD cases and 242 healthy controls were recruited from a population-based birth defects surveillance system in Northern China. Enzyme-linked immunosorbent assay was used to measure FR autoantibodies in maternal and cord blood. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI).
Results
Plasma FR autoantibodies levels were significantly elevated in mothers of infants with NTDs compared with mothers of healthy controls. Using the lowest tertile as the referent group, 2.20-fold (95% CI, 0.71–6.80) and 5.53-fold increased odds (95% CI, 1.90–16.08) of NTDs were observed for the second and third tertile of immunoglobulin G (IgG), respectively, and the odds of NTDs for each successive tertile of IgM was 0.98 (95% CI, 0.35–2.75) and 3.49 (95% CI, 1.45–8.39), respectively. A dose–response relationship was found between FR autoantibodies levels and risk of NTDs (P < 0.001 for IgG, P = 0.002 for IgM). The same pattern was observed in both subtypes of spina bifida and anencephaly. No significant difference in levels of cord blood FR autoantibodies was observed.
Gain-of- and loss-of-function studies have demonstrated that changes in bone morphogenetic protein (BMP) signaling during embryo development cause craniofacial malformations, including cleft palate. It remains uncertain whether BMP signaling could be targeted pharmacologically to affect craniofacial morphogenesis.
Methods
Pregnant C57Bl/6J mice were treated with the BMP type I receptor inhibitor LDN-193189 at the dose of 3, 6, or 9 mg/kg twice a day by intraperitoneal injection from embryonic day 10.5 (E10.5) to E15.5. At E16.5, embryos were investigated by facial measurement analysis and histology to determine the optimal concentration for malformation. Subsequent embryonic phenotypes were analyzed in detail by histology, whole-mount skeletal staining, micro-computed tomography, and palatal organic culture. We further used immunohistochemistry to analyze protein expression of the BMP-mediated canonical and noncanonical signaling components.
Results
The optimal concentration of LDN-193189 was determined to be 6 mg/kg. In utero, LDN-193189 exposures induced partial clefting of the anterior palate or complete cleft palate, which was attributed to a reduced cell proliferation rate in the secondary palate, and delayed palatal elevation caused by micrognathia. Analysis of signal transduction in palatal shelves at E12.5 and E13.5 identified a significant reduction of BMP/Smad signaling (p-Smad1/5/8) and unchanged BMP noncanonical signaling (p-p38, p-Erk1/2) after treatment with LDN-193189.
Iris A.L.M. van Rooij, Loes F.M. van der Zanden, Ernie M.H.F. Bongers, Kirsten Y. Renkema, Charlotte H.W. Wijers, Michelle Thonissen, Elisabeth M.J. Dokter, Carlo L.M. Marcelis, Ivo de Blaauw, Marc H.W.A. Wijnen, Peter M. Hoogerbrugge, Jos P.M. Bokkerink, Michiel F. Schreuder, Linda Koster-Kamphuis, Elisabeth A.M. Cornelissen, Livia Kapusta, Arno F.J. van Heijst, Kian D. Liem, Robert P.E. de Gier, Anne Marie Kuijpers-Jagtman, Ronald J.C. Admiraal, Stefaan J. Bergé, Jan Jaap van der Biezen, An Verdonck, Vincent Vander Poorten, Greet Hens, Jasmien Roosenboom, Marc R. Lilien, Tom P. de Jong, Paul Broens, Rene Wijnen, Alice Brooks, Barbara Franke, Han G. Brunner, Carine E.L. Carels, Nine V.A.M. Knoers, Wout F.J. Feitz, Nel Roeleveld
BACKGROUND
Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection.
METHODS
Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information.
RESULTS
So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms’ tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts.
Emma G. Thomas, M. Hassan Toufaily, Marie-Noel Westgate, Anne-Therese Hunt, Angela E. Lin, Lewis B. Holmes
Background
The number of affected infants and the types of malformations identified by a malformation surveillance programs can be impacted if elective terminations for malformations are not included.
Methods
The occurrence of malformations in all newborn infants was determined in a daily review of the findings in the pediatricians' examinations and those of all consultants. In addition, the findings in autopsies of all elective terminations were reviewed to identify all fetuses with structural abnormalities. A severity scale was used to subdivide the malformations. To establish the impact of elective termination, the malformed infants identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston were analyzed for the 2 years before and after the hospital decreased significantly the number of elective terminations temporarily (1999–2000 vs. 2001–2002). The effect on the number of malformations identified at birth, as well as malformations of greater severity, was determined.
Results
The number of terminated fetuses with malformations decreased dramatically after termination services were interrupted (p < 0.0001). There were no differences in the prevalence rates of all malformations in the 2 years before and after the change in access to elective terminations. However, there were significant decreases in the number of infants identified with lethal/life-limiting and severe/handicapping malformations.
Christy M. McKinney, Araya Pisek, Bowornsilp Chowchuen, Timothy DeRouen, Benja Muktabhant, Suteera Pradubwong, Cathy Yeung, Waranuch Pitiphat
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.
Suzan L. Carmichael, Wei Yang, Chen Ma, Eric Roberts, Susan Kegley, Paul English, Edward J. Lammer, John S. Witte, Gary M. Shaw
Background
We examined risks associated with joint exposure of gene variants and pesticides.
Methods
Analyses included 189 cases and 390 male controls born from 1991 to 2003 in California's San Joaquin Valley. We used logistic regression to examine risks associated with joint exposures of gene variants and pesticides that our previous work identified as associated with hypospadias. Genetic variables were based on variants in DGKK, genes involved in sex steroid synthesis/metabolism, and genes involved in genital tubercle development. Pesticide exposure was based on residential proximity to commercial agricultural pesticide applications.
Results
Odds ratios (ORs) were highest among babies with joint exposures, who had two- to fourfold increased risks; for example, the OR was 3.7 (95% confidence interval [CI], 0.8–16.5) among subjects with the risk-associated DGKK haplotype and pesticide exposure; OR, 1.5 (95% CI, 0.7–3.1) among subjects with the haplotype and no pesticide exposure; and OR, 0.9 (95% CI, 0.5–1.6) among subjects without the haplotype but with pesticide exposure, relative to subjects with neither. However, results did not provide statistical evidence that these risks were significantly greater than expected on an additive scale, relative to risks associated with one exposure at a time.
Mauro Cozzolino, Chiara Riviello, Gertrud Fichtel, Mariarosaria Di Tommaso
Background
Sirenomelia is a rare, but deadly condition characterized by fusion of the lower limbs, lower spinal column defects, severe malformations of the urogenital and lower gastrointestinal tract, and an aberrant abdominal umbilical artery.
Methods
The two main hypotheses, not mutually exclusive, that have been advanced to explain the pathogenesis of sirenomelia are the blastogenetic theory and the vascular disruption theory.
Results
We describe a case of sirenomelia, probably associated with the use of methylergonovine maleate, an ergot alkaloid, during the first weeks of pregnancy.
Andrea Accogli, Marco Pavanello, Patrizia Accorsi, Patrizia De Marco, Elisa Merello, Mattia Pacetti, Paolo Nozza, Chiara Fiorillo, Lorenzo Pinelli, Armando Cama, Andrea Rossi, Martin Catala, Valeria Capra
Background
Congenital spinal lipomas are closed spinal dysraphisms belonging to the neural tube defects (NTDs) group. They include a broad spectrum of lesions ranging from simple lipomas of the filum terminale to complex malformations. On histological evaluation, various tissue components of ectodermal, mesodermal or endodermal origin are found within the lipomas, with prevalence for nerves and striated muscle and, more rarely, cartilage and bone. Overall, rib malformations have been occasionally observed in patients with NTDs and in NTD mouse models. However, an ectopic rib arising within the spinal lipoma and articulating with the iliac crest has not been reported in either animal models or in humans.
Cases
We describe four patients affected by lipomyeloschisis or lipomyelomeningocele, with an unusual fibrocartilaginous protuberance arising within the lipoma and connecting to one iliac crest, strongly resembling an ectopic rib. Histological evaluation confirmed the presence of cartilaginous tissue.
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