Reduced Head Circumference Research Articles

A Novel Frameshift Mutation in Abnormal Spindle-Like Microcephaly (ASPM) Gene in an Iranian Patient with Primary Microcephaly: A Case Report

Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder, leading to the defect of neurogenic brain development. Individuals with MCPH reveal reduced head circumference and intellectual disability. Several MCPH loci have been identified from several populations. Genetic heterogeneity of this disorder represents molecular testing challenge. An 8 yr old female, born from consanguineous parents, was attended to Fardis Central Lab, Alborz, Iran. Based on the reduced circumference and intellectual disability, MCPH was diagnosed. Whole exome sequencing of the patient identified a novel homozygous frameshift mutation (c.2738dupT, p.Cys914fs) in exon 9 Abnormal Spindle-like Microcephaly (ASPM) gene. By Sanger sequencing, segregation analysis showed that both parents were heterozygous carriers for this variant. The novel frameshift mutation likely truncates the protein, resulting in loss of normal function ASPM in homozygous mutation carriers. The study might add a new pathogenic variant in mutations of the ASPM gene as a causative variant in patients with MCPH and might be helpful in genetic counseling of consanguineous families.

Impact of maternal smoking associated lyso-phosphatidylcholine 20:3 on offspring brain development

Maternal smoking during pregnancy affects fetal neurological development. Metabolomic studies in the general population suggest that smoking is associated with characteristic metabolic alterations. We investigated the association between the maternal smoking status, the fetal metabolome and head circumference at birth, as a surrogate parameter of brain development. 320 mother/newborn pairs of the Berlin Birth Cohort were investigated. Anthropometric parameters, including head circumference, of newborns of smoking mothers, former smoking mothers, and never smoking mothers were compared to assess the impact of maternal smoking behavior. Associations between maternal smoking behavior and 163 cord blood metabolites and associations between newborn head circumference and concentrations of smoking behavior related metabolites were analysed. Male newborns of smoking mothers had a reduced head circumference when compared with newborns from former smoking and never smoking mothers (p < 0.05). Using linear regression models corrected for established confounding factors, maternal smoking during pregnancy showed an independent association with head circumference (95% CI: -0.75～-0.41 cm, p = 2.45×10−11). In a stepwise linear regression model corrected for known confounding factors of brain growth lyso-phosphatidylcholine 20:3 (95% CI: 6.68～39.88 cm, p = 4.62×10-4) was associated with head circumference in male offspring only. None of the metabolites were associated with head circumference of female newborns. In conclusion, maternal smoking during pregnancy impacted on male offspring’s development including brain development. The smoking related metabolite lyso-phosphatidylcholine 20:3 was associated with head circumference of male offspring.

Association of Maternal Exposure to Persistent Organic Pollutants in Early Pregnancy With Fetal Growth

Prenatal exposure to persistent organic pollutants (POPs) has been associated with birth size, but data on fetal growth and among racially/ethnically diverse pregnant women remain scarce. To assess the association between maternal plasma POPs in early pregnancy and fetal growth and by infant sex and maternal race/ethnicity. This cohort study used the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, which recruited nonobese, low-risk pregnant women before 14 weeks' gestation between July 1, 2009, and January 31, 2013, in 12 community-based clinics throughout the United States. Participants self-identified their race/ethnicity, self-reported their behavioral risk factors, and were followed up throughout their pregnancy. Data were analyzed from July 31, 2018, to June 3, 2019. Levels of 76 POPs in early gestation plasma were measured: 11 perfluoroalkyl and polyfluoroalkyl substances, 1 polybrominated biphenyl, 9 polybrominated diphenyl ethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 organochlorine pesticides (OCPs). The bayesian kernel machine regression method was used to examine chemical class mixtures, and generalized additive mixed model was used to analyze individual chemicals. Fourteen fetal biometrics were measured, including head circumference, abdominal circumference, and femur length, within 5 ultrasonography appointments. A total of 2284 low-risk pregnant women were included: 606 women (26.5%) self-identified as white with a mean (SD) age of 30.3 (4.4) years, 589 (25.8%) as black with a mean (SD) age of 25.5 (5.5) years, 635 (27.8%) as Hispanic with a mean (SD) age of 27.1 (5.5) years, and 454 (19.9%) as Asian with a mean (SD) age of 30.5 (4.5) years. A comparison between the 75th and 25th percentile of exposure revealed that the OCP mixture was negatively associated with most fetal growth measures, with a reduction of 4.7 mm (95% CI, -6.7 to -2.8 mm) in head circumference, 3.5 mm (95% CI, -4.7 to -2.2 mm) in abdominal circumference, and 0.6 mm (95% CI, -1.1 to -0.2 mm) in femur length. Higher exposure to the PBDE mixture was associated with reduced abdominal circumference (-2.4 mm; 95% CI, -4.0 to -0.5 mm) and femur length (-0.5 mm; 95% CI, -1.0 to -0.1 mm), and the dioxin-like PCB mixture was associated with reduced head circumference (-6.4 mm; 95% CI, -8.4 to -4.3 mm) and abdominal circumference (-2.4 mm; 95% CI, -3.9 to -0.8 mm). Associations with individual chemicals were less consistent. There were some interactions by fetal sex, although most of the results did not vary by maternal race/ethnicity. For example, oxychlordane (-0.98 mm; 95% CI, -1.60 to -0.36 mm; P for interaction <.001), trans-nonachlor (-0.31 mm; 95% CI, -0.54 to -0.08 mm; P for interaction = .005), and p,p'-dichlorodiphenyldichloroethylene (-0.19 mm; 95% CI, -0.22 to -0.09 mm; P for interaction = .006) were associated with shorter femur length among boys only. This study found that, among pregnant women with low POP levels, a mixture of OCPs was negatively associated with most fetal growth measures and that mixtures of PBDEs and dioxin-like PCBs were associated with reduced abdominal circumference. These findings suggested that, although exposures may be low, associations with fetal growth are apparent.

Prenatal exposure to metal mixture and sex-specific birth outcomes in the New Hampshire Birth Cohort Study.

In utero exposure to individual metals may impact fetal growth, though little is known about the effects of exposure to metal mixtures. Therefore, we investigated joint effects of in utero exposure to a mixture of As (arsenic), Mn (manganese), and Pb (lead) on newborn outcomes in a United States population. Concentrations of As, Mn, and Pb were determined in maternal postpartum toenail samples, a biomarker of in utero exposure, from 989 maternal-infant pairs (492 females and 497 males). Newborns' anthropometric characteristics, including head circumference, length, and weight, were obtained from medical records. The joint effects of the three metals were modeled using Bayesian kernel machine regression and linear regression. Both sex-combined and sex-stratified statistical analyses were performed. We observed an inverted-U-shape association between maternal toenail Mn concentrations and newborn head circumference, particularly among female infants. Concentrations of Pb were related to reduced head circumference, weight, and length, especially among females at lower concentrations of the other metals. Overall, toenail As concentrations were related to reduced head circumference, especially among males, and an increase in birth length and weight among females. We found little evidence of As interactions with other metals within the mixture. Our findings suggest that in utero metal mixture exposures may influence birth outcomes, and that such relations may differ by infant sex.

Maternal Imbalance of Vitamin B12 and Folic Acid Alters the Expression of Fetal Growth-related Imprinted Genes in Placenta (P24-033-19)

ObjectivesThe present study aimed to elucidate the trans-generational influence of low dietary vitamin B12 with different levels of folic acid in mice model on fetal growth and expression of fetal growth-related imprinted genes in placenta. MethodsC57BL/6 mice (four-week-old) were assigned into four dietary groups: (test groups)-BDFN*, BDFO*, BDFD* & (control group)-BNFN* and were fed diet accordingly for two generations (F0 and F1). Mating was carried out and on 20th day of gestation pregnant mice were sacrificed for fetus collection in both F1 & F2 generation. In F1 generation after weaning period a sub-group of F1 offsprings born to F0 dams were rehabilitated to control diet in each test group (transient) while others were continued on same diet as their mothers (sustained) and further mating was carried out. Vitamins and homocysteine levels in serum were evaluated. Expression of genes, global DNA methylation in placenta and growth-parameters of fetuses were studied. ResultsOur data suggests that deficiency of both vitamins significantly reduced the total body weight and circulating levels of these vitamins in serum. Dietary modulation of vitamins impaired the normal fetal growth as head circumference and crown-rump length was found reduced in BDFO transient & sustained group (P < 0.01), fetal birth weight was reduced in B12 deficient conditions in both F1 & F2 generation and a decrease in placental weight was also found in BDFD & BDFO sustained group (F0 & F1, P < 0.01). Placental expression of imprinted genes were reduced in F0 while it was found to be increased in F1 in all test groups. Over-expression of PHLDA2 in F1 placenta (P < 0.001) can be corelated to the reduced placental weight (BDFD & BDFO sustained group F1, P < 0.01). GRB10 expression was increased in all vitamin B12 deficient sustained groups (F1, P < 0.001 & < 0.01). Enhanced expression of MEST was observed in FO conditions (F1 transient and sustained, P < 0.05) which can be corelated to reduced head circumference, moreover DLK1 was over-expressed in both vitamin deficiency conditions.*Abbreviations: BN: B12 Normal FN: Folate Normal FD: Folate deficient FO: Folate over supplementation BD: B12 deficient. ConclusionsDietary imbalance of vitamin B12 and folic acid levels during the pre-& post-natal development bring about growth anomalies at genetic & phenotypic level in subsequent generation. Funding SourcesThis work is funded by Department of science and technology- Science and Engineering board, New Delhi, India.

Placental metal concentrations and birth outcomes: The Environment and Childhood (INMA) project.

To examine the association of placental levels of arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb), manganese (Mn), and chromium (Cr) with birth outcomes (birth weight, length, and head circumference, low birth weight [LBW], gestational age, preterm delivery, and small for gestational age [SGA]) in mother-child pairs from the Environment and Childhood (INMA) Project in Spain. Metal concentrations were measured in placenta tissue samples randomly selected from five INMA cohorts. Data on birth outcomes were obtained from medical records. Associations were assessed in a sub-sample of 327 mother-infant pairs by regression models adjusted for confounding factors and for all metals simultaneously. Effect modification by sex was also evaluated. Elevated placental Cd levels (>5.79 vs. <3.30 ng/g) were associated with reduced birth weight (-111.8 g, 95%CI = -215.6; -8.06, p-trend = 0.01) and length (-0.62 cm, 95%CI = -1.20; -0.04, p-trend = 0.02), while a 10% increase in Cd was associated with 1.21-fold increased odds (95%CI = 1.01; 1.43) of LBW in the global sample but with 14% lower odds (95%CI = 0.78; 0.96) of preterm delivery in males (Pinteraction = 0.10). Detected (vs. undetected) Hg was associated with reduced head circumference (-0.49 cm, 95%CI = -1.00; 0.03) in females (Pinteraction = 0.03). A 10% increase in placental Mn was associated with slight increases in gestational age (0.04 weeks, 95%CI = 0.01; 0.07) in the global sample and in head circumference (0.05 cm, 95%CI = -0.01; 0.10) in females (Pinteraction = 0.03). Elevated Cr levels (>99.6 vs. <56.1 ng/g) were associated with reduced birth length (-0.68 cm, 95%CI = -1.33; -0.04, p-trend = 0.02) and slightly increased gestational age (0.35 weeks, 95%CI = -0.07; 0.77, p-trend = 0.08) in the global sample. As and Pb were detected in few placentas (27% and 13%, respectively) and were not associated with any studied birth outcome. Data suggest that in utero exposure to Cd, Hg, and Cr could adversely affect fetal growth, whereas Mn and Cr appear to have a positive effect on gestational age. Given the relatively small number of subjects, sex-specific associations should be interpreted with caution.

Infants' Neurodevelopmental Effects of PM2.5 and Persistent Organohalogen Pollutants Exposure in Southern Taiwan

ABSTRACT Several studies have stated the harmful effects of PM2.5 to population health, including disruption of neurological development. However, the mechanism behind the neurodevelopmental effects of ambient PM2.5 and postnatal PBDEs and OCPs exposure is still unknown. Our goal was to determine influence of breastmilk residues, polybrominated diphenyl ethers (PBDEs) and organochlorine pesticides (OCPs), to the infants’ neurodevelopment with respect to high and low PM2.5 exposure areas. The participants were recruited from high PM2.5 exposure areas (n = 32) and low PM2.5 exposure areas (n = 23) of southern Taiwan. The extracted 14 PBDEs and 20 OCPs compounds were analyzed using gas chromatography coupled with mass spectrometer. The infants, aging from 8-12 months, were examined by Bayley Scales of Infants and Toddlers Development, Third Edition (Bayley-III) for neurodevelopment. Results showed that high PM2.5 exposure caused reduced head circumference and had significant effects on the motor skill and social emotional development. For breastmilk PBDEs, a positive correlation between BDE-196 and social emotion, after multivariate analysis with adjustment of confounders, was observed while BDE-99, 196, 197, and 207 showed higher magnitudes in low PM2.5 areas than in high PM2.5 areas. For OCPs, only γ- hexachlorcyclohexanes (γ-HCH) presented the significant difference between high and low PM2.5 exposure areas. Most breastmilk OCPs residues, including 4,4’-dichlorodiphenyltrichloroethane (4,4’-DDT), γ-HCH, endrin, and heptachlor epoxide showed negative impact on the Bayley-III scores after multivariate analysis. In conclusion, infants’ neurodevelopment was significantly correlated with the location of PM2.5 exposure and breastmilk intake of certain PBDEs and OCPs. Breastmilk OCPs might obviously affect infants’ neurodevelopment more compared to breastmilk PBDEs based on our finding. Moreover, this study further employs awareness about viable effects of PM2.5 in infants’ neurodevelopment.

342: The effect of opioid exposure in utero on neonatal body composition

Opioid use in pregnancy has been associated with low birth weight as well as reduced head circumference. Whether these differences are due to changes neonatal body composition (i.e. lean mass and fat mass) has not been established. The goal of this study is to investigate the differences in body composition among neonates exposed to opioids in utero, compared with those who are not exposed. This is a retrospective cohort study of singleton pregnancies delivered at term. Subjects with opioid exposure during pregnancy were identified and subjects without opioid exposure were used for comparison. Exposed subjects were matched 1:2 with unexposed subjects for variables known to affect neonatal body composition; this included gestational age at delivery (±7 days), neonatal sex, smoking, and maternal race. Neonatal anthropometric measurements and skin fold data were used to determine neonatal percent body fat. Anthropometric data was expressed as mean ± SD and analyzed by Mann-Whitney U test. Demographic data was compared using Student’s t test and chi-squared analysis where appropriate. All statistical analysis performed using R statistical software. P <0.05 was considered significant. 24 neonates exposed to opioids in utero were identified and matched with 48 unexposed neonates. The groups were similar in terms of maternal age, race, neonatal sex, and gestational age at delivery. The exposed versus unexposed subjects differed in maternal BMI at delivery (28.4 vs 35.3, p = 0.001), gestational weight gain (14.3 lb vs 28.6 lb, p = <0.05), nulliparity (17% vs 48%, p = 0.02) and smoking status (66% vs 33%, p = 0.02). The analysis of our results did not demonstrate a statistically significant difference in birth weight, skin fold measurement, fat mass, lean mass, or percent body fat between the two groups. However, we found birth length and head circumference to be significantly different (p = 0.03 for both, Table 1). In this cohort, opioid exposure in utero was not associated with changes in neonatal body composition. However, we identified statically significant decreases in birth length and head circumference when compared with unexposed neonates. This work suggests that opioid exposure does not affect neonatal body composition but may impact other neonatal anthropometric measures.

Spatial identification of environmental health hazards potentially associated with adverse birth outcomes.

Reduced birth weight (RBW) and reduced head circumference (RHC) are adverse birth outcomes (ABOs), often linked to environmental exposures. However, spatial identification of specific health hazards, associated with these ABOs, is not always straightforward due to presence of multiple health hazards and sources of air pollution in urban areas. In this study, we test a novel empirical approach to the spatial identification of environmental health hazards potentially associated with the observed RHC and RBW patterns. The proposed approach is implemented as a systematic search, according to which alternative candidate locations are ranked based on the strength of association with the observed birth outcome patterns. For empirical validation, we apply this approach to the Haifa Bay Area (HBA) in Israel, which is characterized by multiple health hazards and numerous sources of air pollution. We identified a spot in the local industrial zone as the main risk source associated with the observed RHC and RBW patterns. Multivariate regressions, controlling for personal, neighborhood, and geographic factors, revealed that the relative risks of RHC and RBW tend to decline, other things being equal, as a function of distance from the identified industrial spot. We recommend the proposed identification approach as a preliminary risk assessment tool for environmental health studies, in which detailed information on specific sources of air pollution and air pollution dispersion patterns is unavailable due to limited reporting or insufficient monitoring.

A novel non sense mutation in WDR62 causes autosomal recessive primary microcephaly: a case report

BackgroundAutosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development characterized by a reduced head circumference at birth with no remarkable anomalies of brain architecture and variable degrees of intellectual impairment. Clinical and genetic heterogeneity in genetic disorders represent a major diagnostic challenge.Case presentationTwo patients, 11 and 9 years old, born from consanguineous parents, were referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of MCPH was made, based on reduced head circumference without brain architecture abnormalities. The two patients were subject to the whole-exome sequencing, which allowed to diagnose a novel homozygous mutation c.1027C > T; p.Gln343* in exon 8 of WDR62, a gene already known to be related to MCPH. Sanger sequencing confirmed the segregation of the mutation in the family.ConclusionOur data expends the spectrum of mutations in WDR62 gene, proves the efficiency and cost-effectiveness of whole exome sequencing for the molecular diagnosis of genetically heterogeneous disorders such MCPH. Exome sequencing led to the rapid and cost-effective identification of a novel homozygous mutation in WDR62 gene, thereby facilitating genetic counseling.

Sex-specific and lasting effects of a single course of antenatal betamethasone treatment on human placental 11β-HSD2

IntroductionWe have previously shown that even a single course of antenatal betamethasone (BET) as an inductor for lung maturity reduces birth weight and head circumference. Moreover, animal studies link BET administration to alterations of the hypothalamic-pituitary-adrenal-gland-axis (HPA). The unhindered development of the fetal HPA axis is dependent on the function and activity of 11β-hydroxysteroiddehydrogenase type 2 (11β-HSD2), a transplacental cortisol barrier. Therefore, we investigated the effects of BET on this transplacental barrier and fetal growth. MethodsPregnant women treated with a single course of BET between 23 + 5 to 34 + 0 weeks of gestation were compared to gestational-age-matched controls. Placental size and neonatal anthropometrics were taken. Cortisol and ACTH levels were measured in maternal and umbilical cord blood samples. Placental 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1) protein levels and 11β-HSD2 protein and activity levels were determined. Parameters were analyzed independent of sex, and in subgroups divided by gender and gestational age. ResultsIn term born females, BET administration was associated with reduced head circumference and decreased 11β-HSD2 protein levels and enzyme activity. Males treated with BET, especially those born prematurely, showed increased 11β-HSD2 protein levels. ConclusionA single course of BET alters placental glucocorticoid metabolism in a sex-specific manner. Decreased 11β-HSD2 levels in term born females may lead to an increased placental transfer of maternal cortisol and therefore result in a reduced head circumference and a higher risk for altered stress response in adulthood. Further research is needed to conclude the significance of increased 11β-HSD2 levels in males.

Maternal, fetal and neonatal consequences associated with the use of crack cocaine during the gestational period: a systematic review and meta-analysis.

Crack cocaine consumption is one of the main public health challenges with a growing number of children intoxicated by crack cocaine during the gestational period. The primary goal is to evaluate the accumulating findings and to provide an updated perspective on this field of research. Meta-analyses were performed using the random effects model, odds ratio (OR) for categorical variables and mean difference for continuous variables. Statistical heterogeneity was assessed using the I-squared statistic and risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. Ten studies met eligibility criteria and were used for data extraction. The crack cocaine use during pregnancy was associated with significantly higher odds of preterm delivery [odds ratio (OR), 2.22; 95% confidence interval (CI), 1.59-3.10], placental displacement (OR, 2.03; 95% CI 1.66-2.48), reduced head circumference (- 1.65cm; 95% CI - 3.12 to - 0.19), small for gestational age (SGA) (OR, 4.00; 95% CI 1.74-9.18) and low birth weight (LBW) (OR, 2.80; 95% CI 2.39-3.27). This analysis provides clear evidence that crack cocaine contributes to adverse perinatal outcomes. The exposure of maternal or prenatal crack cocaine is pointedly linked to LBW, preterm delivery, placental displacement and smaller head circumference.

A new association between CDK5RAP2 microcephaly and congenital cataracts.

Primary microcephaly type 3 is a genetically heterogeneous condition caused by a homozygous or compound heterozygous mutation in CDK5 regulatory subunit associated protein 2 (CDK5RAP2) and characterized by reduced head circumference (<5th percentile) with additional phenotypes varying from pigmentary abnormalities to sensorineural hearing loss. Until now, congenital cataracts have not been reported in patients with primary microcephaly type 3. We report multiple affected family members from a consanguineous Saudi family with microcephaly and congenital cataracts. We utilized a next-generation sequencing-based microcephaly gene panel that revealed a CDK5RAP2 variant (c.4055A>G; p.Glu1352Gly) as the most plausible candidate for the likely etiology in this family. Then we performed family segregation analysis using Sanger sequencing, autozygosity mapping, and whole exome sequencing, all of which revealed no other possible disease-causing variants. Here we report on a new clinical manifestation of CDK5RAP2 and expand the phenotype of primary microcephaly type 3.

Fever in pregnancy and offspring head circumference

PurposeTo examine whether maternal fever during pregnancy is associated with reduced head circumference and risk of microcephaly at birth. MethodsA prospective study of 86,980 live-born singletons within the Danish National Birth Cohort was carried out. Self-reported maternal fever exposure was ascertained in two interviews during pregnancy and information on head circumference at birth was extracted from the Danish Medical Birth Registry. ResultsFever in pregnancy was reported by 27% of the mothers, and we identified 3370 cases of microcephaly (head circumference less than or equal to third percentile for sex and gestational age) and 1140 cases of severe microcephaly (head circumference less than or equal to first percentile for sex and gestational age). In this study, maternal fever exposure was not associated with reduced head circumference (adjusted β = 0.03, 95% confidence intervals [CI]: 0.01–0.05), increased risk of microcephaly (odds ratio: 0.95, 95% CI: 0.88–1.03) nor severe microcephaly (odds ratio: 1.01, 95% CI: 0.88–1.15) in the offspring. These findings were consistent for increasing numbers of fever episodes, for increasing fever severity, and for exposure in both early pregnancy and midpregnancy. ConclusionsIn this most comprehensive study to date, we found no indication that maternal fever in pregnancy is associated with small head size in the offspring.

Novel Insights Into the Phenotypical Spectrum of KIF11-Associated Retinopathy, Including a New Form of Retinal Ciliopathy.

This study sought to characterize the ophthalmic and extraocular phenotype in patients with known and novel KIF11 mutations. Four patients (3, 5, 36, and 38 years of age, on father-daughter constellation) from three unrelated families were characterized by retinal examination including multimodal retinal imaging, investigation for syndromic disease manifestations, and targeted next-generation sequencing. The subcellular localization of Kif11 in the retina was analyzed by light and electron microcopy. There was considerable interindividual and intrafamilial phenotypic heterogeneity of KIF11-related retinopathy. Two patients presented with a progressive retinal dystrophy, one with chorioretinal dysplasia and one with familial exudative vitreoretinopathy (FEVR) in one eye and thinning of the photoreceptor layer in the fellow eye. Obvious syndromic disease manifestations were present only in the youngest patient, but minor signs (e.g. reduced head circumference) were present in the three other individuals. Immunohistochemistry results demonstrated Kif11 localization in the inner segment and ciliary compartments of photoreceptor cells and in the retinal pigment epithelium. Progressive retinal degeneration in KIF11-related retinopathy indicates a role for KIF11 not only in ocular development but also in maintaining retinal morphology and function. The remarkable variability of the ocular phenotype suggests four different types of retinopathy which may overlap. KIF11 should be considered in the screening of patients with retinal dystrophies because other syndromic manifestations may be subtle. Evaluation of head circumference may be considered as a potential shortcut to the genetic diagnosis. The localization of Kif11 in photoreceptor cells indicates a retinal ciliopathy.

Concurrent exposures to nonylphenol, bisphenol A, phthalates, and organophosphate pesticides on birth outcomes: A cohort study in Taipei, Taiwan

Prenatal exposure to phenols, phthalates (PAEs), and organophosphate (OP) pesticides may increase the risk of abnormal birth outcomes. However, many previous studies have examined exposure to a limited number of chemical classes or exposure profiles limited to a specific stage of pregnancy. This study aims to characterize the concurrent exposure scenario throughout pregnancy by simultaneously monitoring internal doses of several endocrine-disrupting compounds (EDCs), including 2 phenols (nonylphenol (NP) and bisphenol A (BPA)), 9 PAEs, and 6 OP pesticide metabolites and to assess the relationships between concurrent exposure to EDCs and infant birth weight, length, and head and chest circumference. One hundred and sixty two women provided three spot urine samples at approximately 11 and 26weeks gestation and at delivery. We applied multivariable linear regression and ridge regression models to estimate the effects of separate and correlated exposures. Multivariable linear regression models revealed that women with short birth-length infants had significantly higher urinary second-trimester NP levels (50th percentile, 5.03μg/g creatinine) (β=−0.47cm; 95% CI=−0.93 to −0.01). Similarly significant relationships were observed between second-trimester mono-methyl phthalate (MMP) exposure and short birth length, second-trimester ΣPAEs and short birth length, second-trimester ΣPAEs exposure and reduced head and chest circumference, second-trimester diethylphosphate (DEP) exposure and reduced birth weight and length, and second-trimester ΣDEPs exposure and short birth length. Women with urinary BPA above the 75th percentile or ΣPAEs levels above the 50th percentile in the third trimester had infants with significantly reduced head circumference. These observations suggest that the second trimester may be the critical stage of susceptibility for fetal development. In ridge regression models, for which women with fewer measures for exposure to NP, BPA, MMP, ΣPAEs, DEP and ΣDEPs simultaneously were available, no relationships were found with infant size at birth. Additional studies with larger sample sizes are warranted.

OP 27 Methyldopa during the first trimester and pregnancy outcome – A prospective observational cohort study

Introduction An increased risk of congenital malformations in offspring of mothers with chronic hypertension is discussed. Although methyldopa is recommended as first line treatment for hypertensive disorders in pregnancy in most countries, published experience on 1st trimester exposure is still limited. Objectives The primary aim of our study was to analyze the risk of birth defects and spontaneous abortions in women treated with methyldopa during the first trimester. Patients and methods The pattern of antihypertensive drug regimen during the first trimester was analyzed in 1152 prospectively ascertained pregnancies reported to the German Embryotox pharmacovigilance institute. Pregnancy outcomes were then evaluated in a subgroup of women treated with methyldopa ( n = 261) and compared to a non-hypertensive comparison group ( n = 526). Results At conception 51% of women were treated with beta-blockers, 47% with RAAS-inhibitors and only 14% with methyldopa; monotherapy with one antihypertensive drug occured in 66% of pregnancies. The rate of major birth defects among women exposed to methyldopa during 1st trimester was not significantly increased compared to non-hypertensive women (3.7% vs. 2.5%; ORadj 1.24, 95% CI 0.4–4.0). There was a tendency towards a higher rate of spontaneous abortions in methyldopa exposed women. The risk of preterm birth was significantly higher and adjusted birth weight scores were significantly lower in the methyldopa group. Head circumferences were significantly reduced in exposed boys only. In a sensitivity analysis comparing pregnancies methyldopa monotherapy to metoprolol monotherapy, there was neither evidence for an increased risk for birth defects or early pregnancy loss nor for growth restriction or a reduced head circumference. However, the significantly increased risk of preterm birth in methyldopa treated pregnancies was confirmed. Conclusions Our study supports the evidence of safety of methyldopa during pregnancy. Further studies are needed to clarify the influence of hypertension and treatment with antihypertensives on preterm birth and intrauterine growth. This work was performed with financial support from the German Ministry of Health (BMG) and the German Federal Institute for Drugs and Medical Devices (BfArM).

Pregnancy Outcome After First Trimester Use of Methyldopa: A Prospective Cohort Study.

URL: https://drks-neu.uniklinik-freiburg.de/drks_web/. Unique identifier: DRKS00010502.

Molecular genetic analysis of consanguineous families with primary microcephaly identified pathogenic variants in the ASPM gene.

Autosomal recessive primary microcephaly is a rare genetic disorder that is characterized by reduced head circumference and a varying degree of intellectual disability. Genetic studies on consanguineous families with primary microcephaly have identified 15 (MCPH) causative genes that include MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6 MFSD2A ANKLE2 and CIT (Khan et al. 2014; Yamamoto et al. 2014; Alakbarzade et al. 2015;Morris-Rosendahl and Kaindl 2015; Basit et al. 2016). Physiologically, most of these MCPH proteins are involved in cell cycle and its regulation. In the present clinical genetic study, we have present two consanguineous Pakistani families segregating primary microcephaly and intellectual disability. These families were ascertained from the Saraiki ethnic part of Khyber-Pakhtunkhwa province in Pakistan. Whole exome sequencing in one family revealed a novel 1-bp deletion NM_018136.4: c.10013delA (p.Asp3338Valfs*2), while the other family showed a previously reported nonsense mutation NM_018136.4: c.9730C>T (rs199422195 (p.Arg3244*)) in ASPM gene. The novel frame-shift mutation (p.Asp3338Valfs*2) in ASPM presumably truncates the protein synthesis that results in loss of armadillo-type fold domain.

Autosomal Recessive Primary Microcephaly (MCPH): An Update.

Autosomal recessive primary microcephaly (MCPH; MicroCephaly Primary Hereditary) is a genetically heterogeneous neurodevelopmental disorder characterized by a significantly reduced head circumference present already at birth and intellectual disability. Inconsistent features include hyperactivity, an expressive speech disorder, and epilepsy. Here, we provide a brief overview on this rare disorder pertinent for clinicians.