Cause Of Congenital Malformations Research Articles

Symmetry and fluctuation of cell movements in neural crest-derived facial mesenchyme.

ABSTRACTIn the face, symmetry is established when bilateral streams of neural crest cells leave the neural tube at the same time, follow identical migration routes and then give rise to the facial prominences. However, developmental instability exists, particularly surrounding the steps of lip fusion. The causes of instability are unknown but inability to cope with developmental fluctuations are a likely cause of congenital malformations, such as non-syndromic orofacial clefts. Here, we tracked cell movements over time in the frontonasal mass, which forms the facial midline and participates in lip fusion, using live-cell imaging of chick embryos. Our mathematical examination of cell velocity vectors uncovered temporal fluctuations in several parameters, including order/disorder, symmetry/asymmetry and divergence/convergence. We found that treatment with a Rho GTPase inhibitor completely disrupted the temporal fluctuations in all measures and blocked morphogenesis. Thus, we discovered that genetic control of symmetry extends to mesenchymal cell movements and that these movements are of the type that could be perturbed in asymmetrical malformations, such as non-syndromic cleft lip.This article has an associated ‘The people behind the papers’ interview.

The role of herpesviruses in development of diseases of the urogenital tract and infertility in women

This review presents the data on the spreading of all known human herpesviruses (НHVs) in female urogenital tract. According to the WHO almost 500 million people worldwide suffer from genital infection caused by НHVs. НHVs were detected in various inflammatory diseases of female upper and lower genital tract (vaginitis and cervicitis), in extrauterine pregnancy (in fallopian tubes), in infertility (cervical channel, endometrium and ovaries). Herpes simplex virus 1 (HSV‑1) was identified for the first time in oocytes after failed in vitro fertilization (IVF). НHVs produce negative effect on the entire reproductive process from conception to childbirth. It was established that HSV, cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6) markedly increase the risk of spontaneous abortion, preterm birth and stillbirth. Intrauterine НHV infection is a major cause of congenital malformations. Data on humoral and cell immunity in genital herpesvirus infections (НHVI) are also reviewed. Intravaginal HSV‑2 infection changes cell composition of vaginal mucosa, i.e., together with cells mobilized from the blood, protective role is performed by resident memory T‑cells (TRM), natural killer cells (NK‑cells) and regulatory T‑cells (Treg) whose function consists in maintaining the balance of the activities of lymphocytes. Constant НHVI spreading is largely explained by transition of primary infection to potentially reactivating latent form, since latent virus is unavailable to immune recognition and medicines. The genome editing system CRISPR/Cas9 can recognize and modify not only active but also latent viruses. The promising pilot results with the use of this system offer the possibility of developing innovative technologies for НHV elimination and НHVI eradication.

10 Segmental cervical aplasia in a mare with mosaic X-chromosome aneuploidy

Segmental cervical aplasia is a congenital Müllerian abnormality characterised by the complete or partial failure of cervical development resulting from abnormal fusion of the Müllerian ducts to the urogenital sinus. In the present case report, we describe a congenital segmental cervical aplasia in a Colombian creole mare. The mare was presented to the Animal Reproduction Clinic of Universidad Nacional de Colombia for diagnosis because the external orifice of her cervix was not detected when a uterine lavage was attempted as a therapy for detectable uterine fluid accumulation. The mare had a history of 20-day oestrous cycles confirmed by receptivity to a mature stallion and had no history of natural service or artificial insemination. A complete breeding soundness evaluation of the mare including transrectal palpation, ultrasonography, vaginoscopy, endoscopy, transvaginal aspiration of the uterine fluid and cytogenetic analysis, and an oestrous cycle follow-up were performed. Clinical and ultrasonographic evaluation of the genital tract revealed normal-size ovaries with structures suggestive of regular ovarian activity. Ovulation was confirmed by the formation of a corpus haemorrhagicum followed by a mature corpus luteum in diestrus. In addition, granular free-floating fluid material distending the uterus was detected. Upon vaginal examination, the organ ended in a blind bag with a small papilla with no evident external os cervix. Cytology of the uterine fluid obtained by transvaginal aspiration showed predominant neutrophils with diplococcus bacteria and inflammatory cells compatible with inflammatory content. Cytogenetic analysis of 134 metaphase lymphocytes showed that the mare had an abnormal karyotype [64,XX]/[63,XO]/[65,XXX] with a ratio of 45%, 45%, and 10%, respectively. G- and C-banded analysis was conducted for the X chromosome. Mosaicism of the X chromosome was diagnosed, and the observed congenital segmental cervical aplasia was proposed as the clinical consequence of the mosaicism detected. To our knowledge, this is the first case of this reproductive pathology in a Colombian mare with regular ovarian activity and X chromosome aneuploidy in mosaic form. The cause of the persistently contaminated uterine content in this mare was not clear; it is possible that via the systemic or transcervical route, bacterial contamination could have colonized the uterus, resulting in chronic inflammation and fluid accumulation. This case report demonstrates the importance of performing an adequate routine gynaecological examination in mares to determine their reproductive health. In most cases, the diagnosis of congenital pathologies of the cervix is an incidental finding when performing breeding programs or therapeutic strategies for managing uterine inflammatory conditions. Furthermore, cytogenetic analysis is an important complementary tool for clinical reproductive examination, to accurately identify causes of congenital malformations, and to determine additional causes of reproductive failure in mares.

Сучасні підходи до діагностики та лікування вродженої цитомегаловірусної інфекції: клінічний випадок

Cytomegalovirus infection (CMV) is one of the most common causes of fetal infection. Recently fetal infections cause from 11% to 45% of perinatal losses, according to various authors, and are considered to be one of the most likely causes of congenital malformations, which lead to infants disability and reduce quality of life. CMV-infection clinical picture is very diverse, disguised as other diseases. There may be clinical manifestations of both generalized infection and single organ damage, because the virus has tropism to various organs and tissues. Timely diagnosis and treatment are the key to successful therapy of even severe manifestations of congenital CMV-infection in infants. Antiviral drugs usage can be sufficiently justified in patients with severe infection and can prevent complications. A clinical case of a manifest form of cytomegalovirus infection with severe hepatitis in an infant is presented and the therapeutic efficacy and safety of the ganciclovir and valganciclovir antiviral drugs are shown. The study is performed in accordance with principles of the Declaration of Helsinki. The research protocol was approved by the Local Ethics Committee of the institution mentioned in the article. Informed consent of parents was obtained for the research. The authors declare no conflict of interest. Key words: infants, congenital cytomegalovirus infection, ganciclovir, valganciclovir, clinical case.

Strigolactone Analogs Are Promising Antiviral Agents for the Treatment of Human Cytomegalovirus Infection.

The human cytomegalovirus (HCMV) is a widespread pathogen and is associated with severe diseases in immunocompromised individuals. Moreover, HCMV infection is the most frequent cause of congenital malformation in developed countries. Although nucleoside analogs have been successfully employed against HCMV, their use is hampered by the occurrence of serious side effects. There is thus an urgent clinical need for less toxic, but highly effective, antiviral drugs. Strigolactones (SLs) are a novel class of plant hormones with a multifaceted activity. While their role in plant-related fields has been extensively explored, their effects on human cells and their potential applications in medicine are far from being fully exploited. In particular, their antiviral activity has never been investigated. In the present study, a panel of SL analogs has been assessed for antiviral activity against HCMV. We demonstrate that TH-EGO and EDOT-EGO significantly inhibit HCMV replication in vitro, impairing late protein expression. Moreover, we show that the SL-dependent induction of apoptosis in HCMV-infected cells is a contributing mechanism to SL antiviral properties. Overall, our results indicate that SLs may be a promising alternative to nucleoside analogs for the treatment of HCMV infections.

NAD deficiency due to environmental factors or gene–environment interactions causes congenital malformations and miscarriage in mice

Causes for miscarriages and congenital malformations can be genetic, environmental, or a combination of both. Genetic variants, hypoxia, malnutrition, or other factors individually may not affect embryo development, however, they may do so collectively. Biallelic loss-of-function variants in HAAO or KYNU, two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice. The variants affect normal embryonic development by disrupting the synthesis of NAD, a key factor in multiple biological processes, from its dietary precursor tryptophan, resulting in NAD deficiency. This study demonstrates that congenital malformations caused by NAD deficiency can occur independent of genetic disruption of NAD biosynthesis. C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy. When the dietary undersupply was combined with a maternal heterozygous variant in Haao, which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene-environment interaction. Maternal and embryonic NAD levels were deficient. Mild hypoxia as an additional factor exacerbated the embryo outcome. Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes. Instead, monoallelic genetic variants and environmental factors can result in similar outcomes. The results expand our understanding of the causes of congenital malformations and the importance of sufficient NAD precursor consumption during pregnancy.

Congenital Heart Disease-A Retrospective Study of 156 Cases in Senegal

Introduction: Congenital heart disease (CHD) is the leading cause of congenital malformations. CHD is a real public health problem in our developing countries due to delays in diagnosis and medical and surgical treatment. The general objective of our work was to study the epidemiological, clinical, paraclinical and therapeutic profile of CHD in a university hospital in Dakar. Methodology: We conducted a retrospective study for a period of 3 years (1st January 2015 to 31st December 2017). Results: During the study period, we retained 156 files with a hospital prevalence of 2.4%. The average pulse oxygen saturation of the patients was 89%. Ventricular septal defect (VSD) was the most frequent (45%), followed by atrial septal defect (ASD) (40%), patent ductus arteriosus (PDA) (26%), pulmonary stenosis (16%), atrioventricular septal defect (ASD) (4%) and Tetralogy of Fallot (2%). The sex ratio was 0.89. 93.10% of the patients were aged up to 24 months (n=148) against 6.90% aged over 24 months (n=11). The average pulse oxygen saturation of the patients was 89%. Ventricular septal defect (VIC) was the most frequent (45%), followed by atrial septal defect (ASD) (40%), patent ductus arteriosus (PCA) (26%), pulmonary stenosis (16%), atrioventricular septal defect (VAD) (4%) and Tetralogy of Fallot (2%).The sex ratio was 0.89. Among the patients, 93.10% were aged up to 24 months (n=148) compared to 6.90% aged over 24 months (n=11). The average age of children was 9 months. Conclusion: CHD are a reality in Africa, their frequencies in all reported series are certainly underestimated due to the very limited means of diagnosis.

Cytomegalovirus infection in day care centres: A systematic review and meta-analysis of prevalence of infection in children.

Maternofetal transmission of cytomegalovirus (CMV) is the most common infectious cause of congenital malformation in developed countries. Maternal infection often results from close contact with infected children, and this may occur in day care centres (DCCs). A systematic review of observational studies was conducted to examine the prevalence of CMV infection among children attending DCCs. Meta-analysis using the random effect model was performed for studies including controls. Sources included PubMed, EMBASE (until August 2018), and references from identified publications. Inclusion criteria were studies reporting CMV infection prevalence among childcare children aged less than 7years of age. Controls were children without childcare exposure. CMV infection was defined as viral excretion detected by culture, polymerase chain reaction, or CMV seropositivity. Twenty-eight publications including 8347 participants met the eligibility criteria. The pooled prevalence of CMV infection among children in childcare from all studies was 32% (95% CI 23-41). Within case-controlled studies, prevalence among children attending DCCs was 34% (95% CI 25-44), whereas prevalence among those without childcare exposure was 22% (95% CI 15-30). Meta-analysis showed a significant association between DCC attendance and CMV infection (odds ratio 2.69, 95% CI 1.68-4.30; heterogeneity χ2 /df=8; I2 =84%, P<0.00001). Attendance at DCCs is significantly associated with increased risk of childhood CMV infection. Prevention strategies to reduce risk of CMV infection of pregnant women and children should involve review of DCC exposure and consideration of preventative hygiene strategies.

Exhaustive TORCH Pathogen Diagnostics Corroborate Zika Virus Etiology of Congenital Malformations in Northeastern Brazil.

The Latin American 2015-2016 Zika virus (ZIKV) outbreak was associated with an increase in microcephaly predominantly in northeastern Brazil. To comparatively investigate infectious causes of congenital malformations, we performed a nested case-control study in 32 mothers of cases of suspected congenital Zika syndrome (CZS) and 160 age-matched controls from Bahia, northeastern Brazil. We collected clinical and imaging data and assessed past exposure to ZIKV, Chikungunya virus (CHIKV), dengue virus, and 8 established TORCH (Toxoplasma gondii, Treponema pallidum, rubella virus, cytomegalovirus, herpes simplex virus 1 [HSV-1] and HSV-2, varicella-zoster virus, parvovirus B19) pathogens using multiple serological tests. Heterogeneous symptoms prevented unequivocal diagnosis of CZS on clinical grounds. Only ZIKV and CHIKV seroprevalence rates differed significantly between cases and controls (93.8% versus 67.8% for ZIKV [Fisher's exact text, P = 0.002] and 20.7% versus 8.2% for CHIKV [χ2, P = 0.039]). High ZIKV seroprevalence rates in cases could not be explained by previous dengue virus infections potentially eliciting cross-reactive antibody responses affecting ZIKV serological tests. In conditional logistic regression analyses, only ZIKV was significantly associated with congenital malformations (P = 0.030; odds ratio, 4.0 [95% confidence interval, 1.1 to 14.1]). Our data support an association between maternal ZIKV exposure and congenital malformations. Parallels between the discrepant ZIKV and CHIKV seroprevalence rates between cases and controls and similar seroprevalence rates between cases and controls for the sexually transmitted T.pallidum and HSV-2 may suggest the occurrence of predominantly vector-borne transmission in our study population. High seroprevalence of TORCH pathogens suggests that exhaustive diagnostics will be necessary in the aftermath of the ZIKV outbreak and provides baseline data for longitudinal studies on ZIKV pathogenesis.IMPORTANCE The Latin American Zika virus (ZIKV) outbreak had a major impact on reproductive health worldwide. The reasons for the massively increased reports of neonatal microcephaly in northeastern Brazil are still unclear. Beyond the technical limitations of laboratory diagnostics, unambiguous diagnosis of ZIKV as the cause of congenital malformations is hampered by similar clinical pictures elicited by other pathogens known as TORCH pathogens. We performed a case-control study comparing mothers of children with congenital malformations to age-matched controls from Salvador, Brazil, one of the areas most extensively affected by the ZIKV outbreak. The ZIKV and Chikungunya virus seroprevalence rates differed significantly, whereas the levels of maternal exposure to TORCH pathogens were similar between cases and controls. Our data support a link between maternal ZIKV infection and congenital malformations and suggest the occurrence of predominantly vector-borne ZIKV transmission in these cases. In addition, some highly prevalent TORCH pathogens may be misinterpreted as representative of ongoing ZIKV activity in the absence of exhaustive diagnostics in northeastern Brazil.

Defecto amplio del tubo neural. A propósito de un caso

Los defectos del tubo neural representan la segunda causa de malformación congénita más frecuentes del desarrollo prenatal y constituyen el 10% de las mismas. Su origen suele ser multifactorial, dando lugar a un cierre incompleto o defectuoso del neuroporo anterior y/o posterior, y ocasionando diferentes niveles de defectos en el sistema nervioso central. A pesar de toda la investigación realizada, nuestros conocimientos sobre la etiología genética de esta malformación son todavía muy limitados. Se desconoce cuántos genes pueden conferir riesgo de anomalía en el desarrollo del tubo neural. El diagnóstico se basa principalmente en el estudio ecográfico del sistema nervioso central en el segundo trimestre de la gestación, aunque su valoración en el primer trimestre nos permite una aproximación diagnóstica bastante confiable por la presencia de marcadores ecográficos descritos hace pocos años. Una vez confirmado el diagnóstico el manejo depende (en países como España en donde se permite el aborto) de la voluntad de los padres de continuar o no con la gestación; y en caso de continuar, existen opciones de tratamiento quirúrgico intrauterino o posterior al nacimiento. El pronóstico de esta malformación suele ser variable y depende de localización, tamaño y su asociación o no con hidrocefalia.

The Active Malformations Surveillance Program, Boston in 1972-2012: Methodology and demographic characteristics.

Malformations surveillance programs have been carried out in consecutive populations of newborn infants at single hospitals, as well as in several hospitals in defined populations. A surveillance program begins with the review of the findings recorded by the examining pediatrician in each infant's medical record. The results of diagnostic tests, consultations, and imaging studies are obtained, also, from that infant's medical record. Some malformations surveillance programs identify additional malformations over several months, as the infants have hospitalizations and additional diagnostic testing. 289,365 infants (liveborn, stillborn, and fetuses in pregnancies terminated because of anomalies) were surveyed from 1972 to 2012 at an urban maternity center in Boston to identify each infant with one or more malformations. Each mother was interviewed to obtain demographic characteristics, results of prenatal testing, family history, and information about exposures in pregnancies. Specific diagnoses were established by the study geneticists. 7,020 (2.4%) of the 289,365 infants surveyed had one or more malformations. The etiologies identified included chromosome abnormalities, phenotypes attributed to dominant or recessive autosomal or X-linked mutations, vascular disruption, environmental factors, and complications of twinning. The surveillance of a large consecutive population of newborn infants, stillbirths, and aborted fetuses can identify with high reliability all infants with one or more malformations. This process of ascertainment of affected newborns can be used to improve genetic counseling, identify "new" phenotypes, and serve as a system for testing new technologies to establish more causes of congenital malformations.

Ethics, health policy, and Zika: From emergency to global epidemic?

Zika virus was recognised in 2016 as an important vector-borne cause of congenital malformations and Guillain-Barré syndrome, during a major epidemic in Latin America, centred in Northeastern Brazil. The WHO...

Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis.

Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system.

Pediatric Drug Nitazoxanide: A Potential Choice for Control of Zika.

Zika virus (ZIKV) infection can be the cause of congenital malformations, including microcephaly in infants and can cause other disorders such as Guillain-Barré syndrome, meningoencephalitis, and myelitis, which can also occur in some infected adults. However, at this time, there is no drug approved to treat ZIKV infection. Drug repurposing is the promptest way to obtain an effective drug during a global public health emergency such as the spread of Zika virus. In this study, we report a US Food and Drug Admistration-approved drug that is safe for pediatric use. Nitazoxanide and its bioactive metabolite, tizoxanide, have anti-ZIKV potential in vitro, and we identified that they exerts antiviral effect possibly by targeting the viral postattachment step.

Update on treatment of cytomegalovirus infection in pregnancy and of the newborn with congenital cytomegalovirus.

The purpose of this review is to assess the recent studies of therapy of pregnant women and neonates, aimed at preventing the consequences of congenital cytomegalovirus (CMV) infection. A recent randomized controlled trial of treatment of CMV during pregnancy with hyperimmune globulin did not show significant efficacy in prevention of foetal infection and morbidity, although there was a trend towards improvement with treatment. Trials of antiviral therapy of the mother during pregnancy have involved small numbers only, confounded by ethical and practical difficulties, and further studies are needed to demonstrate whether or not antivirals are useful and well tolerated in this setting.Antiviral treatment of neonatal CMV acquired congenitally has been studied in well controlled trials and the antiviral valganciclovir has shown efficacy in reducing the more severe outcomes. Trials are ongoing of the use of antivirals in less severe disease, although results are likely to take several years. Congenital CMV infection is the most frequent cause of congenital malformation in developed countries, with a symptomatic prevalence of 0.64% of all live births. Infection may result in neurodevelopmental delay, foetal or neonatal death, and most frequently, sensorineural hearing loss. Successful control of viral infections during pregnancy and in the newborn period is essential in reducing early and late morbidity and mortality. Control of congenital CMV infection may be via primary prevention methods such as reducing contact with the pathogen, improved hygiene - both for the pregnant mother and for the neonate, or secondary prevention via reduction of vertical transmission from mother to foetus and reduction in consequences of infection by treatment of infected pregnant women and infected neonates.

Unexpected regulation of miRNA abundance during adaptation of early-somite mouse embryos to diabetic pregnancy

Maternal diabetes is one of major causes of congenital malformations in offspring, but the underlying mechanism is still unclear. MiRNAs play an important role in transcriptional and post-transcriptional regulation of gene expression. However, no miRNA expression profiling of hyperglycemic offspring are thus far available. Female mice were made diabetic with streptozotocin, treated with slow-release insulin tablets, and mated. MiRNA expression profiling with Next Generation Sequencing on the SOLiD5 platform was performed on 8 control and 5 hyperglycemic embryonic day (ED)8.5 and 9 control and 6 hyperglycemic ED9.5 embryos. Differential expression was analyzed with the Wald test. On ED8.5, the abundance of expressed miRNAs was similar in control and hyperglycemic ED8.5 embryos. The spectrum of expressed miRNAs had not changed in ED9.5 embryos, but the abundance of most miRNAs increased ∼5-fold in control embryos. However, hyperglycemic D9.5 embryos were unable to mount this increase in prevalence. Only 3 miRNAs were differentially expressed in control and hyperglycemic ED9.5 embryos, but their putative target genes were underrepresented in the Jackson database of genes causing cardiovascular or neural malformations.

Screening for viral infection and anemia among pregnant women with bad pregnancy outcome in Egyptian population

Hepatitis C virus (HCV) is a major public health concern worldwide and in Egypt. Viral hepatitis during pregnancy is closely related to high risks of maternal complications Human Cytomegalovirus (CMV) is considered the most common cause of congenital malformation that results from viral intrauterine infection in developed countries. Anemia is one of the common complications that is associated with increased risk of bad pregnancy outcome including low birth weight and preterm birth. The aim of this study was to screen for HCV, CMV and anemia among pregnant women in Egyptian population. This prospective study was conducted at the Prenatal Diagnosis clinic in the National Research Centre between April 2013 and August 2015 and a total of 200 pregnant women during their second trimester of pregnancy were enrolled and divided into case group (150/200) with current or history of bad pregnancy outcome and control group (50/200) with no previous history of bad pregnancy outcome. All blood samples were tested for complete blood picture and liver enzyme tests and were screened by ELISA for Anti-HCV and CMV-IgG and IgM. After all investigations including medical and family history for all pregnant women included in the study, all data was statistically analyzed using spss version 19. Anemia was diagnosed in pregnant women with hemoglobin level below 11 g/dl and it was detected in 24 % (48/200) of the total pregnant females included in the study. Five cases tested positive for Anti-HCV antibody among all cases enrolled in the study and was found in the cases group 3.33% (5/150) while all pregnant women in the control group showed negative results. Screening for CMV showed 100 % CMV-IgG while we found 0 % CMV-IgM. Screening for anemia and serological screening for CMV and HCV antibodies should be routine tests especially among pregnant women.

Congenital cytomegalovirus infection in pregnancy: a review of prevalence, clinical features, diagnosis and prevention.

Human cytomegalovirus (CMV) is under-recognised, despite being the leading infectious cause of congenital malformation, affecting ~0.3% of Australian live births. Approximately 11% of infants born with congenital CMV infection are symptomatic, resulting in clinical manifestations, including jaundice, hepatosplenomegaly, petechiae, microcephaly, intrauterine growth restriction and death. Congenital CMV infection may cause severe long-term sequelae, including progressive sensorineural hearing loss and developmental delay in 40-58% of symptomatic neonates, and ~14% of initially asymptomatic infected neonates. Up to 50% of maternal CMV infections have nonspecific clinical manifestations, and most remain undetected unless specific serological testing is undertaken. The combination of serology tests for CMV-specific IgM, IgG and IgG avidity provide improved distinction between primary and secondary maternal infections. In pregnancies with confirmed primary maternal CMV infection, amniocentesis with CMV-PCR performed on amniotic fluid, undertaken after 21-22 weeks gestation, may determine whether maternofetal virus transmission has occurred. Ultrasound and, to a lesser extent, magnetic resonance imaging are valuable tools to assess fetal structural and growth abnormalities, although the absence of fetal abnormalities does not exclude fetal damage. Diagnosis of congenital CMV infection at birth or in the first 3 weeks of an infant's life is crucial, as this should prompt interventions for prevention of delayed-onset hearing loss and neurodevelopmental delay in affected infants. Prevention strategies should also target mothers because increased awareness and hygiene measures may reduce maternal infection. Recognition of the importance of CMV in pregnancy and in neonates is increasingly needed, particularly as therapeutic and preventive interventions expand for this serious problem.

Association of facilitated glucose transporter 2 gene variants with the myelomeningocele phenotype.

Neural tube defects (NTDs) remain the second most common cause of congenital malformations. Myelomeningocele (MM), the most common NTD compatible with survival, results from genetic and environmental factors. Epidemiologic studies and murine models support the hypotheses that obesity, diabetes and hyperglycemia confer increased risk of NTDs. Presence of wild-type facilitated glucose transporter, Glut2, in mouse embryos has been shown to increase risk for NTDs in hyperglycemic pregnancy. The GLUT2 gene of 96 MM patients was amplified, sequenced and compared with the reference sequence (NM_000340). Variants previously unreported in the single nucleotide polymorphisms (SNP) database were considered novel. Allele frequencies of reported SNPs were compared with reference populations using Fisher's exact test. Analysis revealed three novel variants: a substitution in the core promoter region (c.-331c>t), a substitution (c.-182g>a) in the 5'-untranslated region, and a single base pair deletion (c.1441delT) in the coding sequences. Polymorphic alleles for 10 SNPs were also identified. Seven SNPs are significantly associated with MM in the Mexican American patients tested (p < 0.05) and two of the seven remained significant after Bonferroni correction. We identified three novel variants and seven SNPs associated with MM. The novel variants in the core promoter and in the 5'-untranslated region could affect GLUT2 mRNA transcription and stability and translation efficiency. The c.1441delT variant is predicted to alter the reading frame and prematurely terminate translation of the GLUT2 protein at the C-terminus, affecting GLUT2 protein function. Presence of GLUT2 variants may disrupt GLUT2 activity and influence MM susceptibility.

Congenital cytomegalovirus: the invisible problem

It is a great pleasure mixed with some sadness to write this editorial. The entire November issue is around the subject of congenital infection, with the focus on the most common, serious cause of congenital malformation in Australia – congenital cytomegalovirus. Infection with cytomegalovirus (CMV) causes serious disease in children globally, resulting in congenital infections present in ~2000 Australian newborns every year, of whom most are asymptomatic, with ~450 per annum (pa) affected by hearing loss, mental disability and other illnesses. Some of the key clinical features of congenital infection are outlined here in articles by Wendy van Zuylen, Klaus Hamprecht and Robert George, and the pathogenetic features in Lenore Pereira’s paper. Treatment and vaccination are moving ahead (as discussed in papers from some key Italian groups), although not fast enough for many of us – as parents of children with CMV discuss in two papers here. We also include papers on other causes of congenital infection that are much less common than congenital CMV in Australia. Although these are not related to congenital CMV clinically, with very different medical and epidemiological settings, it is important to put congenital CMV in context, as well as to draw attention to other important causes of congenital infection.