Common congenital anomalies: Environmental causes and prevention with folic acid containing multivitamins

Congenital anomalies, congenital defects, or birth defects are significant causes of death in infants. The most common congenital defects are congenital heart defects (CHDs) and neural tube defects (NTDs). Defects induced by genetic mutations, environmental exposure to toxins, or a combination of these effects can result in congenital malformations, leading to infant death or long‐term disabilities. These defects produce significant mortality and morbidity in the affected individuals, and families are affected emotional and financially. Also, society is impacted on many levels. Congenital anomalies may be reduced by dietary supplements of folic acid and other vitamins. Here, we review the evidence for specific roles of toxins (alcohol, cigarette smoke) in causing common severe congenital anomalies like CHDs, NTDs, and ocular defects. We also review the evidence for beneficial effects for dietary supplementation, and highlight gaps in our knowledge, where research may contribute to additional benefits of intervention that can reduce birth defects. Extensive discussion of common severe congenital anomalies (CHDs, NTDs, and ocular defects) illustrates the effects of diet on the frequency and severity of these defects. Birth Defects Research (Part C) 108:274–286, 2016. © 2016 Wiley Periodicals, Inc.     

BMP signaling in congenital heart disease: new developments and future directions

Congenital heart malformations are the most common of all congenital human birth anomalies. During the past decade, research with zebrafish, chick, and mouse models have elucidated many fundamental genetic pathways that govern early cardiac patterning and differentiation. This review highlights the roles of the bone morphogenetic protein (BMP) signaling pathway in cardiogenesis and how defective BMP signals can disrupt the intricate steps of cardiac formation and cause congenital heart defects.     

Oculo-facio-cardio-dental syndrome in a girl and her mother

Congenital heart defects are known to be associated with facial dysmorphism and other congenital anomalies. Oculo-facio-cardio-dental (OFCD) syndrome is one such rare multiple congenital anomaly syndrome inherited as an X-linked dominant condition characterized by congenital cataracts, multiple minor facial dysmorphic features, congenital heart defects and dental anomalies. It is unrecognized by many medical and dental professionals. Only 21 cases have been reported so far. This syndrome is often misrecognized as rubella embryopathy because of association of congenital cataract with cardiac anomalies. It is usually the orthodontists who diagnose the syndrome based on typical findings on dental panoramic radiographs. But we suspected our patient to be having OFCD syndrome based on typical facial dysmorphism, ocular and cardiac defects, and finally it was confirmed after noticing typical dental radiographic findings.     

The genetics of cardiac birth defects

Congenital heart disease likely results from a complex mixture of environmental and genetic factors. Recent work has elucidated rare single gene mutations that cause a variety of cardiac defects, but the etiologies of more common disease remains unknown. Here, we review the known genetic causes of cardiac malformations and discuss future approaches for addressing sporadic congenital heart disease as a complex trait.     

Partitioning the heart: mechanisms of cardiac septation and valve development

Heart malformations are common congenital defects in humans. Many congenital heart defects involve anomalies in cardiac septation or valve development, and understanding the developmental mechanisms that underlie the formation of cardiac septal and valvular tissues thus has important implications for the diagnosis, prevention and treatment of congenital heart disease. The development of heart septa and valves involves multiple types of progenitor cells that arise either within or outside the heart. Here, we review the morphogenetic events and genetic networks that regulate spatiotemporal interactions between the cells that give rise to septal and valvular tissues and hence partition the heart.     

ENU induced mutations causing congenital cardiovascular anomalies

We used non-invasive high frequency ultrasound to screen N-ethyl-N-nitrosourea mutagenized mouse fetuses for congenital cardiovascular anomalies. We ultrasound scanned 7546 mouse fetuses from 262 mutagenized families, and identified 124 families with cardiovascular defects. Represented were most of the major congenital cardiovascular anomalies seen clinically. The ENU-induced mutations in several families were mapped using polymorphic microsatellite DNA markers. One family with forelimb anomalies and ventricular septal defects, phenotypes similar to Holt-Oram syndrome, and one family with transposition of the great arteries and heart situs anomalies were mapped to different regions of mouse chromosome 4. A third mutation causing persistent truncus arteriosus and craniofacial defects, phenotypes reminiscent of DiGeorge syndrome, was mapped to mouse chromosome 2. We note that mouse chromosomes 4 and 2 do not contain Tbx5 or Tbx1, genes previously linked to Holt-Oram and DiGeorge syndromes, respectively. In two other families, the ENU-induced mutation was identified--Sema3CL605P was associated with persistent truncus arteriosus with interrupted aortic arch, and the Gja1W45X connexin43 mutation caused conotruncal malformation and coronary aneurysms. Although our screen was designed as a recessive screen, a number of the mutations showed cardiovascular phenotypes in both heterozygote and homozygote animals. These studies show the efficacy of ENU mutagenesis and high-throughput ultrasound phenotyping in recovering mutations causing a wide spectrum of congenital heart defects. These ENU-induced mutations hold promise in yielding new insights into the genetic basis for human congenital heart disease.     

A rare case of congenital heart disease with ambiguous genitalia

Birth defects have become the important cause of mortality and morbidity in the perinatal period. Congenital heart disease (CHD) is the most common birth defect which includes the varying forms of cardiac abnormalities and occurs with an incidence of 1 per 100 live births. In most of the cases, CHD is an isolated malformation, but about 33% have associated anomalies. Ambiguous genitalia are one such rare anomaly that is associated with CHD among other genital abnormalities. The possible causes for this association could be pseudohermaphroditism, which in turn, may be due to congenital adrenal hyperplasia. The government of any country should consider providing for its people a free prenatal diagnosis for susceptible disorders.     

DNA methylation abnormalities in congenital heart disease

Congenital heart defects represent the most common malformation at birth, occurring also in ∼50% of individuals with Down syndrome. Congenital heart defects are thought to have multifactorial etiology, but the main causes are largely unknown. We have explored the global methylation profile of fetal heart DNA in comparison to blood DNA from control subjects: an absolute correlation with the type of tissue was detected. Pathway analysis revealed a significant enrichment of differential methylation at genes related to muscle contraction and cardiomyopathies in the developing heart DNA. We have also searched for abnormal methylation profiles on developing heart-tissue DNA of syndromic and non-syndromic congenital heart defects. On average, 3 regions with aberrant methylation were detected per sample and 18 regions were found differentially methylated between groups. Several epimutations were detected in candidate genes involved in growth regulation, apoptosis and folate pathway. A likely pathogenic hypermethylation of several intragenic sites at the MSX1 gene, involved in outflow tract morphogenesis, was found in a fetus with isolated heart malformation. In addition, hypermethylation of the GATA4 gene was present in fetuses with Down syndrome with or without congenital heart defects, as well as in fetuses with isolated heart malformations. Expression deregulation of the abnormally methylated genes was detected. Our data indicate that epigenetic alterations of relevant genes are present in developing heart DNA in fetuses with both isolated and syndromic heart malformations. These epimutations likely contribute to the pathogenesis of the malformation by cis-acting effects on gene expression.     

Evaluation of the General Practice Research Database congenital heart defects prevalence: comparison to United Kingdom national systems

BACKGROUND: As part of an effort to validate the General Practice Research Database (GPRD) for future studies of medication use in pregnancy, this study examined whether the rates of all, and specific types of, congenital heart defects obtained from the GPRD are similar to those obtained from UK national systems. METHODS: The prevalence rates of heart defects for 2001-2003 were determined from the GPRD and compared with both the National Congenital Anomaly System (NCAS) and the European Concerted Action of Congenital Anomalies and Twins (EUROCAT). Rate ratios (RRs) and 95% CIs were calculated comparing the prevalence of all congenital heart defects as well as specific types of heart defects in the three data sources. In addition, the effect of the child's age on the frequency of heart defects in the GPRD was determined. RESULTS: The prevalence of heart defects in the GPRD was more than twice as high as in the NCAS and slightly higher than in the EUROCAT. All differences were statistically significant. The prevalence of specific heart defects varied across the GPRD, NCAS, and EUROCAT. The measured prevalence of congenital heart defects in the GPRD was higher if calculated including children up to age 6. CONCLUSIONS: The comparisons of the GPRD prevalence rates to national prevalence estimates demonstrate that the GPRD can serve as a more complete source of background prevalence for the most commonly occurring congenital heart defects, which is essential to properly assess possible associations between maternal exposures and congenital heart defects.     

Identification of cardiac malformations in mice lacking <Emphasis Type="Italic">Ptdsr</Emphasis>using a novel high-throughput magnetic resonance imaging technique

Background  

Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo.     

Molecular and developmental mechanisms of congenital heart valve disease

Congenital heart disease occurs in approximately 1% of all live births and includes structural abnormalities of the heart valves. However, this statistic underestimates congenital valve lesions, such as bicuspic aortic valve (BAV) and mitral valve prolapse (MVP), that typically become apparent later in life as progressive valve dysfunction and disease. At present, the standard treatment for valve disease is replacement, and approximately 95,000 surgical procedures are performed each year in the United States. The most common forms of congenital valve disease include abnormal valve cusp morphogenesis, as in the case of BAV, or defects in extracellular matrix (ECM) organization and homeostasis, as occurs in MVP. The etiology of these common valve diseases is largely unknown. However, the study of murine and avian model systems, along with human genetic linkage studies, have led to the identification of genes and regulatory processes that contribute to valve structural malformations and disease. This review focuses on the current understanding and therapeutic implications of molecular regulatory pathways that control valve development and contribute to valve disease.     

Granulomatous skin lesions complicating Varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: case report

Acro-cardio-facial syndrome (ACFS) is a rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and mental retardation. Up to now, 9 patients have been described, and most of the reported cases were not surviving the first days or months of age. The spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. The diagnosis is based on clinical criteria, since the genetic mechanism underlying ACFS is still unknown. The differential diagnosis includes other disorders with ectrodactyly, and clefting conditions associated with genital anomalies and heart defects. An autosomal recessive pattern of inheritance has been suggested, based on parental consanguinity and disease's recurrence in sibs in some families. The more appropriate recurrence risk of transmitting the disease for the parents of an affected child seems to be up to one in four. Management of affected patients includes treatment of cardiac, respiratory, and feeding problems by neonatal pediatricians and other specialists. Prognosis of ACFS is poor.     

Congenital malformations at birth in Central India: A rural medical college hospital based data

OBJECTIVE:

To study the incidence of congenital anomalies and the associated risk factors in Department of Pediatrics at Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, a rural medical college hospital in central Maharashtra.

MATERIALS AND METHODS:

All the intramural deliveries between 1 January 2005 and 31 July 2007 comprised 9386 births and their 9324 mothers (62 mothers gave birth to twin babies). The newborns were examined and assessed systematically for the presence of congenital anomalies, system wise distribution of anomalies and risk factors attributable.

RESULTS:

Out of the total 9386 deliveries, 9194 were live births and 192 were stillbirths. The total number of babies with congenital malformations was 179 (1.91%). Out of the 9262 singleton births, 177 (1.05%) were malformed, whereas 2 of the 62 pairs of twins had birth defects. Nine of the 179 malformed babies (5.02%) were still born. Prematurity, increased maternal age, increasing birth order and low birth weight were found to have a higher risk of congenital anomalies. Cardiovascular malformations were most common in live births, followed by musculoskeletal and genitourinary anomalies.

CONCLUSION:

Congenital anomalies are a major cause of stillbirths and infant mortality. Evaluation of cardiovascular system to rule out congenital heart disease in high-risk mothers’ babies is the important factor to be considered.     

Xenopus: An emerging model for studying congenital heart disease

Congenital heart defects affect nearly 1% of all newborns and are a significant cause of infant death. Clinical studies have identified a number of congenital heart syndromes associated with mutations in genes that are involved in the complex process of cardiogenesis. The African clawed frog, Xenopus, has been instrumental in studies of vertebrate heart development and provides a valuable tool to investigate the molecular mechanisms underlying human congenital heart diseases. In this review, we discuss the methodologies that make Xenopus an ideal model system to investigate heart development and disease. We also outline congenital heart conditions linked to cardiac genes that have been well studied in Xenopus and describe some emerging technologies that will further aid in the study of these complex syndromes.     

Associated anomalies in asymmetric crying facies and 22q11 deletion

Congenital asymmetric crying facies, a minor congenital anomaly due to unilateral absence or hypoplasia of the depressor anguli oris muscle, is associated at times with major congenital anomalies. A large number of asymmetric crying facies cases with chromosome 22q11 microdeletions have presently been reported. Fluorescence in situ hybridization (FISH) analysis for 22q11 deletion was performed on 8 infants with asymmetric crying facies. Five of our patients had at least one associated systemic anomaly. Two of 5 patients had conotruncal heart disease (Cayler cardiofacial syndrome). In three of the affected infants, we failed to reveal additional congenital malformation. The 22q11 deletion was present in only one patient. This baby had congenital hypoparathyroidism, severe neonatal hypocalcaemia and tetralogy of Fallot. We suggest, a 22q11 deletion should be excluded not in all cases but in cases with Cayler cardiofacial syndrome and in ACF associated with additional congenital anomalies.     

Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development

About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease.     

Incidence of Heart Disease in Children in the City of Toronto

A special registry of children with heart disease in the City of Toronto was set up (a) to provide for follow-up of all children with heart disease in that community, (b) to remove the “cardiac” label from children with functional murmurs, (c) to acquaint parents with facilities available for the management of children with heart disease, and (d) to record useful data regarding heart disease in children.The 1961-62 Cardiac Registry showed that 542 of 156,775 pre-school and school children had evidence of heart disease; 464 were congenital and 68 rheumatic in origin: 121 children with congenital heart defects had been treated surgically. Congenital cardiac disease ranked fifth in frequency among the causes of death in children. There was a diminution of acute rheumatic fever and rheumatic heart disease in children in 1961-62 when compared with data for previous years. Seventy-eight per cent of children in this series with a history of rheumatic fever were receiving continuous prophylaxis.     

Mouse models of cardiac chamber formation and congenital heart disease

Congenital heart defects are among the most prevalent and serious birth anomalies in humans. These defects usually involve abnormalities in the formation of specific structures of the developing heart, such as individual chambers or the structures separating one chamber from another. The molecular and cellular pathways responsible for normal heart formation are not well understood, but recent data on single gene knockouts has begun to shed light on the crucial processes that when disrupted result in congenital heart defects.