An update on cardiovascular malformations in congenital rubella syndrome

BACKGROUND : Congenital rubella syndrome (CRS) has long been characterized by the triad of deafness, cataract, and cardiovascular malformations (CVMs). While initial reports identified patent ductus arteriosus (PDA) as the primary CVM in CRS, the exact nature of the CVMs found in CRS has not been well established. METHODS : We searched the English literature from 1941 through 2008 to identify studies that used cardiac catheterization or echocardiography to evaluate the CVMs in CRS. RESULTS : Of the 121 patients in the 10 studies with catheterization data, 78% had branch pulmonary artery stenosis, and 62% had a PDA. In 49% of cases, both branch pulmonary artery stenosis and PDA were present, whereas isolated branch pulmonary artery stenosis and isolated PDA were found in 29 and 13% of cases, respectively. Of the 12 patients in the 10 studies with echocardiographic data, PDA was more common than branch pulmonary artery stenosis, but this finding is greatly limited by the small numbers of patients and limitations of echocardiography. Although published studies of CVMs in CRS have in general reported PDA as the CVM phenotype most commonly associated with CRS, among CRS cases evaluated by catheterization, branch pulmonary artery stenosis was actually more common than PDA. Moreover, although the combination of branch pulmonary artery stenosis and PDA was more common than either branch pulmonary artery stenosis or PDA alone, isolated branch pulmonary artery stenosis was twice as common as isolated PDA. CONCLUSION : Among children with suspected CRS, clinical evaluations for the presence of CVMs should include examinations for both branch pulmonary artery stenosis and PDA. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

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.     

Simulations of rubella vaccination strategies in China

Many infants whose mothers have rubella infections during their first trimester of pregnancy have birth defects called congenital rubella syndrome (CRS). China does not routinely vaccinate against rubella in the public sector, but may need to start as its 'one child per couple' policy changes the population age distribution and the dynamics of rubella epidemiology, so that the incidence of rubella in pregnant women increases. Computer simulations with demographic transitions and rubella transmission dynamics predict that, with no or limited rubella vaccination, CRS incidence in China in the 30 years after 2020 will be more than twice the level in 2005. Comparisons of rubella vaccination strategies using computer simulations show that routine vaccination of over 80% of 1-year-old children would be effective in reducing total CRS cases in 2005-2051 and eliminating rubella in China by 2051. Routine immunizations at higher levels and the addition of early mass vaccinations of 2-14-year-old children and women of childbearing ages would further reduce total CRS cases and speed up the elimination of rubella.     

Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project

BACKGROUND: Maternal folic acid supplementation has been associated with a reduced risk for neural tube defects and may be associated with a reduced risk for congenital heart defects and other birth defects. Individuals with Down syndrome are at high risk for congenital heart defects and have been shown to have abnormal folate metabolism. METHODS: As part of the population‐based case‐control National Down Syndrome Project, 1011 mothers of infants with Down syndrome reported their use of supplements containing folic acid. These data were used to determine whether a lack of periconceptional maternal folic acid supplementation is associated with congenital heart defects in Down syndrome. We used logistic regression to test the relationship between maternal folic acid supplementation and the frequency of specific heart defects correcting for maternal race or ethnicity, proband sex, maternal use of alcohol and cigarettes, and maternal age at conception. RESULTS: Lack of maternal folic acid supplementation was more frequent among infants with Down syndrome and atrioventricular septal defects (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.08–2.63; p = 0.011) or atrial septal defects (OR, 1.69; 95% CI, 1.11–2.58; p = 0.007) than among infants with Down syndrome and no heart defect. Preliminary evidence suggests that the patterns of association differ by race or ethnicity and sex of the proband. There was no statistically significant association with ventricular septal defects (OR, 1.26; 95% CI, 0.85–1.87; p = 0.124). CONCLUSIONS: Our results suggest that lack of maternal folic acid supplementation is associated with septal defects in infants with Down syndrome. Birth Defects Research (Part A), 2011. © 2011 Wiley‐Liss, Inc.     

The association of split hand foot malformation (SHFM) and congenital heart defects

BACKGROUND: Split hand foot malformation (SHFM) (cleft hand, central ray deficiency) is a highly variable malformation that shows genetic heterogeneity with at least five loci mapped to date. SHFM occurs as an isolated finding or in association with other anomalies, including congenital heart defects (CHDs). METHODS: In total 48 SHFM1, 52 SHFM3, 48 SHFM4, 21 SHFM5, and four chromosome 8 patients were evaluated. In addition, we performed a literature review to identify “unmapped” SHFM patients with CHD to evaluate the various etiologies of this combination of findings. The London Dysmorphology Database also served as a resource to identify syndromes with this combination of phenotypic findings. Only patients presenting with both SHFM and CHD were included in the analysis. Classification of CHD among mapped and unmapped SHFM patients was performed utilizing the revised Clark classification. A closer inspection of the types of CHD found in this patient group was performed in order to investigate possible pathogenetic mechanisms. RESULTS: CHDs were found in 10% of SHFM1 patients, 47% of SHFM5 patients, but were not reported in SHFM2, SHFM4 patients, or patients mapped to chromosome 8. Forty‐two syndromic cases and 15 cases of unrecognized syndromes were identified. CONCLUSIONS: The higher frequency of heart defects seen in SHFM1 and SHFM5 of the mapped patient group raises the question as to whether common mechanisms/genetic players are involved. Candidate genes for SHFM1 and SHFM5 include members of the DLX homeobox gene family. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies

BACKGROUND: This study examined the association between maternal smoking and alcohol use (including binge drinking) during the periconceptional period (i.e., 2 months before through 2 months after conception) and the risk of orofacial clefts, NTDs, and conotruncal heart defects in offspring. METHODS: Data were drawn from a population‐based case‐control study of fetuses and live‐born infants among a cohort of California births between July 1999 and June 2003. The 1,355 cases comprised of 701 orofacial clefts, 337 NTDs, and 323 conotruncal heart defects. Information on smoking and alcohol consumption was obtained via telephone interviews with mothers of 1,355 (80% of eligibles) cases and 700 (77% of eligibles) nonmalformed, live‐born controls. RESULTS: Maternal smoking of five cigarettes or less per day was associated with reduced risks of NTDs (OR 0.7; 95% CI: 0.3, 1.4), whereas the risk associated with higher cigarette consumption was lower for conotruncal heart defects (OR 0.5; 95% CI: 0.2, 1.2). Maternal intake of alcohol less than 1 day per week was associated with a 1.6‐ to 2.1‐fold higher risk of NTDs (95% CI: 0.9, 2.6), d‐transposition of the great arteries (95% CI: 1.1, 3.2), and multiple cleft lip with or without cleft palate (CLP) (95% CI: 0.8, 4.5). Risks associated with more frequent alcohol intake were 2.1 for NTDs (95% CI: 1.1, 4.0) and 2.6 for multiple CLP (95% CI: 1.1, 6.1). CONCLUSIONS: This study observed that maternal alcohol intake increased the risk for d‐transposition of the great arteries, NTDs, and multiple CLP in infants. By contrast, smoking was associated with a lower risk of NTDs and conotruncal heart defects. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

先天性CMV感染致中枢神经系统畸形发育机制

胎儿中枢神经系统(central nervous system,CNS)是人类巨细胞病毒(human cytomegalovirus,HCMV)先天性感染的主要靶器官。胚胎期CMV感染常常导致严重CNS畸形的发生,其前提条件是CNS中的神经前体(干)细胞、神经元及神经胶质细胞对CMV普遍易感。发育期CNS感染CMV具有以下特点:⑴神经系统细胞对CMV的容纳性在CNS的不同发育阶段有所不同;⑵受累的细胞数随着发育的进展而增多;⑶CNS不同部位的细胞对CMV的敏感性存在明显的差异;⑷感染发生时细胞所处细胞周期的时相也与感染严重程度密切相关。CMV感染能诱导宿主细胞特异性的染色体折断,影响Homeobox基因(胚胎发育的主控基因)的表达,进而阻断细胞周期(G1期滞留)、诱导细胞凋亡,导致CNS细胞数量减少与迁徙异常,最终导致C N S发育畸形。     

Neural crest derivatives in ocular development: Discerning the eye of the storm

Neural crest cells (NCCs) are vertebrate‐specific transient, multipotent, migratory stem cells that play a crucial role in many aspects of embryonic development. These cells emerge from the dorsal neural tube and subsequently migrate to different regions of the body, contributing to the formation of diverse cell lineages and structures, including much of the peripheral nervous system, craniofacial skeleton, smooth muscle, skin pigmentation, and multiple ocular and periocular structures. Indeed, abnormalities in neural crest development cause craniofacial defects and ocular anomalies, such as Axenfeld‐Rieger syndrome and primary congenital glaucoma. Thus, understanding the molecular regulation of neural crest development is important to enhance our knowledge of the basis for congenital eye diseases, reflecting the contributions of these progenitors to multiple cell lineages. Particularly, understanding the underpinnings of neural crest formation will help to discern the complexities of eye development, as these NCCs are involved in every aspect of this process. In this review, we summarize the role of ocular NCCs in eye development, particularly focusing on congenital eye diseases associated with anterior segment defects and the interplay between three prominent molecules, PITX2, CYP1B1, and retinoic acid, which act in concert to specify a population of neural crest‐derived mesenchymal progenitors for migration and differentiation, to give rise to distinct anterior segment tissues. We also describe recent findings implicating this stem cell population in ocular coloboma formation, and introduce recent evidence suggesting the involvement of NCCs in optic fissure closure and vascular development. Birth Defects Research (Part C) 105:87–95, 2015. © 2015 Wiley Periodicals, Inc.     

A case of bilateral tibial hemimelia type VIIa

Congenital absence of tibia is a rare anomaly, and may be total or partial, unilateral or bilateral. Total absence is more frequent than partial, unilateral absence occurs more often than bilateral, with right limb more commonly affected than the left. In partial defect, almost always the distal end of the bone is affected, and of the bilateral cases, there may be total absence on both sides, or total on one side and partial on the other. Males are slightly more commonly affected than the females. Though, the family history is usually negative for congenital abnormalities and other diseases, there is a considerable chance of occurrence of congenital defect of the tibia or of other abnormalities, in near or remote relatives. We report a case of newborn having bilateral tibial hemimelia type VIIa.     

Transvenous pacing in complex post-operative congenital heart disease guided by angiography: A case report

Transvenous pacing in patients with postoperative complex congenital heart disease (CHD) can be challenging and pose technical challenges to lead placement because of the complex anatomy, distortions produced by the surgical procedures, and the altered relationship of cardiac chambers. We describe the utility of angiography for transvenous dual chamber pacemaker implantation in a post-operative complex congenital heart disease.