153881例围产儿中生殖泌尿系统先天畸形发病情况研究

目的：探讨生殖泌尿系统畸形的发生率、特征及风险因素。方法：监测1985年12月－1990年12月孕28周至产后7天内的153881例围产儿中先天畸形,尤其是生殖泌尿系统畸形的发生情况,并对其中181例生殖泌尿系畸形儿设1：1对照研究。结果：共检出先天畸形2558例,先天畸形发生率为16．62‰,其中生殖泌尿系统畸形240例,发生率为1．56‰,占总畸形数的9．38％。生殖泌尿系统畸形中多发畸形162例,占67．5％,其中以合并中枢神经系统畸形最多。生殖泌尿系统畸形儿的存活率为35．83％,存活者依次以足月隐睾、尿道下裂及外阴性别不明畸形最多见,三者共占总活产数的89．53％。181例配对研究发现孕期感冒发烧,接触有害物质,丈夫吸烟及有家族史为生殖泌尿系统畸形的风险因素。结论：生殖泌尿系统畸形为较常见的畸形。应加强孕期防范,对存活者适时矫治。     

Association of parental consanguinity with congenital malformations among Arab newborns in Jerusalem

The aim of this work was to determine the impact of parental consanguinity on congenital malformations in a mixed urban and rural Arab community in Jerusalem, Israel. Arab mothers admitted to four hospitals in west Jerusalem were interviewed after delivery. Demographic and obstetric data were recorded. Neonatal data were extracted from the medical records of the nursery. When malformations were suspected, a 4- to 10-month follow up was achieved for confirming the diagnosis. Of 561 infants, 253 (45%) were born to consanguineous couples. The incidence of major congenital malformations in the offspring was 8.7, 7.1 and 2.6% in cases of first cousins, all consanguineous, and non-consanguineous couples, respectively. No association was found between parental consanguinity and prematurity (p = 0.357) or low birth weight (p = 0.589). Parental consanguinity was also associated with an increased incidence of death in previous siblings (p < 0.000). The increased incidence of congenital malformations and infant mortality in cases of inbreeding prompt the necessity of establishing programs to avoid these complications in the offspring.     

Risk tables for genetic counselling in some common congenital malformations

Tables of estimated recurrence risks for some 180 specific family histories are presented for three common congenital malformations. It is hoped that the tables will provide standards and be useful in genetic counselling.     

Using CSF biomarkers to replicate genetic associations in Alzheimer's disease

Defining cases and controls on the basis of biomarkers rather than clinical diagnosis may reduce sample sizes required for genetic studies. The aim of this study was to assess whether characterizing case/control status on the basis of cerebrospinal fluid (CSF) profile would increase power to replicate known genetic associations for Alzheimer's disease (AD). Independent of clinical diagnosis, Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with 2 CSF biomarkers for AD (Aβ1-42 < 192 pg/mL and tau phosphorylated at threonine 181 (p-tau) > 23 pg/mL, "CSF-positive") were compared with those without CSF evidence for AD (Aβ1-42 > 192 pg/mL and 181-phosphorylated tau < 23 pg/mL, "CSF-negative"). Minor allele frequency (MAF) and odds ratios (ORs) between these 2 groups were calculated for 7 single-nucleotide polymorphisms (SNPs) of interest. Two hundred thirty-two individuals were CSF-positive and 94 CSF-negative. There were no differences in age (74.7 ± 7.2 vs. 75.0 ± 6.5 years, p = 0.7), but significant differences in Mini Mental State Examination (MMSE) (25.9 ± 2.6 vs. 28.2 ± 1.7, p < 0.001) between the CSF-positive and CSF-negative groups. Significant differences in MAF (p < 0.05, uncorrected) were seen for CR1 (rs1408077; OR, 1.59; 95% confidence interval [CI], 1.01-2.49), PICALM (rs541458; OR, 0.68, 95% CI, 0.47-0.98), TOMM40 (rs2075650; OR, 4.30; 95% CI, 2.61-7.06); and possession of 1 or more APOE ε4 alleles (OR, 9.84; 95% CI, 5.48-17.67). These results suggest that using biomarkers of AD pathology to define case and control status may increase power in genetic association studies.     

Usefulness of a registry of congenital malformations for genetic counseling and prenatal diagnosis

During three years, 39,924 infants born consecutively in the area covered by our registry of congenital malformations were surveyed; 775 had major congenital malformations. Recurrence risks for the major malformation was estimated and classified as high (greater than 10%, 5.3% of the cases), low (1 to 10%, 85.3% of the cases) or occasional (less than 1%, 9.4% of the malformed). Feasibility of prenatal diagnosis was considered. On the basis of the recurrence risk of 1% or higher and the feasibility of prenatal diagnosis, such a procedure should be considered in future pregnancies in 64.1% of the mothers. Genetic counseling has to be given to couples at risk of having a malformed child. For this purpose, as is shown in our study, the best way is the possibility of using a registry of congenital malformations.     

Mutations in sarcomeric protein genes not only lead to cardiomyopathy but also to congenital cardiovascular malformations

Noncompaction of the ventricular myocardium is associated with de novo mutation in the beta-myosin heavy chain gene
Budde et al. (2007)
PLoS ONE 2: e1362
Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy
Xin et al. (2007)
Am J Med Genet 143: 2662–2667
Alpha-cardiac actin mutations produce atrial septal defects
Matsson et al. (2008)
Hum Mol Genet 17: 256–265     

A comparison of three statistical models for IDDM associations with HLA

The association between HLA-DQ haplotypes and insulin-dependent diabetes mellitus (IDDM) was studied in 48 children from 44 families ascertained from the high incidence area around Umeå, Sweden. Numerous hypotheses have been proposed to explain associations between HLA and IDDM, but comparisons of statistical models based on these hypotheses have not been attempted. The aim of the present study was to compare the goodness-of-fit and predictive abilities among different statistical models. A likelihood-based analysis rather than a conventional analysis based on contingency tables was therefore adopted. We first used parental haplotype information in a conditional likelihood analysis (1) and then compared this analysis with that of an unaffected control group which used information on geographically matched controls. Under the analysis conditional on parental haplotype, a statistical model motivated by the hypothesis that the entire DQ heterodimer is involved in EDDM pathogenesis fit the data significantly better and had greater predictive ability than either a model motivated by the explanation that an IDDM gene is linked to DQB1 or that the DQB1 chain itself is involved in IDDM pathogenesis, or a model arising from the hypothesis that single amino acids at codon 57 of DQB1 and codon 52 of DQA1, respectively, confer susceptibility. Under the case-control analysis, the identity of the best-fitting or most predictive statistical model was not as clear, although both approaches to analyzing risk suggested that the single-amino-acids model had significantly poorer fit compared to the remaining two models.     

Reassessment of models used to test xenobiotics for oestrogenic potency is overdue

Product safety bioassays need to include data from animals with susceptible genotypes or the potential for environmental compounds to disrupt reproductive development in hormonally sensitive populations may be greatly underestimated. The continued use of resistant animal models is likely to result in allowable releases of toxic levels of oestrogenic agents that could differentially disrupt reproductive development and function of sensitive genotypes, leading to reproductive failure and loss or extinction of susceptible individuals, populations and species. Rather than ignoring the role of genetic differences in susceptibility to oestrogenic agent-induced carcinogenicity and endocrine disruption, government agencies should support efforts to identify the genetic mechanisms involved in these responses, and to screen for and develop strains of mice and rats which are sensitive to the induction of genotoxicity/carcinogenicity as well as the inhibition of reproductive development and function by oestrogenic agents. Such sensitive strains would be even more optimal for testing chemicals for endocrine disruptor activity.     

The inclusion of an assay for inherited congenital malformations in the assessment of mutagenicity

A number of national guidelines and regulations on the mutagenicity of chemical substances mandate the assessment of inherited genetic effects. While inherited congenital malformations represent a major component of genetically-based adverse human health effects, tests for such effects are not used by regulatory agencies to evaluate inherited genetic effects. This paper is intended to highlight some of the salient characteristics of inherited congenital malformations which promote a rationale for their use in a regulatory context.     

Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study

Offspring of childhood cancer survivors may be at risk of genetic disease due to the mutagenic cancer treatments received by their parents. Congenital malformations were evaluated in a population-based cohort study of 1715 offspring of 3963 childhood cancer survivors and 6009 offspring of 5657 survivors' siblings. The Danish Central Population Register, Cancer Registry and Hospital Register were used to identify study subjects and congenital malformations. Gonadal and uterine radiation doses were characterized based on standard radiation-treatment regimens. The prevalence of congenital malformations at birth in offspring of survivors (44 cases, 2.6%) was slightly higher but not statistically different from that of offspring of siblings (140 cases, 2.3%) [prevalence proportion ratio (PPR), 1.1; 95% confidence interval, 0.8–1.5] or of the general population (observed-to-expected ratio, 1.2; 0.9–1.6). Including malformations diagnosed later in life did not change the ratios appreciably. The risk for malformations was slightly higher in the offspring of irradiated parents than in that of non-irradiated parents (PPR 1.2 vs 1.0) but was unrelated to gonadal dose. This study provides evidence that cancer therapy of children does not increase the risk for malformations in their offspring. Continued monitoring of genetic risks among their offspring, however, is warranted.     

Major congenital malformations in United Arab Emirates (UAE): need for genetic counselling

Between January 1992 and January 1995 a total of 24233 babies born consecutively in Corniche Hospital which is the only maternity hospital in Abu Dhabi, the capital of UAE, were surveyed for the presence of major congenital malformations. A total of 401 infants (16.6/1000) had a major defect. Of these malformations, 267 (67%) were associated with an estimated recurrence risk greater than 1%, and 95 (24%) carried an estimated recurrence risk greater than 10%. This included a total of 91 cases of single gene disorders and 4 cases of cleft lip and palate where a mother and another sibling were affected putting their estimated recurrence risk in the high category group. When antenatal diagnosis is feasible, this should be considered in 60% of mothers (a total of 242). In 59% (a total of 237) the estimated recurrence risk was >1% and the antenatal diagnosis of the disorder was possible. The importance of Genetic Counselling is revealed in our study since more than three quarters of mothers were under 36 years old, and may well plan future pregnancies.     

Insights from examination of hearts from adults dying suddenly to the understanding of congenital cardiac malformations

Congenital heart disease is a rare but important finding in adults who experience sudden death. Examination of the congenitally malformed heart has historically been considered esoteric and best left to those with expertise. The Cardiac Risk in the Young cardiovascular pathology laboratory based at St George's University of London has now received over 6,000 cases. Of these, 21 congenitally malformed hearts were retained for research and educational purposes. Hearts were assessed using sequential segmental analysis, and causes of death were adjudicated based on thorough macroscopic examination and histology. Congenital malformations that were encountered included atrial septal defects, ventricular septal defects, tetralogy of Fallot, and transposition of the great arteries in both its regular and congenitally corrected variants. Findings also included hearts with mirror-imaged and isomeric atrial appendages. Direct causes of death included myocardial fibrosis, pulmonary hypertension, and hemorrhage. A small but notable proportion did not reveal a substrate for arrhythmia, raising the question of whether the terminal event was due to the congenital heart disease itself, or an underlying channelopathy. Here, we demonstrate the value of simple sequential segmental analysis in describing and categorizing the cases, with the concept of the “morphological method” serving to identify the distinguishing features of the cardiac components. Clin. Anat. 33:394–404, 2020. © 2019 Wiley Periodicals, Inc.     

Transient increase in VEGF-A leads to cardiac tube anomalies and increased risk of congenital heart malformations

Vascular endothelial growth factor (VEGF) plays a critical role during early heart development. Clinical evidence shows that conditions associated with changes in VEGF signaling in utero are correlated with an increased risk of congenital heart defects (CHD) in newborns. However, how malformations develop after abnormal VEGF exposure is unknown. During embryogenesis, a primitive heart, consisting of an endocardial tube enveloped by a myocardial mantle, is the first organ to function. This tubular heart ultimately transforms into a four-chambered heart. To determine how a transient increase in VEGF prior to heart tube formation affects heart development leading to CHD, we applied exogenous VEGF or a control (vehicle) solution to quail embryos in ovo at Hamburger-Hamilton (HH) stage 8 (28–30 hr of incubation), right before heart tube formation. Light microscopy analysis of embryos re-incubated after treatment for 13 hrs (to approximately HH11/HH12) showed that increased VEGF leads to impaired heart tube elongation accompanied by diameter expansion. Micro-CT analysis of embryos re-incubated for 9 days (to approximately HH38), when the heart is fully formed, showed that VEGF treatment increased the rate of cardiac malformations in surviving embryos. Despite no sex differences in survival, female embryos were more likely to develop cardiac malformations. Our results further suggest that heart tube malformations after a transient increase in VEGF right before heart tube formation may be reversible, leading to normal hearts.     

Orbital cyst in addition to congenital cerebral and focal dermal malformations: A new entity?

Two patients with similar congenital malformations, consisting of orbital cyst, cerebral malformations and focal dermal hypo- and aplasia are described. There is some similarity to the Goltz and Goldenhar syndromes; however, the delineation of a new entity or syndrome seems possible.