Biomedical subjects

E E Castilla

Publications and source records attributed to E E Castilla.

At least 19 recordsLinked to original sources

PubMed2003

MSX1 and TGFB3 contribute to clefting in South America.

MSX1 and TGFB3 have been proposed as genes in which mutations may contribute to non-syndromic forms of oral clefts; however, an interaction between these genes has not been described. The present study attempts to detect transmission distortion of MSX1 and TGFB3 in 217 South American children from their respective mothers. With transmission disequilibrium test analysis, cleft lip with/without cleft palate, cleft lip with palate plus cleft palate only, and all datasets combined showed evidence of association with MSX1 (p = 0.004, p = 0.037, and p = 0.001, respectively). With likelihood ratio test analysis, "cleft lip only" showed association with MSX1 (p = 0.04) and "cleft palate only" with TGFB3 (p = 0.02). A joint analysis of MSX1 and TGFB3 suggested that there may be an interaction between these two loci to increase cleft susceptibility. These results suggest that MSX1 and TGFB3 mutations make a contribution to clefts in South American populations.

Alleles↗

PubMed2002

Genetic origins in a South American clefting population.

It has been proposed that susceptibility to clefting in South America is related to Amerindian ancestry, where clefting is present at a higher frequency than in the other admixed populations (Caucasian and African) that make up the diverse racial mix of current South Americans. To clarify the genetic origins and establish a method for genetic mapping, mitochondrial DNA variation and Y-chromosome markers were studied in a South American population affected with clefting. Two-hundred and seventeen subjects and matched controls were selected through the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). The case group showed a higher frequency of Native American haplogroups and a lower frequency of African haplogroups (p < 0.00001). In addition, the case group showed a much higher frequency of the specific native American haplogroup D than the control group (p < 0.00001). For the Y-chromosome markers, the case group showed a lower frequency of the African-specific marker, YAP (p = 0.002), and a higher frequency of the Native American-specific marker, DYS199 (p < 0.00001). Even though differences were found in the frequencies of the markers studied, the contribution of each founder population was similar for both groups. Results suggest a strong Native American maternal contribution and a strong Caucasian (Spanish and Portuguese) paternal contribution to the population studied. The implications of this finding include the possibility of using admixture mapping approaches to this population.

Chromosomes, Human, Y↗

PubMed2001

Search for ethnic, geographic, and other factors in the epidemiology of Down syndrome in South America: analysis of data from the ECLAMC project, 1967-1997.

We have analyzed data on 3,157 cases of Down syndrome (DS) from nine South American countries in consecutive series of hospital live births over a 30-year period, with particular emphasis on possible ethnic or geographic variations in maternal age-adjusted incidence. The data constitute the largest series of DS cases assembled to date from an area lacking advanced health care systems. Absolute incidence rates were estimated from total hospital live births; relative rates were estimated from matched case-control data using conditional logistic regression. Maternal age-adjusted rates were closely similar to those reported elsewhere, and showed little or no dependency on other factors investigated, including paternal age, birth order, ancestral origin, country of birth, maternal educational level, maternal ABO and Rhesus blood groups, interval to and outcome of mother's previous pregnancy, and parental consanguinity. The absence of an effect of high birth order was particularly notable because of the relatively large number of grand multipara resulting from high fertility in this population. The study adds to a body of evidence suggesting that maternal age-adjusted DS rates vary little across human populations, and are therefore unlikely to be greatly influenced by genetic or environmental factors that differ between them. An unusual finding was of a markedly lower sex ratio (98 males per 100 females) than has been reported in other DS samples.

Adult↗

PubMed2001

Parental consanguinity in specific types of congenital anomalies.

Parental consanguinity, as a recognized risk factor for congenital anomalies, has mainly been studied with a focus on the types of parental relationships and their effects on genetic syndromes or birth defects in general. The present work analyzed the association between parental consanguinity and congenital anomalies, split, when possible, into clinical subtypes, in an attempt to obtain some insight into their recognized etiological heterogeneity. The material consisted of 34,102 newborn infants, affected by one of 47 selected congenital anomaly types, ascertained by the Latin-American Collaborative Study of Congenital Malformations (ECLAMC) during the period from 1967 to 1997. The consanguinity rate for each congenital anomaly type was compared with that of the population under study (0.96%), and the potentially confounding effect of six selected variables was controlled through a conditional logistic regression analysis for those congenital anomalies significantly associated with consanguinity. Pre-occurrence rates for the same congenital anomaly in sibships of consanguineous and non-consanguineous cases were compared. A significant association with parental consanguinity was observed for three congenital anomaly types: hydrocephalus, postaxial hand polydactyly, and bilateral cleft lip +/- cleft palate, while three additional anomalies, namely, cephalocele, microcephaly, and hand + foot postaxial polydactyly, showed a positive association, but statistical significance disappeared after adjustment for confounders, probably owing to sample size reduction. The association between consanguinity and Down syndrome was mainly due to the confounding effect of maternal age, while for hydrops fetalis and 2-3 toe syndactyly, the observed positive association could not be tested for confounders due to sample size reduction.

Cleft Lip↗

PubMed2001

VATER non-random association of congenital malformations: study based on data from four malformation registers.

This study was undertaken to find a strict, unbiased epidemiological delineation of the VATER non-random association of congenital malformations and, based on registry information, to identify a group of probable VATER association infants suitable for etiological analyses. Information on 5,260 infants with multiple malformations was collected from four large registers of congenital malformations. Data were analyzed using a statistical method in which various putative confounders were controlled for. Our results indicate the existence of a distinct group of malformations corresponding to the VATER association: esophageal atresia, anal atresia, upper preaxial limb reduction defects, and costo-vertebral malformations. A subdivision into an upper and a lower group of VATER association was indicated, with heart malformations associated with the upper group and kidney malformations associated with the lower group. Restricting the inclusion criteria for VATER association to the above mentioned core malformations, few infants seem to belong to the VATER association, thus limiting the possibilities of carrying out etiological analyses. A relatively large number of infants may belong to a family of related conditions among which VATER association is a subgroup. In the search for risk factors, a strict definition of the VATER association is needed in order to not dilute the study material with irrelevant cases. The present study provides such strict inclusion criteria.

Abnormalities, Multiple↗

PubMed2001

Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly.

Holoprosencephaly (HPE) is genetically heterogeneous with four genes, SIX3, SHH, TGIF, and ZIC2 that have been identified to date and that are altered in 12% of patients. To analyze this prevalence in a South American population-based sample (57 HPE cases in 244,511 live and still births or 1 in 4300), we performed a mutational study of these genes in 30 unrelated children (26 newborns and 4 non-newborns) with HPE being ascertained by ECLAMC (Latin American Collaborative Study of Congenital Malformations). We identified three novel mutations: two were missense mutations of the SHH gene (Cys183-->Phe; His140-->Pro); the third mutation was a 2-bp deletion in the zinc-finger region of the ZIC2 gene. These molecular results explained 8% (2/26 newborn samples) of the HPE cases in this South American population-based sample, a proportion similar to our previously published data from a collection of cases.

Base Sequence↗

PubMed2001

Epidemiological methods to assess the correlation between industrial contaminants and rates of congenital anomalies.

The present knowledge of epidemiological methods, applied to assess the correlation between industrial contaminants and rates of congenital anomalies is reviewed. The concept of congenital anomalies may be extended to include other adverse reproductive outcomes, such as malformations, infant mortality, stillbirths, spontaneous abortions, intrauterine growth retardation, ectopic pregnancies, multiple births, altered secondary sex ratio, and parental sub-fertility. The review of occupational exposures associated with congenital anomalies indicated: (1) inconsistency of the reported associations; (2) more positive than negative associations; (3) solvents are the best studied, and the most frequently reported teratogenic chemicals; (4) common congenital anomalies are the most frequently studied diagnostic categories, while other defects are grouped into larger categories, with little biological meaning. The review of environmental exposures indicated that: (1) single-site studies outnumber multi-site ones; (2) results are heterogeneous; (3) congenital anomalies are, in general, unspecific, and grouped into large categories, such as those defined by anatomic systems. Recent developments in molecular biology anticipate the possibility to measure exposures directly, instead of by different "proxies", as well as to analyze the genetic predisposition for the teratogenic response to given environmental agents. The strategy of building up large banks of biological materials has already started in several birth defects registries. The following procedural guidelines to assess the teratogenicity of a pollutant are recommended: (1) strength of the association; (2) consistency of findings in different studies; (3) specificity of the association; (4) time-exposure relationship; (5) existence of a dose-response gradient between exposure and disease occurrence; (6) biological plausibility; (7) coherence of the evidence with natural history of the disease; (8) experimental (or quasi-experimental) evidence and (9) reasoning by analogy.

Congenital Abnormalities↗

PubMed2001

Consanguinity in South America: demographic aspects.

A sample of 53,552 nonmalformed liveborn infants was ascertained by the Latin-American Collaborative Study of Congenital Malformations between 1967 and 1996. The mean consanguinity rate was 0.96%, with significantly higher values in Brazil and Venezuela, and lower in Argentina. Low paternal education and occupation levels were positively associated with consanguinity. First-cousin matings represented almost half of all consanguineous couples. The consanguinity was mainly of more closely related types in Brazil, while in Venezuela more remote types predominated. This could reflect differences in migration patterns and rates between these two countries.

Consanguinity↗

PubMed2001

Correlation between molecular and conventional genealogies in Aicuña: a rural population from Northwestern Argentina.

Aicuña is a village in the northwest of Argentina, located about 300 km south of La Rioja city, in the province of La Rioja. The population of Aicuña derives from a founder couple established in the uninhabited Aicuña valley in the early years of the 17th century. Due to land ownership litigation, the descendants maintained a well-documented genealogy that extends for 12 generations, comprising more than 8,000 individuals. From the historical pedigree of Aicuña, we selected 14 males with direct patrilineal descent from the 2 most ancient male founders, and 23 donors (9 females and 14 males) with direct matrilineal descent from the most ancient female founder. All 3 founders lived in the 17th century. We collected DNA from buccal swabs and characterized the mitochondrial DNA (mtDNA) and Y haplotypes using 14 Y-specific markers, 11 mtDNA polymorphic markers and sequencing of the mt hypervariable regions 1 and 2. We found four different Y haplotypes: Y1 and Y2 haplotypes of European origin corresponding to the founder ancestors Francisco Páez de Espinoza and Apolinario Ormeño, which were shared by 6 and 3 donors, respectively. Three males selected as Ormeño patrilineal descendants showed a different Y haplotype (Y3), probably originated by erroneous paternity registration due to illegitimacy. The remaining case (haplotype Y4), also assumed to belong to the Ormeño lineage, was probably also due to an erroneously registered paternity. Twenty-two donors showed an association of mtDNA markers corresponding to the Amerindian haplotype A2. The founder of this matrilineage could be traced back for more than 14 generations. The haplotype B of one remaining female did not correspond with the historical pedigree and could be due to an error in the genealogy registration. Our results showed an 85% agreement between conventional and molecular genealogies, with mtDNA markers being Amerindian, and Y markers being European. The methodology used in this report is a tool which could potentially be employed as a precedent for land ownership by Aicuña villagers and Amerindian populations.

Argentina↗

PubMed2001

[ECLAMC: 30-year study of epidemiological surveillance of neural tube defects in Chile and Latin America].

BACKGROUND: There is an urgent need to assess the impact, on the incidence of neural tube defects, of the recently implanted flour fortification with folic acid in Chile. The Collaborative Study of Congenital Malformations in Latin America (ECLAMC) has carried out an uninterrupted register of congenital malformations in the last thirty years. AIM: To assess the epidemiology of neural tube defects in Chile and determine the most adequate base period to evaluate the effects of Folic acid fortification. MATERIAL AND METHODS: Analysis of ECLAMC database that has registered all births over 500 g from 1967. RESULTS: From 1967 to 1999, there were 434.624 births in 18 hospitals in Chile and 3.586.569 births in 155 hospitals in the rest of Latin America. The rate of neural tube defects in Chile was 17.03 per 10.000, significantly higher than the rest of ECLAMC (14.88 per 10.000). The prevalence of neural tube defects has a statistically significant secular tendency to increase in the study period and is higher among stillbirths, newborns with a birth weight of less than 1500 g, women and offspring of mothers aged less than 19 years old. CONCLUSIONS: The period 1982-1999 is considered the best period for reference comparisons of the effects folic acid supplementation.

Adult↗

PubMed2000

Isolated small intestinal atresias in Latin America and Spain: epidemiological analysis.

Stenosis, atresia, or absence of part of the duodenum, jejunum, or ileum are generally considered small intestinal atresias (SIAs). SIAs occur as isolated defects, in combination with other unrelated congenital anomalies, or as part of syndromes. We performed an epidemiological study of infants with isolated SIAs using data from two large congenital defects registries, one from Latin America (ECLAMC) and the other from Spain (ECEMC). The overall prevalence of SIAs is similar in both programs, being 1.32 per 10,000 livebirths in Spain and 1.29 per 10.000 livebirths in Latin America. Our results suggest that infants with isolated SIAs are characterized epidemiologically on the basis of shorter gestational age and low birthweight, an association with twinning, the parents are more frequently consanguineous, and their pregnancies are more frequently complicated by vaginal bleeding. The results also suggest an association between some maternal infections and ileal atresia. The fact that these characteristics have been observed in children with these types of anomalies occurring in different geographical areas and populations supports the conclusion that these characteristics are causally related to these defects.

Adult↗

PubMed2000

Limb defects associated with major congenital anomalies: clinical and epidemiological study from the International Clearinghouse for Birth Defects Monitoring Systems.

Although limb defects associated with other congenital anomalies are rarely studied, they may provide insights into limb development that may be useful for etiologic studies and public health monitoring. We pooled data from 11 birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring Systems. We identified 666 infants, born from 1983 through 1993, who had a non-syndromal limb defect plus at least one other major malformation (rate 12.9/100,000 population). We used observed/expected ratios and log-linear models to detect association patterns. We found that specific limb defects occurred with relatively distinct sets of malformations. Preaxial limb defects occurred more frequently with microtia, esophageal atresia, anorectal atresia, heart defects, unilateral kidney dysgenesis, and some axial skeleton defects; postaxial defects with hypospadias; transverse defects with craniofacial defects, micrognathia, ring constrictions, and muscular defects; intercalary defects with omphalocele; split hand/foot with encephalocele; and amelia with anorectal atresia, omphalocele, severe genitalia defects, unilateral kidney dysgenesis, gastroschisis, and ring constriction. Log-linear modeling identified higher order associations among some of these same malformations.

Cleft Palate↗

PubMed2000

OEIS complex--a population study.

Using a novel method for the analysis of infants with multiple malformations, we investigated the cluster of associated malformations called the OEIS (omphalocele, bladder exstrophy, imperforate anus, spine defect) complex among 5,260 infants with multiple malformations identified in four large registers of congenital malformations, corresponding to 5.84 million births. The existence of the OEIS complex was clearly demonstrated and malformations entering it could be defined. Other than the four classical malformations, omphalocele, bladder exstrophy, imperforate anus, and spine malformation, a strong association with spina bifida and intersex was stressed. Spine malformations occurred not only in the lumbosacral level but also more cranially, and an association also with upper spina bifida could be demonstrated. No specific association with any other malformation, including cardiac defects, was apparent. The OEIS complex is an unusually clearly defined entity among the various nonrandom associations which have been described.

Abnormalities, Multiple↗

PubMed2000

Epidemiological assessment of misoprostol teratogenicity.

OBJECTIVE: To verify if any of the 15 congenital defects already reported in association with misoprostol can be found within an epidemiological registry of congenital defects. DESIGN: Case-control study including case-sick and case-health controls. METHODS: Comparison of misoprostol exposure for each specific defect, using the exposure for the rest of defects as a reference group. POPULATION: Four thousand six hundred seventy-three consecutive newborn infants with malformations of unknown aetiology, in the Latin American Collaborative Study of Congenital Malformation. RESULTS: There was no difference in exposure rate between the malformed (34/4,673) and nonmalformed (23/4,980) newborns. Four of the five more frequently cited defects in the literature were found to be in excess: constriction ring, terminal transverse-limb defects, hydrocephalus, and arthrogryposis. Equinovarus feet had a normal frequency in our study. Thirteen different defects not described in the literature were seen in our misoprostol exposed cases, but only holoprosencephaly and bladder exstrophy significantly exceeded the expected number. CONCLUSIONS: The confirmation from an epidemiological registry of an association for four of the five more commonly observed congenital defects among misoprostol exposed children described in the literature seems indicative of a real teratogenic effect. The defects are of vascular disruption type. However, additional attempts to achieve abortion could not be excluded as a concurrent contribution.

Abnormalities, Drug-Induced↗

PubMed2000

Teratogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE).

PURPOSE: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations. METHODS: Information on all malformed infants (1990-1996) with maternal first-trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as infants presenting with a specific malformation, and controls were defined as infants presenting with any other birth defect. Exposure was defined by the use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios with 95% confidence intervals and testing their homogeneity among registries. RESULTS: Among 8005 cases of malformations, 299 infants were exposed in utero to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbital, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs. Associations were found for spina bifida with valproic acid. Infants exposed to phenobarbital and to methylphenobarbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic acid, and carbamazepine. Hypospadias was associated with valproic acid. Porencephaly and other specified anomalies of brain, anomalies of face, coarctation of aorta, and limb reduction defects were found to be associated with valproic acid. CONCLUSIONS: Using the MADRE system, we confirmed known teratogenic effects of AEDs. We also found increased risks for malformations that had never been reported associated with AEDs or for which the association was suggested by case reports.

Abnormalities, Drug-Induced↗

PubMed2000

Economic activity and congenital anomalies: an ecologic study in Argentina. ECLAMC ECOTERAT Group.

In this study, we analyze the association between industrial activity and the occurrence of 34 congenital anomalies. We selected 21 counties in Argentina during 1982-1994 and examined a total of 614,796 births in these counties in consecutive series. We used the International Standard Industrial Classification of All Economic Activities (United Nations, 1968) as an indicator of exposure to 80 specific industrial activities. Incidence rate ratios for each congenital anomaly were adjusted by the socioeconomic level of the county according to a census index of social deprivation. For a given exposure/anomaly association to be considered as significant and relevant, the exposure had to be a statistically significant risk for the occurrence of the anomaly and an increase in the birth prevalence rate of the congenital anomaly type involved had to be observed in those counties where the putative causal activity was being performed. Significant associations (p < 0.01) were identified between textile industry and anencephaly, and between the manufacture of engines and turbines and microcephaly. These observations are consistent with previous reports on occupational exposure, and their further investigation by means of case-control studies is recommended.

Argentina↗

PubMed1999

Altitude as a risk factor for congenital anomalies.

The birth prevalence of specific types of congenital anomalies at low and high altitudes in South America were compared after adjustment for prenatal growth, ethnicity, and socioeconomic status. The material includes all 1,668,722 consecutive births occurring in 53 hospitals participating in the Latin-American Collaborative Study of Congenital Malformations (ECLAMC), having registered at least 100 malformed/control pairs between 1967 and 1995. The lowland subsample (below 2,000 m above the sea level) included 46,729 case-control pairs, ascertained in 1,539,432 births from 49 hospitals in 38 cities. The highlands (above 2,000 m) comprised 3,498 case-control pairs from 129,301 births, occurring in four hospitals from three cities. Unconditional logistic regression was used to estimate the relative risks for the exposure at high altitudes, adjusted by ethnicity (Amerindian yes/no), type of health service (public/private), and birth weight (below/equal and greater than 2, 500 g). The adjusted relative risks showed significantly (P < 0.01) higher values in the high than in the lowlands for four types of defects: cleft lip [relative risks (RR): 1.57; 95% confidence interval (CI): 1.27-1.94], microtia (RR: 3.21; 95% CI: 2.35-4.79), preauricular tag (RR: 2.09; 95% CI: 1.86-2.36), branchial arch anomaly complex (RR: 1.79; 95% CI: 1.23-2.61), constriction band complex (RR: 1.92; 95% CI: 1.11-3.31), and anal atresia (RR: 1.61; 95% CI: 1.01-2.57). Conversely, lower risks in the highlands were registered for two neural tube defects: anencephaly (RR: 0.33; 95% CI: 0.20-0.54), spina bifida (RR: 0.57; 95% CI: 0.37-0.78), as well as for hydrocephaly (RR: 0.41; 95% CI: 0.22-0.77) and pes equinovarus (RR: 0.70; 95% CI: 0.51-0.96). Even though some of these differences may be caused by undetected confounders, the coincidental finding of four types of craniofacial defects with higher, and two types of neural tube defect with lower frequencies in the highlands, suggest a real biological foundation.

Altitude↗

PubMed1999

Congenital malformations in twins: an international study.

Data provided by nine registries based in European and Latin America countries were analyzed to assess whether there is an excess of malformations in twins compared to singletons. Specific congenital malformations were coded according to the ninth revision of the International Classification of Diseases (ICD). Malformation rates and rate ratios (RR) for twins compared to singletons were calculated for each registry, and the homogeneity of the RRs was tested using the test of Breslow and Day. If departure from homogeneity in the different registries was not significant, registry-adjusted RRs with 95% confidence intervals were calculated. Overall, among 260,865 twins, 5,572 malformations were reported. A total of 101 different types of malformations or groups of defects was identified, and a homogeneous estimate of the RRs among registries was found for 91.1% of the malformations. Thirty-nine of the 92 malformations with homogeneous estimates of RRs were more common in twins than in singletons. For the remaining nine malformations, heterogeneous estimates of RRs were obtained. This study confirms the majority of already known associations and further identifies previously unreported malformations associated with twins. In conclusion, there is an excess of malformations in twins compared with singletons, and all anatomical sites are involved. The number of specific malformations associated with twins is higher than that previously reported in smaller studies.

Congenital Abnormalities↗