Osvaldo Mutchinick

Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase ( MTHFR ): findings from over 7000 newborns from 16 areas world wide

Since its biochemical characterisation in 19911 and its genetic identification in 1995,2 677C>T allele (T allele) of the 5,10 methylenetetrahydrofolate reductase ( MTHFR ) gene has been a focus of increasing interest from researchers world wide. The expanding spectrum of common conditions linked with the 677C>T allele now includes certain adverse birth outcomes (including birth defects), pregnancy complications, cancers, adult cardiovascular diseases, and psychiatric disorders.3–8 Although several of these associations remain unconfirmed or controversial,4 their scope is such that it becomes of interest to explore the geographical and ethnic distribution of the allele and associated genotypes.9 Accurate information on such distribution can contribute to studies of gene-disease associations (by providing reference population data) and population genetics (by highlighting geographical and ethnic variations suggestive of evolutionary pressures),10 as well as help to evaluate health impact (by allowing estimates of population attributable fraction). Current population data, however, show gaps and even for some ethnic groups or large geographical areas (for example, China) few data are available.3 Our aim was to supplement the available data by collecting a large and diverse sample of newborns from different geographical areas and ethnic groups, and to examine international variations in the distribution of the 677C>T allele. We present findings relating to more than 7000 newborns from 16 areas around the world. The study was conducted under the auspices of the International Clearinghouse for Birth Defect Monitoring Systems (ICBDMS) and was coordinated through its head office, the International Center on Birth Defects (ICBD). ### Sample selection Participating programmes, in consultation with the coordinating group, identified a population sampling approach that would be simple yet minimise sampling bias with respect to the MTHFR genotype. We made an explicit attempt to sample systematically the newborn population. Details of each programme’s approach are listed below, and further …

The spectrum of congenital anomalies of the VATER association: An international study

The spectrum of the VATER association has been debated ever since its description more than two decades ago. To assess the spectrum of congenital anomalies associated with VATER while minimizing the distortions due to small samples and referral patterns typical of clinical series, we studied infants with VATER association reported to the combined registry of infants with multiple congenital anomalies from 17 birth defects registries worldwide that are part of the International Clearinghouse for Birth Defects Monitoring Systems (ICB-DMS). Among approximately 10 million infants born from 1983 through 1991, the ICB-DMS registered 2,295 infants with 3 or more of 25 unrelated major congenital anomalies of unknown cause. Of these infants, 286 had the VATER association, defined as at least three of the five VATER anomalies (vertebral defects, anal atresia, esophageal atresia, renal defects, and radial-ray limb deficiency), when we expected 219 (P<0.001). Of these 286 infants, 51 had at least four VATER anomalies, and 8 had all five anomalies. We found that preaxial but not other limb anomalies were significantly associated with any combination of the four nonlimb VATER anomalies (P<0.001). Of the 286 infants with VATER association, 214 (74.8%) had additional defects. Genital defects, cardiovascular anomalies, and small intestinal atresias were positively associated with VATER association (P<0.001). Infants with VATER association that included both renal anomalies and anorectal atresia were significantly more likely to have genital defects. Finally, a subset of infants with VATER association also had defects described in other associations, including diaphragmatic defects, oral clefts, bladder exstrophy, omphalocele, and neural tube defects. These results offer evidence for the specificity of the VATER association, suggest the existence of distinct subsets within the association, and raise the question of a common pathway for patterns of VATER and other types of defects in at least a subset of infants with multiple congenital anomalies.

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.

Gastroschisis and associated defects: An international study†

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non‐isolated cases. Case‐by‐case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non‐isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio‐vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb‐body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non‐syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non‐isolated cases and a thorough case‐by‐case review.

International trends of Down syndrome 1993-2004: Births in relation to maternal age and terminations of pregnancies

BACKGROUND The aim of this study was to examine trends of Down syndrome (DS) in relation to maternal age and termination of pregnancies (ToP) in 20 registries of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). METHODS Trends of births with DS (live-born and stillborn), ToP with DS, and maternal age (percentage of mothers older than 35 years) were examined by year over a 12-year period (1993-2004). The total mean number of births covered was 1550,000 annually. RESULTS The mean percentage of mothers older than 35 years of age increased from 10.9% in 1993 to 18.8% in 2004. However, a variation among the different registers from 4-8% to 20-25% of mothers >35 years of age was found. The total mean prevalence of DS (still births, live births, and ToP) increased from 13.1 to 18.2/10,000 births between 1993 and 2004. The total mean prevalence of DS births remained stable at 8.3/10,000 births, balanced by a great increase of ToP. In the registers from France, Italy, and the Czech Republic, a decrease of DS births and a great increase of ToP was observed. The number of DS births remained high or even increased in Canada Alberta, and Norway during the study period. CONCLUSIONS Although an increase in older mothers was observed in most registers, the prevalence of DS births remained stable in most registers as a result of increasing use of prenatal diagnostic procedures and ToP with DS.

The cyclops and the mermaid: an epidemiological study of two types of rare malformation.

Infants with cyclopia or sirenomelia are born at an approximate rate of 1 in 100,000 births. Eight malformation monitoring systems around the world jointly studied the epidemiology of these rare malformations: 102 infants with cyclopia, 96 with sirenomelia, and one with both conditions were identified among nearly 10.1 million births. Maternal age is somewhat increased for cyclopia, indicating the likely inclusion of some chromosomally abnormal infants which were not identified. About half of the infants are stillborn. There is a female excess among infants with cyclopia. Excess twinning occurred for cyclopia and possibly also for sirenomelia. An analysis of associated malformations indicates the similarity between the two conditions, which is in agreement with recent embryological analysis.

International Trends of Down Syndrome 1993-2004: Births in Relation to Maternal Age and Terminations of Pregnancies

BACKGROUND The aim of this study was to examine trends of Down syndrome (DS) in relation to maternal age and termination of pregnancies (ToP) in 20 registries of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). METHODS Trends of births with DS (live-born and stillborn), ToP with DS, and maternal age (percentage of mothers older than 35 years) were examined by year over a 12-year period (1993-2004). The total mean number of births covered was 1550,000 annually. RESULTS The mean percentage of mothers older than 35 years of age increased from 10.9% in 1993 to 18.8% in 2004. However, a variation among the different registers from 4-8% to 20-25% of mothers >35 years of age was found. The total mean prevalence of DS (still births, live births, and ToP) increased from 13.1 to 18.2/10,000 births between 1993 and 2004. The total mean prevalence of DS births remained stable at 8.3/10,000 births, balanced by a great increase of ToP. In the registers from France, Italy, and the Czech Republic, a decrease of DS births and a great increase of ToP was observed. The number of DS births remained high or even increased in Canada Alberta, and Norway during the study period. CONCLUSIONS Although an increase in older mothers was observed in most registers, the prevalence of DS births remained stable in most registers as a result of increasing use of prenatal diagnostic procedures and ToP with DS.

Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: Searching for population variations

BACKGROUND Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median maxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate. METHODS We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This study is based on more than 7 million births in various areas from North and South America, Europe, and Australia. RESULTS A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations. CONCLUSIONS The data do not suggest large differences in total prevalence of HPE among the studied populations that would be useful to generate etiological hypotheses.

Mutations of the 5α-reductase Type 2 gene in eight Mexican patients from six different pedigrees with 5α-reductase-2 deficiency

BACKGROUND AND OBJECTIVE Male pseudohermaphroditism due to 5α‐reductase deficiency was originally described in 1974. Recently, 5α‐reductase Type 2 gene defects have been found generally to be due to point mutations within the 5 exons of the 5α‐reductase‐2 gene. In this report, we describe the molecular study of patients with 5α‐reductase deficiency.

Conjoined twins: A worldwide collaborative epidemiological study of the International Clearinghouse for Birth Defects Surveillance and Research†‡

Conjoined twins (CT) are a very rare developmental accident of uncertain etiology. Prevalence has been previously estimated to be 1 in 50,000 to 1 in 100,000 births. The process by which monozygotic twins do not fully separate but form CT is not well understood. The purpose of the present study was to analyze diverse epidemiological aspects of CT, including the different variables listed in the Introduction Section of this issue of the Journal. The study was made possible using the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) structure. This multicenter worldwide research includes the largest sample of CT ever studied. A total of 383 carefully reviewed sets of CT obtained from 26,138,837 births reported by 21 Clearinghouse Surveillance Programs (SP) were included in the analysis. Total prevalence was 1.47 per 100,000 births (95% CI: 1.32–1.62). Salient findings including an evident variation in prevalence among SPs: a marked variation in the type of pregnancy outcome, a similarity in the proportion of CT types among programs: a significant female predominance in CT: particularly of the thoracopagus type and a significant male predominance in parapagus and parasitic types: significant differences in prevalence by ethnicity and an apparent increasing prevalence trend in South American countries. No genetic, environmental or demographic significant associated factors were identified. Further work in epidemiology and molecular research is necessary to understand the etiology and pathogenesis involved in the development of this fascinating phenomenon of nature.