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Background: Diabetes mellitus affects 3 to 10% of pregnant women. The reported frequency of congenital malformations (CM) in diabetic mothers is 5.5 to 10%, contributing these defects to approximately 40% of the neonatal mortality in children of diabetic mothers (CDM)., Objective: To investigate the frequency and type of congenital malformations in a sample of livebirths of diabetic mothers from the Mexican population., Material and Methods: The analyzed information was obtained from the RYVEMCE (Registro y Vigilancia Epidemiológica de Malformaciones Congénitas). We analysed the type and frequency of the different CM diagnosed. These frequencies were compared with the whole amount of those CM included in the database of our registry (20,381). As part of the analysis, other maternal and neonatal variables were also compared between CDM and the control group., Results: A total of 314 CDM (0.77%), 234 malformed and 80 non malformed were identified. The frequencies of cleft palate (CP), limb reduction defect (LRD) and microcephaly (MIC) were significantly higher in CDM than in the rest of malformed newborns of not diabetic mothers of the RYVEMCE (OR: 9.9, 3.8 and 10.0, respectively). A higher frequency of macrosomia was observed in CDM (18.0%) than in controls (6.1%), OR: 3.4, p < 0.001, in the frequency of preterm birth (28.5% than controls 13.0%), OR: 3.02, p < 0.0001 and in caesarean delivery (71.5% than controls 44.4%) OR: 3.15, p < 0.00001., Conclusions: Our results confirm the higher frequency of CM in CDM and in particular a higher risk for CP, LRD and MIC. Pregnancy and delivery complications such as macrosomia and preterm and caesarean delivery were also more frequent in CDM that controls. Certain associations of CM not described previously, were observed in the studied sample. Our results confirm the need of pregnancy planning including a pre-gestational and gestational control of maternal glycaemia, particularly in a population with such a high prevalence of diabetes mellitus as the observed in the Mexican one.

Background: A 776C-->G variant (dbSNP ID: rs1801198) in the transcobalamin gene (TCN2; MIM# 275350) decreases the cellular and plasma concentration of transcobalamin and thereby influences the cellular availability of vitamin B(12)., Objective: To evaluate the worldwide prevalence of this variant and its association with homocysteine plasma level., Methods: The study was performed in 1433 apparently healthy subjects, including Afro-Americans and Afro-Africans and in 251 Afro-Africans participants with severe malaria., Results: The frequencies of the 776G allele were the highest in China (0.607; 95% CI 0.554 to 0.659), low in West Africa (Bénin and Togo, 0.178; 0.154 to 0.206), and intermediate in France (0.445; 0.408 to 0.481), Italy (0.352; 0.299 to 0.409), Morocco (0.370; 0.300 to 0.447) and Mexico (0.374; 0.392 to 0.419). The 776G genotype was more frequent in Afro-Americans from New York (16.7; 8.4 to 30.7) and in Afro-African patients with severe malaria (6.0%; 95% CI 3.7 to 9.6) than in healthy Afro-African volunteers (p = 0.0004 and p = 0.033, respectively), while no difference was observed for MTHFR 677TT and 677T alleles. A disequilibrium of TCN2 genotype distribution was recorded in patients with severe malaria, with a twofold higher GG genotype than expected (p = 0.010). An association between the TCN2 polymorphism and homocysteine was observed only in Mexico and France, the two countries with the highest rate of low plasma concentration of vitamin B(12) (<100 pmol/l)., Conclusion: Given the dramatic heterogeneity of the 776G allele frequency worldwide, this polymorphism may be prone to a selective pressure or confers an evolutionary advantage in confronting environmental factors, one of which is malaria.

Primary immunodeficiencies as well as autoimmune diseases have been associated to X chromosome abnormalities. Furthermore, the functional biology of the X chromosome is unique because genes located in this chromosome can undergo inactivation, and subsequently transcriptional silencing. Non-random X chromosome inactivation has been hypothesized to be involved in the development of autoimmunity. Recently X chromosome monosomy has also been proposed as a common etiologic mechanism for some autoimmune diseases. Herein, we review some of these findings above mentioned.

The study evaluated the sex distribution of major isolated malformations and common trisomies among a large and geographically varied sample. Eighteen registries from 24 countries contributed cases, which were centrally reviewed and classified in three clinical types as isolated, associated, or syndromic. We selected cases of 26 major defects (n = 108,534); trisomy 21, 18, and 13 (n = 30,114); other syndromes (n = 2,898); and multiple congenital anomalies (n = 24,197), for a total of 165,743 cases. We observed a significant deviation of sex distribution (compared to a sex ratio of 1.06 or male proportion of 51.4%) for 24 of the 29 groups (a male excess in 16, a female excess in 8), and in 8 of such groups these estimates varied significantly across registries. A male excess was noted for two left obstructive cardiac defects (hypoplastic left heart and coarctation of the aorta) and a female excess for all the main types of neural tube defects. A male excess was seen for omphalocele but not gastroschisis. For neural tube defects the female excess tended to be stronger in areas with historically high prevalence for these defects. For 15 of the 26 birth defects the sex distribution differed among isolated, associated, and syndromic cases. Some of these epidemiologic commonalities are consistent with known or putative developmental processes. Further, the geographic variation for some defects may reflect local prevalence rates and risk factors. Finally, the findings underscore the need for clinical classification (e.g., into isolated, multiple, syndromes) in studies of birth defects.

We report a Mexican boy with isolated ectrodactyly (split hand malformation) in whom a new mutation was identified in exon 3 of the TP63 gene. In contrast to previously reported patients with isolated split hand/foot anomaly and mutations in the DNA binding domain of Tp63, the mutation described herein induce an amino acid substitution (R97C) in the canonical transactivation (TA) domain. To our knowledge, this is the first naturally occurring mutation described so far in this part of the protein. Based on the genotype-phenotype correlation observed in our patient, we hypothesize that integrity of the TA domain of Tp63 is critical for normal limb development.

Objective: To report a rare case of gonadal agenesis with rudimentary paramesonephric ducts derivatives in a female with a 46,XX normal karyotype., Design: Case study., Setting: National Institute of Health., Patient(s): An 18-year-old female with primary amenorrhea and lack of secondary sexual development., Intervention(s): Clinical, gynecological, endocrine, and genetic evaluation. Laboratory studies conducted included measurement of pituitary, ovary, and thyroid hormones; analyses of G-banded chromosomes in peripheral blood and fibroblast cultures; search for genomic Y-chromosome DNA by fluorescence in situ hybridization and molecular biology techniques; X-ray, ultrasonography, echocardiographic and laparoscopic studies for the assessment of bone age, and genitourinary and other associated malformations., Main Outcome Measure(s): Clinical, hormonal, anatomical, and genetic characteristics of the patient., Result(s): The studies performed confirmed a prepubertal female with hypergonadotrophic hypogonadism, bilateral gonadal agenesis, a rudimentary uterus and fallopian tubes, a normal vagina, kidney, and urinary tract structures, and a 46,XX normal karyotype. The search for centromeric Y-chromosome DNA and SRY and ZFY genes was negative., Conclusion(s): A primary deficiency confined to the gonadal blastema and the nearby coelomic epithelium is proposed as an alternative embryologic mechanism to explain the occurrence of this singular sexual developmental defect.

It has been reported that Vitamin D receptor polymorphisms are associated with osteoporosis, particularly those demonstrated by the BsmI and FokI restriction enzymes. Herein we report the results of a case-control study performed in postmenopausal Mexican women. We studied 65 osteoporotic women (< or = -2.5 SD bone mineral density [BMD] of young normal females) and 57 controls (over 90% > or = -1.5 SD BMD of young normal females. Restriction enzymes BsmI and FokI were used to identify polymorphisms. Odds ratios and their 95% confidence intervals were calculated, and analysis was performed controlling for age as a covariate. The BsmI genotypes revealed a higher frequency of the bb genotype in cases than in controls, contradicting much of the literature that suggests this genotype protects females against osteoporosis. Regarding the FokI genotypes, we were unable to confirm that the FF genotype has a protective effect against osteoporosis. The inconsistencies found in the literature and the results obtained in the present work suggest to us that other genetic and nongenetic factors are involved in the occurrence of osteoporosis, confounding the results of the possible association of osteoporosis and VDR polymorphisms.

Deletions of 17p13.3, including the LIS1 gene, result in the brain malformation lissencephaly, which is characterized by reduced gyration and cortical thickening; however, the phenotype can vary from isolated lissencephaly sequence (ILS) to Miller-Dieker syndrome (MDS). At the clinical level, these two phenotypes can be differentiated by the presence of significant dysmorphic facial features and a more severe grade of lissencephaly in MDS. Previous work has suggested that children with MDS have a larger deletion than those with ILS, but the precise boundaries of the MDS critical region and causative genes other than LIS1 have never been fully determined. We have completed a physical and transcriptional map of the 17p13.3 region from LIS1 to the telomere. Using fluorescence in situ hybridization, we have mapped the deletion size in 19 children with ILS, 11 children with MDS, and 4 children with 17p13.3 deletions not involving LIS1. We show that the critical region that differentiates ILS from MDS at the molecular level can be reduced to 400 kb. Using somatic cell hybrids from selected patients, we have identified eight genes that are consistently deleted in patients classified as having MDS. In addition, deletion of the genes CRK and 14-3-3 epsilon delineates patients with the most severe lissencephaly grade. On the basis of recent functional data and the creation of a mouse model suggesting a role for 14-3-3 epsilon in cortical development, we suggest that deletion of one or both of these genes in combination with deletion of LIS1 may contribute to the more severe form of lissencephaly seen only in patients with MDS.

Hyperhomocysteinemia is considered one of the emerging risk factors for the development of coronary artery disease (CAD). In order to know the prevalence of this metabolic disorder in a Mexican population with early CAD (< 50 years), we studied a group of these patients and compared the levels of homocysteine with a group of patients, paired by age and gender, without angiographic evidence of coronary atherosclerosis. Preliminary results show that the population with early CAD has more traditional risk factors, specially diabetes mellitus, and higher levels of homocysteine in plasma. Moreover there is a genetic factor with higher incidence of a TT homozygotic mutation of the MTHFR that increases homocysteine because of an altered folate metabolism.

Mitochondria from a patient diagnosed with Kearns-Sayre syndrome (KSS) exhibited severely diminished cytochrome c oxidase activity and at least four mitochondrial DNA (mtDNA) species: 9%-11% of the fulllength mtDNA (16.6 kb), 70%-75% of a 11.7-kb population (harboring the 4,977-bp common deletion), 2%-3% of a 10.5-kb population, and 12%-17% of a 8.9-kb population. The 8.9-kb mtDNA exhibited a secondary deletion that extended 7,704 bp from nucleotide 7,979 in the cox2 gene to nucleotide 15,683 in the cytb gene. To our knowledge, this is the first description of the presence of at least two large-scale deletions of mtDNA in KSS.

Neural tube defects (NTD) are highly prevalent in the Mexican population. According to data from the Registry and Epidemiological Surveillance of External Congenital Malformations (RYVEMCE), at least 1 in 250 conceptions that reach 20 weeks of pregnancy or more has a NTD. This number is three to four times higher than that observed in other related ethnic groups. A common novel mutation (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene is considered an associated risk factor for NTD and other malformations. Studies in different populations agree that the prevalence of the homozygote for the mutated allele is higher in cases of NTD than in controls. In a meta-analysis recently published, the mean prevalence of the homozygote for the mutation was 9.2% for different groups of European controls and 16.4% in NTD cases from the same populations. This prompted us to investigate the frequency of the normal (C) and the mutant (T) alleles and the prevalence of the expected (CC, CT and TT) genotypes in 250 healthy Mexican women from different parts of the country. The proportion of CC (17.6%), CT (47.6%), and TT (34. 8%) genotypes found, and the gene frequencies of 0.414 and 0.586% for the C and T alleles, respectively, confirmed the very high prevalence of the mutant allele and the TT genotype in the sample studied. Comparisons with studies done in Holland, Ireland, the United States, Japan, and other ethnic groups showed highly significant differences, with an average OR of 5.8 (95% Cl 3.4-10.3) for a Mexican being homozygous for the mutation. These findings may explain an important part of the high prevalence of NTD observed in our population., (Copyright 1999 Academic Press.)

Trisomy 5p and Miller-Dieker syndromes frequently are the result of unbalanced segregations of reciprocal translocations of chromosomes 5 and 17 with other autosomes. The critical regions for the expression of the mentioned syndromes have been mapped to 5p13-->pter, and 17p13.3-->pter. In this report, we describe an 8-year-old girl with mental retardation, postnatal growth deficiency, generalized muscular hypotonia, seizures, microcephaly, cortical atrophy, partial agenesis of corpus callosum, cerebral ventriculomegaly, facial anomalies, patent ductus arteriosus, pectus excavatum, long fingers, and bilateral talipes equinovarus caused by the presence of a 46,XX,der(17)t(5;17)(p13.1;p13.3)mat chromosome complement. Cytogenetic studies of the family confirmed a balanced reciprocal translocation (5;17)(p13.1;p13.3) in her mother, maternal grandfather, maternal aunt, and a female first cousin. Fluorescence in situ hybridization studies on the mother and the proposita using three probes, which map to distal 17p, confirmed the reciprocal translocation in the mother and a terminal deletion in the patient, which resulted in the retention of LIS1 and D17S379 loci and deletion of the 17p telomere. These findings and the phenotype of the proposita, strongly suggest that genes telomeric to LIS1 and locus D17S379 are involved in many clinical findings, including the minor facial anomalies of the Miller-Dieker syndrome.

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.

Mothers of boys with hypospadias and control mothers were interviewed in eight malformation monitoring programs around the world. Hormone therapy was used quite frequently in five but rarely in three of the programs. The odds ratio for hypospadias after hormone therapy during pregnancy was 2.8 (95% confidence limits 1.2, 6.9) but there was no correlation between the timing of hormone therapy and the location of the urethral orifice, nor between the severity of the malformation and hormone therapy. Programs with the highest hormone exposure rate showed the lowest odds ratio for pregnancy bleeding, the most common reason for hormone therapy. These latter findings cast doubts on the causal association between hormone therapy and isolated hypospadias. Alternative explanations are recall or interviewer bias or unidentified confounders.