Cribado bioquímico-ecográfico de las aneuploidías en el primer trimestre. Metodología y resultados / First-trimester biochemical-ultrasound aneuploidy screening. Methodology and results

Objetivo: Valorar la eficacia del cribado bioquímico-ecográfico de las aneuploidías en el primer trimestre de la gestación así como describir detalladamente la metodología utilizada. Sujetos y métodos: Estudio prospectivo en 3.492 gestantes, portadoras de un feto único, en las que se realiza el cribado bioquímico mediante la fracción beta libre de la gonadotropina coriónica humana y la proteína plasmática A asociada al embarazo, entre las 8 y las 13 semanas de gestación, y el cribado ecográfico, entre las 11 y las 13 semanas, con la medición de la longitud cefalocaudal y del grosor de la translucencia nucal. Se exponen los procedimientos epidemiológico-matemáticos utilizados para estimar el riesgo de que una gestante sea portadora de un feto afectado de aneuploidía. Resultados: El cribado bioquímico ecográfico del primer trimestre ha permitido detectar, en esta serie, el 83 por ciento (10 de 12) de las trisomías 21, el 86 por ciento (18 de 21) de las trisomías autosómicas y el 82 por ciento (23 de 28) de todas las aneuploidías, para una tasa de falsos positivos del 5,4 por ciento. Conclusiones: Este tipo de cribado presenta una alta efectividad pero precisa una metodología adecuada para la obtención de resultados óptimos (AU)

Interrupción voluntaria del embarazo por anomalías congénitas en Mallorca en la década de los noventa / Induced abortion due to birth anomalies in Majorca in the 1990s

Objetivos: Calcular la proporción de interrupciones voluntarias del embarazo para ciertas anomalías congénitas con el fin de valorar el acceso al diagnóstico prenatal en Mallorca, y comparar con datos análogos correspondientes a registros españoles de base poblacional. Material y métodos: Se obtuvo información sobre nacidos de madres residentes en Mallorca desde las 20 semanas de gestación y sobre interrupciones voluntarias de embarazo con historia clínica abierta en nuestros hospitales públicos. Resultados: Con relación a los registros poblacionales de malformaciones durante el período 1990-1996, nuestra proporción de interrupciones voluntarias del embarazo es significativamente menor que la de Asturias para defectos del tubo neural y que la del País Vasco para gastrosquisis, y mayor que en Asturias para las cromosomopatías y la trisomía 21. Si comparamos los quinquenios 1990-1994 y 1995-1999 en Mallorca, las proporciones aumentan para las anomalías del tubo neural, las cromosomopatías totales y la trisomía 21.Conclusiones: El incremento evolutivo de interrupciones gestacionales por defectos del tubo neural y aneuploidías podría deberse al cribado bioquímico. El mayor acceso al diagnóstico prenatal no se corresponde con un aumento de interrupciones por gastrosquisis y uropatías obstructivas. Es preceptivo mejorar el diagnóstico prenatal de las cardiopatías (AU)

Prevalencia total de una seriede anomalías congénitas enla isla de Mallorca durante ladécada de los noventa / Total prevalence of a series of birth defects in Majorca (Spain) in the ninetils

Objetivos: Cálculo de tasas de prevalencia total para ciertas anomalías congénitas en Mallorca durante la última década. Material y método: Recopilación de información sobre nacidos desde las 20 semanas de gestación e interrupciones voluntarias de embarazo con historia clínica abierta en nuestros hospitales públicos. Nos valemos de la centralización asistencial existente en nuestra comunidad autónoma para obtener cifras de ámbito poblacional. Resultados: Respecto a los registros poblacionales españoles de malformaciones durante 1990-1996, nuestra prevalencia total (por 10.000) para los defectos del tubo neural es superior a la de Barcelona (12,9 frente a 7,1; p = 0,003), y para la gastrosquisis es más alta que en el País Vasco (2,7 frente a 0,7; p = 0,002), Asturias (0,8; p = 0,028) y Barcelona (0,6; p = 0,007). Por el contrario, para la agenesia renal bilateral es inferior a la del País Vasco (0,7 frente a 2,2; p = 0,035), y para las cromosomopatías es más baja que en el País Vasco (23,7 frente a 31,9; p = 0,006) y el Vallès (33,7; p = 0,012). Si comparamos los quinquenios 1990-1994 y 1995-1999 en Mallorca, aumentan significativamente las prevalencias totales de las cardiopatías septales (30,4 frente a 42,3; p = 0,01), las hidronefrosis (13,1 frente a 19,3; p = 0,048) y las cromosomopatías (19,8 frente a 34,0; p < 0,001).Conclusiones: Las diferencias con los registros poblacionales considerados pueden ser reales u obedecer a discrepancias metodológicas. El aumento evolutivo de la prevalencia total de defectos septales, hidronefrosis y cromosomopatías refleja principalmente una mayor disponibilidad del diagnóstico prenatal (AU)

Factors that contribute to biomarker responses in humans including a study in individuals taking Vitamin C supplementation.

It is possible in many situations to identify humans exposed to potentially toxic materials in the workplace and in the environment. As in most human studies, there tends to be a high degree of interindividual variability in response to chemical insults. Some non-exposed control individuals exhibit as high a level of damage as some exposed individuals and some of these have levels of damage as low as many of the controls. Thus, it is only the mean values of the groups that can substantiate an exposure-related problem; the data on an individual basis are still of limited use. While human lymphocytes remain the most popular cell type for monitoring purposes, sperm, buccal, nasal, epithelial and placental cells are also used. However, for interpretation of responses, the issue of confounding factors must be addressed. There are endogenous confounding factors, such as age, gender, and genetic make-up and exogenous ones, including lifestyle habits (smoking, drinking, etc.) There are biomarkers of exposure, effect/response and susceptibility and the last may be influenced by the genotype and polymorphism genes existing in a population. From our own studies, confounding effects on cytogenetic damage and ras oncoproteins will be considered in relation to workers exposed to vinyl chloride and petroleum emissions and to volunteers taking Vitamin C supplementation. Smoking history, exposure and duration of employment affected the worker studies. For petroleum emissions, so did gender and season of exposure. For the non-smoking volunteer Vitamin C supplementation study, cholesterol levels, plasma Vitamin C levels, lipid peroxidation products and DNA damage in the Comet assay were also measured. Gender affected differences in Vitamin C levels, antioxidant capacity and the number of chromosome aberrations induced by bleomycin challenge in vitro. The results were the same for both high and low cholesterol subjects. The relationship between biomarkers and the various factors which affect them is complex. Sometimes the variables are not completely independent of each other.

Validation of biomarkers as early predictors of disease.

The development and validation of biomarkers that link environmental exposures to the pathogenesis of human disease is a leading priority in the field of environmental research. The validation of biomarkers as early predictors of clinical disease can enhance health risk assessment and contribute to effective new disease prevention policies in environmental and occupational settings. The process of validating biomarkers involves dealing with a range of characteristics that include the intrinsic qualities of the biomarker, its determinants, and the analytic procedure. We discuss here a three phase approach to validation. The final phase, consisting of longitudinal studies, is reached after the biomarker has been determined to be technically reliable and after the effect of external variables on the association with the outcome has been evaluated. We provide some examples of biomarkers reputed to be early predictors of cancer and cardiovascular disease (CVD). We then present original data to support the potential of DNA adducts to predict cancer and show, through re-evaluation of the Italian database on cytogenetic biomarkers, a lack of association between the frequency of chromosomal aberrations in circulating lymphocytes and CVD mortality rates -- a finding that should not be considered conclusive. In general, whenever a biomarker has been determined to be a valid predictor of disease, it should be used in risk assessment and public health policy.

Chromosomal imbalances in gastric and esophageal adenocarcinoma: specific comparative genomic hybridization-detected abnormalities segregate with junctional adenocarcinomas.

The incidence of adenocarcinoma arising at the esophagogastric junction (EGJ) is increasing at a rate greater than that for any other form of solid malignancy. Commensurate with this, the incidence of histologically similar tumors arising in the gastric body and antral mucosa is declining. The increased incidence of the proximal group of tumors may reflect, in part, the higher prevalence of Barrett esophagus. These epidemiological features suggest that histologically similar tumors arising at the EGJ and from the distal stomach are different, which may be reflected in the genetic abnormalities that characterize the two groups of tumors. The purpose of this study was to screen genomic DNA from adenocarcinomas of the esophagus and stomach for regions of chromosomal imbalance, using comparative genomic hybridization to determine whether tumors at the EGJ (junctional tumors) have a different profile compared with tumors of the distal stomach. Tumor samples were derived from a series of 48 gastroesophageal adenocarcinomas (20 junctional and 28 distal) that were acquired prospectively from patients undergoing esophagogastrectomy. These tumors are characterized by several regions of chromosomal imbalance with no obvious correlation between most regions of abnormal copy number and tumor type. However, our study shows for the first time cytogenetic abnormalities (5p+ and 18q-) that identify statistically significant differences (P < 0.02 and < 0.05, respectively) between junctional and distal gastric tumors. These differences are gain of 5p (55% [11/20] of junctional tumors vs. 21% [6/28] of distal gastric tumors) and loss of 18q (25% [5/20] cases of junctional tumors vs. 4% [1/28] of distal tumors) segregating with tumors of the EGJ. These abnormalities may distinguish distinct tumor subtypes that are recognized in epidemiological and clinical studies but that are otherwise histologically identical.

Preimplantation genetic diagnosis: applications for molecular medicine.

Preimplantation genetic diagnosis is an alternative to prenatal diagnosis for the detection of genetic disorders. Tests are conducted on single cells biopsied from embryos before they are implanted, allowing the selection of unaffected embryos before a pregnancy has been established. Thus, the issue of pregnancy termination is circumvented. The use of preimplantation genetic diagnosis might have a significant impact on in vitro fertilization success rates as well as allowing the diagnosis of inherited disease.

Fetal transcerebellar diameter and chromosomal abnormalities.

OBJECTIVE: To evaluate the association between chromosomal abnormalities and fetal cerebellar size. DESIGN: A retrospective cross-sectional study. METHODS: Ultrasound measurements of transcerebellar diameter, head and upper-abdominal circumference from 88 fetuses with chromosomal abnormalities were analyzed. Abnormalities included trisomy 21 ( n = 23), trisomy 18 ( n = 17), 'other numerical chromosomal abnormalities' ( n = 9), sex chromosomal abnormalities ( n = 9), mosaicism ( n = 12), balanced translocations ( n = 9) and unbalanced translocations ( n = 9). Multiple regression analysis was performed to compare transcerebellar diameters between the reference group and each of the subsets of chromosomal abnormalities and between trisomies 18 and 21. Also, in the latter two subsets, comparison of the transcerebellar diameter before and after 25 weeks of gestation was carried out. RESULTS: Fetal transcerebellar diameter was reduced in relation to gestational age but was normal when control was made for fetal size in all chromosomal subsets, except for balanced translocations. The transcerebellar diameter in trisomy 18 was significantly smaller than that in trisomy 21. No difference in cerebellar size was found when comparing the gestational age period before and after 25 weeks in each of these two subsets. CONCLUSIONS: A reduction in fetal transcerebellar diameter was demonstrated in all chromosomal abnormalities with imbalance of genetic material. Cerebellar hypoplasia was more severe in trisomy 18 than in trisomy 21. The degree of reduction in fetal transcerebellar diameter in these subsets seems to be independent of the time period during which the transcerebellar diameter measurement was performed.

Sonographic findings of the umbilical cord: implications for the risk of fetal chromosomal anomalies.

In this review we summarize current knowledge on sonographic findings of the umbilical cord and the risk they impose for chromosomal abnormalities of the fetus. A Medline search of the literature was performed and the pertinent English-language literature was reviewed. Anatomical and Doppler abnormalities of the umbilical cord may be associated with an increased risk of chromosomal aberrations in the fetus. Therefore, level II prenatal sonography should also include a careful examination of the umbilical cord.

Chromosomal abnormalities and polymorphisms in infertile men.

The aim of this study was to determine the prevalence of alterations and normal variable chromosome features in males from infertile couples. Karyotyping was performed to 84 men attending the infertility clinic at the Hospital Clinic i Provincial of Barcelona (Spain). Sex chromosome abnormalities were detected in 19 patients (26.62%): 14 (16.67%) aneuploidies 47,XXY and 47,XYY, 3 (3.57%) Y-chromosome long arm deletions; 1 (1.19%) mosaic 45,x/46,XY and 1 (1.19%) Robertsonian translocation (45.X-15-Y+t(15p: Yq). Chromosomal polymorphisms were observed in 29 patients. Yqh+ was the most frequent variant in sex chromosomes and increased length in heterochromatin and satellites were present in autosomal chromosomes. The high prevalence of chromosomal abnormalities observed in infertile men justify the use of karyotyping to evaluate males enrolled in new assisted reproductive technologies programs.

One hundred three consecutive patients with anorectal malformations and their associated anomalies.

OBJECTIVE: A long-term retrospective analysis of 103 infants with anorectal malformations (ARMs) was conducted to describe any associated congenital anomalies and surgical classifications. DESIGN: Retrospective medical record review. SETTING: This case series was conducted on all infants with ARMs born at, or referred to, any of 3 major medical centers in Wichita, Kan, for close to a 22-year period. PATIENTS: The 103 infants in this study represent a consecutive sample of patients with ARMs. Patients were separated into 2 groups: isolated ARMs without associated anomalies (n = 30), and ARMs with associated anomalies (n = 73). The male-female ratio was 2:1. MAIN OUTCOME MEASURES: Patients with associated anomalies were further classified into groups of ARMs with minor anomalies; major anomalies; chromosomal abnormalities; and malformation syndromes, associations, or sequences. Only anomalies that occurred more than once were reported. Malformations were also classified according to major organ systems. RESULTS: The incidence of ARMs in our study was approximately 1 in 2500 live births. Additional anomalies were found in 71% of infants with ARMs. Associated anomalies by major organ system included genitourinary anomalies (49%), musculoskeletal anomalies (43%), craniofacial anomalies (34%), cardiovascular anomalies (27%), gastrointestinal anomalies (18%), respiratory anomalies (13%), and central nervous system anomalies (12%). The most common chromosomal abnormalities were trisomies (8%), and ARMs were associated with VATER complex (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal anomalies) in 11 cases (11%) and VACTERL (vertebral, anal, cardiac, tracheal, esophageal, renal, and limb anomalies) in 4 cases (4%). CONCLUSIONS: Patients with ARMs have a high incidence of associated congenital anomalies. Evaluation of the most commonly affected organ systems in these infants is essential because it is these associated anomalies that account for most of the morbidity and mortality that is associated with this condition.

Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England.

OBJECTIVE: This study was undertaken to provide epidemiologic data on the prevalence of holoprosencephaly and to assess the sensitivity of routine ultrasonographic screening in a low-risk population. STUDY DESIGN: A population-based register of congenital abnormalities was used to identify reported cases of holoprosencephaly between 1985 and 1998. Sources included fetal losses, termination for fetal anomaly, stillbirths, and live births. Prenatal diagnoses and pregnancy outcomes were determined. RESULTS: Sixty-eight cases of holoprosencephaly were found among 531,686 births. The total prevalence (including pregnancy terminations) was 1.2 cases/10,000 registered births, and the birth prevalence (affected live births and stillbirths at >24 weeks' gestation) was 0.49 cases/10,000 births. Prenatal diagnosis was achieved in 71% of cases, rising to 86% during the second half of the study period; the mean gestational age at diagnosis was 19.8 weeks' gestation. Chromosomal abnormalities (75% of which were trisomy 13) were present in 38% of cases in which a karyotype was established. All those with aneuploidy (80% diagnosed prenatally) had other nonfacial anomalies; additional anomalies were also common in the euploid group (61% diagnosed prenatally), with 90% having facial abnormalities and 70% having other abnormalities. CONCLUSION: The prevalence of holoprosencephaly in second-trimester pregnancies was about 1 in 8000. Prenatal detection reached 86% with a routine anomaly scanning program. The etiology could usually be determined, which has important implications for recurrence risks.

Cytogenetics study in severely mentally retarded patients.

OBJECTIVE: To study the frequency of chromosomal abnormalities in severely mentally retarded Iraqi patients. Secondly, to determine the types of chromosomal abnormalities that play a major role in the causation of mental retardation and to compare our results with those reported elsewhere. METHODS: Twenty one patients with severe mental retardation were subject to chromosomal analysis. The lymphocyte culture was carried out according to standard methods. RESULTS: Fourteen of the subjected mentally retarded patients had chromosomal abnormalities, 13 autosomal abnormalities, and only one had sex chromosomal abnormalities. However, structural autosomes were found to be the most prominent abnormalities and only 2 patients were demonstrated to have diagnosable syndrome. CONCLUSION: Chromosomal abnormalities are an important cause of mental retardation and its frequency increased with the severity of mental retardation. We concluded that chromosomal studies in mentally retarded patients help in accurate diagnosis and proper prognosis followed by genetic counseling and management rehabilitation.

Prevalence of tetraploid metaphases in semidirect and cultured chorionic villi.

OBJECTIVE: Investigation of the normal frequency of tetraploid metaphases in semidirect (STC) and cultured (LTC) chorionic villi. METHODS: Fifty metaphases in STC- and in LTC-villi slides of 100 women of advanced maternal age were screened for tetraploidy. RESULTS: Up to three tetraploid metaphases were encountered in 27% of the STC-villi preparations; the scores fitted a Poisson distribution. In all LTC-villi preparations tetraploid cells were seen; the scores fitted a log-Gaussian distribution. CONCLUSIONS: On the basis of these distributions, we propose a protocol for the management of tetraploid metaphases in chorionic villi, strongly reducing the number of prenatal follow-up investigations.

[Pregnancy outcome and infant follow-up after diagnosis of nuchal anomalies at the 1st or 2nd trimester ultrasound examination]. / Etude de l'issue des grossesses et du devenir des enfants nés après un diagnostic de pathologie de la nuque à l'échographie du 1er ou 2e trimestre.

OBJECTIVES: The aim of this study was to determine pregnancy outcome and investigate infant follow-up after diagnosis of nuchal anomalies at the first or second trimester ultrasound examination in order to identify prognosis factors and improve prenatal counseling. PATIENTS AND METHODS: Between January 1994 and June 2000, double skin fold 3mm or cystic hygroma at the first trimester ultrasound, or thicken nuchal anomaly at second trimester ultrasound explorations were diagnosed at the Robert Debré maternity ward. RESULTS: One hundred fifty-nine pregnancies were terminated and 131 infants were delivered and followed with four pediatric examinations during the first two years of life. Among the 131 newborns, 104 (79%) progressed normally, 16 had a major malformation (heart, kidney, skeletal; 9 (6.8%) with a unique anomaly and 7 (5.3%) with malformation syndromes), and 14 (10.6%) presented nonspecific retardation of psychomotor development either alone (7 cases) or associated with an identified genetic syndrome (7 cases). DISCUSSION: Neonates who presented a nuchal anomaly during pregnancy are a high-risk population, particularly for retardation of psychomotor development which is not always diagnosed during the neonatal period. Careful postnatal follow-up is required to identify developmental disorders undiagnosed at birth. CONCLUSION: This series is the largest reported in the literature in terms of number of infants and also for postnatal pediatric follow-up and homogeneous pedratrician follow-up.

Displasia torácica asfixiante de Jeune. A propósito de un caso / Asphyxiating thoracic dysplasia

Presentamos un caso de Displasia torácica de Jeune en un lactante varón de 3 meses de edad con manifestaciones esqueléticas sugerentes de la enfermedad y moderado compromiso respiratorio apreciado desde el nacimiento. El diagnóstico fue inequívocamente confirmado por las radiografías de tórax y pelvis (AU)

Nuchal translucency: an ultrasound marker for fetal chromosomal abnormalities

CONTEXT: The literature shows an association between several ultrasound markers and chromosome abnormality. Among these, measurement of nuchal translucency has been indicated as a screening method for aneuploidy. The trisomy of chromosome 21 has been most evaluated. OBJECTIVE: To define the best fixed cutoff point for nuchal translucency, with the assistance of the ROC curve, and its accuracy in screening all fetal aneuploidy and trisomy 21 in a South American population. TYPE OF STUDY: Validation of a diagnostic test. SETTING: This study was carried out at the State University of Campinas, Campinas, Brazil. PARTICIPANTS: 230 patients examined by ultrasound at two tertiary-level private centers, at 10 to 14 weeks of gestation. DIAGNOSTIC TEST: The participants consisted of all those patients who had undergone ultrasound imaging at 10 to 14 weeks of gestation to measure nuchal translucency and who had had the fetal or neonatal karyotype identified. MAIN MEASUREMENTS: Maternal age, gestational age, nuchal translucency measurement, fetal or neonatal karyotype. RESULTS: Prevalence of chromosomal defects -- 10 percent; mean age -- 35.8 years; mean gestational age -- 12 weeks and 2 days; nuchal translucency (NT) thickness -- 2.18 mm. The best balance between sensitivity and specificity were values that were equal to or higher than 2.5 mm for overall chromosomal abnormalities as well as for the isolated trisomy 21. The sensitivity for overall chromosomal abnormalities and trisomy 21 were 69.5 percent and 75 percent, respectively, and the positive likelihood ratios were 5.5 and 5.0, respectively. CONCLUSION: The measurement of nuchal translucency was found to be fairly accurate as an ultrasound marker for fetal abnormalities and measurements equal to or higher than 2.5 mm were the best fixed cutoff points

[Cytogenetic disorders in workers of coal-tar chemical industry]. / Tsitogeneticheskie narusheniia u rabochikh koksokhimicheskogo proizvodstva.

The authors studied frequencies of chromosomal aberration (CA) and sister chromatid exchanges (SCE) in workers of coal-tar chemical plant (34 individuals). The studies revealed significant increase of CA frequency (7.97 +/- 0.63%), when compared with reference groups 3.37 +/- 0.39% and 3.64 +/- 0.37%.

Disease associated balanced chromosome rearrangements: a resource for large scale genotype-phenotype delineation in man.

Disease associated balanced chromosomal rearrangements (DBCRs), which truncate, delete, or otherwise inactivate specific genes, have been instrumental for positional cloning of many disease genes. A network of cytogenetic laboratories, Mendelian Cytogenetics Network (MCN), has been established to facilitate the identification and mapping of DBCRs. To get an estimate of the potential of this approach, we surveyed all cytogenetic archives in Denmark and southern Sweden, with a population of approximately 6.6 million. The nine laboratories have performed 71 739 postnatal cytogenetic tests. Excluding Robertsonian translocations and chromosome 9 inversions, we identified 216 DBCRs ( approximately 0.3%), including a minimum estimate of 114 de novo reciprocal translocations (0.16%) and eight de novo inversions (0.01%). Altogether, this is six times more frequent than in the general population, suggesting a causal relationship with the traits involved in most of these cases. Of the identified cases, only 25 (12%) have been published, including 12 cases with known syndromes and 13 cases with unspecified mental retardation/congenital malformations. The remaining DBCRs were associated with a plethora of traits including mental retardation, dysmorphic features, major congenital malformations, autism, and male and female infertility. Several of the unpublished DBCRs defined candidate breakpoints for nail-patella, Prader-Willi, and Schmidt syndromes, ataxia, and ulna aplasia. The implication of the survey is apparent when compared with MCN; altogether, the 292 participating laboratories have performed >2.5 million postnatal analyses, with an estimated approximately 7500 DBCRs stored in their archives, of which more than half might be causative mutations. In addition, an estimated 450-500 novel cases should be detected each year. Our data illustrate that DBCRs and MCN are resources for large scale establishment of phenotype-genotype relationships in man.