Congenital abnormalities and indicators of germinal mutations in the vicinity of an acrylonitrile producing factory.

The results of an environmental mutation and teratologic epidemiological study are presented which was performed in inhabitants living in the surrounding region of an acrylonitrile factory in Nyergesújfalu. The endpoint of the study was congenital abnormalities in 46,326 infants born to mothers living in the 30 settlements of the study region within a 25 km radius of the acrylonitrile factory between 1980 and 1996. The ascertainment of cases with congenital abnormalities was based on the dataset of the Hungarian Congenital Abnormality Registry complemented with the review of pediatric, pathology and cytogenetic records. A particular attention was paid to the indicators of germinal mutations as sentinel anomalies, Down syndrome and unidentified multiple congenital abnormalities and the indicators of teratogens as the specific pattern of multiple congenital abnormalities. Three congenital abnormalities: pectus excavatum in Tata, 1990-1992 (OR with 95%CI: 78.5, 8.4-729.6), undescended testis in Nyergesújfalu between 1980 and 1983 (8.6, 1.4-54.3) and in Esztergom, 1981-1982 (4. 2, 1.3-13.5) and clubfoot in Tata, 1980-1981 (5.5, 1.5-20.3) showed significant time-space clusters in the study region. There was a decrease in risk of undescended testis with increasing distance from the acrylonitrile factory. An unusual increase was found in the combination of oral cleft and cardiac septal defects in multimalformed babies in Tatabánya, 1990. The detailed analysis of congenital abnormalities in all settlements of a given territory may help to detect clusters of congenital abnormalities and their possible relation to the environmental hazards.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 10. A new approach to germinal mutation surveillance: pair-wise evaluation of component elements in unidentified multiple congenital abnormalities

In the Hungarian population-based surveillance of germinal mutations, 3 indicator conditions of offspring are being followed, namely 15 sentinel anomalies, Down syndrome and unidentified multiple congenital abnormality. The latter is discussed here as a possible indicator of germinal dominant gene and chromosomal mutations. The component congenital abnormalities of unidentified multiple congenital abnormalities are classified into 45 groups. The component congenital abnormalities were reduced to pairs. A pair is a set of 2 independent component congenital abnormalities in index patients with 2 or more congenital abnormalities. Baseline figures of all component congenital abnormality pairs in 3722 unidentified multiple congenital abnormalities were determined in the study period 1973-1982. The observed data for 1983 were compared with expected occurrences based on baseline figures. This pair-wise evaluation of component elements within unidentified multiple congenital abnormalities seems to be an adequate surveillance method to detect any time cluster of congenital abnormality pairs due to environmental factors including germinal mutagens.     

Description and mission evaluation of the Hungarian case-control surveillance of congenital abnormalities, 1980-1996

BACKGROUND: The Hungarian Case-Control Surveillance of Congenital Abnormalities was established in 1980. This article describes how the Hungarian Case-Control Surveillance of Congenital Abnormalities was first organized and is currently maintained. The baseline statistics are provided and potential venues of postmarketing surveillance of drug teratogenicity and other public health tasks and research are proposed. METHODS: Cases with congenital abnormalities and patient controls with Down syndrome were selected from the Hungarian Congenital Abnormality Registry. Population controls without congenital abnormalities were selected from the National Birth Registry on the basis of three matching criteria: sex, week of birth, and district of parent's residence. Three sources of information concerning drug exposures, maternal disorders, and pregnancy complications, among others, were used: (1) prospective and medically recorded data from antenatal care logbooks and discharge summaries; (2) retrospective maternal self-reported data obtained with a structured questionnaire in all the three study groups; and (3) data collected by regional nurse in house visits to nonrespondent cases and patient controls. Twenty-five congenital abnormality groups were evaluated. During the 17-year period of data collection, 22,843 cases, 38,151 population controls, and 834 patient controls were incorporated into the data set, constituting the largest population-based case-control data set of congenital abnormalities to date. RESULTS: Demographic features of pregnant women and informative offspring are presented along with the distribution of 25 main groups of congenital abnormalities. CONCLUSIONS: This system is appropriate for postmarketing the surveillance of drug teratogenicity, for the improvement of congenital abnormality diagnosis, to get informed consent, to have a communication with parents and to provide material for research.     

Smoking during pregnancy and congenital limb deficiency.

OBJECTIVE--To examine genetic and environmental factors in the origin of isolated congenital limb deficiencies. DESIGN--Case-control study with questionnaire at a family interview of cases of isolated congenital limb deficiencies (six types), negative controls (matched for age, sex, and place of residence), and positive controls (cases of sentinel anomalies). SETTING--The database of the Hungarian Congenital Abnormality Registry, 1975-84, complemented by three other sources of ascertainment (1,575,904 births). SUBJECTS--537 case-control pairs; 392 positive controls. MAIN OUTCOME MEASURES--Smoking during pregnancy, congenital limb deficiencies. RESULTS--The adjusted rate of smoking during pregnancy was significantly higher in the mothers of cases of terminal transverse defect (relative odds 1.48; 95% confidence interval 0.98 to 2.23; P = 0.017). This finding supports the hypothesis of vascular disruption as a cause of congenital limb deficiency. CONCLUSIONS--Maternal smoking during pregnancy raises the relative odds for terminal transverse limb deficiencies.     

A new approach to germinal mutation surveillance: pair-wise evaluation of component elements in unidentified multiple congenital abnormalities

In the Hungarian population-based surveillance of germinal mutations, 3 indicator conditions of offspring are being followed, namely 15 sentinel anomalies, Down syndrome and unidentified multiple congenital abnormality. The latter is discussed here as a possible indicator of germinal dominant gene and chromosomal mutations. The component congential abnormalities of unidentified multiple congenital abnormalities are classified into 45 groups. The component congenital abnormalities were reduced to pairs. A pair is a set of 2 independent component congenital abnormalities in index patients with 2 or more congenital abnormalities. Baseline figures of all component congenital abnormality pairs in 3722 unidentified multiple congenital abnormalities were determined in the study period 1973–1982. The observed data for 1983 were compared with expected occurrences based on baseline figures. This pair-wise evaluation of component elements within unidentified multiple congenital abnormalities seems to be an adequate surveillance method to detect any time cluster of congenital abnormality pairs due to environmental factors including germinal mutagens.     

Hungarian surveillance of germinal mutations

Summary The Hungarian surveillance of germinal mutations is based on three indicator conditions seen in offspring, i.e., 15 sentinel anomalies, Down syndrome and component anomaly pairs of unidentified multiple congenital anomalies. It is an opportunistic program, because the necessary data are available from the Hungarian Congenital Malformation Registry. This system is described and the criteria of a good registry are summarized. The analysis of indicator conditions caused by germinal mutations did not reveal any measurable mutagenic effects in Hungary following the accident at the Chernobyl nuclear power plant. The pros and cons of germinal mutation surveillance are discussed.     

Hirschsprung disease in a large birth cohort

The incidence of Hirschsprung disease was studied in a series of almost 700,000 consecutive livebirths in British Columbia from 1964-1982, by means of the records of a health surveillance registry that uses multiple sources of ascertainment. The estimated liveborn incidence rate for Hirschsprung disease was 1 in 4,417 livebirths (156 cases out of 689,118 livebirths). Data pertaining to sex ratio, additional anomalies, recurrence, and mortality were also analyzed over the caseload period 1952 to 1983. A total of 29.8% of cases had some additional anomaly--the majority being nonregional anomalies in other systems or more distantly in the gastrointestinal tract. Cardiovascular and gastrointestinal anomalies not a direct consequence of Hirschsprung disease were the most frequent additional anomalies found, occurring in 10 and 12 of 178 cases, respectively. Sensorineural anomalies were also frequent, occurring in 12 of 178 cases. Clinical implications arising from the study regarding the neonatal assessment of infants with these anomalies are discussed.     

Neural crest anomaly syndromes in children with spina bifida.

A hereditary contribution to the etiology of neural tube defects (NTDs) has been suggested by clinical studies and animal models. To evaluate the hypothesis that common genes are important for both neural tube defects and neural crest anomalies, we examined children with developmental abnormalities of the spinal cord for anomalies of neural crest-derived structures. Neural crest anomalies, particularly auditory and pigmentary disorders, were identified and classified according to inheritance and type of anomaly. Of the 515 children screened, 44 (8.5%) had neural crest anomalies, 20 (3.9%) of which were apparently familial. Another 19 (3.7%) families had neural crest anomalies in two or more close relations, but the NTD subject was unaffected. Sixteen (3.1%) children with NTDs had a recognizable syndrome, including nine (1.7%) with a subtype of the Waardenburg syndromes. The coincidence of familial neural crest anomaly syndromes in subjects with spina bifida implies that defects in genes underlying neural crest development may contribute to the etiology of neural tube defects in a fraction of cases. The rate of anomalies and familial syndromes of neural crest-derived structures must be assessed in an adequate control sample to evaluate whether or not these abnormalities constitute risk factors for NTDs.     

Thrombophilia gene mutations in oculoauriculovertebral spectrum

Oculoauriculovertebral spectrum or Goldenhar syndrome is a phenotypically and probably genetically heterogeneous disorder characterized by hemifacial microsomia (unilateral ear abnormalities and ipsilateral mandibular hypoplasia) as well as vertebral anomalies and epibulbar dermoid/lipodermoids. Although most cases of the Goldenhar syndrome are sporadic, both autosomal recessive and dominant inheritance have been reported so far. In this report, we describe the clinical aspects of two familial cases with evidence of autosomal dominant inheritance and a non-familial case, and compare them with the reports in the literature. One of our familial cases was a ten day old female infant of a mother with left hemifacial microsomia. She had multiple bilateral preauricular tags and a "fleshy masse" on her right cheek. The other familial case was a two months old male infant whose father had hemifacial asymmetry. He had unilateral microtia, and abnormal antihelix, a skin tag in the contralateral ear associated with bilateral sensorineural hearing loss. The third case was a sporadic case who was 2 years old boy with preauricular skin tag, right hemifacial microsomia and limbal dermoid at the temporal limbus of the right eye. As there were no other associated defects, the cases we presented here were thought to be mild variations of the Goldenhar spectrum. The most commonly encountered mutations of thrombophilia genes were studied. We believe that the interfamilial and intrafamilial clinical variabilities observed in these cases reinforce the necessity of a careful examination for the whole family with regards to the stigmata of Goldenhar syndrome.     

Patterns of combined limb malformations.

Seven different limb malformations types were defined in 544 affected newborns, apparently free from other anomalies, obtained from a series of 297,299 livebirths. These seven malformation types were: polydactyly, limb reduction, brachydactyly, symphalangy, syndactyly and split hand/foot. One anomaly type was present in 472 newborns (1.58/1,000) and two or three in 72 (0.24/1,000). The observed combinations of two or three limb malformation types cannot be explained as chance association. Therefore, a common etiopathogenic mechanism has to be considered when two or more limb malformation types are combined in a given individual. The most frequent observed combinations were: reduction-brachydactyly, reduction-syndactyly, brachydactyly-syndactyly, polydactyly-syndactyly, and reduction-brachydactyly-syndactyly. Based on affected limb distribution, sex ratio, and familial recurrence rates, it is suggest that a reduction anomaly is the primary component in all tested combinations while syndactyly tends to be a secondary one when combined with any other limb anomaly type.     

The gene for cherubism maps to chromosome 4p16.3.

Cherubism is a rare familial disease of childhood characterized by proliferative lesions within the mandible and maxilla that lead to prominence of the lower face and an appearance reminiscent of the cherubs portrayed in Renaissance art. Resolution of these bony abnormalities is often observed after puberty. Many cases are inherited in an autosomal dominant fashion, although several cases without a family history have been reported. Using two families with clinically, radiologically, and/or histologically proved cherubism, we have performed a genomewide linkage search and have localized the gene to chromosome 4p16.3, with a maximum multipoint LOD score of 5. 64. Both families showed evidence of linkage to this locus. Critical meiotic recombinants place the gene in a 3-cM interval between D4S127 and 4p-telomere. Within this region a strong candidate is the gene for fibroblast growth factor receptor 3 (FGFR3); mutations in this gene have been implicated in a diverse set of disorders of bone development.     

MPA given orally during the first trimester for threatened miscarriage carries no specific risk for foetal abnormalities albeit the rate is higher than non-threatened pregnancies

This observational study examines the outcomes of pregnancies arising in women referred for infertility, where those who experienced threatened miscarriage were treated with medroxyprogesterone acetate (MPA) tablets. The 14-year study period covers comprehensive real-time data entries into the validated electronic database including details of the infertility management, pregnancy outcomes and any foetal anomalies among the infants, each being tracked and recorded. Of 4057 clinical pregnancies, 1343 received MPA for threatened miscarriage; 934 (69.6 %) of which continued to livebirths. These were compared with the remaining 2714 clinical pregnancies without threatened miscarriage or MPA and which resulted in 2075 (76.5 %) livebirths. There were 134 developmental abnormalities recorded among the 3009 livebirths of which 78 (2.6 %) were categorised appropriate for the Western Australian Developmental Abnormalities Register; WARDA. These comprised 55 in the MPA group, 36 of which were categorised as serious (being 2.7 % of clinical pregnancies and 3.9 % of births). In the group without MPA, there were 79 abnormalities, of which 42 were categorised as serious (being 1.7 % of clinical pregnancies and 2.2 % of births). Specifically, there were no cases of androgenisation noted among the female infants. The abnormality rates were low overall and well within the annual WARDA ranges. We cautiously suggest that oral MPA can be considered for studies throughout pregnancy including the early first trimester to assess a potential role in reducing miscarriage, as well as advanced pregnancies to evaluate a potential role in reducing stillbirths and preterm delivery.     

Incidence and survival of childhood cancer in the French islands of Reunion and Mayotte (2005–2011)

The aim of this study is to describe childhood cancer incidence and survival in the French islands of Reunion and Mayotte for the period 2005–2011. Data were taken from the population-based Cancer Registry of Reunion Island. All incident cases of malignant tumours and benign tumours of the Central Nervous System diagnosed between 2005 and 2011 in children under the age of 15 and living in Reunion or Mayotte were included. A total of 236 cases were registered (176 in Reunion, 60 in Mayotte). Age-standardised incidence rates (ASRs, world standard) for all cancers were 125.0 and 101.8 per million for Reunion and Mayotte, respectively. ASRs for the main cancer groups were lower than those described in mainland France for the same period. The 5-year overall survival rate for all patients was 78.5% (95%CI 71.9- 83.7), slightly lower than that reported in mainland France.     

Sentinel lymph node biopsy in Hungary. Results with a revolutionary new method in surgical oncology

This review deals with results attained by Hungarian authors in the field of sentinel nodes and presents the current status of sentinel lymphadenectomy in Hungary. After a short historical overview, results with melanoma and breast cancer are summarized, and feasibility studies on other possible sites (gastrointestinal tract, thyroid gland) are also mentioned. Pathological aspects are also dealt with in a separate section. The summary of these results suggests that Hungarian authors have investigated several facets of sentinel node biopsy, their results are in keeping with international results. Despite the favourable results, the method still needs time to be more widely accepted and reflected in the literature.     

Congenital anomalies and childhood cancer in Great Britain.

The presence of cancer and a congenital anomaly in the same child may be explained in certain cases by an underlying genetic abnormality. The study of these associations may lead to the identification of genes that are important in both processes. We have examined the records of 20,304 children with cancer in Britain, who were entered into the National Registry of Childhood Tumors (NRCT) during 1971-86, for the presence of congenital anomalies. The frequency of anomalies was much higher among children with solid tumors (4.4%) than among those with leukemia or lymphoma (2.6%; P < .0001). The types of cancer with the highest rates of anomalies were Wilms tumor (8.1%), Ewing sarcoma (5.8%), hepatoblastoma (6.4%), and gonadal and germ-cell tumors (6.4%). Cases of spina bifida and abnormalities of the eye, ribs, and spine were more common in children with cancer than among population-based controls. Future studies may be directed toward identifying the developmental pathways and the relevant genes that are involved in the overlap between pediatric cancer and malformation.     

Limb reduction defects in over one million consecutive livebirths

Limb reduction defects occurring among 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 inclusive were reviewed. A total of 659 cases of limb reduction defects were identified, 393 of them involving the long bones and 190 of them more than one limb. The time period 1966-1984, during which ascertainment was consistent, was evaluated, and an incidence of 5.97 per 10,000 livebirths (1 in 1,692 live births) was found. The data were evaluated for trends over time, sex ratio, and regional and ethnic distribution. Associated anomalies of other organ systems in these cases were analyzed, and overall about one-half of the cases have additional defects. The majority of these additional defects affect the musculoskeletal system and include such entities as clubfoot, hip dislocation, and congenital contractures. Defects are also frequent in other organ systems, such as the cardiovascular, gastrointestinal, and genitourinary systems. By far the most common limb defects are terminal longitudinal defects then terminal transverse defects. Of all cases of limb defects, 75% are upper limb and 25% lower limb. We found no evidence that one side is affected more frequently. About 6.5% of cases had another family member registered with a skeletal defect; 12.9% of cases died within the first year of life, the majority (85%) of those dying having additional defects. Etiological considerations are discussed for some subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amelia: incidence and associated defects in a large population

Amelia, or complete absence of a limb, is a very rare congenital anomaly. The incidence of amelia in a population of 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 was studied using the records of a population-based registry with multiple sources of ascertainment. There were 18 cases of amelia, giving a minimal incidence rate of 0.15 per 10,000 livebirths for this birth defect. Amelia occurred equally frequently in upper and lower limbs, and 11 of 18 (61%) liveborn cases also had malformations of other organ systems. In the group with lower limb amelia a specific pattern of associated malformations, which included omphalocele and diaphragmatic defects, was identified. There was no evidence for familial recurrence of amelia. Conditions to be considered in differential diagnosis are discussed.     

Ascertainment of pregnancies terminated because of birth defects: effect on completeness of adding a new source of data

BACKGROUND: When evaluating preventive programs such as folate promotion and rubella vaccination, it is critically important to include terminations of pregnancy for neural tube defects and congenital rubella syndrome. Data from birth defects registries are often used for this purpose. The Western Australian Birth Defects Registry ascertains cases of birth defects in livebirths, stillbirths, and terminations of pregnancy for fetal abnormality, using multiple sources of ascertainment. METHODS: Data on terminations of pregnancy for fetal abnormality from the Western Australian Hospital Morbidity Data System 1980-1997 (not previously available to the Registry) were used to estimate the completeness of ascertainment of such cases by the Registry. Ascertainment-adjusted prevalences were calculated using capture-recapture methods. RESULTS: A total of 702 terminations with birth defects were identified among hospital discharges, most of which were already known to the Registry (87.9%). Of the 85 new cases, seven had a neural tube defect, 23 had a chromosomal defect, and 12 had confirmed maternal rubella infection during pregnancy. The ascertainment-adjusted prevalence was not importantly [corrected] different for birth defects overall or for these individual conditions, although the 95% confidence intervals for all birth defects, and for all chromosomal defects, did not include the prevalence based on registered cases only. CONCLUSIONS: The Western Australian Birth Defects Registry ascertains a high proportion of pregnancies terminated for fetal abnormality, and should therefore be a reliable source of data with which to assist in monitoring the effectiveness of preventive programs.     

Ionizing radiation and genetic risks. IV. Current methods, estimates of risk of Mendelian disease, human data and lessons from biochemical and molecular studies of mutations

This paper is aimed at a synthesis of conclusions and concepts from the first three papers of this series and an inquiry of their relevance to the estimation of the risk of autosomal dominant and X-linked diseases in man, due to exposure to ionizing radiation. For a population under conditions of continuous irradiation, the doubling-dose method (DD method) enables the prediction of the excess risk of dominant and X-linked diseases at equilibrium. Per unit dose, this quantity is the product of the natural prevalence of these diseases (assumed to be 10,000/10(6) livebirths) and the reciprocal of the DD. The DD currently used is 1 Gy and is based primarily on data on the induction of recessive specific-locus mutations in male mice. The estimate of risk to the first generation is derived from that at equilibrium; the figure is about 15% of the equilibrium value (i.e., 15 cases/10(6) livebirths/cGy). With the direct method, the first-generation risk of dominant disease is estimated using data on the induction of dominant skeletal and cataract mutations in male mice and a number of correction factors. The estimates are about 10-20 cases and 0-9 cases, respectively, for irradiation of males and females, per 10(6) livebirths/cGy. In the Japanese studies, no significant adverse genetic effects, attributable to exposure of the parents to the atomic bombs, could be demonstrated with respect to any of the endpoints used. Most of the latter are clinically and socially relevant but mutationally insensitive. On the basis of these data, Neel and colleagues have estimated that the gametic DD for genetic effects of radiation in man is at least about 4-5 times the 1 Gy value thus far used. The concepts, assumptions, and the data-base used with the DD method have been re-examined. Arguments are advanced to support the thesis that ionizing radiation is probably not very efficient in inducing the very specific molecular changes that are known to underlie spontaneous mutations which cause naturally occurring dominant genetic diseases. It is suggested that (i) the DD estimate of 1 Gy that is used to estimate risk for autosomal dominant and X-linked diseases is conservative and (ii) the 1% prevalence figure for these diseases that is used for this purpose may be too high. If these suggestions are correct, then the estimate of risk for the dominant and X-linked diseases may need to be revised downwards.(ABSTRACT TRUNCATED AT 400 WORDS)