The congenital anomalies registry in Belarus: a tool for assessing the public health impact of the Chernobyl accident.

A national population-based malformation registry (BNR) has been in operation since 1979 in Belarus, one of the countries most heavily exposed to the contamination from the Chernobyl accident of 26 April 1986. We describe its methodology and its compliance with established criteria, evaluate the completeness of its reporting, and analyze the data collected in four administrative regions with contrasting contamination levels from 1983 through 1999. Nine easily diagnosed malformations have been monitored since 1983. Reporting completeness exceeds 85% for all periods and all regions. In all periods, the prevalence at birth of these malformations was lower in the most contaminated regions and showed a similar positive time trend in areas of low and high contamination. We conclude that the BNR is a reliable tool for studying the possible effects on congenital malformations caused by the Chernobyl accident. Although the trend we observed may be explained by better ascertainment and prenatal diagnosis, a real increase cannot be ruled out.

Expression of the sonic hedgehog gene in human embryos with neural tube defects.

BACKGROUND: To estimate the rate of malformations observed during early human development, a series of 38,913 first-trimester abortions were studied. Neural tube defects (NTD) were found in 57 cases. METHODS: A histological study of serial sections performed in 25 embryos revealed a spectrum of axial structure abnormalities. Expression of the SHH gene was studied by in situ hybridization in one case of CRS and in two cases of SB. RESULTS: A cervical notochord duplication was always found in craniorachischisis (CRS, n = 8), but not in spina bifida (SB, n = 10) or diplomyelia (split cord malformation, n = 3). In the embryo with CRS, expression of SHH was found in both domains, corresponding to the duplicated part of the notochord, whereas a single signal was observed in the nonduplicated part. This expression was associated at the cervical level of the open neural tube with a broad SHH expression domain and with two or even three domains in its lumbar region, suggesting multiple functional floor plates. Similarly, in two embryos with SB, two domains of SHH expression were found in the ventral neural tube. CONCLUSIONS: Our findings suggest that notochord splitting in the cervical region might be involved in the pathogenesis of CRS. Interestingly, similar notochord abnormality and altered expression of the shh gene are observed in Lp mice with NTD. This suggests that the Lp gene could be a candidate gene for human CRS. Further studies are needed to establish the primary event responsible for the notochord splitting and for the abnormal expression of the SHH gene in the floor plate in embryos with CRS and SB.

Changes in registered congenital anomalies in the Republic of Belarus after the Chernobyl accident.

A descriptive analysis of birth defects and malformations was performed to assess whether the rates of these defects correlate with the geographic areas of Belarus that received different levels of 137Cs contamination resulting from the Chernobyl catastrophe. Since this accident in 1986, the frequency of both congenital and fetal abnormalities in the Republic of Belarus has apparently increased. This increase is most prominent in areas with at least 555 9Bq/m2 radioactive contamination, although it has not been possible to correlate the individual dose received by a pregnant woman with the incidence of congenital malformations. The types of anomalies that were most increased in frequency were multiple congenital malformations, polydactyly, and reduction limb defects. These malformations are commonly associated with dominant new mutations. Chromosomal disorders such as occur in Down syndrome were not increased in frequency, nor could teratogenic effects be attributed to exposure to ionizing radiation. Preventive measures have apparently reduced the number of births with congenital abnormalities but have had no apparent effect on the frequency of fetal defects. Results of our analysis are consistent with the hypothesis that ionizing radiation released during the Chernobyl accident may have placed fetuses and neonates at risk for congenital malformations. Epidemiological studies are now required to determine whether a mother's radiation dose correlates with congenital malformations in her children.

The cerebro-reno-digital syndromes: a new community.

Two "new" syndromes of multiple congenital malformations with autosomal-recessive inheritance are presented. One syndrome, found in 2 sibs of nonconsanguineous parents, included microcephaly, agencies of the corpus callosum, pterygium colli, cystic renal dysplasia (CRD) and postaxial polydactyly (PP). The other, found in 2 female sibs of consanguineous parents, included micropolygyria, CRD, PP, and polysplenia. The literature review allows the delineation of a community of 19 "cerebro-reno-digital" syndromes with autosomal recessive inheritance, 14 of which include cerebral anomalies, CRD and PP. Three more autosomal recessively inherited syndromes had CRD (or renal fibrosis) and cerebral anomalies (without digital anomalies), three others involved cerebral and digital anomalies (without renal anomalies), and one further syndrome showed CRD and ectrodactyly (without cerebral defects). Such phenotypical similarity may be attributed to the fact that there are common links in the pathogenesis of the syndromes under study.

The absence of type II collagen and changes in proteoglycan structure of hyaline cartilage in a case of Langer-Saldino achondrogenesis.

Structural analysis of hyaline cartilage extracellular matrix components from the ribs and knee joint of a stillborn female with type II achondrogenesis was carried out. The absence of type II collagen, a decrease in the amount of proteoglycans (PG), and structural changes in PG, namely, increased electrophoretic mobility of PG, lower relative content of chondroitin 4-sulfate (Ch4-S), lower molecular weight and decreased total chondroitin sulfate (ChS) sulfation, were detected. Increased amounts of type I and type III collagens, atypical for hyaline cartilage, were revealed. Among the link proteins (LPs), a large protein with a mol. wt. of 48 kDa was predominant. Molecular and cellular mechanisms of the pathogenesis of achondrogenesis ("chondrogenesis imperfecta") are discussed. The data obtained suggest that the primary defect in type II achondrogenesis involves ChS or type II collagen synthesis.

Cerebral abnormalities in the Neu-Laxova syndrome.

Cerebral abnormalities are considered an obligatory manifestation of the Neu-Laxova syndrome and include lissencephaly, severe microcephaly, aplasia of the corpus callosum, hypoplasia of the cerebellum, and other pathological changes. We present data on 3 cases with central nervous system anomalies, two of which have not been described previously, and summarize the literature on the subject. The problem of distinguishing type III lissencephaly is discussed.

Campomelic syndrome: concepts of the bowing and shortening in the lower limbs.

A comprehensive study (bone roentgenography, arteriography, gross dissection, microscopy of the long bones, and biochemical study of proteoglycan-aggregates in the hyaline cartilage) of the lower limbs in a full-term stillborn with the campomelic syndrome was performed. Hyaline cartilage immaturity of the long bones, dysplasia of growth plates, focal shaft dysplasia, and a defective length of the posterior femur and crus muscles were revealed. The genesis of the bowing and shortening of the long bones in the lower limbs is discussed.

Prenatal morphology of partial monosomy 18q.

Prenatal diagnosis, performed in a woman with reciprocal translocation (9:18), disclosed partial monosomy 18q in a fetus. Morphologic studies of this fetus revealed dysplastic face and ears, a high palate, hypomotility of joints, an accessory spleen and anomalous dermatoglyphics. Biochemical examination detected a decrease of most amino acids, which is typical for many chromosomal syndromes.

Partial trisomy 5q and partial monosomy 5q within the same family.

The observation of partial trisomy for 5q31-5qter and partial monosomy for the same segment in two offspring within the same family is presented. Their normal mother was a balanced carrier of a reciprocal translocation 46,XX,t(5;10) (q31.3;q26). The trisomic female had craniofacial dysplasia, a short neck, clinodactyly of the 5th fingers, a small umbilical hernia, arhinencephalia, cerebellar hypoplasia, atrial septal defect, an accessory spleen, bifid uterus and vagina, hypoplastic ovaries. Potter syndrome with cystic dysplasia of the left kidney and agenesis of the right, urethral atresia, uterus unicornus with utero-urethral fistula, true hermaphroditism with two ovaries and one testicle were found in her stillborn sister. Analysis of the manifestations of monosomy 5q and trisomy 5q in the same family supports a well known fact that the effects of deletions are more pronounced than those of duplications for the same segments.

Elaboration of the phenotypic changes of the upper limbs in the Neu-Laxova syndrome.

We present two new cases and data from a detailed study of the upper limbs (structural changes, the state of peripheral nerves, arteries, muscles and bones) of three stillborn infants with the Neu-Laxova syndrome. The morphogenesis of many of the examined anatomical structures in these fetuses was anomalous. The origin of these anomalies is discussed.

Pancreas annulare in human embryos.

2 cases of pancreas annulare with duodenal stenosis were found among 3,307 induced abortuses of 5-12 weeks where the pancreatoduodenal area was available for examination. This corresponds to a 0.06% incidence, greatly exceeds the occurrence of the anomaly in neonates and suggests partial prenatal elimination of embryos with pancreas annulare and duodenal stenosis. Microscopic examination of serialed embryonic sections gives evidence of (1) the origin of the ring from the ventral anlage; (2) the underdevelopment of the ring material, which later may cause fibrosis of the annulus, usually observed in neonates; (3) the origin of duodenal stenosis in case of pancreas annulare till 8 weeks of fetal life; (4) the development of such stenosis not only due to atrophy of duodenal segment, resulted from compression by the pancreatic ring, but also due to anomalous differentiation of intestinal segment, the cause of which may be the disturbance of morphogenetic correlations.

The Smith-Lemli-Opitz syndrome. A detailed pathological study as a clue to a etiological heterogeneity.

An analysis of 33 autopsied cases with the Smith-Lemli-Opitz syndrome (including 8 cases from our practice) is presented. Polydactyly in dead SLOS children was found in 51% (17/33) of cases and occurred significantly more often in this group than in the whole group of SLOS (20-22%). Certain morphological differences in the type of renal, cerebral, pulmonary and pancreatic anomalies indicate the existence of two phenotypically similar SLOS: 1) with polydactyly; 2) without it. The presented data initiate SLOS heterogeneity.

The Wolf-Hirschhorn syndrome. II. Pathologic anatomy.

Most cases of Wolf-Hirschhorn syndrome occurring among children who die during the perinatal period are not diagnosed by morphologists. However, analysis of the morphological data on the Wolf-Hirschhorn syndrome revels that association of typical external features and abnormalities ofthe brain (shortening of the H2 area of Ammon's horn, dystonic dysplastic gyrae in the cerebellum), eyes (colobomata, microphthalmos, retinal dysplasia) and kidneys (bilateral or unilateral agenesis, cystic dysplasia or polycystosis) with diaphragmatic hernia allows the establishment of a diagnosis of the syndrome without cytogenetic investigation.

The Wolf-Hirschhorn syndrome. I. Genetics.

Four new cases of the Wolf-Hirschhorn syndrome are presented, two of which were due to t(4;22)mat. Review of the literature (more than 100 cases of the Wolf-Hirschhorn syndrome) showed that 13 % of all the reported cases were not mutations but segregations of parental chromosomal aberrations, primarily translocations. Similar data were obtained previously for other deletions (5p--, 18p--, 18q--). Analysis of data on some "new" deletion syndromes (4q--, 8p--, 9p--, 10p--, 11p--, 11q--) revealed that 14.5 % were inherited cases. Thus, all human autosomal deletions have virtually the same genetic pattern.

Difficulties in classification of the short rib-polydactyly syndromes.

A case of "short rib-polydactyly" (SRP) syndrome (type II-Saldino-Noonan) with a detailed study of the bones, muscles and peripheral nerves in the extremities is presented. Analysis of the literature (35 cases with different forms of SRP) and the comparison of clinical, genetic and morphological data lead us to consider that different types of SRP may be related to different alleles of the same gene. Genetic heterogeneity (mutations of different genes) is also possible.

Partial trisomy 11q as the result of sporadic translocation.

Partial trisomy 11q due to a sporadic translocation was found in a mentally retarded girl with multiple abnormalities. The proportion of sporadic translocations involved in the total incidence of partial trisomies is discussed.

Trisomy 8p due to the 3:1 segregation of the balanced translocation t(8;15)mat.

An additional small G-like chromosome was found in a newborn female with multiple abnormalities and hemorrhagic diathesis. G banding showed that the index patient was trisomic for the short arm of chromosome 8 and revealed the anomaly t(8;15)(q12;p11) in her mother. The relationship between chromosome 8 and multiple hemorrhages is discussed.