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The 1100delC mutation of the cell cycle checkpoint kinase 2 (CHEK2) gene confers an increased risk for breast cancer, but the clinical impact of other CHEK2 gene variants remains unclear. We determined the frequency of two functionally relevant CHEK2 gene mutations, I157T and IVS2+1G > A, in two large series of breast cancer cases and controls from two independent populations. Our first series consisted of a hospital-based cohort of 996 German breast cancer cases and 486 population controls, and the second series consisted of 424 breast cancer patients and 307 population controls from the Republic of Belarus. The missense substitution I157T was identified in 22/996 cases (2.2%) vs. 3/486 controls (0.6%; OR = 3.6, 95% CI 1.1-12.2, p = 0.044) in the German population and in 24/424 cases (5.7%) vs. 4/307 controls (1.3%; OR = 4.5, 95% CI 1.6-13.2, p = 0.005) in the Byelorussian cohorts. The splicing mutation IVS2+1G > A was infrequent in both populations, being observed in 3/996 German and 4/424 Byelorussian patients (0.3% and 0.9%, respectively) and in 1/486 German controls (0.2%; adjusted OR = 4.0, 95% CI 0.5-30.8, p = 0.273). Heterozygous CHEK2 mutation carriers tended to be diagnosed at an earlier age in both populations, but these differences did not reach statistical significance. Family history of breast cancer did not differ between carriers and noncarriers. Our data indicate that the I157T allele, and possibly the IVS2+1G > A allele, of the CHEK2 gene contribute to inherited breast cancer susceptibility., (Copyright 2005 Wiley-Liss, Inc.)

Evaluation of the effects of radioactive contamination on human populations is important for an understanding of the present and future risk for human health, including the genetic risk. This review centers on the results of population monitoring of developmental anomalies among human embryos and congenital malformations among newborn in the Republic of Belarus before and after Chemobyl accident. The data revealed that the incidences of developmental anomalies and congenital malformation from the mostly radionuclide-contaminated rural regions of Belarus reliably exceed the indices in control areas.

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.

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.

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.

Two cases of the Smith-Lemli-Opitz syndrome are described, together with the autopsy findings. In both cases, the typical appearance and visceral malformations were present. Hypoplasia of the frontal lobes and corpus callosum, and aplasia of the splenium constitute abnormalities of the brain which may be useful in the diagnosis of this disorder at autopsy. The autosomal recessive mode of inheritance of this syndrome was confirmed.

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.

We report on a postnatally dead, postterm male infant with aprosencephaly and the oculofacial manifestations usually seen in the most severe form of alobar holoprosencephaly -- namely cyclopia and absence of derivatives of the frontonasal process; in addition the infant had the radius aplasia field defect bilaterally, a high VSD, mobile cecum, and penile hypospadias with cryptorchidism. The same syndrome was reported recently by Garcia and Duncan [2]; however, in that case the brain defect was designated "atelencephaly." Since atelencephaly is a less severe form of aprosencephaly we chose to designate the condition in these two patients as "the aprosencephaly (XK) syndrome." Atelencephaly and aprosencephaly may occur also as a single and sporadic malformation. The cause of the aprosencephaly (XK) syndrome is unknown.

The detailed morphological description of 4 cases with cebocephaly, 3 of which were karotyped (one with D trisomy and 2 with normal karyotypes), are presented. Analysis of all cytogenetically studied cases with this malformation reveals that cebocephaly with a normal karyotype may result from more than one mutant gene, and so it may be accompanied by different extracranial abnormalities. On the other hand an absence of visceral malformations does not exclude chromosomal aberrations; thus 18p- syndrome, where cebocephaly is frequent, may have no visceral abnormalities.

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.

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.

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.

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.

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.

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.

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.

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.

We report a stillborn girl with a complex syndrome of microcephaly, lissencephaly, severe subcutaneous edema, atrophic muscles, camptodactyly, syndactyly of toes and fingers, hypoplastic genitalia, and numerous structural changes of the brain and eyes. Similar cases have been reported by Neu et al [1], Laxova et al [2] and Povysilova et al [3]. The above-mentioned syndrome complex is a distinct genetic syndrome, for which we propose the eponym "the Neu-Laxova syndrome." Affected patients resemble each other strikingly and there is usually no doubt about the diagnosis. The Neu-Laxova syndrome is apparently transmitted as an autosomal recessive trait.

Four perinatally dying infants with multiple congenital malformations, including pulmonary hypoplasia, multiple ankyloses, abnormalities of the face and camptodactyly are presented. The differences both for severity of pulmonary hypoplasia and for the type of associated malformations suggest that this complex of abnormalities is not a single syndrome but a complex of related entities. These entities and some other genetical syndromes may form a "community of malformations" involving facial, skeletal (arthrogryposis, camptodactyly) and placental abnormalities.

The analysis of 206 families with reciprocal translocations revealed thanks to a patient who was a carrier of an unbalanced translocation demonstrated the risk of a child suffering from the disease at about 16.4%, in the case of a meiotic segregation 2 : 2. In the case of translocation with meiotic segregation 3 : 1, the risk is much less, i.e. 7.6% for female carriers and significantly less than 3/83 for male carriers. It is extremely important to take this difference into account when evaluating the risks during genetic counselling. On the other hand, the freqeuncy of spontaneous abortions is practically the same for carriers of translocations with these two types of segregation and rises to nearly 23%; i.e. the postzygotic selection influences, to the same degree, zygotes with one chromosome too many, one two few, and zygotes with 46 chromosomes, but of which one has a defect or an excess of genetic material. Such selection depends rather on an interaction between the abnormal genome of the zygote (embryo) and the genome of the mother, whilst the prezygotic selection operates against the gametes having one chromosome too many or one too few. A large asymmetry in the length of the exchanged fragments could be one of the causes of the 3 : 1 segregation. This is proved by a more frequent participation (48/60) of the acrocentric chromosomes in the translocations with segregation 3 : 1. On the other hand, in translocations with segregation 2 : 2, acrocentrics are found much more rarely (66/146).

Data from the world literature about the pathology of the urinary system in autosomal chromosomal disorders are analyzed and compared with our own morphological investigations of this system in 63 cases of chromosomal disorders (Patau's, Edwards', Down's, Orbeli's, Wolf-Hirschhorn's syndromes, partial trisomy B and inversion of chromosome 2). The urinary system is most frequently involved in "cat-eye", triploidy, Orbeli's, Patau's and Edwards' syndromes. All known malformations of the urinary system are observed in children with chromosomal diseases, except infantile polycystic kidney and medullary "sponge" kidney. The authors recognize specific and nonspecific abnormalities of the urinary system. Nonspecific abnormalities, as simple renal dysgenesis, may be observed in all chromosomal disorders. Specific abnormalities are found only in certain chromosomal diseases. These malformations are an excess of embryonal lobulation of the kidney with the increase of its weight and cystic changes (Patau's syndrome), crossed renal ectopy with fusion and horseshoe kidney (Edwards' syndrome), unilateral renal agenesis (Orbeli's syndrome), hypospadia (Wolf-Hirschhorn's syndrome). A possible pathogenesis of malformations of the urinary system in chromosomal disorders is discussed.

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.

Two cases of partial 10p trisomy due to a t(10;20)(p12;p12) in two generations of a family are presented. Analysis of 20 known cases of such aberrations confirmed the opinion of Schleiermacher et al. (1974) that partial trisomy 10p is a distinct clinically recognizable entity. The most important diagnostic features of this syndrome are dolichocephaly, prominent forehead, wide open sutures and fontanelles, broad root of the nose, cleft lip and palate, clubfoot, and cystic changes in kidneys.

An analysis of data about the +p9 syndrome revealed that this clinical entity may occur in some different genetic forms. The recurrence risk in cases with familial translocations is due to the type of meiotic segregation, 2:2 or 3:1. It was shown a nonrandomness of involvement of chromosomes 15 and 22 in translocations with chromosome number 9.

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.