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 IVS211G > 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 5 3.6, 95% CI 1.1-12.2, p 5 0.044) in the German population and in 24⁄424 cases (5.7%) vs. 4⁄307 controls (1.3%; OR 5 4.5, 95% CI 1.6-13.2, p 5 0.005) in the Byelorussian cohorts. The splicing mutation IVS211G > 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 5 4.0, 95% CI 0.5-30.8, p 5 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 IVS211G > A allele, of the CHEK2 gene contribute to inherited breast cancer susceptibility. ' 2005 Wiley-Liss, Inc.Key words: breast cancer; CHEK2; Germany; Belarus Cell-cycle checkpoint kinase 2 (CHEK2) is a central mediator of cellular responses to DNA damage.1,2 Ionizing radiation activates the CHEK2 protein via ATM-mediated phosphorylation, 3,4 and activated CHEK2 kinase can phosphorylate several substrates, including Cdc25A, p53 and E2F1, which mediate cell cycle arrest and apoptosis.1,2,5 CHEK2 phosphorylation of the breast cancer susceptibility protein BRCA1 regulates DNA double-strand break repair, 6 and deletion of CHEK2 potentiates the incidence of mammary carcinomas in BRCA1 conditional mutant mice.7 A truncating variant of CHEK2, the 1100delC mutation, has been identified as a low-penetrance breast-cancer susceptibility allele. 8,9 Heterozygous 1100delC carriers have an approximately 2-fold increased risk for breast cancer.10 Furthermore, a potential association of the 1100delC mutation with colorectal and prostate cancers has been reported. 11-13The role of variants in CHEK2 other than 1100delC is less clear. Most studies have led to the conclusion that other CHEK2 mutations do not make a major contribution to breast cancer susceptibility.14-16 However, one more recent investigation suggests that the common I157T mutation may be associated with increased breast cancer risk. 17 Parallel work has provided evidence that the missense substitution I157T as well as the splicing mutation IVS211G>A may confer an elevated risk for prostate cancer. 13,18 To assess the role of these CHEK2 varia...

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--, 1Sq-). Analysis of data on some "new" deletion syndromes (4q--, 8p-, 9p-, lop-, l l p -, llq-) revealed that 14.5% were inherited cases. Thus, all human autosomal deletions have virtually the same genetic pattern.

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.

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.

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.