Prenatal management, pregnancy and pediatric outcomes in fetuses with septated cystic hygroma

It has been reported that, compared with simple increased nuchal translucency, fetal cases with septated cystic hygroma (CH) are more likely to face perinatal handicaps. However, pediatric outcomes and proper prenatal counseling for this anomaly have not yet been truly defined. We performed this study to determine pregnancy and pediatric outcomes of fetuses with septated CH. We searched records for cases with septated CH and collected data for structural abnormalities, karyotype analysis, and pregnancy outcomes. Fetuses born with septated CH were also evaluated for their pediatric outcomes. Sixty-nine fetuses with septated CH were enrolled in the study. Results showed that chromosomal abnormalities were present in 28 fetuses (40.6%), and the most common aneuploidy was Turner syndrome (n=14, 20.3%); 16 (23.2%) of the remaining cases, in which aneuploidy was not found, had coexistent structural malformations; 25 (36.2%) cases had normal karyotype and morphology. The total number of live births and infants with unfavorable neurologic follow-up were 13 (18.8%) and 2 (2.9%), respectively. Septated CH is associated with poor perinatal outcomes; therefore, karyotype analysis and ultrasonographic anomaly screening should be performed as initial steps, and expectant management should be offered to couples with euploid fetuses that have normal morphology.

Prenatal management, pregnancy and pediatric outcomes in fetuses with septated cystic hygroma.

It has been reported that, compared with simple increased nuchal translucency, fetal cases with septated cystic hygroma (CH) are more likely to face perinatal handicaps. However, pediatric outcomes and proper prenatal counseling for this anomaly have not yet been truly defined. We performed this study to determine pregnancy and pediatric outcomes of fetuses with septated CH. We searched records for cases with septated CH and collected data for structural abnormalities, karyotype analysis, and pregnancy outcomes. Fetuses born with septated CH were also evaluated for their pediatric outcomes. Sixty-nine fetuses with septated CH were enrolled in the study. Results showed that chromosomal abnormalities were present in 28 fetuses (40.6%), and the most common aneuploidy was Turner syndrome (n=14, 20.3%); 16 (23.2%) of the remaining cases, in which aneuploidy was not found, had coexistent structural malformations; 25 (36.2%) cases had normal karyotype and morphology. The total number of live births and infants with unfavorable neurologic follow-up were 13 (18.8%) and 2 (2.9%), respectively. Septated CH is associated with poor perinatal outcomes; therefore, karyotype analysis and ultrasonographic anomaly screening should be performed as initial steps, and expectant management should be offered to couples with euploid fetuses that have normal morphology.

Tertiary trisomy of 10p15.pter and 14pter.ql3 due to maternal translocation t(10;14)(p15;q13).

Double partial trisomy resulting from 3:1 segregation of the respective chromosomal segments of the chromosomes involved in a balanced translocation in meiosis is rarely reported in the literature. We present here a first patient with multiple congenital malformations associated with double partial trisomy of 10pter-p15 and 14pter-q13 resulting from 3:1 segregation of maternal balanced translocation t(10;14)(p15;q13). Proximal partial trisomy of chromosome 14 and subterminal trisomy of the short arm of the chromosome 10 are rare. The present case is the first case with double partial trisomy of these segments resulting from 3:1 segregation of a maternal balanced translocation.

Double partial trisomy of 6p23-pter and 9pter-q21.2 in a neonate resulting from 4:2 meiotic segregation of a maternal complex t(6;7;9)(p23;p15;q21.2) translocation.

We report, a newborn presenting multiple congenital abnormalities with karyotype; 47,XY,der(7)t(6;7)(pter-p23::p15-->qter),+der(9)t(7;9)(pter-->p15::q21.2--> pter)t(6;7;9)(p23;p15;q21.2)mat[20]. The mother and her phenotypically normal daughter were carriers of a complex chromosomal rearrangement with karyotypes; 46,XX,t(6;7;9)(p23;p15;q21.2)[20]. Paternal chromosomes were normal. In our case the extra derivative chromosome was the result of a 4:2 segregation of the chromosomes involved in translocation during oogenesis. Double partial trisomy in newborns resulting from 4:2 segregation is a rare event, and double partial trisomies of the 6p23-pter and trisomy 9pter-q22 regions have not reported to date.

Mosaic Intrachromosomal Triplication of (12)(p11.2p13) in a Patient with Pallister-Killian Syndrome.

Pallister-Killian syndrome (PKS) is a rare genetic disorder usually characterized by mosaic tetrasomy of isochromosome 12p detected in cultured fibroblast cells. We describe here a patient with PKS and intrachromosomal triplication of the short arm of chromosome 12. Her karyotype was mos 46,XX,inv trp(12)(p11.2p13)[34]/ 46,XX[16]de novo by conventional cytogenetics and fluorescent in situ hybridization (FISH) analysis. However, this chromosomal abnormality was not detected from the patient's cultured blood lymphocytes. We report here the third patient with intrachromosomal triplication on the short arm of chromosome 12, presenting a PKS phenotype.

Partial trisomy 3q in a child with sacrococcygeal teratoma and Cornelia de Lange syndrome phenotype.

Partial duplication of 3q is a rare chromosomal disorder that leads to multiple congenital abnormalities such as growth retardation, microcephaly and characteristic facial features. Although the phenotype of the patient has similarities with Cornelia de Lange Syndrome they are etiologically different. We report here a 9 months old baby boy with partial duplication of 3q and features similar with Cornelia De Lange syndrome. Conventional cytogenetic analysis revealed a derivative chromosome 21. In order to determine the origin of this chromosome region we used subtelomeric FISH technique. Based on the results of all these cytogenetic studies and the physical examinations, the diagnosis is partial 3q duplication.

De novo supernumerary marker chromosome originating from chromosome 17 resulting in a normal pregnancy outcome.

We report here a prenatal case with de novo supernumerary marker chromosome originating from chromosome 17 in non-mosaic form resulting in normal pregnancy outcome. In this case, a 26-year-old pregnant woman was referred for amniocenthesis and microdeletion Fluorescence In Situ Hybridization (FISH) testing at 18 weeks of gestation due to history of a previous child with Angelman Syndrome. PWS/AS region deletion was excluded by FISH. A de novo supernumerary, non-satellited, monocentric marker chromosome was detected during conventional cytogenetic analysis. With the use of FISH testing, it was found that the marker chromosome originated from chromosome 17. Additionally, the marker chromosome was found not to contain the Smith-Magenis and Miller Dieker syndrome regions. After detailed review of the literature, genetic counseling was given to the family, and the family decided to continue the pregnancy to term. A female child was born at term without any phenotypical abnormalities and clinical complications. Follow-up at 15 months-of-age revealed no developmental abnormalities. To our knowledge, our patient is the first reported prenatal case with a de novo monocentric, supernumerary marker chromosome derived from chromosome 17 in a non-mosaic form that resulting in normal pregnancy outcome.

RLIP76 Gene Variants are not Associated with Drug Response in Turkish Epilepsy Patients.

Approximately 30% of epileptic patients remain untreated, in spite of trials with maximum tolerable doses of more than one drug. The RalA binding protein 1 (RALBP1/RLIP76), a multifunctional, anti-apoptot-ic, multidrug transporter protein, has been proposed as being responsible for the drug resistance mechanism in epilepsy. We have investigated polymorphic differences in the coding regions and exonintron boundaries of the RLIP76 gene, between 146 refractory and 155 non refractory epileptic patients in Turkey, using denaturing high performance liquid chromatography (HPLC) and sequencing analysis techniques. We have detected the following sequence variants: c.160-4G>A, c.187C>G, c.1562-38G>A, c.1670+107G>A, c.1670+93G>A, c.1670+96G>A, c.1670+100C>T, c.1670+130C>T, c.1670+131G>C, c.1670+140 G>C, and found no statistically significant correlation between allele frequencies and drug response status. We conclude that sequence variants of this gene are not involved in drug resistance in epilepsy.

Aplasia ras homologous member I gene and development of glial tumors.

The ARHI (aplasia Ras homologue member I, also known as DIRAS3) gene shows 60.0% sequence homology to the Ras proto-oncogene and was the first mater-nally-imprinted tumor suppressor gene identified in the Ras family. It is constitutively expressed from the paternal allele in normal breast, ovary, heart, liver, pancreas, thyroid and brain tissues, and is lost or markedly down-regulated primarily in breast, ovarian, pancreas and thyroid tumor tissues. We have investigated the expression, LOH (loss of heterozygosity) and methylation status of this gene in glial tumors and peripheral blood samples of 21 patients, and in seven normal brain tissue samples. Gene expression by real time reverse transcriptase polymerase chain reaction (RT-PCR) was found to be increased in 14 and decreased in seven of the 21 tumors. The LOH was detected by fragment analysis, using five labeled polymorphic markers specific for the 1p31 region, in two of the tumors. Methylation status of the CpG island I, II and III was evaluated using COBRA (combined bisulfite restriction analysis) and RFLP (restriction fragment length polymorphism) in 21 tumors and also a hypermethylated healthy volunteer as a positive control, revealed that only two tumors had hypermethylation in CpG island I (of which one also had LOH). These results suggest that LOH and hypermethylation may be one mechanism of silencing the ARHI gene expression and development of glial tumor development.

Turner Syndrome with Isochromosome Xq and Familial Reciprocal Translocation t(4;16)(p15.2;p13.1).

We present here a 16-year-old Turner syndrome patient with a complex karyotype that includes a maternally-inherited balanced translocation between chromosomes 4 and 16 and mosaicism of the isochromosome Xq10. Her karyotype was 45,X,t(4;16) (p15.2;p13.1)[9]/46,X,i(X) (q10),t(4;16)(p15.2;p13.1) [91]. The karyotype of her father was normal, whereas that of her mother had the same balanced translocation and numerical abnormalities of chromosome X and was designated as 45,X,t(4;16)(p15.2;p13.1) [2]/46,XX,t(4;16)(p15.2;p13.1)[93]/47,XXX,t(4;16) (p15.2; p13.1)[5]. The two siblings of the patient also had the same reciprocal translocation. We consider this to be the first such patient with an inherited reciprocal translocation and structural abnormality of the X chromosome (isochromosome Xq).

Prenatal diagnosis of a de novo supernumerary marker chromosome originating from chromosome 16.

Prenatal diagnosis of a de novo supernumerary marker chromosome originating from chromosome 16: A 37 year old pregnant woman was referred for amniocentesis at 18 weeks of gestation due to advanced maternal age and abnormal serum biochemistry. A nonsatellited, monocentric marker chromosome was observed with a frequency of 57% in cultured amniocytes. Parental karyotypes were normal. The marker chromosome was found to be derived from chromosome 16 by FISH using CEP16 and WCP16 probes. Marker chromosomes were not painted with M-FISH probe mixture, indicating an exclusively heterochromatin nature. CGH analysis using genomic DNA isolated from uncultured amniocytes also supported the M-FISH results. Genetic counseling was given to parents and the family decided to continue the pregnancy to term. The baby was born at 36 weeks of gestation without any dysmorphic features. Follow-up at 7 months of age revealed no developmental abnormalities.

Frequencies of four genetic polymorphisms in the CYP1A2 gene in Turkish population.

Cytochrome P450 (CYP) 1A2 gene is involved in the metabolic activation of several carcinogens and altered metabolization of some clinically used drugs. We aimed to investigate the distributions of genetic polymorphisms -3860 (G/A)(CYP1A2*1C) and -2467 (T/del)(CYP1A2*1D) in the 5'-flanking region and -739 (T/G)(CYP1A2*1E) and -163(C/A)(CYP1A2*1F) in the first intron of the CYP1A2 gene in 110 unrelated healthy Turkish volunteers by PCR-RFLP technique. The frequencies of each polymorphism in Turkish population were found as 0.04, 0.92, 0.01, 0.27 for CYP1A2*1C, CYP1A2*1D, CYP1A2*1E, CYP1A2*1F, respectively. Compared with other populations, CYP1A2*1D has been found to be significantly increased in Turkish population. On the other hand, in general, the frequencies of the other polymorphisms were concordant with those in the Egyptian and Caucasian populations, and were different from those in the Japanese, Chinese and Ethiopian populations. Our results suggest that due to increased frequency of CYP1A2*1D in Turkish population, functional significance of CYP1A2*1D should be evaluated. It might be screened to determine the relationship between CYP1A2*1D and CYP1A2 related drug metabolisms in associated groups.

The effect of MDR1 (ABCB1) polymorphism on the pharmacokinetic of tacrolimus in Turkish renal transplant recipients.

There is marked interindividual variability in trough blood levels of tacrolimus (TRL) following standard dosing. TRL is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1)(ABCB1) gene. P-gp acts as a membrane efflux pump, which affects TRL absorption from the gut. Some of the single nucleotide polymorphisms (SNP) of ABCB1 gene are associated with pharmacokinetic characteristics of TRL. The objective of this study was to determine the role of ABCB1 C3435T polymorphism on TRL dose requirements, trough values and dose-adjusted trough TRL concentrations among Turkish renal transplant recipients. Renal transplant recipients receiving TRL (n=92) were genotyped for ABCB1. TRL daily doses, trough concentrations, dose-adjusted trough concentrations, demographic features, and clinical data were obtained at 1, 6, and 12 months after renal transplantation. The frequency of the ABCB1 3435 CC genotype was 30.4%, whereas 47.8% of patients were 3435 CT and 21.7% of patients were 3435 TT. TRL daily doses were significantly lower among patients with the 3435 TT genotype at months 1 and 6. At 6 and 12 months after transplantation patients who were homozygous for the ABCB1 3435 CC showed significantly lower dose-adjusted trough TRL concentrations compared with subjects of 3435 TT and CT genotypes. Knowledge of ABCB1 genotype may be useful to adjust the optimal dose of TRL in transplant patients, thereby rapidly achieving target concentrations.

Adenovirus-mediated IKKbetaKA expression sensitizes prostate carcinoma cells to TRAIL-induced apoptosis.

Despite the fact that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells, TRAIL resistance in cancer cells has challenged the use of TRAIL as a therapeutic agent. First, prostate carcinoma cell lines (DU145, LNCaP and PC3) were screened for sensitivity to adenovirus delivery of TRAIL (Ad5hTRAIL). As amplified Ikappa B kinase (IKK) activity is responsible for the constitutive nuclear factor-kappaB (NF-kappaB) activation leading to uncontrolled cell growth and metastasis, a dual vector approach using both an adenovirus vector (Ad) expressing the dominant-negative mutant of IKKbeta (AdIKKbetaKA) and Ad5hTRAIL was employed to determine if prostate cancer cells were sensitized to TRAIL in the setting of IKK inhibition. Inhibition of the NF-kappaB pathway through IKK blockade sensitized all three prostate cancer cell lines to TRAIL, regardless of NF-kappaB activation or decoy receptor gene expression. Moreover, a novel quantitative real-time RT-PCR assay and conventional flow cytometry analysis indicated that TRAIL-resistant DU145 and LNCaP cells, but not TRAIL-sensitive PC3 cells, expressed substantial amounts of TRAIL Decoy Receptor 4. In conclusion, TRAIL decoy receptor expression appeared to be the chief determinant of TRAIL resistance encountered in prostate carcinoma cell lines.

AIDIT and IMPACT: building research collaborations in targeted prostate cancer screening.

AIDIT (Advancing International Co-operation and Developing Infrastructure for Targeted Screening of Prostate Cancer in Men with Genetic Predisposition) is a project funded by the Sixth Framework Programme of the European Community which is endeavouring to facilitate co-operation between European countries in the field of cancer research. The project also aims to raise awareness of familial prostate cancer among health professionals and the public within the associated candidate countries (ACCs) and new member states of the European Union (EU). AIDIT will focus on linking clinical and research teams in the ACCs and new member states with the IMPACT Consortium (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), an international team investigating screening and diagnosis for men with a genetic risk of prostate cancer predisposition genes BRCA1 or BRCA2). Cancer research has been targeted as a high priority for the European Community; however, research is most successful when centralised and well coordinated, avoiding the duplication and fragmentation associated with smaller, isolated studies. AIDIT will consolidate the current IMPACT consortium and allow research partners from across the world to benefit from shared knowledge and experience. To date, the AIDIT team has established a website to facilitate communication between project collaborators (www.impact-study.co.uk), has been represented at several international meetings and has facilitated a conference for the IMPACT study to bring together international research teams, clinicians and policy makers.

M-FISH applications in clinical genetics.

Until recently, presence of de novo marker or derivative chromosomes was quite problematic for genetic counseling especially in prenatal diagnosis, because characterization of marker and derivative chromosomes by conventional cytogenetic techniques was nearly impossible. However, recently developed molecular cytogenetic technique named Multicolor Fluorescence in Situ Hybridization (M-FISH) which paints all human chromosomes in 24 different colors allows us to characterize marker and derivative chromosomes in a single hybridization. In this study, we applied M-FISH to determine the origin of 3 marker and 3 derivative chromosomes. Marker chromosomes were found to originate from chromosome 15 in two postnatal and one prenatal case. Of these, one of the postnatal cases displayed clinical findings of inv dup (115) syndrome and the other of infertility, and the prenatal case went through amniocentesis due to the triple test results. Karyotypes of the patients with derivative chromosomes were designated as 46,XY,der (21)t(1;21)(q32;p11), 46,XX,der(8)t(8;9)(p23;p22) and 46,XX,der(18)t(18;20)(q32;p11.2) according to cytogenetic and M-FISH studies. All of the M-FISH results were confirmed with locus specific or whole chromosome painting probes. The case with der (8)t(8;9) had trisomy 9(p22-pter) and monosomy 8(p23-pter) due to this derivative chromosome. The case with der(18)t(18;20) had trisomy 20(p11.2-pter) and monosomy 18(q32-qter). Parental origins of the derivative chromosomes were analyzed using microsatellite markers located in the trisomic chromosomal segments. Patients' clinical findings were compared with the literature.