Search

Purpose: The GRIN2A gene has been associated with epilepsies ranging from benign focal childhood epilepsies to severe epileptic encephalopathies. The aim of this study was to evaluate genotypes and phenotypes in individuals with GRIN2A deletions or variants. Method: We compared genotypes and phenotypes in six newly identified patients with GRIN2A variants with those of 149 individuals with GRIN2A variants from the literature. Results: Six new patients with epilepsy, developmental and/or behavioral problems and GRIN2A deletions (n = 3), missense (n = 2) or splice-site variants (n = 1) are presented. In 125 (84%) of the 149 individuals with GRIN2A variants previously reported, a specific epilepsy syndrome was diagnosed, most often classified as Benign Epilepsy with Centro-Temporal Spikes (BECTS; n = 44) or Landau-Kleffner syndrome/ Continuous Spike-And-Waves during Slow-wave sleep (LKS/ CSWS; n = 42). Problems of speech and language development (81%), cognition (68%), motor skills (50%) or behavior (42%) were common. Missense variants were seen in 52% of the patients reported earlier, more often in individuals with BECTS (71%) compared to those with LKS/ CSWS (48%). Certain missense variants in or close to the ligand-gated ion channel domain were associated with a severe phenotype, as was also observed in two of our patients with severe epilepsy and cognitive impairment. Conclusion: Individuals with GRIN2A gene variants or deletions have an extremely variable phenotype without a clear genotype-phenotype correlation. Variants in or close to the ligand-gated ion channel can be associated with a severe phenotype.

Objective: The GRIN2A gene has been associated with both benign childhood epilepsies and severe epileptic encephalopathies. This study evaluates the genotype-phenotype correlations in patients with GRIN2A variants. Methods: A systematic literature search was performed, identifying all patients reported before May 2014 with GRIN2A variants. Patients were classified in two groups based on their GRIN2A genotype. Group I genotypes had an expected detrimental effect on protein expression: nonsense, frameshift, splice site, or initiation codon sequence variants, translocations with breakpoints within GRIN2A, or deletions comprising GRIN2A. Group II genotypes were expected to result in an altered protein structure or function: missense or in-frame sequence variants. Results: Of 136 patients, 74 were included in group I and 62 in group II. Epilepsy was diagnosed in 86% of patients in both groups, with focal seizures being most common (82%). Benign epilepsy with centrotemporal spikes (BECTS) was significantly more often diagnosed in group II than in group I (51% versus 27%, p=0.03). Continuous spikes and waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) occurred more often in group I than in group II (50% versus 37%), although not statistically significant (p=0.29). Mild to severe developmental problems related to speech and language (80%), cognition (66%), and motor skills (48%), and behavioural problems (61%) were present in both groups. Speech and language problems were significantly more often reported in group I than in group II (90% versus 69%, p=0.02), also in patients with no LKS/CSWS (94% versus 50%, p=0.01). Conclusion: GRIN2A variants are associated with a spectrum of epilepsies, mainly accompanied by language developmental problems. This epilepsy-aphasia syndrome spectrum ranges from relatively mild BECTS to more severe LKS/CSWS. This study shows that GRIN2A genotypes with an expected milder effect on protein function are associated with a relatively more benign phenotype including BECTS without language problems.

Otocephaly-dysgnathia complex is characterized by mandibular hypo- or aplasia, ear abnormalities, microstomia, and microglossia. Mutations in the orthodenticle homeobox 2 (OTX2) and paired related homeobox 1 (PRRX1) genes have recently been identified in some cases. We screened 4 otocephalic cases for these 2 genes and identified OTX2 mutations in 2 of them, thus confirming OTX2 is implicated in otocephaly. No PRRX1 mutation was identified. Interestingly, ocular involvement is not a constant feature in otocephalic cases with an OTX2 mutation. In one case, the mutation was inherited from a microphthalmic mother. The mechanism underlying this intrafamilial phenotypic variability remains unclear, but other genetic factors are likely to be necessary for the manifestation of the otocephalic phenotype.

Wanneer je in het buitenland een gesprek over voetbal begint, zal je buitenlandse gesprekspartner vaak komen met de welbekende naam van Johan Cruyff. Zijn naam lijkt voor eeuwig verbonden te zijn met het Nederlandse voetbal. Maar de kans is groot dat zijn naam in de toekomst steeds meer genoemd zal worden vanwege de door hem opgerichte stichting die op maatschappelijk niveau belangrijke problemen aanpakt.

Het CDA heeft voor de komende gemeenteraadsverkiezingen een masterplan opgesteld om Rotterdam gezinsvriendelijker te maken. Een dergelijk masterplan was ook wenselijk, want sinds de jaren zeventig is het eerder regel dan uitzondering dat gezinnen de stad verlaten voor één van de randgemeenten. Uit statistieken is gebleken dat drie keer zoveel gezinnen de stad verlaten dan het aantal die zich in Rotterdam vestigen. (http://www.kiesgeluk.nl/)

The detection of chromosomal aberrations is essential for the diagnosis and therapy of acute myeloid leukaemia (AML). We report two cases of de novo AML with translocations involving the breakpoint 6p22 first detected at relapse. Chromosomes were identified by conventional and molecular cytogenetics. At diagnosis, one patient presented a normal karyotype and the other one a trisomy 11 and a del(7)(q31q36). In the first case, cytogenetic analyses at relapse revealed a t(3;6)(q21;p22). The second patient showed a t(1;6)(q21;p22) at relapse. Detailed characterization of the breakpoints on the short arm of chromosome 6 was performed using array comparative genomic hybridization (CGH) on a platform specific for chromosome 6. In both cases, array CGH showed a terminal deletion and a small internal duplication of the short arm of chromosome 6. The region 6p22 is involved in several aberrations in tumours. Translocation partners are distributed throughout the human genome. We identified 3q21, a recurrent breakpoint in AML, for the first time as a translocation partner. The fragile site FRA6C, located in 6p22.2, and possibly the genes that reside within it, may play a role in tumorigenesis. The occurrence of translocations involving 6p22 after chemotherapy or radiation therapy suggests that one or more therapeutic agents might play a role in their origin.

We describe several relatives within one renal cell cancer (RCC) family sharing a constitutional t(2;3) (q35;q21). Based on molecular studies on several independent primary tumors in this family, a causative role for this translocation in tumor development was suggested. Subsequent positional cloning of the 3q21 chromosomal breakpoint revealed that this breakpoint disrupts a novel gene, DIRC2 (disrupted in renal cancer 2). This gene encodes an evolutionary conserved transmembrane protein and represents a novel member of the MFS superfamily of transporters. To evaluate whether DIRC2 is also targeted in sporadic RCC cases with cytogenetically defined 3q21 breakpoints, fluorescence in situ hybridization analysis was performed on metaphase spreads and/or interphase nuclei of 12 primary sporadic RCC using genomic clones from a 3q21 breakpoint-spanning contig as probes. Three breakpoints were mapped proximal to the familial breakpoint and nine breakpoints were mapped distal to this breakpoint. Two of the latter breakpoints were mapped in the contig within 1 Mb distance from the familial breakpoint. Because these clustered 3q21 breakpoints do not coincide with the familial 3q21 breakpoint, they most likely affect genes distinct from DIRC2. (C) 2002 Elsevier Science Inc. All rights reserved.

Item does not contain fulltext We describe several relatives within one renal cell cancer (RCC) family sharing a constitutional t(2;3) (q35;q21). Based on molecular studies on several independent primary tumors in this family, a causative role for this translocation in tumor development was suggested. Subsequent positional cloning of the 3q21 chromosomal breakpoint revealed that this breakpoint disrupts a novel gene, DIRC2 (disrupted in renal cancer 2). This gene encodes an evolutionary conserved transmembrane protein and represents a novel member of the MFS superfamily of transporters. To evaluate whether DIRC2 is also targeted in sporadic RCC cases with cytogenetically defined 3q21 breakpoints, fluorescence in situ hybridization analysis was performed on metaphase spreads and/or interphase nuclei of 12 primary sporadic RCC using genomic clones from a 3q21 breakpoint-spanning contig as probes. Three breakpoints were mapped proximal to the familial breakpoint and nine breakpoints were mapped distal to this breakpoint. Two of the latter breakpoints were mapped in the contig within 1 Mb distance from the familial breakpoint. Because these clustered 3q21 breakpoints do not coincide with the familial 3q21 breakpoint, they most likely affect genes distinct from DIRC2.

Two sisters affected with renal cell carcinoma (RCC) is an extremely rare finding, and may indicate a hereditary pattern or the presence of other predisposing factors. We describe here 2 sisters presenting with clear cell renal cell cancer. Examination for von Hippel-Lindau (VHL)-related features and tuberous sclerosis (M. Bourneville) was negative and both had a normal constitutional karyotype. Cytogenetic analysis of the tumor tissue of both patients showed a translocation involving chromosomes 3 and 5, resulting in loss of 3p sequences and gain of part of 5q. The 5q breakpoints were similar, but the breakpoints at 3p appeared to differ. Allelic imbalance analysis supported our observations. Microsatellite analysis revealed that both sisters inherited different chromosome 3 parental alleles. For chromosome 5, 3 different haplotypes could be deduced, but the chromosome 5 alleles overrepresented in the different tumor tissues were from different parental origin. The development of the 2 RCCs in these 2 sisters thus cannot be explained by the inheritance of a mutated VHL gene located at 3p25, nor by the inheritance of other gene defects at chromosomes 3p or 5q. Although the chance that 2 sisters develop sporadic RCC is very low, in the presented case it is probably coincidental or related to another genetic predisposition.

Multichannel Urethral Pressure Profilometry (MCUPP) is a method used to get more information on the pressure distribution within the female urethra. This information may be of value in the diagnostic work up of women with urinary incontinence. Different systems are used for this technique. The pump is an important part of such a system. The catheter is perfused with water pumped through the side hole of the catheter. Air bubbles inside one or more of the eight channels alter the elastic properties of the catheter making the results unreliable. In daily urodynamic practice it is important that the system is patient and user-friendly, is quick to set up, and the performance of measurements is easy. For this reason a new type of pump was developed that is able to produce a pressure stable continuous flow through the eight channels of the catheter. The problem of air bubbles has been solved and different measurements can be performed serially in a short time. The system currently used by us is described

A combination of Southern blot analysis on a panel of tumor-derived somatic cell hybrids and fluorescence in situ hybridization (FISH) techniques was used to map a series of DNA markers relative to the 1q21 breakpoint of the renal cell carcinoma (RCC)-associated (X;1)-(p11;q21) translocation. This breakpoint maps between several members of the S100 family which are clustered in the 1q21 region and a conserved region between man and mouse containing the markers SPTA1-CRP-APCS-FcER1A-ATP1A2-APOA2. The location of the breakpoint coincides with the transition of a region of synteny of human chromosome 1 with mouse chromosomes 3 and 1.

An intracranial teratoma in which six distinct dysmorphic fetuses were included was studied at autopsy. Karyotopic studies showed a normal chromosomal number in the child and the same karyotype in the three tumoral parts that were examined. This is the second tumor of this type reported. Copyripht (C) 1995 by W.B. Saunders Company

Many of the reported oncocytomas have different chromosome abnormalities, indicating that they comprise a cytogenetically heterogenous group of tumors consisting of potentially cytogenetic subgroups. We have performed cytogenetic studies on nine renal oncocytomas. Clonal abnormalities were present in eight tumors. The findings most observed were the loss of the Y chromosome, and abnormalities of chromosomes 1 and 22. We also observed telomeric associations (tas) in two tumors and structural aberrations of chromosomes 9p and 19q, as well as monosomy 10. In two cases we found a similar reciprocal t(5;11)(q35;q13) in two cases. Review of the literature disclosed one other oncocytoma with a t(5;11)(q35;q13). This suggests that t(5;11)(q35;q13) defines a (second) subset of oncocytomas apart from the subgroup specifically associated with the loss of chromosomes 1 and Y.

Chondrosarcomas are a heterogeneous group of bone neoplasms of which the basic neoplastic tissue is cartilaginous. Frequently the histologic diagnosis and grading of chondrosarcomas is difficult and the histologic appearance does not always reflect the biologic behavior of these rumors. Therefore, it is important to find other parameters that can be of help in the proper diagnosing and grading of these neoplasms. To this end, we attempted to correlate the chromosomal pattern of chondrosarcomas to their histologic subtypes and grades. The cytogenetic analysis of two intermediate-grade chondrosarcomas of bone, and a review of the literature, are presented.

A malignant fibrous histiocytoma (MFH) of bone arising in the fibula of a 21-year-old woman is described. Clinical, radiologic, and histologic findings demonstrated rapid tumor progression. Chromosomal analysis of the biopsy specimen showed great karyotypic heterogeneity, whereas the resection specimen four weeks later displayed a rather homogeneous karyotype. Both revealed a clonal t(14;22)(q11;p12). Several other clonal and non-clonal chromosomal aberrations were observed. Some of these were previously described in giant cell tumor of bone (GCTB) and may correlate with aggressive behavior, e.g., aberrations involving 8p11, 19q13, and 20q13. The change from karyotypic heterogeneity to relative homogeneity may be related to tumor progression. The chromosomal findings further suggest that the giant cell type of MFH of bone may be related to malignant GCTB. (C) 1994 Wiley-Liss, Inc.

BACKGROUND: Both DNA flow cytometry and cytogenetic analysis have been used to study soft tissue tumors. With flow cytometry, the DNA content of a relatively large number of cells can be examined, but cytogenetic analysis gives more detailed information about genomic changes. EXPERIMENTAL DESIGN: In order to compare the advantages and drawbacks of DNA flow cytometry versus chromosomal analysis, 92 primary or recurrent malignant, 16 borderline malignant, and 13 benign soft tissue tumors were karyotyped after short-term culture. DNA ploidy was determined by flow cytometry of suspensions prepared from frozen or paraffin-embedded samples. From 97 patients, 121 samples were analyzed. RESULTS: On the basis of the results, four groups were distinguished: DNA-euploid tumors with normal diploid karyotypes (group a) or with abnormal (group b) karyotypes, and DNA-aneuploid tumors with normal (group c) or abnormal (group d) karyotypes. The findings in group b show that structural chromosomal abnormalities or minor numerical aberrations of chromosomes are not detected by DNA flow cytometry. In group c, the finding of tumors with an aneuploid DNA-profile and cells with normal karyotypes is most likely due to overgrowth of fibroblasts during culture and subsequent karyotyping of normal cells. CONCLUSIONS: The findings show that a) DNA flow cytometry has a higher succes rate than karyotyping, b) both techniques are complementary, such that DNA flow cytometry gives an ''overview'', whereas karyotyping gives more detailed information; comparison of both techniques in individual cases leads to a better understanding of the chromosomal events that occurred during oncogenesis, c) histologically low grade tumors are generally DNA-diploid, but may have an abnormal karyotype, and d) histologically high-grade sarcomas tend to have an aneuploid DNA-profile; they are generally more difficult to karyotype.