Showing papers on "Ring chromosome published in 2010"

Fusion of short telomeres in human cells is characterized by extensive deletion and microhomology, and can result in complex rearrangements.

Abstract: Telomere fusion is an important mutational event that has the potential to lead to large-scale genomic rearrangements of the types frequently observed in cancer. We have developed single-molecule approaches to detect, isolate and characterize the DNA sequence of telomere fusion events in human cells. Using these assays, we have detected complex fusion events that include fusion with interstitial loci adjacent to fragile sites, intra-molecular rearrangements, and fusion events involving the telomeres of both arms of the same chromosome consistent with ring chromosome formation. All fusion events were characterized by the deletion of at least one of the telomeres extending into the sub-telomeric DNA up to 5.6 kb; close to the limit of our assays. The deletion profile indicates that deletion may extend further into the chromosome. Short patches of DNA sequence homology with a G:C bias were observed at the fusion point in 60% of events. The distinct profile that accompanies telomere fusion may be a characteristic of the end-joining processes involved in the fusion event.

Ring chromosome instability evaluation in six patients with autosomal rings.

Abstract: Ring chromosomes are often associated with abnormal phenotypes due to loss of genomic material and also because of ring instability at mitosis after sister chromatid exchange events. We investigated ring chromosome instability in six patients with ring chromosomes 4, 14, 15, and 18 by examining 48- and 72-h lymphocyte cultures at the first, second and subsequent cell divisions after bromodeoxyuridine incorporation. Although most cells from all patients showed only one monocentric ring chromosome, ring chromosome loss and secondary aberrations were observed both in 48- and 72-h lymphocyte cultures and in metaphase cells of the different cell generations. We found no clear-cut correlation between ring size and ring instability; we also did not find differences between apparently complete rings and rings with genetic material loss. The cytogenetic findings revealed secondary aberrations in all ring chromosome patients. We concluded that cells with ring chromosome instability can multiply and survive in vivo, and that they can influence the patient's phenotype.

Low grade mosaic for a complex supernumerary ring chromosome 18 in an adult patient with multiple congenital anomalies

Abstract: Background Several cases have been reported of patients with a ring chromosome 18 replacing one of the normal chromosomes 18. Less common are patients with a supernumerary ring chromosomes 18. High resolution whole genome examination in patients with multiple congenital abnormalities might reveal cytogenetic abnormalities of an unexpected complexity.

Genetic investigations on 8 patients affected by ring 20 chromosome syndrome

Abstract: Background Mosaic Chromosome 20 ring [r(20)] is a chromosomal disorder associated with a rare syndrome characterized by a typical seizure phenotype, a particular electroclinical pattern, cognitive impairment, behavioural problems and absence of a consistent pattern of dysmorphology. The pathogenic mechanism underlying seizures disorders in r(20) syndrome is still unknown. We performed a detailed clinical and genetic study on 8 patients with r(20) chromosome, aimed at detecting the genetic mechanism underlying r(20) syndrome.

Short communication Fusion of the FUS and CREB3L2 genes in a supernumerary ring chromosome in low-grade fibromyxoid sarcoma

Abstract: Low-grade fibromyxoid sarcoma (LGFMS) is a rare, low-grade malignant soft tissue tumor that is often mistaken for either benign or more malignant tumor types. Commonly, this tumor affects young adults and typically arises in the deep proximal extremities or trunk with frequent recur- rences and can metastasize to the lungs many years later. Most cases have a recurrent balanced translocation involving chromosomes 7 and 16, t(7;16)(q32-34;p11), which leads to the fusion of the FUS and CREB3L2 genes. However, supernumerary ring chromosomes have been identified in a subset of FUS/CREB3L2-positive LGFMS, but it has not yet been formally demonstrated that such ring chromosomes harbor the FUS/CREB3L2 fusion gene. Here, we report the genetic findings of a supernumerary ring chromosome from an LGFMS from a 77-year-old man. Chromosome banding analysis revealed a supernumerary ring chromosome, and further studies with fluorescence in situ hybridization and reverse transcriptaseepolymerase chain reaction (RT-PCR) showed that the ring contained material from chromosomes 7 and 16, that the FUS gene was present in two rearranged copies, and that it expressed the FUS/CREB3L2 fusion gene. Moreover, an assessment of previously reported cases showed that tumors with ring chromosomes relapsed more often than tumors with a balanced t(7;16), suggesting that ring formation in LGFMS is correlated with tumor

Boy with a ring 7 chromosome: a case report with special reference to dermatological findings.

Abstract: A ring chromosome 7 was found in an 8-year-old boy investigated on account of short stature and facial dysmorphism. He had a fair skin, almost white hair, cafe-au lait spots and many black atypical pigmented naevi. Electron microscopy of his skin revealed structural changes in melanocytes and keratinocytes, suggesting disturbed cell growth and differentiation.

Cytogenetic and molecular evaluation and 20-year follow-up of a patient with ring chromosome 14.

Abstract: We present a 20-year follow-up on a patient with a ring chromosome 14. The ring chromosome was studied by fluorescence in-situ hybridization (FISH), multiplex-ligation probe amplification (MLPA), and genome wide SNP array, and no deletions of chromosome 14 were detected, although the telomeric repeat sequence was absent from the ring chromosome. The patient had skeletal abnormalities, and susceptibility to infections, as well as seizures and retinal pigmentation, which are commonly found in individuals with a ring 14. Our patient corroborates the idea that even when no genes are lost during ring formation, a complete ring chromosome can produce phenotypic alterations, which presumably result from ring instability or gene silencing due to the new chromosomal architecture.

Mosaic ring chromosome 18, ring chromosome 18 duplication/deletion and disomy 18: perinatal findings and molecular cytogenetic characterization by fluorescence in situ hybridization and array comparative genomic hybridization.

Abstract: SUMMARY Objective: To present the perinatal findings and molecular cytogenetic analysis of a rare chromosomal abnormality involving structural and numerical abnormalities of chromosome 18. Materials, Methods and Results: A 36-year-old woman, gravida 5, para 3, underwent amniocentesis because of her advanced maternal age. Amniocentesis revealed a karyotype of 46,XY,r(18) [27]/45,XY,-18[5]/46,XY[5]. The parents decided to continue the pregnancy. Level II ultrasound revealed ventriculomegaly. At 38 weeks of gestation, a 3,725 g male fetus was delivered. The fetus had microcephaly, hypertelorism, epicanthal folds, cleft palate, a broad flat nose, simian creases, broad hands, tapered fingers, clubfeet, micropenis, a sacral dimple, hypotonia, ventriculomegaly, and a ventricular septal defect. The peripheral blood lymphocytes revealed a karyotype of 46,XY,r(18)[81]/45,XY,-18[3]/46,XY,idic r(18)[3]/46,XY[13]. Fluorescence in situ hybridization using chromosome 18 centromeric probe (cep18) and subtelomeric (18pter, 18qter) identified four types of cells, r(18), idic r(18), monosomy 18, and disomy 18. Array comparative genomic hybridization analysis of the blood demonstrated a 14.9-Mb deletion at chromosome 18p [arr cgh 18p11.32p11.21 (0–14,941,330) × 1] and a 29.6Mb deletion at chromosome 18q [arr cgh 18q21.2q23 (46,533,430–76,117,153) × 1]. The proband’s karyotype was 46,XY,r(18)(p11.21q21.2)[81]/45,XY,-18[3]/46,XY,idic r(18)(p11.21q21.2;p11.21q21.2)[3]/46,XY[13].

Ring chromosome 18 abnormality in acute myelogenous leukemia: the clinical dilemma

Abstract: The ring chromosome is a circular, structural abnormality composed of either multiple chromosomes or a single chromosome with loss of genetic material at one or both ends. This chromosomal rearrangement is often unstable with frequent recombinations and may be accompanied by either loss or amplification of genetic material[1]. Considering that ring chromosomes are rare in acute myelogenous leukemia (AML), it is difficult to risk stratify patient prognosis, particularly when the ring chromosome occurs as the sole abnormality. Here we report a case of a ring chromosome 18 abnormality in a patient with newly diagnosed AML with monocytic differentiation. Cytogenetic analysis demonstrated 46, XY, r(18)(p11q21) karyotype in 19 of 34 evaluated metaphase cells. The patient received induction chemotherapy and subsequent allogeneic cord blood transplant from a sex-matched donor, and remained in hematologic and cytogenetic remission for 120 days post transplant. Soon after, he developed post transplant lymphoproliferative disorder and died of multi-organ failure. Although r(18) chromosomal abnormalities were not classified in the recent updated evidence-and expert opinion-based recommendations for the diagnosis and management of AML (likely due to the small number of reported cases), the patient was treated as high risk with stem cell transplantation. This was based on the unstable nature of the ring chromosome and the poor outcomes described in the literature of patients with sole ring 18 abnormalities.

Male with mosaicism for supernumerary ring X chromosome: analysis of phenotype and characterization of genotype using array comparative genome hybridization.

Abstract: Supernumerary, derivative, and ring X chromosomes are relatively common in Turner syndrome females but have been reported rarely in males. To date, less than 10 cases have been published, of which only 2 have been partially characterized in defining the breakpoints and genetic content of the derivative X chromosome. We describe a male with mosaicism for a supernumerary X chromosome (46,XY/47,XY, r(X)) who has multiple congenital anomalies, including features of craniofrontonasal dysplasia (Mendelian Inheritance in Man 304110) and the presence of ectopic female reproductive organs. Using comparative genomic hybridization array mapping, we determined that the derivative X is composed of a 24-Mb fragment that contains the regions Xp11.3 through Xq13.1 and lacks the XIST gene. This is the first report to describe a detailed molecular characterization of a ring X chromosome in a male by comparative genomic hybridization array analysis. We compare the clinical and molecular findings in this patient to other 46,XY, r(X) patients reported in the literature and discuss the potential role of disomy for known genes contained on the ring X chromosome.

Detection of premature segregation of centromeres in persons exposed to ionizing radiation.

Abstract: We have analyzed the frequency of premature centromeric division (PCD) in medical personnel professionally exposed to low doses of radiation. They had chromosome aberrations (CAs) involving dicentric chromosomes, ring chromosomes, acentric fragments, chromosome breaks, and chromatid breaks. The study included 30 exposed subjects and 23 controls who were each analyzed by a conventional cytogenetics procedure and subsequently by fluorescent in situ hybridization (FISH). The latter was applied particularly in order to verify PCD in a specific chromosome (chromosome 18) in both metaphases and interphase nuclei. The results revealed a significant difference (p < 0.001) in frequencies between the two groups (exposed and controls) for all the observed variables (CAs), metaphases with PCD (MPCD), total number of chromosomes with PCD (TPCD), number of PCD metaphases in acrocentric chromosomes (MAPCD), and the total number of acrocentric chromosomes with PCD (TAPCD). The doses of ionizing radiation absorbed by the subjects' bodies were measured with thermoluminescent dosimeters once a month during the duration of occupational exposure. They were expressed in mSv, as mean annual effective doses for the period of exposure. The Spearman rank test showed a high positive correlation between total life effective dose and frequency of CAs and PCD. Based on the results obtained in this study, we suggest that PCD, as a phenomenon manifesting chromosomal instability (CIN), should be considered as a suitable cytogenetic biomarker for individuals occupationally exposed to ionizing radiation.

Increasing role of cytogenetics in pediatric practice.

Abstract: Karyotyping was done in 100 children suspected of having chromosomal abnormalities of genetically uncertain syndromes, multiple congenital anomalies, short stature, dysmorphic features, unclassified mental retardation, and Down syndrome. A total of 56 patients had an abnormal karyotype: ring chromosome of 13 was seen in 1 patient (1.78%), and trisomy 21 was seen in 29 patients (51.78%) who were diagnosed as Down syndrome patients. Among them, 9 were male patients (31.03%) (47,XY+21) and 18 were female patients (47,XX+21) (62.06%); 2 patients showed 47,XY+21/46,XY (mosaicism) (6.89%). Chromosomal rearrangements involving chromosome numbers 13, 14, and 21 were seen in three patients. Among them, one patient had t(13;21) [45,XX,t(13;21)] and two patients had 45,XY,t(14;21). Trisomy 22 was seen in three patients (5.3%), marker chromosome was seen in two patients (3.57%), 46,XY,16qh variant was seen in one patient (1.78%), 46,XX,der(2) was seen in one patient (1.78%), 46,XX,14ps+ was seen in two patients (3.57...

Constitutional ring chromosome 11 mosaicism in a Wilms tumor patient: Cytogenetic, molecular and clinico-pathological studies.

Abstract: We report on a boy with three cell lines: 46,XY, r(11)(p15.5,q25)[90]/45,XY,-11 [8]/47,XY, r(11)(p15.5,q25)x2[2], with minor anomalies and mental retardation who developed asynchronous bilateral Wilms tumors (WTs). Array comparative genomic hybridization (CGH) performed on peripheral blood leukocytes of the patient led to the identification of a constitutional duplication of 4.8 Mb at 11p15.5–11p15.4. This duplication was found to involve the chromosome of paternal origin, and occurred in tandem on the ring chromosome 11. Despite the constitutive duplication of the paternal 11p15 chromosome region, the patient showed no sign of Beckwith-Wiedemann syndrome. However, the molecular characterization of the two neoplasias was consistent with their independent origin and showed that they arose from the two distinct cellular clones with the ring chromosome, indicating that this anomaly is likely to have caused the patient's susceptibility to WT development. © 2010 Wiley-Liss, Inc.

Ring chromosome 14 mosaicism: an unusual case associated with developmental delay and epilepsy, characterized by genome array-CGH.

Abstract: Ring Chromosome 14 Mosaicism: An Unusual Case Associated With Developmental Delay and Epilepsy, Characterized by Genome Array-CGH Anna Lisa Nucaro,* Melania Falchi, Tiziana Pisano, Rossano Rossino, Francesca Boscarelli, Giusi Stoico, Angela Milia, Caterina Montaldo, Carlo Cianchetti, and Dario Pruna INN-CNR, Cittadella Universitaria, Monserrato, Cagliari, Italy Clinica di Neuropsichiatria Infantile, Azienda Ospedaliero-Universitaria, Cagliari, Italy Dipartimento di Scienze Pediatriche e Medicina Clinica, Azienda Ospedaliero-Universitaria, Cagliari, Italy Dipartimento di Scienze Chirurgiche e Odontostomatologiche, Universit a di Cagliari, Cagliari, Italy Technogenetics Bouty, Company, Sesto San Giovanni, Italy Dipartimento di Biologia Sperimentale, Universit a di Cagliari, Cagliari, Italy

Ring/marker chromosome derived from chromosome 7 in childhood acute megakaryoblastic leukemia with monosomy 7.

Abstract: In some cases of childhood acute megakaryoblastic leukemia (AMKL), G-band analysis reveals supernumerary ring/marker chromosomes along with monosomy 7. However, their origin and relevance are poorly understood. We experienced three patients with AMKL, one of whom had Down’s syndrome, whose blasts at the first visit exhibited both monosomy 7 and a ring/marker chromosome. For one case, precise molecular-cytogenetic techniques revealed that the ring chromosome was derived from a chromosome 7. It was strongly suggested that the ring chromosome was derived from a chromosome 7 in another case. The ring or one of the 2 marker chromosomes was derived from a chromosome 7 in the other case. All patients responded well to initial induction therapy. While it is not clear whether the ring/marker chromosome 7 affects the long-term prognosis of acute myeloid leukemia with monosomy 7, it may be of prognostic relevance to distinguish pure monosomy 7 from monosomy 7 with a ring/marker chromosome 7. For this purpose, conventional G-banding could be complemented with additional techniques such as spectral karyotyping or fluorescence in situ hybridization, which characterize the aberration in more detail. These methods may be useful for determining the optimal treatment and for elucidating the etiology of AMKL itself.

Chromosomal breakpoints characterization of two supernumerary ring chromosomes 20.

Abstract: The occurrence of an additional ring chromosome 20 is a rare chromosome abnormality, and no common phenotype has been yet described. We report on two new patients presenting with a supernumerary ring chromosome 20 both prenatally diagnosed. The first presented with intrauterine growth retardation and some craniofacial dysmorphism, and the second case had a normal phenotype except for obesity. Conventional cytogenetic studies showed for each patient a small supernumerary marker chromosome (SMC). Using fluorescence in situ hybridization, these SMCs corresponded to ring chromosomes 20 including a part of short and long arms of chromosome 20. Detailed molecular cytogenetic characterization showed different breakpoints (20p11.23 and 20q11.23 for Patient 1 and 20p11.21 and 20q11.21 for Patient 2) and sizes of the two ring chromosomes 20 (13.6 Mb for case 1 and 4.8 Mb for case 2). Review of the 13 case reports of an extra r(20) ascertained postnatally (8 cases) and prenatally (5 cases) showed varying degrees of phenotypic abnormalities. We document a detailed molecular cytogenetic chromosomal breakpoints characterization of two cases of supernumerary ring chromosomes 20. These results emphasize the need to characterize precisely chromosomal breakpoints of supernumerary ring chromosomes 20 in order to establish genotype-phenotype correlation. This report may be helpful for prediction of natural history and outcome, particularly in prenatal diagnosis.

De novo ring chromosome 6 in a child with multiple congenital anomalies.

Abstract: Ring chromosome 6, especially if it is de novo, is a rare occurrence. The phenotype of patients with ring chromosome 6 can be highly variable ranging from almost normal to severe malformations and mental retardation. The size and structure of the ring chromosome as well as the level of mosaicism are important factors in determining the clinical phenotype. Here we report an eight month-old child, a product of a non consanguineous marriage, who presented with developmental retardation, hypertelorism, microcephaly, flat occiput, broad nasal bridge, large ears, micrognathia, wide spaced nipples, protruding umbilicus, short stubby fingers, clinodactyly, single palmar crease, short neck with no obvious webbing, and congenital heart defect. Conventional karyotyping and Whole Chromosome Paint of the peripheral leukocytes showed 46,XY,r(6)(p25q27) karyotype with plausible breakpoints at p25 and q27 end. Conventional karyotyping of both parents showed normal karyotype. To the best of our knowledge, this is the first report of a Malay individual with ring chromosome 6, and this report adds to the collective knowledge of this rare chromosome abnormality.

A fetus with ring chromosome 21 characterized by aCGH shows no clinical findings after birth

Abstract: Ioannis Papoulidis1*, Emmanouil Manolakos2, Elisavet Siomou1, Kostantinos Kefalas2, Loretta Thomaidis3, Thomas Liehr4, Annalisa Vetro5, Apostolos Athanasiadis6, Orsetta Zuffardi5 and Michael B. Petersen1 1Eurogenetica S.A., Thessaloniki, Greece 2Laboratory of Molecular cytogenetics, Bioiatriki S.A., Kifisias Av. 132 and Papada, Athens 11526, Greece 3Department of Pediatrics, University of Athens, Aglaia Kyriakou Children’s Hospital, Athens GR-11527, Greece 4Institute of Human Genetics and Anthropology, Friedrich-Schiller-University, Jena, Germany 5Dipartmento di Patologia Umana ed Ereditaria, Universita di Pavia, Pavia, Italy 6School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

Monozygotic twins with discordant karyotypes following preimplantation genetic screening and single embryo transfer: case report

Abstract: Purpose To report a case of monozygotic monochorial diamniotic twins with discordant karyotypes.

Phenotypic correlations in a patient with ring chromosome 22.

Abstract: Ring chromosome 22, a rare cytogenetic anomaly, has been described in over 60 cases in the medical literature. The aim of this report was to present a case carrying ring chromosome 22, and her family. It is a case report of a patient presented at Medical Faculty of Ηukurova University in Turkey. An 8-year-old girl with ring chromosome 22 and her family were evaluated cytogenetically and clinically. A chromosome analysis of the proband revealed a de novo 46,XX,r(22)(p11.2;q13) karyotype. Our subject demonstrated the prominent features of this syndrome including profound mental retardation, language impairment, dysmorphic features, lack of speech, hyperactivity, and behavioral disorders. There is lack of consistency between the physical abnormalities that we observed in our subject and those observed for such patients in the literature. The wide range of manifestations observed in patients with this cytogenetic alteration is probably due to size differences in the deleted region.

Phenotypic map in ring 14 syndrome.

Abstract: We read with interest the letter by Nucaro et al. commenting on our paper [Zollino et al., 2009] and published in this issue of the Journal. This letter deals with an unusual case of ring 14 (r14) syndrome, in which, in addition to a duplicated r14 detected in 2 of 50 analyzed cells, discontinuous 14q deletions within the ring were detected by a-CGH and confirmed by FISH. These small deletions, limited to a single BAC clone, occurred within the 14q32.33, 14q24.2, and 14q22.1 chromosome regions, respectively. Interestingly, the 14q24.2 deleted segment encompasses the SLC8A3 gene, which is a sodium–calcium exchanger likely involved in epileptogenesis. Recently we reported on a large series (n1⁄4 20) of patients with r14 syndrome, all characterized by multiple FISH analyses with a contig covering the terminal 14q32 region. Half of them were also characterized by a-CGH and no deletions within the 14q22q24 region were detected [Zollino et al., 2009]. In the same article, clinical and genetic findings of three patients with a linear 14q deletion limited to 14q11.2q12 were also reported. Clinical manifestations included epilepsy and visual impairment due to retinal abnormality. Epilepsy also occurred in a patient with a balanced t(10;14) translocation with a breakpoint in 14q12. High resolution a-CGH in this latter patient gave normal results, leading us to speculate that a gene for epilepsy resides on 14q12, and that this gene underwent disruption by the breakage event. Based on these observations, we suggested that retinal abnormalities, epilepsy, microcephaly and mental retardation in r14 syndrome map within the proximal 14q11.2q12 region and that the respective gene could undergo dysregulation by position effect [Zollino et al., 2009]. Based on their findings, Nucaro et al. [in press] confirm the strict correlation between r14 and epilepsy and stress the possible aggravating role of r14 duplication, quoting the report by Tzoufi et al. [2007] of a patient in whom, however, the duplicated ring was found in 20% of the cells, much above 2% seen in their own case. Given the known instability of ring chromosomes, a 2% mosaicism could very well originate in vitro, during the 72-hr blood culture. In fact, we observed it in most of our cases [Zollino et al., 2009], independent of the severity of clinical presentation, and considered it an in vitro occurrence, not worth reporting. Nucaro et al.’s patient also showed three microdeletions, apparently not correlated with the formation of the ring. The authors discuss the meaning of these findings, without providing evidence on whether these microdeletions were de novo or inherited. In any case, one of these, of about 150 kb, at 14q32.33, is a common variant. The second, identified by BAC clone RP11-255G12, mapping in 14q22.1, includes the PCNX gene, involved in spermatogenesis. This is an interesting finding, although it is not clear how it should correlate with the presence of micropenis, as argued by the authors. Even more interesting is the third microdeletion, identified by BAC clone RP11-164G17, mapping in 14q24.2 and including the SLC8A3 gene, definitely a candidate for epilepsy. We suggest that this observation is not in contrast with our hypothesis that gene(s) for epilepsy are located more proximally, within the 14q.11.2q12 region [Zollino et al., 2009]. In our opinion, the most likely conclusion at this point is that within chromosome 14 there are several genes with a potential role in epileptogenesis, either by deletion or by position effect.

Variegated-like mosaicism and ring syndrome in a r(4) boy. Appraisal of 38 patients with a fairly complete ring 4.

Abstract: A 13-month-old boy with normal development and growth failure of prenatal onset but no other physical stigmata had a 46,XY,r(4)(p1 6.3q35).ish (4psubtel-, WHS1+, 4qsubtel+, pantel-) de novo karyotype. The analysis of 50-106 metaphases from each of four lymphocyte cultures (three of 72 h including one without colchicine and one of 96 h) revealed a dynamic mosaicism in 22-36% of cells. We did not observe a normal cell line. Hypoploidies (excluding ring losses) were observed in 2-7% of metaphases from colchicine-arrested cultures whereas tetraploidies were observed in 2-12% of metaphases from all four lymphocyte cultures. Further FISH studies were carried out on interphase nuclei from uncultured buccal cells and lymphocytes using two alphoid (CEP 1 and 9), a dual CEP X/SRY, and (in the former only) a subtel 4p probes. We scored 70-131 nuclei per assay and found apparent heteroploidies in approximately 1-47% of cells for CEP 1, CEP 9, subtel 4p, and SRY but not for CEP X. The patient's phenotype was typical of the ring syndrome and comparable to 9/37 previous r(4) cases. Moreover, all 38 patients were alive at the time of reporting and none has developed cancer. The 2-7% rate of hypodiploid cells in colchicine-arrested cultures and the approximately 1-47% rate of apparent heteroploidies in nuclei of uncultured cells evoke the in vitro and in vivo findings in patients with mosaic variegated aneuploidy (MVA). We conclude that our observation highlights the clinical and cytogenetical overlapping between the ring syndrome and the MVA syndrome; the crucial difference is the high risk of cancer related to BUB1B mutations in the latter.

Variegated aneuploidy and ring chromosome syndromes overlap.

Abstract: The cytogenetic profile of a male infant karyotyped because of a clinical suspicion of mosaic variegated aneuploidy (MVA) and found to have a r(4)(p16.3q35) with loss of the 4p subtelomere but not of the WHSCR or the 4q subtelomere, led us to realize the striking clinical and cytogenetic similarities between MVA and the so-called ring chromosome syndrome (RCS). Clinical features common to MVA and RCS are severe growth retardation of prenatal onset, lack of major malformations, and developmental delay or intellectual disability so variable that it may be absent [Kosztol anyi, 1987; Gardner and Sutherland, 2004; Garc ıa-Castillo et al., 2008). In contrast, a significant cancer risk characterizes the MVA but not the RCS (see below). Although such a clinical overlap was alluded to by Plaja et al. [2001] in their report on three MVA patients, to the best of our knowledge the cytogenetic resemblance of both conditions has gone unremarked. In addition to large dicentric and small rings, double rings, rods, and other dynamic mosaicism features, the analysis of 100 lymphocyte mitoses revealed 19 aneuploid metaphases: there were 7 hypodiploid (range 34–45 chromosomes) cells with the r(4), including 3 with a rod/open ring at 4q27 or ring 4-derived markers, and 12 polyploid (mostly 4n or near 4n) metaphases, among which 6 were clearly aneuploid with a range from 74 to 96 chromosomes and 6 exhibited partial or complete premature chromosome condensation including some rogue configurations (Fig. 1). Except for occasional chromosomes, no premature centromere division or anaphase-C mitotic figures were observed. The chromosomal MVA-like features here described, namely a sizeable proportion of heteroploid cells, recall similar findings seen in some patients with a large constitutional ring such as those involving chromosomes 1, 2, 4, or 12 [e.g., Sutherland and Carter, 1978; Vigfusson et al., 1980; Zuffardi et al., 1980; Freyberger et al., 1991] and further highlight the phenotypical similarities between MVA and RCS [Plaja et al., 2001]. By the way, it seems that such a resemblance has in part been overlooked due to the less extensive metaphase counts done in more recent ring chromosome instances. Such a clinical and cytogenetic overlap can be related to the continuous generation of aneuploid/unbalanced cells in both entities regardless of the underlying mechanisms [Plaja et al., 2001]. Although biallelic or monoallelic mutations in the mitotic checkpoint gene BUB1B have been demonstrated in most MVA families tested [Hanks et al., 2004; Matsuura et al. 2006], genetic heterogeneity in this autosomal recessive syndrome seems likely [Gardner and Sutherland, 2004; Hanks et al., 2004; Micale et al., 2007; Garc ıa-Castillo et al., 2008]. In ring chromosomes, particularly if a large chromosome is involved, sister chromatid exchanges result in rings being interlocked, broken, doubled or otherwise abnormal and in turn lead to monosomic and other aneuploid daughter cells. This continuous generation and loss of unbalanced cells or ‘‘dynamic mosaicism’’ undermines the growth rate since early embryogenesis but may not be teratogenic [Kosztol anyi, 1987; Gardner and Sutherland, 2004]. Although an increased cancer risk is a notable characteristic of the MVA syndrome, it seems to be restricted only to patients with BUB1B mutations: a review of 21 patients screened for such mutations showed that 9/13 BUB1Bþ patients had developed a neoplasm whereas none of 8 BUB1B individuals had did [Garc ıa-Castillo et al., 2008]. This differential risk compares with the apparently low cancer predisposition inherent to constitutional rings of most chromosome pairs, including chromosome 15 which harbors the BUB1B gene. Indeed, the diverse malignancies (retinoblastoma, Wilms tumor, leukemia, schwannoma, meningioma, melanoma, seminoma) found in some patients with a constitutional ring of chromosomes 7, 10, 11, 13, 21, and 22

Analysis of ring chromosome 9 syndrome with fluorescence in situ hybridization

Abstract: Objective To investigate the mechanism of the ring chromosome 9 formation by cytogenetic analysis of one case affected with ring chromosome 9 syndrome. Methods Routine chromosome GTG-binding analysis and dual color fluorescence in situ hybridization （FISH） with TelVision 9p and 9q probes were applied to characterize the case. Results The G-binding revealed that the patient had ring chromosome 9 with the following karyotype： 45,X,-9/46,XX, r（9）（p24q34）/46,XX, r（9;9）（p24q34; p24q34）[4/92/4]. The dual color FISH analysis with TelVision 9p and TelVision 9q probes failed to detect a hybridization signal on the ring chromosome in the case, which indicated that at least 115 kb were deleted on the terminal 9p and 95 kb were deleted on the terminal 9q. Comparing to the cases reported in the literatures, our patient shared some common features of the 9p- and 9q syndrome. Conclusion The clinical features of patients with identical r（9） breakpoints present variable phenotypes. The possible cause might be the submicroscopic variation in the deletion breakpoints, variation in the ring stability, the modification of the expression of the deleted by the individual＇s genetic background, or the effect of changes in the fetal environment. The haploinsufficieney of genes located in the deleted regions may play critical roles in the patient phenotype as well. Key words: ring chromosome 9 syndrome; dual-color fluorescence in situ hybridization; clinical phenotypes

Atypical Down syndrome phenotype in a girl with 21;21 translocation trisomy.

Abstract: Summary: Atypical Down syndrome phenotype in a girl with 21;21 translocation trisomy: We describe a girl with microcephaly, short stature, coarse face, severe growth and developmental delay, seizures, hypertonia, bilateral flexion contractures of the knees, and a de novo 21 ;2 1 translocation trisomy 2 1 in peripheral blood lymphocytes. Fluorescence in situ hybridization (FISH) analysis confirmed the trisomy 21 translocation using whole chromosome painting probe 21 (WCP21). Chromosome analysis which was also performed on skin fibroblasts and revealed mosaicism for a translocation trisomy 21 cell line (22.3%) as well as a second cell line consisting of one normal chromosome 21 and a small ring chromosome 21 derived from the translocation 21q21q (61%) and a third line consisting of monosomy 21 (16.7%). FISH analyses by LSI21 probe for the critical (2Iq22.2-22.3) region of Down syndrome (DS) on interphase blood cells resulted with 30% two signals and 70% three signals, skin fibroblasts showed 84% single signal, 9% two signals and 7% three signals. The size of ring chromosome 21 in skin fibroblasts was very small and probably there was a large, more proximally located deletion including chromosome 21q22 band. We consider that the atypical DS phenotype of the patient originated from the small ring chromosome 21 and the monosomy 21 in the skin fibroblasts and other tissues not available for analysis. Therefore, the clinical findings of the patient were most similar to monosomy 21 mosaicism syndrome. Key-words: Down syndrome - Monosomy 21 - Mosaicism- Ring 21 INTRODUCTION Down Syndrome (DS) is the most common chromosomal disorder associated with mental retardation and typical facial features. Previous reports have indicated that most of phenotypical features can be correlated with trisomie condition of the DS 21q22.2 critical region (3, 5). In 1974, Orye and Craen (6) and later in 1982 Dallapiccola et al. (2) reported t(2 1 q2 1 q)/r[t(2 1 q2 1 q)] mosaic karyotypes in blood lymphocytes of unrelated infants with mild manifestations of DS. Avramopoulos et al. (1) presented a patient also with an atypical or mild phenotype of DS with full free trisomy 21 in blood and skin fibroblasts while placental mosaicism was present. Recently, Keppler-Noreuil et al. (4) reported a patient who had a 21;21 translocation trisomy 21 in blood cells while mosaicism in skin fibroblast cells with an atypical DS phenotype consisting of microcephaly, downslanting palpebral fissures, short stature, severe developmental delay, seizures and hypertonia. CASE REPORT A 10-years-old female patient was admitted to our unit because of dysmorphic features and severe developmental delay. She was the fourth child of non-consanguineous parents, a 45-year-old father and a 37-year-old mother, who were both in good health. She had two brothers and one sister who were all healthy. The pregnancy was uncomplicated. She was born on the 38th gestational week with intrauterine growth retardation (birth weight: 1300 g). Her psychomotor development was severely delayed; head control was gained at 12 months, she was sitting supported at 5 years, could not walk without support and could not speak any word at the age of 10 years. She had three seizures between 7 months and 5 years. Her weight, height and head circumferences were 13.5 kg (-3.6 SD), 1 03 cm (- 5.3 SD) and 44.5 cm ( Abdominal ultrasonography was normal. The cranial MRI revealed cortical atrophy and corpus callosum agenesis. …

An adult female patient with ring chromosome 21: behavioural phenotype and results of high-resolution molecular characterisation.

Abstract: Verhoeven WMA, Bon BV, Egger JIM, Hoischen A, Doelman JC. An adult female patient with ring chromosome 21: behavioural phenotype and results of high-resolution molecular characterisation.ObjectiveA female adult patient with mild to moderate mental retardation and minor dysmorphisms was referred for neuropsychiatric examination because of psychotic and autistic symptoms and impulsive behaviours.MethodsStandardized neuropsychiatric and neuropsychological assessment as well as detailed somatic and neurological examination was performed. For genetic analysis, karyotyping, whole genome array analysis, and high-resolution detailed analysis of chromosome 21 were carried through.ResultsKaryotyping showed a de novo ring chromosome 21: 46,XX,der(21)r(21)(p11q22.3). High-resolution array analysis demonstrated a complex aberration consisting of an interstitial duplication in 21q21.1, an interstitial deletion in 21q22.2q22.3, an interstitial deletion in 21q22.3 and a terminal deletion of 21q22.3. Apart from mild dysmorphisms, visual and auditory impairments, and infertility, no somatic or neurological abnormalities were found. A formal psychiatric diagnosis could not be established. The behavioural problems and the supposed psychiatric symptoms could be related to her disharmonic social cognitive profile. The behaviour normalized after the patient returned to a stable and structured living environment.ConclusionHigh-resolution micro-array analysis techniques are essential to substantiate the genotype–phenotype correlation in patients with r(21) and other genetic disorders. Moreover, the results of this study stress the importance of the recognition of alexithymia as a potential cause for behavioural problems and psychiatric symptoms in patients with mental retardation in general.