Supernumerary Ring Chromosome Research Articles

Contribution of array CGH in prognosis and genetic counselling of prenatally diagnosed supernumerary ring chromosome 20

Contribution of array CGH in prognosis and genetic counselling of prenatally diagnosed supernumerary ring chromosome 20

Erratum to: Characterization of a prenatally assessed de novo supernumerary minute ring chromosome 20 in a phenotypically normal male

Erratum to: Characterization of a prenatally assessed de novo supernumerary minute ring chromosome 20 in a phenotypically normal male

Pallister–Killian syndrome caused by mosaicism for a supernumerary ring chromosome 12p

Pallister-Killian syndrome (PKS) is a rare but distinctive chromosomal syndrome distinguished by severe intellectual impairment, characteristic facial features, and variable structural anomalies. The characteristic cytogenetic abnormality in PKS is a supernumerary isochromosome 12p that confers mosaic tetrasomy. We describe a female child with PKS in whom tetrasomy 12p resulted from a supernumerary ring chromosome containing two copies of chromosome 12cen --> p13, a novel cytogenetic finding. The ring chromosome exhibited tissue-limited mosaicism, being absent in blood but detected in 38% of buccal mucosa cells and 41% of skin fibroblasts. Our patient demonstrated the typical dysmorphic characteristics of PKS, but her development was relatively advanced in comparison to children with isochromosome PKS. Her milder developmental phenotype may be attributable to differences in the mosaic distribution or the genomic content of the ring chromosome compared to mosaic isochromosome 12p.

Characterization of a prenatally assessed de novo supernumerary minute ring chromosome 20 in a phenotypically normal male

BackgroundThe heterogeneous group of small supernumerary marker chromosomes (sSMCs) presents serious counseling problems, especially if they are present de novo and diagnosed prenatally. The incidence has been estimated at 1 in 1000 prenatal samples. We present a case of mosaic sSMC diagnosed prenatally after amniocentesis. The sSMC was characterized by various molecular cytogenetic techniques and determined to be a r(20) chromosome. After genetic counseling, the parents decided to continue the pregnancy, and a boy with minor phenotypic variants was born after 39 weeks of pregnancy. The case is compared with four other cases of prenatally detected r(20) mosaicism.ResultsHere we describe a 3 months old male child with normal pre- and postnatal development and with a de novo ring supernumerary marker chromosome in amniocytes cultures. Using new fluorescence in situ hybridization (FISH) techniques, three distinguishable sSMCs (cryptic mosaicism), all derived from chromosome 20, were observed, including ring and minute chromosomes. This heterogeneity was impossible to detect by the conventional G-banding technique or conventional FISH technique that were used before the application of new FISH techniques (subcentromere-specific multicolor-FISH [subcenM-FISH]) and a probe, specific for the 20p12.2 band. The sSMC present in 25% of the cells was present as r(20)(::p12.2~12.3->q11.1::)[5]/r(20;20)(::p12.1->q11.1::q11.1 >p12.1::)[2]/min(20;20)(:p12.1->q11.1::q11.1->p12.1:)[1]. The final karyotype was 47,XY,+r(20)[25%]/46,XY[75%].ConclusionWe emphasize the importance of application of molecular cytogenetics in a prenatally diagnostic laboratory and description of more cases to enable a better genetic counseling and risk evaluation.

Molecular cytogenetic characterization of a de novo mosaic supernumerary ring chromosome 7: Report of a new patient

Molecular cytogenetic characterization of a de novo mosaic supernumerary ring chromosome 7: Report of a new patient

Variability of origin for the neocentromeric sequences in analphoid supernumerary marker chromosomes of well-differentiated liposarcomas

Well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas are cytogenetically characterized by the presence of supernumerary ring or giant chromosomes containing amplified material from the 12q14-15 region. These chromosomes contain neocentromeres, which are able to bind the kinetochore proteins and to ensure a stable mitotic transmission although they do not show detectable alpha-satellite sequences. WDLPS is the sole solid tumor for which the presence of a neocentromere is a consistent and specific feature. By immunostaining with anti-centromere antibodies in combination with FISH analysis (immunoFISH) in four cases of WDLPS, we have shown that sequences from the region 12q14-21 region were not located at the neocentromere site. In addition, we have microdissected the neocentromeric region from a giant supernumerary chromosome in the 94T778 WDLPS cell line. By using immunoFISH and positional cloning we have shown that the neocentromere of this cell line originated from a region at 4p16.1, rich in AT sequences and in long interspersed nucleotide element (LINE)1, that was co-amplified with 12q14-15. We have observed that this 4p sequence was not involved in the neocentromere of the supernumerary giant chromosome present in the 93T449 WDLPS cell line derived from a metachronous recurrence of the same primary WDLPS than 94T778. Altogether, these results indicate that the neocentromeres in WDLPS originate from amplified chromosomal regions other than 12q14-15 and do not involve a specific and recurrent DNA sequence. These sequences might be activated for centromeric function by epigenetic mechanisms.

Monosomy 7 and absence of 12q amplification in two cases of spindle cell liposarcomas

Spindle cell liposarcoma (SCL) is a rare malignant adipose tissue tumor presently regarded as a variant of well-differentiated liposarcoma (WDLPS). While WDLPS is cytogenetically characterized by the presence of supernumerary ring or giant chromosomes containing MDM2 amplification, data concerning the genomic alterations of SCL are scarce. Here, we describe the molecular cytogenetic characterization of two SCL cases. In these two cases, we did not identify supernumerary ring or giant chromosomes containing 12q amplification or any other chromosome 12 rearrangement. Instead, we observed a partial or complete monosomy 7 as the sole anomaly or among a few additional simple numeric and structural abnormalities. Monosomy 7 is not usual in adipose tissue tumors. It has been described in myelodysplastic syndromes and acute myeloid or lymphoblastic leukemias, as well as in several benign or malignant solid tumors. Our data suggest that the loss of material from chromosome 7 might play a crucial role in the pathogenesis of some SCL probably through the inactivation of tumor suppressor genes located on chromosome 7. On the basis of cytogenetic and molecular findings, some SCL may constitute an independent entity rather than being regarded as variants of WDLPS.

Complex t(5;8) involving the CSPG2 and PTK2B genes in a case of dermatofibrosarcoma protuberans without the COL1A1-PDGFB fusion

Dermatofibrosarcoma protuberans (DFSP) is a rare, dermal neoplasm of intermediate malignancy. It is made of spindle-shaped tumor cells in a storiform pattern positive for CD34. Cytogenetically, DFSP cells are characterized by either supernumerary ring chromosomes composed of sequences derived from chromosomes 17 and 22 or more rarely of translocations t(17;22). These chromosomal rearrangements lead to the formation of a specific chimeric gene fusing COL1A1 to PDGFB. So far, the COL1A1-PDGFB fusion gene remains the sole fusion gene identified in DFSP. However, some observations suggest that genes, other than COL1A1 and PDGFB, might be involved in some DFSP cases. We report in this paper a DFSP case presenting as a unique chromosomal abnormality a complex translocation between chromosomes 5 and 8. This is the first report of a DFSP case where the lack of chromosomes 17 and 22 rearrangement and the absence of COL1A1-PDGFB fusion gene have been demonstrated. Using fluorescence in situ hybridization analysis, we showed that the CSPG2 gene at 5q14.3 and the PTK2B gene at 8p21.2 were disrupted by this rearrangement. Although rare, the existence of cases of DFSP negative for the COL1A1-PDGFB fusion has to be taken in consideration when performing molecular diagnosis for a tumor suspected to be a DFSP.

Genomic gains of COL1A1‐PDFGB occur in the histologic evolution of giant cell fibroblastoma into dermatofibrosarcoma protuberans

Giant cell fibroblastoma (GCF) is a subcutaneous mesenchymal neoplasm characterized by the chromosomal t(17;22), which results in the formation of the fusion gene COL1A1-PDGFB. This same fusion gene is also seen in the supernumerary ring chromosome of dermatofibrosarcoma protuberans (DFSP). Several studies have addressed the molecular genetics of DFSP but molecular cytogenetic characterization of individual areas and cell components in pure GCF and GCF/DFSP hybrids have not been performed. Herein, we studied the frequency and genomic copy number of COL1A1-PDGFB in pure GCF and GCF/DFSP hybrids, and identified the molecular cytogenetic signatures in individual cells in each component. Four pure GCF and nine GCF/DFSP hybrids were studied. All tumors exhibited classical histological features and CD34 expression. COL1A1 and PDGFB rearrangements were evaluated by fluorescence in situ hybridization (FISH) using probes for COL1A1 and PDGFB on paraffin-embedded thin tissue sections. All GCF and GCF/DFSP hybrids showed unbalanced rearrangements of COL1A1-PDGFB at the molecular cytogenetic level. Genomic gains of COL1A1-PDGFB were found predominantly in the DFSP component of GCF/DFSP hybrids but in none of the pure GCF, suggesting that these gains are associated with the histologic evolution of GCF into DFSP. The molecular cytogenetic abnormalities were found not only in the spindle/stellated cells but also in individual nuclei of the multinucleated giant cells, suggesting that these cells may result from the fusion of individual neoplastic cells.

Dedifferentiated liposarcoma of the pleura mimicking a malignant solitary fibrous tumor and associated with dedifferentiated liposarcoma of the mediastinum: Usefulness of cytogenetic and molecular genetic analyses

Dedifferentiated liposarcoma of the pleura is an extremely rare malignancy mimicking a variety of tumors, such as other sarcomas, mesothelioma, and malignant solitary fibrous tumor of the pleura. Liposarcoma of the pleura can be combined with mediastinal involvement, and in most cases it may be impossible to be certain where the primary tumor originated. In this report, we describe a very rare occurence of a dedifferentiated liposarcoma of the pleura in a 76-year-old woman associated with a distinct second dedifferentiated liposarcoma of the mediastinum. Histologically, the pleural tumor demonstrated spindle cells arranged in a fascicular pattern, whereas the mediastinal tumor was mostly adipocytic with small areas of spindle cells. Vimentin and protein S100 were focally expressed by the tumor cells. The differential diagnosis of the pleural mass included malignant solitary fibrous tumor. Cytogenetic analysis showed supernumerary ring chromosomes in the pleural tumor, as well as strong amplification of MDM2 and CDK4 genes in both tumors. Array comparative genomic hybridization showed amplifications of chromosome arms 6q, 12q, and 15q, shared by both tumors and strongly pointing to a common origin.

Array‐based genotype–phenotype correlation in a case of supernumerary ring chromosome 12

Supernumerary ring chromosomes (SRC) account for approximately 10% of prenatal marker chromosomes and 60% of these SRCs are associated with an abnormal phenotype of the patient carrying them. SRCs have, with few exceptions, not been characterized at the molecular genetic level. Here, we present the first case of a SRC 12 thoroughly investigated with tiling resolution array-based comparative genomic hybridization (array CGH); multicolor, centromere, subtelomeric and whole chromosome painting fluorescence in situ hybridization. In addition, to be able to correlate phenotypic manifestations with a possible pathogenetic outcome of the SRC 12, we retrospectively compared and reviewed all 14 cases of SRC 12 reported, including our present case. Our analyses revealed that the SRC comprised 25.53-46.40 Mb of chromosome 12, a region known to harbor 47 annotated genes of which nine were of putative pathogenetic relevance. Reviewing the previously described cases of SRC 12, we could not establish any specific recurrent features associated with this type of SRC. This most probably reflects heterogeneity in break-point distribution among the reported cases, resulting in differently sized ring chromosomes and hence varying phenotypic traits of the patients. Detailed genomic evaluation, by array CGH or similar techniques may thus be of importance to predict the clinical course in individual cases.

Dermatofibrosarcoma protuberans COL1A1-PDGFB fusion is identified in virtually all dermatofibrosarcoma protuberans cases when investigated by newly developed multiplex reverse transcription polymerase chain reaction and fluorescence in situ hybridization assays

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous, locally aggressive spindle cell tumor of intermediate malignancy. Tumor cells are reactive for CD34 and characterized by a t(17;22) translocation or a supernumerary ring chromosome that results in the fusion of exon 2 of PDGFB to various exons of the COL1A1 gene. We developed a multiplex reverse transcription polymerase chain reaction (RT-PCR) assay to detect fusion transcripts for all possible COL1A1 breakpoints. Twenty-seven formalin-fixed, paraffin-embedded DFSP cases were analyzed using 18 COL1A1 forward primers and 1 exon 2 PDGFB reverse primer. Sequence analysis was performed to definitively characterize breakpoints. Results were correlated with histology, immunohistochemistry, PDGFB break-apart fluorescence in situ hybridization analysis, and cytogenetics when available. Fusion transcripts were detected by RT-PCR in all but one DFSP case. Sequencing revealed a PDGFB exon 2 breakpoint in all cases. COL1A1 breakpoints were in exons 7 (1 patient), 10 (1), 29 (2), 40 (1), 46 (3), and 49 (2), and intronic between exons 13:14 (1), 26:27 (2), 30:31 (1) 33:34 (1), 43:44 (7), 45:46 (1), and 46:47 (1). Three novel COL1A1 breakpoints were identified, intronic between exons 13:14 (1), 30:31 (1) and in exon 49 (2). There was no correlation found between breakpoints and age, sex, or histologic variants. Using this sensitive multiplex RT-PCR assay in combination with fluorescence in situ hybridization, we found COL1A1-PDGFB rearrangements appear more prevalent in DFSP than previously reported. Its detection may be particularly helpful in the differential diagnosis of atypical, fibrosarcomatous, and metastatic DFSP.

Supernumerary ring chromosomes accompanied with near-tetraploidy following chemotherapy and cranial radiation in a girl with a relapsed acute lymphoblastic leukemia

Supernumerary ring chromosomes of different sizes and near-tetraploidy were presented in the bone marrow cells of 12-year-old girl with relapsed acute lymphoblastic leukemia who had been treated previously with chemotherapy and cranial radiation. Despite significant chromosomal abnormalities, complete hematologic and cytogenetic remissions were achieved.

Myxoinflammatory fibroblastic sarcoma: investigations by comparative genomic hybridization of two cases and review of the literature

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma of the distal extremities characterized by a myxohyaline stroma, a dense inflammatory infiltrate and virocyte- and lipoblast-like giant cells. Up to now, only two cases have been investigated cytogenetically, showing complex and heterogeneous karyotypes, in part with supernumerary ring chromosomes. We characterized two further cases of MIFS immunohistochemically and performed comparative genomic hybridization as well as DNA image cytometry analyses. Both tumors showed the characteristic histomorphological pattern of MIFS and were positive for Vimentin and CD68. Moreover, both cases presented aberrant karyotypes including distinct DNA copy number changes involving chromosome 7 and disclosed DNA aneuploidy.

P16 as a marker to differentiate atypical lipomatous tumor/well-differentiated liposarcoma from deep seated lipoma: An immunohistochemical analysis of 51 cases

10070 Background: Atypical lipomatous tumor (ALT)/well-differentiated (WD) liposarcoma is a locally aggressive malignant mesenchymal neoplasm characterized by supernumerary ring and giant marker chromosomes with amplification of MDM2 gene. These cytogenetic characteristics can be very helpful to distinguish ALT from deep-seated lipomas. As ALTs have only rare presence of lipoblasts, they can resemble benign lipomas rendering difficulty in morphological diagnosis. P16INK4 is a specific inhibitor of CDK4/CDK6. CDK6 gene is often found co-amplified with MDM2 gene in ALTs. P16 overexpression is a hallmark of cervical dysplasia. Our study investigates the value of p16 expression in cytogenetically confirmed ALTs and deep-seated lipomas. Design: Fifty-one (51) cases of lipomatous neoplasms, with cytogenetic results, from forty-three (43) patients were collected for the study from the archives in department of pathology, UMDNJ/NJMS during 1998 - 2005. These include 18 cases of deep-seated lipoma, one hibernoma, and 32 cases of ALT / well-differentiated liposarcoma (24 patients, five patients with recurrence, and four cases with de-differentiation). Immunohistochemical staining for p16 was performed on representative paraffin blocks. Staining results were scored according to intensity (negative 0, weak 1+, intermediate 2+, and strong 3+) and percentage of positive cells. Results: Twenty-eight cases (28/32, 87.5%) of ALT/WD liposarcoma, including all four cases of dedifferentiated liposarcoma, showed strong nuclear p16 expression. In cases of recurrence, the primary and recurrent tumor showed the same pattern of p16 staining. Four cases (4/32, 12.5%) of ALT/WD liposarcoma showed negative p16 expression. All cases of deep-seated lipoma (18/18, 100%) and single hibernoma showed negative p16 staining except focal positivity in areas of fat necrosis in two cases (p16 positivity, 87.5 vs. 0%, P <0.00001, Fisher's exact test). Conclusion: 1). P16 appears to be a valuable marker to differentiate ALT and deep-seated lipomas. 2). P16 expression remains unchanged in progression and transformation of ALT. 3). P16 related signal transduction pathway most likely is an early event in tumorogenesis of ALT. No significant financial relationships to disclose.

Supernumerary minute ring chromosome 14 in a man with primary infertility and left varicocele

To describe a case of supernumerary minute ring chromosome (SMRC) in an infertile man, with the concurrent finding of a left varicocele. Case report. Urologic infertility clinic in a university hospital. Male patient presenting with primary infertility. Karyotyping, genetic counseling, and microsurgical left varicocelectomy. Sperm concentration and motility, chromosomal number and structure. Fluorescence in situ hybridization revealing SMRC 14. Sperm concentration and motility improved after left varicocele repair. A karyotype should be included in the evaluation of severe oligospermia. Although SMRC 14 may be associated with fertility problems, repair of a coexisting varicocele should be considered in these patients.

Pseudo-Bartter's Syndrome due to Hirschsprung's disease in a neonate with a ringchromosome 8

Chromosome 8 is the largest chromosome found to be trisomic among live-born infants. Live-born infants usually have trisomy 8 mosaicism. The supernumerary chromosome in a trisomic condition may additionally also be a ring chromosome, known as supernumerary ring chromosomes. This condition leads to congenital anomalies overlapping with trisomy 8 syndrome. Hirschsprung's disease is the main genetic cause of functional intestinal obstruction and is known to be associated with trisomy 8 mosaicism. Hirschsprung's disease is characterized by the absence of parasympatic intrinsic ganglion cells in the submucosal and myenteric plexuses and leads to intestinal obstruction with abdominal distention, intestinal stasis and vomiting. This may produce hypokalemic and hypochloremic metabolic alkalosis with secondary hyperreninemia and hyperaldosteronism, known as pseudo-Bartter's syndrome. We describe a case of pseudo-Bartter's syndrome due to Hirschsprung's disease in a neonate with supernumerary ring chromosome 8 (46XX, 47XX + r(8)). Symptoms resolved partially after symptomatic treatment with fluid and electrolyte repletion and completely disappeared after colostomy by taking away the causal factor.

Five cases of supernumerary small ring chromosomes 1: Heterogeneity and genotype–phenotype correlation

Genetic counselling of patients with small supernumerary ring chromosomes (sSRCs) can be difficult, especially in prenatal testing, due to the complexity in establishing a karyotype–phenotype correlation. In fact, it has been estimated that about 10% of extra ring(1) chromosomes are associated with an unremarkable phenotype. We report on five new cases of extra ring chromosomes(1) manifesting different clinical outcome. One case was familial, segregating from a mother with mosaic karyotype, while the others were de novo. Ring chromosomes were characterised by FISH. In three subjects the involvement of the same euchromatic 1p region was demonstrated. Present observations corroborate previous results and provide some insight into the identification of the harmless ring(1) structures.

Formation of the 12q14-q15 Amplicon Precedes the Development of a Well-differentiated Liposarcoma Arising From a nonchondroid Pulmonary Hamartoma

Pulmonary hamartoma is a benign neoplasm that rarely recurs or undergoes malignant transformation. Herein, we report a 48-year-old woman with a history of an incomplete excised nonchondroid pulmonary hamartoma presenting as an indolent tumor recurrence. Excision of the tumor revealed a well-differentiated liposarcoma arising from the hamartomatous component. Fluorescence in situ hybridation analysis for HMGA2 and MDM2 was performed on both hamartomatous and liposarcomatous component. MDM2 and HMGA2 amplification were found in a subset of stromal cells in the hamartomatous component and in most cells of the well-differentiated liposarcoma. No rearrangement HMGA2 was found in the pulmonary hamartoma component. These findings suggest that the formation of the 12q14-q15 chromosome amplicon, the characteristic cytogenetic finding of well-differentiated liposarcomas and the structural genomic component of the supernumerary ring and giant rod chromosomes, occurred before the morphologic changes characteristic of these malignant adipose tissue tumors and likely represents a very early molecular event in their development.

A case of mosaic supernumerary ring chromosome 15 with two copies of the segment 15p11.1–q14

Although supernumerary marker chromosomes derived from chromosome 15 (SMC(15)) are the most common marker chromosome in humans, ring SMC(15)s are rare. Here we report on a 16-month-old patient who has a ring SMC(15) with two copies of the segment 15p11.1-q14 region. She exhibits hypotonia, developmental delay, speech delay, microstomia, micrognathia, and other mild dysmorphic features. The ring was present in 22% of her peripheral blood lymphocyte cells. FISH study revealed that the ring was derived from chromosome 15, and had neither telomere sequence nor satellite III paracentromeric DNA. It had alpha satellite DNA, and two copies of the segment 15q11.2 to CTD 2125J1 (at 15q14, 2.2 Mbp telomeric of the common breakpoint 5). The ring-containing cells had four copies of 15p11.1-q14. The ring can be described as r(15)(::p11.1 --> q14::q14 --> p11.1::). Southern-blot analysis of the methylation pattern in the PW/AS critical region showed biparental inheritance, and the ring was maternally derived. This patient's phenotype was comparable to ring SMC(15) patients with three copies of the Prader-Willi/Angelman syndrome (PWS/AS) critical region.