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The karyotypic picture of a female patient with acute myelomonocytic leukemia (A.M.M.L.) consisted in the loss of a sex chromosome and a ring chromosome 21. It is suggested that in A.M.M.L. the loss of sex chromosome may represent an early event, the monosomic cells being the object of further chromosome rearrangements, which involve more frequently a chromosome 21.
Two mutant alleles of the meiotic locus, mei-9, have been examined for their effect on magnification of a rod Xbb chromosome and transmission of a ring Xbb chromosome under magnifying conditions. Our results indicate that the effects of these two mutations are allele-specific: mei-9a strongly inhibits both rod chromosome magnification and ring chromosome loss under magnifying conditions, while mei-9b has a smaller inhibitory effect on rod chromosome magnification and on the transmission of ring chromosomes under magnifying conditions. These observations can be explained by a difference in leakiness between the two alleles. Our results demonstrate that mutants defective in excision repair and repair replication inhibit ribosomal gene magnification. This suggests that a component of the excision repair pathway is involved in the process of magnification.
Ring chromosomes offer an opportunity to measure sister-chromatid exchange (SCE) frequencies without the use of an agent to differentiate sister chromatids: SCE frequencies can be determined from the number of dicentric rings formed in cells from a cell line carrying a monocentric ring chromosome. Ash is a pseudotetraploid Chinese hamster ovary cell line in which approximately 40% of metaphase cells have a large ring chromosome. We have used this cell line to investigate the spontaneous rate of SCE by determining the rate of dicentric ring formation and have compared this with the rate of loss of the ring chromosomes over time. In the absence of both [3H]thymidine and bromodeoxyuridine, the spontaneous rate of SCE in Ash cells was 0.12 SCEs/ring/cell cycle; this rate was increased by bromodeoxyuridine, by the polyfunctional alkylating agent mitomycin C, and by the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide. This indicates that spontaneous SCE occurs in this line and that not all 3-amino-benzamide-induced SCEs are dependent upon incorporated bromodeoxyuridine. Ring chromosomes were not lost over time as rapidly as predicted by the SCE frequencies observed. Non-disjunction of the dicentric ring, or anaphase bridge breakage followed by reunion to form one or two monocentric rings, are the most likely explanations for this discrepancy.
Ring chromosome 22, a rare cytogenetic finding, was first described by Weleber et al. in 1968. Since then approximately 50 patients have been reported in the medical literature. We describe five previously unreported subjects with ring chromosome 22 syndrome, summarize the clinical findings of reported patients from the literature and discuss the involvement of the ring chromosome and clinical outcome. Our subjects demonstrated the prominent features of this syndrome including mental retardation, hypotonia, motor delay, lack of speech, full eyebrows, and large ears. In addition, two of our subjects had central nervous system malformations and regression. The lack of consistent physical abnormalities in our subjects further supports no consistent phenotype manifestations in this cytogenetic syndrome. The variable clinical manifestations seen in ring chromosome 22 subjects may be associated with loss of chromosome 22 sequences near the telomere or attributed to the genetic background of each subject. Similarly, recessive alleles unmasked by the deletion could also contribute to the phenotype.
We studied the mechanism of ring chromosome 21 (r(21)) formation in 13 patients (11 unique r(21)s), consisting of 7 from five families with familial r(21) and 6 with de novo r(21). The copy number of chromosome 21 sequences in the rings of these patients was determined by quantitative dosage analyses for 13 loci on 21q. Nine of 11 r(21)s, including the 5 familial r(21)s, showed no evidence for duplication of 21q sequences but did show molecular evidence of partial deletion of 21q. These data were consistent with the breakage and reunion of short- and long-arm regions to form the r(21), resulting in deletion of varying amounts of 21q22.1 to 21qter. The data from one individual who had a Down syndrome phenotype were consistent with asymmetric breakage and reunion of 21q sequences from an intermediate isochromosome or Robertsonian translocation chromosome as reported by Wong et al. Another patient, who also exhibited Down syndrome, showed evidence of a third mechanism of ring formation. The likely initial event was breakage and reunion of the short and long arms, resulting in a small r(21), followed by a sister-chromatid exchange resulting in a double-sized and symmetrically dicentric r(21). The phenotype of patients correlated well with the extent of deletion or duplication of chromosome 21 sequences. These data demonstrate three mechanisms of r(21) formation and show that the phenotype of r(21) patients varies with the extent of chromosome 21 monosomy or trisomy.
In situ hybridization of a telomeric (TTA-GGG)n sequence to metaphases from three cases of ring chromosome, involving respectively chromosomes 4, 16, and 20, showed the presence of the cognate sequences in all three rings. To investigate whether these ring chromosomes originated by telomere-telomere fusion, we determined, by in situ hybridization, whether telomere-associated sequences and/or specific distal sequences were still present in the ring chromosomes. The finding that these sequences were preserved in all the ring chromosomes strongly indicates that they originated by telomere-telomere fusion. All three subjects carrying the ring chromosomes are affected by the so-called ring syndrome, with failure to thrive, minor dysmorphic signs and no major anomalies. The r(4) patient has the ring in mosaic form with a normal cell line and has normal intelligence. The r(16) and the r(20) patients have moderate mental retardation and suffer from seizures. We conclude that the ring syndrome, even in its more severe manifestation, is caused by ring chromosome instability.
What appears to be the first hairy cell leukemia case with a 14q+ anomaly is described. In addition to the 14q+ anomaly, a 6q- and a ring chromosome were seen in a blood sample stimulated with lipopolysaccharide, a B-cell mitogen. The clinical course of the present case was short, stormy, and had a poor response to therapy. The correlation between the clinical course and the presence of a ring chromosome in myelo- and lymphoproliferative blood disorders is discussed in relation to the various blood disorders with this karyotype anomaly described in the literature.
We report on r(21) chromosome in a boy and a der(21) chromosome in his mother. Cytogenetic studies revealed a mosaic 45,XY[4]/46,XY,r(21)[96] karyotype in the boy and a 46,XX,der(21)[100] karyotype in the mother. Fluorescence in situ hybridization analysis for D21Z1 at the centromere, AML1 at 21q22.1, LSI21 at 21q22.2, and 21qtel at the telomere region showed that the r(21) chromosome retained single copies of D21Z1, AML1, and LSI21 and lacked the 21qtel, whereas the der(21) chromosome had two copies of the 21qtel on both of its ends and single copies of D21Z1, AML1, and LSI21, with a paracentric inversion of AML1 and LSI21 (21qtel-D21Z1-LSI21-AML1-21qtel). Microsatellite analysis for nine loci on 21q22.3 indicated that the r(21) chromosome was missing a distal 21q22.3 region involving D21S1890, D21S1411, and D21S1903 with no maternally derived alleles, and that the der(21) chromosome was associated with duplication of a distal 21q22.3 region encompassing D21S1890 and D21S1446. The results suggest that a U-type exchange occurred between the homologous distal 21q regions duplicated on the der(21) chromosome, leading to the r(21) formation. This is a novel mechanism put forward for the formation of a monocentric ring chromosome.
Supernumerary rings in the context of a simple karyotype characterize several low-grade malignant tumors of soft tissue and bone. Low-grade fibromyxoid sarcoma is an uncommon low-grade sarcoma, the cytogenetics of which has not yet been reported. Here we describe the first molecular-cytogenetic characterization of a pulmonary metastasis of low-grade fibromyxoid sarcoma. The histology of the primary and recurrent tumors was consistent with the diagnosis of low-grade fibromyxoid sarcoma of the usual type, whereas the pulmonary metastasis was of the "giant rosettes" variant. Cytogenetic analysis revealed a ring chromosome. Because gain of material of chromosomes 7 and 16 was detected by CGH, the ring chromosome is assumed to be composed of material from these respective chromosomes.
In the genesis of hematologic neoplasms gene amplification is a mechanism for illegitimate activation of proto-oncogenes. We report a phenotypically normal patient with a constitutional ring chromosome 21 who developed acute myeloid leukemia (AML). The leukemic cells revealed size-variable ring chromosomes 21 with amplification of the proto-oncogene AML1, located in the chromosomal band 21q22, within the rings. Hitherto, amplification of the proto-oncogene AML1-also in form of a ring chromosome-has been described recently only in one patient with myelodysplastic syndrome (MDS). In AML, gene amplification by ring formation has been demonstrated only in another three patients (amplification of the MLL gene in two cases and of the ETV6 gene in one case). Here we present the new evidence that the internal rearrangement of a constitutional ring chromosome 21 resulted in multiplication of a proto-oncogene in bone marrow cells and provided obviously a selective growth advantage. Moreover the amplification of ribosomal DNA was observed in the ring chromosomes of the tumor cells.
We here describe the first example of the replacement of an autosome by two ring chromosomes originating from the missing chromosome, presented in a patient with a single chromosome 18 and two additional ring chromosomes. Detailed fluorescence in situ hybridization (FISH) analysis revealed the chromosome 18 origin of both ring chromosomes and characterized the small and the large ring chromosome as derivatives of the short and long arm of chromosome 18, respectively. The loss of subtelomeric regions of the short and the long arm of chromosome 18 in the ring chromosomes was confirmed by FISH studies. Molecular studies showed the exclusive presence of the paternal alleles for microsatellite markers located distal to the short and long arm loci D18S843 and D18S474, respectively. This indicates the maternal origin of both rings and provides evidence for substantial deletions of the distal parts of both arms of chromosome 18 in the ring chromosomes. The dysmorphic features of the patient can be explained by these deletions in both chromosome arms, as the clinical findings partly overlap with observations in 18p- and 18q-syndrome and are similar to some cases of ring chromosome 18. Centromere misdivision is suggested as one mechanism involved in the formation of the ring chromosomes.
Ring chromosomes are uncommon findings in prenatal diagnosis. Growth retardation is the most significant manifestation, in particular among patients with rings of larger chromosomes. A 30-year-old gravida 1, para 0 white woman was referred for genetic counseling because of maternal anxiety. Cytogenetic analysis of amniotic fluid cells at 16 weeks gestation revealed an abnormal mosaic female chromosome complement; 46,XX,r(11)(p15q25)[14]/45,XX,-11[7]. The ring 11 showed no detectable loss of chromosomal material at 450 band level. Both parents had a normal karyotype. Fluorescence in situ hybridization demonstrated intact subtelomeric regions in the ring chromosome. A targeted ultrasound evaluation at the time of consultation suggested no significant abnormalities. The parents were counseled and subsequently decided to terminate the pregnancy. The autopsy revealed an immature female fetus with abnormal craniofacial features including brachycephaly, low-set ears and hypertelorism, bicornuate uterus, and calcifications in the renal tubules. The abnormal phenotypes could be a consequence of the ring instability, submicroscopic deletion, and/or alteration of genetic material at the site of fusion.
Inheritance of ring chromosomes is reported infrequently. The authors report on a phenotypically and mentally normal mother with ring chromosome 18 mosaic with a normal cell line and her polymalformed son with non-mosaic 46,XY,r(18) karyotype.
Ring chromosome formation can occur without deletion, through the abnormal pairing of the palindromic DNA base sequences thought to make up the telomeres. The normal occurrence of sister chromatid exchanges within a ring constantly produces further chromosomal anomalies that are less likely to survive when the chromosome involved is large and/or its aneuploidy incompatible with life. These abnormal products (abbreviated pro) were only found in the present case after two or more cell cycles in lymphocyte cultures. Their elimination in vivo implies a very high cellular death rate and an enormous waste of metabolism that should have the same phenotypic effects no matter what chromosome is involved. These phenotypic anomalies form a ring syndrome that can be clinically recognized and consists of severe growth failure, mental retardation and a pleasant personality. The syndrome is usually masked by the more severe abnormalities produced by the deletions present in most cases of ring chromosomes.
Ring chromosome 18 (46,XX,r(18)) has previously been reported in about 70 patients. Another patient with the well-known physical and cytogenetic characteristics and, in addition, skeletal abnormalities in the feet, is presented here.
In this study, two specimens of a parosteal osteosarcoma, a rare primary bone neoplasm comprising only 3-6% of all osteosarcomas, were cytogenetically analyzed utilizing standard techniques. In contrast to the complex karyotypes previously reported in osteosarcoma, this particular histologic subtype was characterized by a single chromosomal aberration, a ring chromosome. Ring chromosomes have been described as characteristic for two other low-grade malignant mesenchymal neoplasms, well-differentiated liposarcoma and dermatofibrosarcoma protuberans. We propose that the observation of a ring chromosome in osteosarcoma also correlates with a low-grade malignant potential.
A case of ring chromosome was reported. By application of different techniques it was identified as 15 r. The boy 19 months old was of a short stature, small skull and slight psychomotoric retardation.
Ring chromosome 15 was detected in a boy with severe growth failure and no dysmorphic features who had previously been found to have an atrophic intestinal mucosa, a finding not observed in about 300 patients with ring autosome reported so far. Of the 137 metaphases examined, 8.1% had secondary aneuploidy produced by the structural and behavioural instability of the ring. Ring derivatives could also be seen in lymphocytes after only one cycle in the culture, indicating that such cells are also generated in vivo. We observed an increased cell death rate in fibroblast culture by Trypan Blue exclusion. These results suggest that there is a continuous in vivo generation of cells with increased mortality resulting in both growth failure and atrophic intestinal mucosa in the patient. The atrophic intestinal mucosa might be a manifestation of ring instability.