Age-dependent differences in Nordic children with ITP.
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Adolescent↗
Biomedical subjects
O G Jonsson
Publications and source records attributed to O G Jonsson.
Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage.
Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0-17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0.001) and doxorubicin (P = 0.005) than non-11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non-rearranged children. The 'AML-profile' common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0.026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high-dose cytarabine in the treatment of 11q23-positive patients both in AML and ALL.
Acute Disease↗
Chronic neutropenia during childhood. A 13-year experience in a single institution.
To evaluate the clinical course and characteristics of children with chronic neutropenia, we reviewed the charts of all such patients seen at our center during a 13-year period. A total of 50 patients with chronic neutropenia were identified. Three patients had documented congenital neutropenia, and two siblings had cyclic neutropenia. The remaining 45 children had chronic neutropenia of unknown origin. All children except two had a remarkably benign course despite markedly reduced granulocyte counts. Of six girls in this group who had abscess or cellulitis of the labia majora, it was a presenting manifestation in three. Resolution of neutropenia was documented in 23 (62%) of 37 patients for whom follow-up information was available, with a median duration of neutropenia of 19 months. No differences were evident between patients with positive antineutrophil antibody test results and those in whom the test yielded negative results or was not performed. Chronic neutropenia in childhood is a relatively uncommon entity, characterized by a benign course and eventual resolution in the majority of patients.
Child↗
Rearrangements of the tal-1 locus as clonal markers for T cell acute lymphoblastic leukemia.
Normal and aberrant immune receptor gene assembly each produce site-specific DNA rearrangements in leukemic lymphoblasts. In either case, these rearrangements provide useful clonal markers for the leukemias in question. In the t(1;14)(p34;q11) translocation associated with T cell acute lymphoblastic leukemia (T-ALL), the breakpoints on chromosome 1 interrupt the tal-1 gene. A site-specific deletion interrupts the same gene in an additional 26% of T-ALL. Thus, nearly one-third of these leukemias contain clustered rearrangements of the tal-1 locus. To test whether these rearrangements can serve as markers for residual disease, we monitored four patients with T-ALL; three of the leukemias contained a deleted (tald) and one a translocated (talt) tal-1 allele. These alleles were recognized by a sensitive amplification/hybridization assay. tald alleles were found in the blood of one patient during the 4th mo of treatment but not thereafter. Using a quantitative assay to measure the fraction of tald alleles in DNA extracts, we estimated that this month 4 sample contained 150 tald copies per 10(6) genome copies. The patient with t(1;14)(p34;q11) (talt) leukemia developed a positive assay during the 20th mo of treatment. By standard criteria, all four patients remain in complete remission 11-20 mo into treatment. We conclude that tal-1 rearrangements provide useful clonal markers for approximately 30% of T-ALLs.
Alleles↗
Methotrexate and childhood leukemia.
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Central Nervous System Diseases↗
Detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin hypervariable region specific oligonucleotide probes.
To develop a sensitive and specific assay for minimal residual disease in acute lymphoblastic leukemia (ALL), we exploited the enormous diversity of genomic sequences created by immune receptor gene rearrangements. To isolate clone-specific sequences, we first synthesized oligonucleotides that match conserved variable (VH) and joining (JH) sequences flanking the third hypervariable region (HVR3) in the rearranged immunoglobulin heavy chain (IgH) locus. In polymerase chain reactions (PCR), these primers were then used to amplify the intervening HVR3 segments from leukemic DNA samples. Of 12 B-lineage ALLs studied, ten generated one or more fragments of the size expected for HVR3 gene segments. Thus, this single pair of amplimers was sufficient to isolate HVR3 sequences from a majority of acute lymphoblastic leukemias. To verify that the amplified fragments originated from HVR3 alleles and to assess their diversity, we sequenced 7 PCR products derived from 6 leukemias. In addition to elements of recognized D segments, each of the 7 fragments contained novel VH-D and D-JH junctional sequences, including N nucleotides, not known to be present in the germline. Each sequence was unique, and allele-specific oligonucleotide probes hybridized only to HVR3 segments from which the probes were derived. Therefore, as anticipated, these HVR3 segments appeared to possess the diversity required to serve as clonal markers for leukemic populations. To demonstrate that these amplified HVR3 alleles could serve as the basis for a sensitive and specific assay to detect rare leukemic cells, we analyzed in detail one pre-B leukemia that had rearranged 2 IgH alleles. The HVR3 sequences were shown to be linked to rearranged JH-containing restriction fragments in digests of genomic DNA, establishing their origin in the leukemic cells. We synthesized oligonucleotides corresponding to the unique junctional sequences in the HVR3 segments. Using these novel amplimers in an allele-specific amplification and hybridization procedure, we showed that this assay can detect 10 leukemic cells in a background of 10(6) normal blood mononuclear cells. In contrast, the leukemic HVR3 sequences were not detected in extracts of normal or unrelated remission leukemic leukocytes. We conclude that the assay for specific IgH HVR3 sequences is a realistic strategy for detection of minimal residual disease in B-lineage ALL.
Alleles↗
Bone pain as an initial symptom of childhood acute lymphoblastic leukemia: association with nearly normal hematologic indexes.
We reviewed the records of all patients with a diagnosis of ALL made at our center during a 13-year period to determine the relationship between bone pain and the hematologic findings at diagnosis of acute lymphoblastic leukemia. Of 296 eligible patients, 179 (60%) had no bone pain (group 1), 65 (22%) had some bone pain (group 2), and 52 (18%) had prominent bone pain that overshadowed other manifestations of the leukemia (group 3). Statistically significant differences were found between the groups for hemoglobin concentration (p less than 0.001), leukocyte count (p = 0.014), absolute neutrophil count (p = 0.002), percentage of circulating blast cells (p = 0.009), and platelet count (p less than 0.001). Children in group 3 had values closer to normal for all these values than those of patients in the other groups. Group 3 patients had symptoms an average of more than 2 weeks longer before diagnosis, and had significantly lower serum uric acid and higher calcium levels than patients in the other groups had. No differences were detected among the groups in age at diagnosis, gender, or survival rate. We conclude that children with acute lymphoblastic leukemia who have prominent bone pain preceding the diagnosis frequently have nearly normal hematologic values and that this feature may contribute to a delay in diagnosis.
Bone and Bones↗
Systemic lupus erythematosus presenting as thrombotic thrombocytopenic purpura.
We describe a 10-year-old girl, who presented with thrombotic thrombocytopenic purpura (TTP) and shortly thereafter developed systemic lupus erythematosus (SLE). The association between TTP and SLE is known, but this is the first report of SLE presenting as TTP.
Child↗
Immunoglobulin class and subclass concentrations after treatment of childhood leukemia.
With greatly increased survival rates after childhood leukemia during the last 3 decades, the long-term effects of the treatment have become more evident. The disease and its treatment impair the immune system, but the duration of this impairment is unknown. The authors studied the serum concentrations of immunoglobulins and IgG subclasses in 20 Icelandic children cured of leukemia on average 8 years and 3 months after their treatment ended. Although no marked deviations were found in the concentrations of the main immunoglobulin classes IgA, IgM, IgG, and IgE, the IgG subclass levels were below reference values. The patients had on average 0.9 of age standardized reference values of IgG1, 0.5 of IgG2, 0.8 of IgG3, and 0.7 of IgG4. However, none had any autoimmune diseases or a markedly increased tendency for infections. The results indicate that although the immunoglobulin classes regain their normal values within a few years after cessation of treatment, recovery of the IgG subclasses, especially IgG2, is impaired.
Adolescent↗