Impact of chromosomal translocations on prognosis in childhood acute lymphoblastic leukemia.

The presence of a chromosomal translocation in the leukemic cells at diagnosis of acute lymphoblastic leukemia (ALL) in children is associated with a high risk for treatment failure. We have reexamined the relationship between translocations and prognosis in 146 children with ALL who received risk-based therapy such that high-risk patients were treated with intensive drug schedules. In univariate analysis, multiple factors were associated with a relatively poor event-free survival (EFS) including age less than 2 years or greater than 10 years (combined group), WBC count greater than 10 x 10(9)/L, French-American-British (FAB) morphologic classification L2, absence of common ALL antigen (CALLA, CD10) expression, absence of hyperdiploidy with a chromosome number of 50 to 60, and presence of the specific translocations t(4; 11)(q21;q23) or t(9;22)(q34;q11) (combined group). However, there was no disadvantage with respect to EFS in patients with translocations compared with those who lacked translocations (73% at 4 years in both groups). Furthermore, when patients with specific cytogenetic abnormalities for which the prognostic significance has been well established (hyperdiploid 50 to 60, t(4;11), and t(9;22] were removed from the analysis, the remaining group with other translocations had a better EFS than the remaining group lacking translocations, although this was not statistically significant (81% v 65% at 4 years, P = .24). In a multivariate analysis, a model including WBC count and FAB classification was the strongest predictor of EFS. The presence or absence of translocations was not an independent predictor of EFS and did not contribute to the ability of any model to predict EFS. In conclusion, when effective intensive therapy is used to treat childhood ALL with high-risk clinical features, categorization of patients on the basis of chromosomal translocations without attention to the specific abnormality is not useful as a prognostic factor.

Pseudoleukemia in Down's syndrome. Analysis of immunophenotype and gene rearrangement.

This report demonstrates a case of transient abnormal myelopoiesis (TAM) evolving in a patient with Down's syndrome. A diagnosis was established after the patient's blast cell count decreased considerably three weeks after the initial leukemic phase. The blast population in the authors' case expressed Leu-9 (CD7), 6D1, and TdT+. Cytochemistries showed some of the blast population to be peroxidase positive and Sudan black positive. Platelet peroxidase by electron microscopic examination showed some positive blasts. Therefore, surface markers and cytochemical studies in this case suggested an abnormal proliferation involving a pluripotential stem cell capable of expressing myeloid and lymphoid characteristics. Cytogenetics was performed at birth and showed 47,XY,+21/48,XY,+21,+mar, confirming the diagnosis of Down's syndrome. The origin of the chromosomal fragment was uncertain. It was of interest that during the remission phase of his pseudoleukemia there was a concomitant decrease in the extra chromosomal fragment. Immunoglobulin and T-cell antigen receptor gene rearrangement studies showed only germline patterns, indicating that the lymphoid cells in the blast population were not clonally expanded. Therefore, immunoglobulin and T-cell antigen receptor rearrangement analysis and immunophenotyping are extremely valuable techniques in distinguishing between TAM and acute lymphoblastic leukemia in patients with Down's syndrome.

Diffuse malignant leptomeningeal gliomatosis in a child: a case report and review of the literature.

Diffuse leptomeningeal gliomatosis is a rare condition characterized by glioma in the leptomeninges without a dominant mass lesion. The difficulty in diagnosis of this condition, its rarity. and its extensive nature have hampered its successful treatment. Most cases of primary diffuse leptomeningeal gliomatosis have occurred in adults. Reported here is a case of this condition in a 9-year-old girl; to the authors' knowledge, she is the youngest patient with diffuse leptomeningeal gliomatosis and the longest survivor of the malignant variety.

Down syndrome complicated by hemoglobin S/beta+ thalassemia. Atypical expression of coexistent disease.

The chance occurrence of Down syndrome and sickle cell disease is an extremely rare event. The patient presented in this article is the only reported case, based on medical literature review, of Down syndrome coexisting with sickle cell disease due to hemoglobin S/beta+ thalassemia. He had multiple recurrent aplastic crises and severe psychomotor and growth retardation. The physiologic basis for the atypical manifestations of both of his disorders is the subject of this report.

High-dose intravenous gammaglobulin (IVG) in neonatal immune thrombocytopenia.

Recent reports suggest that intravenous gammaglobulin (IVG) may be an effective treatment modality in patients with immune thrombocytopenia (ITP). Two newborns with isoimmune thrombocytopenia secondary to HLA-A2 and PLA1 platelet antigen incompatibilities with their respective mothers and two newborns with thrombocytopenia secondary to maternal ITP were treated with IVG 400 mg/kg/day x 5 days. One patient was exposed to steroids in utero; only one mother was thrombocytopenic at the time of delivery. All patients were severely thrombocytopenic on day 1 of treatment with mean platelet count of 5.7 x 10(9)/L. All had petechiae and positive quaiac stools, and patients with isoimmune thrombocytopenia had CT scan evidence of intracranial bleeds. The mean platelet count after 24 hr was 26.7 x 10(9)/L and the average platelet increase was 21 x 10(9)/L and 33 x 10(9)/L at 24 and 48 hr, respectively. The two cases with isoimmune thrombocytopenia had sustained platelet increases; the two cases secondary to maternal ITP had transient platelet elevations. IVG can rapidly elevate the platelet count in these patients, especially those with severe bleeding manifestations.

Chloramphenicol toxicity associated with severe cardiac dysfunction.

A 9-month-old infant experienced severe chloramphenicol toxicity associated with high serum levels (313 micrograms/ml). Cardiovascular collapse with cardiomyopathic changes and impaired left ventricular function was documented by echocardiography. Serial echocardiographic evaluation showed resolution of the cardiomyopathic findings as the chloramphenicol levels were spontaneously cleared. Clinical course was complicated by the development of liver disease and coagulopathy compatible with disseminated intravascular consumption. Patient's recovery was complete and uneventful, nevertheless, chloramphenicol toxicity in childhood is associated with a significant mortality rate of 40%. The related impaired cardiac function, although reversible, appears to play a major role in the pathogenesis and eventual outcome in this syndrome.

High-dose steroids in childhood acute idiopathic thrombocytopenia purpura.

Nine newly diagnosed, previously untreated children (mean age: 4.2 years, range: 1-9 years) with severe acute idiopathic thrombocytopenia purpura (mean platelet count: 5.8 X 10(9)/L, range: 1-12 X 10(9)/L) were treated with high-dose steroids (prednisone 4-8 mg/kg/day). Steroid dose was based on platelet count at presentation: Group I (platelets less than 5 X 10(9)/L) was started on 8 mg/kg/day; Group II (platelets 5-15 X 10(9)/L) received 6 mg/kg/day. All patients had serologic and histologic evidence of acute idiopathic thrombocytopenia purpura. On this protocol, it took a mean number of 1.9 days (1-3 days) to reach a platelet count of at least 20 X 10(9)/L and 9.2 days (3-26 days) to reach a normal platelet count. No significant toxicity was observed except for weight gain ranging from 3-10% and mild behavioral problems. Both groups were on high-dose steroids (4-8 mg/kg/day) for 7.3 +/- 2.1 days. Only one patient had a brief relapse to a platelet count of 18 X 10(9)/L while on therapy (day 14), but responded promptly to an increase in prednisone dose. Presently, all nine patients are in remission and have not required maintenance medication.

Elevated lead levels in a patient with sickle cell disease and inappropriate secretion of antidiuretic hormone.

A five-year-old girl with known sickle cell disease presented with severe hyponatremia and findings compatible with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). She was found to have lead levels in the Class III category. By exclusion, we postulated that the SIADH was in some way related to the high lead levels, since this was the only abnormality the patient exhibited. The toxic lead levels and the elevated vasopressin levels rapidly responded to dimercaprol and calcium EDTA chelation therapy.

Serum LDH values in childhood acute leukemias and non-Hodgkin's lymphoma.

Serum lactate dehydrogenase activity (LDH) was examined in 66 children with acute lymphoblastic leukemia (ALL), 26 with acute non-lymphocytic leukemia (ANLL), and 116 with non-Hodgkin's lymphoma (NHL). The mean serum LDH value for the ALL and ANLL groups was not significantly different: 970 +/- 105 units/L (mean +/- standard error of the mean) and 817 +/- 161 units/L, respectively. The difference between the LDH values in patients with ALL (970 +/- 105 units/L) and NHL (551 +/- 51 units/L) was significant (P = .001). In 32% of the patients with ALL and 23% of the patients with ANLL, serum LDH values were above 1000 units/L, whereas only 13% of the cases with NHL had values above 1000 units/L. In patients with ALL the LDH levels were correlated with white blood cell counts at the time of diagnosis. In NHL, there was no difference in serum LDH levels among the various histologic subtypes. Values of LDH in stage IV NHL and in ALL were similar.

Sinus histiocytosis with massive lymphadenopathy: skeletal involvement.

A 9-year-old girl with known sinus histiocytosis with massive lymphadenopathy (SHML) has been followed since infancy. At age six, she developed swelling and pain in several joints. Subsequently, bone lesions were identified by scintigraphy and radiographs. Biopsy of the bone showed typical features of SHML. Bone lesions in this disease are rare. The lesions in this patient were followed for 3 years and remained unchanged despite chemotherapy.

Acute myeloid leukaemia in a patient with Seckel syndrome.

We report a female patient with Seckel syndrome who developed acute myeloid leukaemia at the age of 26 years. Analysis of bone marrow chromosomes showed an abnormal clone with abnormalities involving multiple chromosomes, including monosomy 7, trisomy 8, trisomy 11, and loss of the long arm of chromosome 5. After treatment with chemotherapy, the patient experienced severe toxicity with profound bone marrow aplasia and died of pneumonia two months later. We suggest that patients with Seckel syndrome may be at risk of developing myelodysplasia and acute myeloid leukaemia. They may also have poor tolerance to cytotoxic therapy.

Diagnosis of intrapericardial tumor in an infant by two-dimensional echocardiography.

Two-dimensional echocardiography is a useful noninvasive tool for diagnosing intrapericardial tumors as a cause of respiratory distress or abnormal cardiomediastinal shadow on chest x-ray. Early recognition of these tumors within the pericardium is important since surgical removal is often curative. Cardiac cineangiography is unnecessary to delineate further the tumor and should be reserved for those in which associated intracardiac defects are suspected.

Neonatal and maternal platelets: activation at time of birth.

Determination of the plasma concentrations of beta-thromboglobulin (BTG), thromboxane B2 (TxB2) and platelet factor 4 (PF4) were made at the time of birth in 18 newborns and their respective mothers. Both groups show significant elevation of all these molecular markers, suggesting marked platelet activation. The elevated TxB2 levels in the newborn group, 25 +/- 8 pg/ml, are compatible with a normally functioning and activated platelet prostaglandin pathway. Mode of delivery, vaginal or caesarean section, does not significantly influence the degree of activation in either group. Ultrastructural platelet examination did not reveal any morphologic differences between maternal and newborn platelets. There appears to be marked activation of the newborn and maternal platelet systems at the time of birth, and we postulate that this may explain in part the transient platelet dysfunction observed in newborns.

Testing for Passovoy defect in children with prolonged activated partial thromboplastin time (APTT)

PURPOSE: To investigate the value of testing for Passovoy defect using the commercially available Passovoy trait plasma (PTP) in children with prolonged activated partial thromboplastin time (APTT). PATIENTS AND METHODS: We studied 13 children with prolonged APTT that corrected in a 1:1 mix with normal human plasma but not with PTP. In most children, a thorough laboratory investigation of the intrinsic pathway factors and von Willebrand factor was performed. RESULTS: Five patients had bleeding manifestations and eight were asymptomatic. Measurement of von Willebrand factor and intrinsic pathway factors revealed abnormal values in eight patients (low von Willebrand activity in six patients, low factor XII in one patient, and the presence of lupus anticoagulant in one patient). CONCLUSION: Our data suggest inability to diagnose Passovoy defect based on a mixing study. This study also raises the question of whether Passovoy defect exists as a distinct coagulation disorder.

Sinus histiocytosis with massive lymphadenopathy: remission with chemotherapy.

A case of sinus histiocytosis with massive lymphadenopathy (SHML) is reported, in which the patient had severe life-threatening complications resulting from SHML. The disease process was extensive involving the respiratory tract, skeleton, integument, orbit and eyelid, uveal tract, and the lymphatic system. Treatment with cytotoxic agents (chlorambucil, prednisone) resulted in resolution of the airway obstruction and was effective in managing these severe complications with minimal observed toxicity.

Neonatal and maternal fibrinolysis: activation at time of birth.

Utilizing chromogenic synthetic substrate-based methods, determination of the plasma concentration of plasminogen, alpha 2-antiplasmin, alpha 2-macroglobulin, and B beta 15-42-related peptides were made at the time of birth in both newborns and mothers. Plasminogen levels were increased in the maternal group (150 +/- 26%), and markedly decreased in the newborn group (67 +/- 14%). The major inhibitors of fibrinolysis, alpha 2-antiplasmin and alpha 2-macroglobulin, were within normal range in both groups. Determination of B beta 15-42-related peptide showed markedly increased levels in the maternal group above control values (115 +/- 102, normal 29 +/- 12); the newborn group showed values only mildly elevated above control values (39 +/- 21). The results demonstrate increased fibrinolytic activity in both groups, though the degree of activation is significantly higher in the maternal group, as reflected by the higher levels of B beta 15-42-related peptides. Fibrinopeptide A levels confirm an activation of coagulation in both maternal and newborn groups (22 +/- 4 ng/ml and 138 +/- 22 ng/ml, respectively) with a significantly increased level in newborns (2-5 ng/ml normal).

Acute megakaryoblastic leukemia in Down's syndrome: report of a case and review of cytogenetic findings.

A case of a child with trisomy 21 and acute megakaryoblastic leukemia (AMBL) is reported. Histological examination of the bone marrow showed progressive fibrosis and replacement with megakaryoblasts. The diagnosis was confirmed by platelet peroxidase reaction and immunofluorescent staining with anti-factor VIII. Serial cytogenetic studies using banding techniques at various stages during the course of the disease (preleukemia, leukemia, remission, and relapse) showed several chromosomal abnormalities (unbalanced translocation between chromosomes 1 and 4 leading to trisomy 1q, trisomy 7q, monosomy 7p, and a reciprocal translocation between chromosomes 10 and 16). AMBL in childhood is probably more common than previously reported. Any association between AMBL and a particular cytogenetic abnormality must await further cytogenetic studies, specifically those employing banding techniques.

Passive transfer of collagen arthritis: heterogeneity of anti-collagen IgG.

Using a combination of affinity chromatography procedures, anticollagen IgG was fractionated into three distinct populations. One population reacted only to conformational determinants, another population reacted only to structural determinants, and the third population reacted to both conformation and structural determinants. When these populations were tested for their arthritogenicity, only those fractions that reacted to conformational and to conformational and structural determinants were active in inducing clinical arthritis. Immunofluorescence analysis of the hind paw of recipient rats indicated that antibodies directed only to conformational and to both conformational and structural determinants bound to articular cartilage and activated the complement system. Antibodies directed strictly to structural determinants did not bind to articular cartilage and were nonarthritogenic.

Type II collagen arthritis: identification of arthritogenic epitopes using fractionated anticollagen IgG.

Affinity-purified anticollagen IgG was fractionated on purified cyanogen bromide-derived collagen peptide Sepharose. The antibody fraction bound to the peptides was eluted and tested for its ability to induce passive arthritis in recipients. Anticollagen IgG bound to peptide 5 (alpha 1(II)-CB8-10 and alpha 1(II)CB11-8) and to peptide 6 (alpha 1(II)CB11) were active in inducing passive arthritis. Other peptide bound fractions were inactive. These observations suggest that the arthritogenic domain in Type II collagen is restricted to alpha 1(II)CB11.