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.

Juvenile myelomonocytic leukemia (JMML) with the hematologic phenotype of severe beta thalassemia.

A 3-year-old Filipino-American child with recurrent fever, splenomegaly, anemia, and thrombocytopenia, was found to have a hemoglobin F level of 76.9%. His reticulocyte count was elevated (4.3%), and erythroblasts were present in his peripheral blood. The child's erythrocytes were microcytic (MCV 66.9 fl) but his serum ferritin level was normal. His bone marrow at initial presentation demonstrated normal cellularity without an increase in blast cells. The disease progressed with worsening anemia, leukocytosis, and thrombocytopenia, with increased blasts in his marrow and the appearance of a mediastinal mass. His liver, spleen, and lymph nodes were found to be infiltrated with myeloblasts, supporting a diagnosis of juvenile myelomonocytic leukemia (JMML). Analysis of the child's Hb F showed a Ggamma/Agamma ratio of 2.2, which was within the characteristic range for JMML. A globin synthesis study using blood reticulocytes showed an alpha/non-alpha globin synthesis ratio of 2.24, typical of severe homozygous beta thalassemia. Southern blot analysis of blood-leukocyte DNA from the patient and his parents demonstrated no apparent abnormality in the beta-globin gene promoter or coding regions. The elevated level of Hb F in this child with JMML appeared to be part of an acquired Cooley's anemia-like hematologic phenotype.

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.

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.

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.

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.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia in children: correlation between chromosomal abnormalities and prior therapy.

We have studied 20 children with therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who were 3 months to 16 years old at diagnosis of their primary neoplasm and 1 to 24 years old at diagnosis of their secondary neoplasm. The median interval from initial treatment for the first malignancy to diagnosis of therapy-related MDS or AML was 46 months (range, 12 to 116 months). Twelve patients had chromosomal abnormalities resulting in loss of material from the long arm of chromosomes 5 and/or 7, three patients had abnormalities of chromosome 11 band q23, one patient had both classes of abnormalities, three patients had other abnormalities, and one patient had a normal karyotype. Ten of 12 patients with chromosome 5 and/or 7 abnormalities had been exposed to an alkylating agent, and two of three patients with 11q23 abnormalities had been exposed to an epipodophyllotoxin. The patient with both classes of abnormalities had been exposed to both types of therapy. We conclude that abnormalities of chromosomes 5 and/or 7 are common in children with therapy-related MDS or AML. The proposed relationships between exposure to alkylating agents and abnormalities of chromosomes 5 and/or 7 and between exposure to epipodophyllotoxins and abnormalities of 11q23 are supported in this pediatric series.

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.

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.

Urokinase therapy for a central venous catheter thrombus.

A 670 g premature infant is described in whom an intracardiac thrombus was documented. This thrombus formation probably resulted as a complication of an indwelling right atrial catheter. Thrombolytic therapy with urokinase was instituted, resulting in total and rapid dissolution. No hemorrhagic complications resulted. We believe that this particular thrombolytic therapy is safe and effective and should be considered when facing this particular complication.

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.

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.

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.

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.

Effect of low dose methotrexate on neutrophil chemotaxis induced by leukotriene B4 and complement C5a.

When mediators of inflammation such as complement component C5a or leukotriene B4 are introduced into an air pouch created in mice, these mediators induce the migration of neutrophils into the air pouch. Pretreatment of mice with low doses of methotrexate inhibits leukotriene B4 or C5a induced neutrophil migration into the air pouch. Inhibition of neutrophil chemotaxis by methotrexate may, at least in part, account for the rapid onset of antiinflammatory activity that was observed in clinical trials with methotrexate in rheumatoid arthritis.

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.

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.

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.

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).