The Programme for Global Paediatric Research.

Millions of children die every year from malaria, tuberculosis, diarrhoea, neonatal disorders, and many other diseases found primarily in low and mid income countries. Many devoted clinicians and scientists have contributed significantly to the understanding and care of these diseases, however research remains disproportionately aimed at diseases affecting those in high income countries.

Distinct gene signatures of transient and acute megakaryoblastic leukemia in Down syndrome.

Approximately 10% of newborns with Down syndrome develop Transient Leukemia (TL), a disorder that is unique to infants with constitutional trisomy 21 (or trisomy 21 mosaicism). TL blasts disappear spontaneously within the first 3 months of life in the majority of cases. Despite the resolution of TL, 20-30% of these newborns will go on to develop acute megakaryoblastic leukemia (AMKL) later in life. In this study, samples from both TL and AMKL patients were examined using cDNA microarrays to study the pathogenic progression from TL to AMKL. TL and AMKL samples partition separately by cluster analysis, and AMKL samples had substantial increases in apolipoprotein C-I, transporter 1, myosin alkali light chain 4, and spermidine/spermine N-acetyltransferase, compared to TL samples. Although these findings will require validation in an independent series of TL and AMKL samples, they indicate that TL and AMKL have distinct gene signatures, and provide a basis for studies of the different mechanisms underlying either the resolution of TL or its progression to AMKL.

The role of p53 in megakaryocyte differentiation and the megakaryocytic leukemias of Down syndrome.

Sequence analysis of the p53 tumor suppressor gene was performed on diagnostic blood and bone marrow samples from nine children with Down syndrome and acute megakaryoblastic leukemia. p53 sequence alterations were not observed in any of seven cases of transient leukemia; however, samples from two of three patients with acute megakaryoblastic leukemia harbored sequence alterations. The acquisition of both mutations (Gly245Val and Arg72Pro) in the transformation from transient leukemia to overt acute megakaryoblastic leukemia suggests a functional role of mutant p53 in the evolution of this disease.

Improved survival in severe acquired aplastic anemia of childhood.

Multi-agent immunosuppressive therapy has produced improved survival for severe acquired aplastic anemia in children. Recently, some investigators have suggested that immunosuppressive therapy may replace bone marrow transplantation as first-line therapy for this disorder. To assess its validity, we compared the outcomes of bone marrow transplantation vs immunosuppressive therapy in one institution from 1987 to 1997. We studied 46 consecutive patients less than 18 years of age who presented between January 1987 and April 1997. Inherited marrow failure syndromes and myelodysplastic syndromes were excluded. Patients received immunosuppressive therapy vs bone marrow transplantation based on availability of HLA-matched donors. The main outcome measures were survival, complete marrow and hematological remission, or partial remission but achieving independence from transfusional support. Twenty patients received multi-agent immunosuppressive therapy (cyclosporine, antithymocyte globulin and methylprednisolone); 11 attained complete remission and three partial remission for a transfusion-independent survival of 70%. Six patients died of infectious and hemorrhagic complications. Twenty-six patients were transplanted and 24 (93%) achieved complete remission; one achieved a PR, 25 remain transfusion independent with a median follow-up of 5.9 years or 70 months. One patient developed AML 34 months after successful transplant and one patient died due to graft failure and complications of transplant. There has been a striking improvement in survival for pediatric patients treated with multi-agent immunosuppression in the last decade. However, transplantation results have also improved and this remains the definitive first-line therapy for severe acquired aplastic anemia in this age group.

Juvenile myelomonocytic leukemia and Noonan syndrome.

A case of juvenile myelomonocytic leukemia (JMML, previously referred to as JCML) in a neonate with Noonan syndrome (NS) is described. The boy presented with bilateral congenital hydrothoraces, nonimmune hydrops, dysmorphic facies, persistent thrombocytopenia, and leukocytosis. The diagnosis of JMML was made on bone marrow cell culture studies. Review of the literature reveals an unusual preponderance of hematologic malignancies, in particular JMML, among patients with NS. Of 40 NS patients admitted to the authors' institution during a 10-year period, there were 4 (10%) with evidence of a monocytic proliferation, which resolved spontaneously. The authors postulate that patients with NS may have an increased incidence of myeloproliferative disorders, which in most cases appears to be benign but may be preleukemic or even lethal.

Essential thrombocythemia in children.

PURPOSE: The objective of this study was to evaluate the clinical course, laboratory findings, and outcomes of children with essential thrombocythemia (ET). PATIENTS AND METHODS: The authors analyzed 36 children, ages 6 weeks to 18 years, by combining descriptions of 2 patients observed at their institution with 34 patients reported in the English medical literature. RESULTS: Fifteen patients (10 at diagnosis and 5 later on) had symptoms directly related to ET, including 9 who had severe thrombohemorrhagic phenomena. Common abnormalities included large platelets, increased marrow megakaryocytes with hyperlobulated forms, and abnormal platelet aggregation. Symptomatic patients had significantly higher platelet counts (2,419 versus 904 x 10(9)/L, P < 0.001); however, three patients with platelet counts that were only moderately elevated (600-800 x 10(9)/L) had thrombotic events. Eleven patients received various therapeutic agents. Interestingly, three patients who had one thrombotic event, and did not receive therapy, went on to have a benign clinical course. Leukemia developed in two treated patients, and they died; two others died of thrombotic complications; and myelofibrosis developed in one patient. Seventeen cases (47%) were familial. Patients with familial cases had significantly lower platelet counts, a lower incidence of hepatomegaly, and no thrombotic complications. CONCLUSIONS: This analysis of children with ET found that severe vascular complications developed in a substantial number. Platelet counts usually, but not always, correlate with the occurrence of complications. The indications for treatment and the best treatment of children with ET are currently not known, and guidelines for the management of children with ET are needed. Familial thrombocythemia is common among children with primary thrombocytosis and appears to be a different disease from ET, with a more benign course.

Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome.

Transient Myeloproliferative Disorder (Transient Leukemia) is found in approximately 10% of newborn infants with Down Syndrome. It is characterized by the large numbers of megakaryoblasts in the peripheral blood, variable thrombocytopenia and, in a minority of cases, by a lethal course with hydrops fetalis or progressive hepatic fibrosis. Evidence is presented that this disease is truly leukemia, which, in most cases, recovers spontaneously. There is evidence that hematopoiesis is abnormal in Down Syndrome children who do not have leukemia. These abnormalities of red cells, platelets, and granulocytes are reviewed.

Prevention of vitamin K deficiency bleeding in newborns.

Newborn babies are born vitamin K deficient; however, the deficiency is not sufficiently severe to cause a vitamin K deficiency coagulopathy and haemorrhagic disease of the newborn (HDN). Severe vitamin K deficiency can develop quickly in breast-fed newborns and can result in the appearance of classic HDN during the first week of life or late HDN during the first 2 months of life. Both forms of the disease can be severe, causing brain damage and death. Classic and late HDN are prevented by the intramuscular administration of vitamin K at birth. Oral prophylaxis prevents classic HDN but is ineffective in preventing late HDN. Despite proven effectiveness of intramuscular vitamin K prophylaxis there have been concerns about the need for, and safety of, this therapy. This review provides evidence that there is need for intramuscular vitamin K prophylaxis for all babies in order to eradicate haemorrhagic disease of the newborn and concludes that there is no evidence that this therapy is harmful.

Transient leukemia with extreme basophilia in a phenotypically normal infant with blast cells containing a pseudodiploid clone, 46,XY i(21)(q10).

PURPOSE: Transient leukemia and extreme basophilia occurred in a phenotypically normal newborn with expression of isochromosome (21)(q10) in the blast population. PATIENTS AND METHODS: A newborn boy was found to have an elevated white blood cell count of 120,800 with 33% blasts. The peripheral blood also contained elevated numbers of basophils and neutrophils with unusual staining properties. The blasts, evaluated by flow cytometry and light and electron microscopy, had the properties of megakaryoblasts. Cytogenetic studies revealed 46,XY karyotype in peripheral blood lymphocytes; however, analysis of the blast cells from the bone marrow showed an abnormal chromosome 21. RESULTS: The blast cells in the peripheral blood disappeared by day 42 without chemotherapy. The red blood cell count and platelet count normalized by 2 months. Chromosomal analysis of skin fibroblasts and bone marrow after the disappearance of the blast cells in the peripheral blood showed a 46,XY phenotype. CONCLUSIONS: The leukemic cell of transient leukemia has the potential of forming cells of basophil and megakaryocyte lineages. Trisomy of the q arm of chromosome 21 contains sufficient genetic information for the development of transient leukemia in a phenotypically normal newborn.

Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP).

Immune thrombocytopenic purpura (ITP) is a disorder for which management remains controversial. The ongoing goal is to define the minimal therapy required for children with acute ITP. A pilot study of short-course oral prednisone (4 mg(-1) kg(-1) d(-1) for 4 d with no tapering) was undertaken in 25 consecutive children with acute ITP and platelet counts under 20 x 10(9) l(-1). Of the 25 children, 22 responded to the prednisone therapy by achieving a platelet count higher than 20 x 10(9) l(-1) within 1 week of commencing treatment. This regimen was found to be safe, inexpensive and effective in increasing the platelet count of children to a haemostatically safe level.

Leukemia and/or myeloproliferative syndrome in neonates with Down syndrome.

Approximately 10% of newborn infants with Down Syndrome develop a form of megakaryoblastic leukemia which usually disappears spontaneously during the first months of life. The evidence that this "Transient Leukemia" is truly leukemia includes the following: it is clonal proliferation, it can be fatal and tissue infiltration of leukemic cells occurs. Also in approximately 25% of cases that recover, Acute Megakaryoblastic Leukemia will develop in the first four years of life, which, if not treated, is fatal. Evidence regarding the megakaryoblastic nature of the leukemic cells is presented as well as a description of the lethal forms of the disease. The study of Transient Leukemia is of considerable importance because it can provide insight into both the nature of leukemia and its relation to trisomy 21.