Chronic neutropenia during childhood involves various underlying conditions. As an external cause factor, infection, administered medicines, bone marrow replacement by malignant cells, allo-or auto-antibodies that cause most chronic neutropenia in infancy, etc., should be considered. Although, the chronic neutropenia caused by intrinsic factors, such as severe congenital neutropenia, are rare, the clinical manifestations are severe. The approach to the diagnostic evaluation of a patient can be guided largely by clinical history and physical examination and does not always require an extensive laboratory evaluation. Recent advances in this field showed several molecular abnormalities in chronic neutropenia caused by intrinsic factors. However, there exist discrepancies between the molecular abnormalities and the clinical manifestations. Further investigations are required to elucidate the precise mechanisms of the disease. In this article, we show clinical manifestations, bone marrow findings, and molecular abnormalities of some representative diseases that cause chronic neutropenia during childhood.

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Hematopoietic stem cell transplantation induces profound and long-lasting immune deficiency secondary to preparative conditioning, the duration and severity of which varies according to graft manipulation (T-cell depletion), choice of graft type (donor and source), development of graft-versus-host disease, infections, and regenerating thymic activity that is dependent on recipient age. This results in significant morbidity and mortality due to infections and leukemia relapse. While early recovery of innate immunity results in reconstitution of protective immunity against many pathogens, both the absolute levels and function of T and B cells with memory, adaptive immunity, remain abnormal for many months to 1-2 years, resulting in prolonged susceptibility to pathogens. This article reviews current knowledge of the reconstitution process.

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After their exposures to replacement therapies, some hemophilia patients develop alloantibody inhibitors, which make subsequent hemostasis management difficult. Many studies have reported the pathogenesis of the inhibitor; however, the long-term course for hemophilia patients with inhibitors has not been elucidated in detail. Therefore, we studied the clinical course of hemophilia patients with inhibitors who were registered in North Kyushu Hemophilia Center between 1984 and 2004. Out of a total of 209 hemophilia patients, persistent or transient inhibitors were detected with a level of 1 or more Bethesda units in 15 patients. Retrospective analysis of their clinical characteristics indicated that age at initial detection of the inhibitor ranged from 3 months to 62 years, with a median of 2 years. The maximum inhibitor levels during the follow-up period ranged from 2 to 1, 000 BU/ml. The disappearance of the inhibitor was observed, in 3 out of 4 patients with low titer inhibitors and in 2 out of 11 patients with high titer inhibitors. Three patients underwent immune tolerance induction therapies (ITI) and inhibitors persisted during ITI; however afterward, two of them got to be able to maintain hemostasis management with factor FVIII concentrates.

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A retrospective study on 209 patients with hemophilia who were treated at the Northern Kyushu Hemophilia Center during the last 20 years revealed a total of 57 episodes of intracranial hemorrhage (ICH) occurring in 33 (15.8%) of these patients. The median age at the onset of ICH was 1 year, and 56% of ICH cases occurred at the age of 2 or below. The incidence of ICH did not significantly differ between the severe ICH (factor VIII activity<1%) and mild-to-moderate ICH (factor VIII activity=1-25%) groups. When the incidence of ICH was compared solely among those who developed ICH for the first time, the incidence of non-traumatic ICH was significantly higher in the severe ICH group than in the mild-to-moderate ICH group (p=0.043). The incidence of subdural hemorrhage was the highest, followed by ICH in the brain parenchyma. ICH occurred simultaneously at several regions in 8.7% of the patients. With regard to the outcome, 3 of the 33 patients died, and 9 had sequelae. ICH initially occurred in 7 of the 9 patients with sequelae before the age of 2. Although the incidence of subdural hemorrhage was the highest, there was no patient with sequelae induced by subdural hemorrhage alone. ICH recurred in 15 (45.5%) of the 33 patients, and 70% of these recurrent ICH cases developed at intervals of 2 years or less. Although the development of excellent coagulation factor preparations markedly improved the hemostatic treatment in hemophilic patients, ICH of hemophilia patients has still occurred frequently in the last years. In addition, once ICH occurs in hemophilia patients, it recurs in almost 50% of such patients. Therefore, the course of hemophilia patients with a past history of ICH should be followed carefully.

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Final height was analyzed in sixty patients (35 : male, 25 : female) who underwent stem cell transplantation (SCT) during childhood between 1983 and 1998. The median age at transplant was 11 years 3 months. Median follow up period after stem cell transplantation was 13 years (range 5 years 5 months to 19 years 9 months). These patients included 37 with acute leukemia, 12 with severe aplastic anemia, 7 with malignant lymphoma, 2 with neuroblastoma and 2 with chronic myeloid leukemia. Irradiation during conditioning regimen included total body irradiation (TBI) in 36 patients, and total lymphoid irradiation (TLI) in 9 patients. The remaining 15 patients were not irradiated. Nine out of 25 patients with acute lymphoblastic leukemia received cranial radiation therapy (CRT, 18-24 Gy). Seven of them were conditioned with TBI. Three children were treated with recombinant human growth hormone, and 18 patients (5 : male, 13 : female) received sex hormone replacement therapy. The difference between height standard deviation score (SDS) at SCT and that of the final height was calculated and was defined as ASDS. Patients conditioned with TBI showed significantly greater reduction in height ΔSDS compared to those conditioned with TLI (p=0.002) or non-irradiated patients (p=0.0007). Patients who received TBI before the age of 6 showed significantly greater loss of final height compared to the older age groups. History of CRT prior to SCT did not influence ΔSDS (p=0.39). By a multivariate analysis male gender, an age under 6 years at SCT and TBI were found to be major factors for longterm height loss.

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We report two cases of an 9-year-old girl and a 6-year-old boy diagnosed with acute lymphoblastic leukemia (ALL). They suffered seizures on day 31 and day 20 following the induction chemotherapy. Magnetic resonance imaging (MRI) of the brain revealed multiple high signal intensity lesions in the bilateral occipital-parietal lobes on T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) conditions. On the basis of typical findings in brain MRI and the improvement of their neurological signs, they were diagnosed as having posterior reversible encephalopathy syndrome (PRES). They developed hypertension and acute pancreatitis at the onset of PRES; hypertension as well as induction chemotherapy seemed to contribute to the occurrence of PRES. Using of drugs for hypertension and seizure helped to complete chemotherapies. PRES should be considered as a complication for children with hypertension receiving chemotherapy.

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We encountered a 12-year-old boy with chronic myelogenous leukemia (CML) who developed delayed hemorrhagic shock due to traumatic splenic rupture. He visited a local doctor because of persistent pain in the left hypochondrial region after slight abdominal trauma. At that time, imaging studies revealed subcapsular hemorrhage of the spleen, and he was transferred to our hospital. Blood and bone marrow examination on admission suggested a diagnosis of CML at the chronic phase. Although the patient was managed by conservative treatment, he acutely showed oliguria, a decrease of blood pressure, and an increase of heart rate 42 hours after the injury. Emergent splenectomy was performed under the diagnosis of delayed intraperitoneal hemorrhage due to splenic rupture. The patient recovered after a favorable postoperative course without any complications. After treatment with hydroxyurea and interferon α, he received an allogeneic marrow graft from his sister and is now in complete remission. Clinical reports of CML with splenic rupture are sparse. Since previous reports are of spontaneous cases, our present case of splenic rupture caused by trauma can be considered as a rare one.

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