Objective. To determine the accuracy of postmortem computed tomography (PMCT) for the assessment of causes in nontraumatic deaths in children. Study Design. We enrolled cases of nontraumatic deaths of infants and children who underwent PMCT at a single center. The presumed cause of death determined by PMCT was prospectively compared with the clinical and pathological diagnoses of deaths. Results. Thirty-eight cases were enrolled for analysis. Among them, seven cases also underwent conventional medical autopsy. PMCT revealed an identifiable cause of death in accordance with the clinical diagnosis of death in 16 cases of the 38 cases (the concordance rate was 42%) and in accordance with the autopsy cause of death in four of the seven autopsy cases (the concordance rate was 57%). Among eight cases with unknown cause of death by clinical diagnosis, four cases (50%) were identified with cardiac tamponade as a cause of death (one case) and intracranial hemorrhage suggesting abuse (3 cases). Conclusions. PMCT seems to be a promising technique that might serve as a substitute for conventional medical autopsy and give us the complementary information to clinical diagnoses particularly in cases of child abuse. Larger multicenter trials are worthwhile to validate the general feasibility of PMCT.
Chronic active Epstein-Barr virus infection (CAEBV) is defined as a systemic EBV-associated lymphoproliferative disease characterized by fever, lymphadenopathy, and splenomegaly in apparently immunocompetent persons. Recent studies have revealed that EBV infects T or natural killer cells in most patients with CAEBV; the etiology of CAEBV, however, remains unknown. Autoimmune lymphoproliferative disorder (ALPS) is an inherited disorder associated with defects in apoptosis, and clinically characterized by lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoimmune disease. ALPS is most often associated with mutations in the FAS gene, which is an apoptosis-signaling receptor important for homeostasis of the immune system. Based on the clinical similarity between ALPS and CAEBV with respect to lymphoproliferation, we have examined the possibility of the co-occurrence of ALPS in patients with a diagnosis of CAEBV. In this study, we have identified FAS gene mutations in three Japanese patients with lymphadenopathy, hepatosplenomegaly, and unusual EBV infection, who were diagnosed with CAEBV. These observations, which indicate that the clinical development of ALPS may be associated with EBV infection, alert us to a potential diagnostic pitfall of CAEBV.
Summary:Reports of cases of mycobacterial infections after SCT are rare. We report a 30-year-old female with a cutaneous infection of Mycobacterium fortuitum 30 months after allogeneic bone marrow transplantation for acute lymphoblastic leukemia. The patient was successfully treated with surgical debridement followed by oral minocycline and clarithromycin. Mycobacterial infections should be considered in SCT patients with undiagnosed refractory chronic cutaneous infection, and surgical debridement is useful for the diagnosis and treatment of such infections. Bone Marrow Transplantation (2001) 28, 709-711.
There is considerable overlap between hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) in terms of aberrant immune response though the etiology of KD remains unknown. We present a case fulfilling the criteria of both HLH and KD complicated by coronary artery dilatation: HLH was confirmed to be triggered by Epstein-Barr virus. This case alarms us the possibility that even patients with HLH may be complicated by coronary artery lesion, which is one of the hallmarks of KD. We would like to draw attention that if features of KD become apparent in patients with HLH, echocardiographic examinations should be performed not to miss coronary artery lesion.
Infantile malignant osteopetrosis (IMO) is a rare and fatal autosomal recessive condition characterized by a generalized increased in bone density. Hematopoietic stem cell transplantation (HSCT) is the only effective and rational therapy with achieving long-term disease-free survival. However, complications with HSCT for IMO remain unclear. Here we describe a male infant with IMO, carrying two novel mutations in the T-cell immune regulator 1 (TCIRG1) gene. The TCIRG1 gene encodes the a3 subunit of vacuolar H + -ATPase that plays an essential role in the resorptive function of osteoclasts. Direct sequencing of all 20 exons of the TCIRG1 gene revealed a single nucleotide change in exon 11 (c1305 G > T), which causes the substitution of Asp (GAT) for Glu (GAG) at position 435, and a two-nucleotide deletion in exon 16 (c1952-1953 del CA), causing a frame-shift mutation. However, the functional consequence of each mutation remains to be determined. Allogeneic HSCT was performed in the patient at the age of nine months. Donor engraftment was achieved, and abnormal bone metabolism and extramedullary hematopoiesis were corrected. Graft-versus-host disease was mild (grade I). However, the patient died of complication of pulmonary arterial hypertension at seven months after the HSCT. Postmortem examination revealed prominent vascular wall thickening of the pulmonary artery and macrophage infiltration to alveoli. It should be noted that a patient with IMO has a risk for pulmonary arterial hypertension, and the evaluation of pulmonary arterial flow should be included in the assessment of each patient with IMO even after HSCT.
Serum electrolytes should be included in the evaluation of children with impaired growth. Although primary aldosteronism is a rare occurrence in children, the condition appears to deserve special attention not only from the viewpoint of growth failure and hypokalaemia but from the occurrence of late organ damage to the kidney and heart.
4585 Malignant infantile osteopetrosis is an autosomal recessive disease characterized by a lack of osteoclastic function with incidence of 1: 200,000 to 1: 300,000. In consequence of disturbed bone building and remodeling, affected patients have osteosclerosis, dense fragile bone, and a marked reduction in the bone marrow cavity. Clinical features, such as anemia, thrombocytopenia, hepatosplenomegaly, bone fractures, bone deformity, and cranial nerve entrapment, appear soon after birth or within the first years of life. In the natural course of the disease, only 30% of children can survive to more than six years old. Because osteoclasts are of hematopoietic origin, allogeneic stem cell transplantation is the only curable therapy. Recently, successful HLA-haploidentical hematopoietic stem cell transplantation (HSCT) has been reported for patients without HLA- matched donors. We also present an infant with malignant infantile osteopetrosis who underwent HLA-haploidentical HSCT. A four-month-old boy was referred to our hospital for splenomegaly and pancytopenia. A physical examination revealed failure to thrive, distention of anterior fontanel, and hepatosplenomegaly. Laboratory findings indicated thrombocytopenia and anemia, and elevated alkaline phosphatase. Osteoclasts were hyperplastic in bone marrow. Radiography showed homogeneous and sclerotic bones with absence of corticomedullary junction, and bone marrow scintigraphy showed no accumulation of bone marrow. Subsequently, TCIRG1 mutations are identified. All these findings are compatible with malignant infantile osteopetrosis and the diagnosis was made. We conducted HSCT to revive his osteoclastic function. However, he didn't have HLA-matched donors not only in relatives but also in the bone marrow bank and the cord blood bank of Japan. We attempted HLA-haploidentical bone marrow transplantation (BMT) from his father with written informed consent. The patient was prepared for BMT at 11 months of age by conditioning with busulfan (6 mg/kg × 4/day × 4 days), cyclophosphamide (360mg/m2 × 2 days) and antithymocyte globulin (2 mg/kg/day × 3 days). Prophylaxis for graft-versus-host disease (GVHD) included tacrolimus and short-term methotrexate. Bone marrow nuclear cells (1×109/kg) were collected from his father and transplanted without any manipulations. The engraftment of neutrophils was confirmed on day 9 after BMT. Acute GVHD was limited to the skin (grade I). At 2 months after BMT, neutrophil counts, platelet counts, and hemoglobin level were all within normal limits. Bone marrow scintigraphy revealed a significant uptake in bone marrow. There have been no chronic GVHD up to six months after BMT.HSCT for patients with osteopetrosis is challenging as it is reported that HLA-haploidentical HSCT has the high rate of acute and chronic GVHD. Fortunately, HLA-haploidentical BMT was successful in our patient. This might be due to our regimen for prophylaxis of rejection and GVHD. We used ATG in conjunction with tacrolimus: this regimen may be prophylactic not only for rejection but also for GVHD as previously reported (Schulz et al. Blood 2002; 99: 3458–3460). In conclusion, HLA-haploidentical family donors should be considered as the alternative hematopoietic stem cell source for patients with malignant infantile osteopetrosis in condition without HLA-matched donors. Disclosures: No relevant conflicts of interest to declare.
Chromosomal translocation t(6;9) (p23;q34) associates with acute myeloid leukemia (AML), although that is found in less than 2% of all cytogenetic events in children with AML. Recent molecular analysis of patients with t(6;9) (p23;q34) has demonstrated a rearrangement of the genes DEK and CAN resulting in the formation of a chimeric DEK-CAN mRNA. The prognosis of patients with t(6;9) is thought tobe very poor, because of poor response to chemotherapy and/or high relapse rate. However, recent reports showed that allogeneic hematopoietic stem cell transplantation may have a potential to improve the prognosis of patients with t(6;9). We report here we were able to monitor DEK-CAN fusion transcripts in the serial points along chemotherapy courses and hematopoietic stem cell transplantation in a child with t(6;9). A 5-yaer-old Japanese boy diagnosed as having AML (M5b). Chromosomal analysis revealed t(6;9)(p23:q34), and real-time quantitative polymerase chain reaction (RQ-PCR) revealed positive chimeric DEK-CAN mRNA. After diagnosis, he received an induction chemotherapy. At the end of the induction chemotherapy, he was in a hematological and cytogenetic complete remission (CR), however DEK-CAN fusion transcript was still positive. After completion of five courses of consolidation therapy, he was in hematological and cytogenetic CR, although molecular minimal residual disease (MRD) was still positive. So he received allogeneic peripheral blood stem cell (PBSC) transplantation from 1 locus mismatched father. Busulfan and Melpharan were used for conditioning regimen. Cyclosoprin A and short course of methotrexate were emplyed for the prophylaxis of graft-versus-host disease (GVHD). Engraftment of PBSC was achieved at day 15. He had mild acute GVHD and no clonic GVHD. Bone marrow analysis at the time of engraftment revealed hematological, cytogenetic, and molecular CR. Now he is still in a persistent molecular negativity of DEK-CAN fusion transcript by RQ-PCR and keeps event-free survival for five years after PBSCT. The monitoring of DEK-CAN fusion transcript in the chemotherapies was reported from some investigators. However, there were very few reports about the monitoring DEK-CAN fusion transcripts before and after hematopoietic stem cell transplantations. In coclusion, we succeeded to exclude DEK-CAN fusioin transcript after hematopoietic stem cell transplantation in a child with t(6;9) AML. We conclude that DEK-CAN molecular monitoring by RQ-PCR in is a useful tool for the management of patients with t(6;9) AML.
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