Although cancer is a rare entity in children, the clinical genetics of childhood cancer continues to make great contribution to the progress of clinical and fundamental cancer research of adults as well as children. The early work of Dr. Robert Miller and his colleagues in NCI on birth defects associated with childhood cancer suggested that human mutagenesis, carcinogenesis and teratogenesis should be studied as a whole to better understand the origin of childhood neoplasia (not just malignancy). Then, chromosomal abnormalities found in lymphocytes from cancer patients with associated congenital abnormalities have given clues to find the gene locus of each cancer. From clinical observation of patients with retinoblastoma in which familial aggregation is seen with a dominant pattern of inheritance, Knudson proposed the “two hit theory” and this led to the discovery of tumor suppressor genes proved by Cavenee from loss of heterozygosity in retinoblastoma tumor cells using RFLP markers. Since then, hereditary cancer has been considered to be inherited by germline mutation of certain tumor suppressor genes. In 1990, germline p53 point mutation was first reported in families with Li-Fraumeni family cancer syndrome characterized by dominantly inherited increased likelihood of developing various neoplasms at an early age in multiple family members. We found novel germline p53 mutations in two Japanese cancer-prone families. This review summarizes the epidemiology and molecular biology relating to the identification of cancer predisposition and discusses various problems of predictive testing for inherited mutation in cancer susceptibility genes.

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We present the cases of four children with advanced rhabdomyosarcoma (RMS) treated with double or triple PBSCT, because of the inability to undergo multidisciplinary treatment or refractory disease. They underwent PBSCT after 6-7 courses of conventional chemotherapy. Hematopoietic recovery in neutrophils even after the 2nd or 3rd course of PBSCT was very rapid and the regimen-related toxicities in every transplant were mild. Two out of 4 patients relapsed but 2 are still alive and disease-free. Repeated PBSCT is a feasible treatment. Multidisciplinary treatment including surgery, radiotherapy and chemotherapy combined with repeated PBSCT may be efficacious and useful for advanced RMS.

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True malignant histiocytosis is rare and its cellular origin is still obscure. We reported two true cases of malignant histiocytosis with a review of the literature, and stress the cytogenetic aspects of this disorder. Case 1 was a boy, aged 11 months, diagnosed as having true malignant histiocytosis. Bone marrow cells which chiefly consisted of mature histiocytes that sometimes showed phagocytosis, and those chiefly consisted of histoblasts, had a similar chromosomal abnormality, 46, XX, -6, +mar. Surface marker analysis of the bone marrow cells showed was negative for T-cell and B-cell markers. Case 2 was a boy, aged 13 years, diagnosed as having true malignant histiocytosis. Blasts in the pleural fluid that showed phagocytosis did not have T-cell and B-cell markers, and showed clonal chromosomal abnormalities, 75 ?, XY, i (1q), der (12) t (1; 12) (q12; p13), add (12) (p13).We also reviewed the cytogenetic findings of previously reported cases with so-called malignant histiocytosis.2p 13 and 5q35 translocations, which have recently been suggested to be specific for Ki-1 lymphoma, 17p13 abnormalities, and hyperdiploidy (ploidy abnormalities) were frequently seen. Although various chromosomal abnormalities were seen, these findings showed cytogenetic heterogeneity of this disorder.

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The levels of serum-soluble interleukin-2 receptor (sIL-2R) and platelet counts in 31 children with acute type idiopathic thrombocytopenic purpura (ITP) were measured. Serum sIL-2R levels of patients before steroid treatment were remarkably higher than those of the control group. Three months after the beginning of the treatment, serum sIL-2R levels of patients were lower than those of patients before treatment, although they were still above the level of control. Six months after the beginning of treatment, the levels of serum sIL-2R in the treated group were further decreased and no significant difference was found in comparison with the control. A negative correlation between serum sIL-2R levels and platelet counts at three and six months after the beginning of treatment was confirmed. The patients with severe clinical manifestations and markedly high levels of serum sIL-2R showed a poor response to steroid therapy, and high levels of serum sIL-2R persisted. The present study indicates that the measurement of serum sIL-2R in acute ITP is useful for evaluation of the patients' condition and their prognosis.

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Though some leukemia cells are recently recognized to have ectoenzymes, their role is still unclear. We investigated whether enkephalin (Enk), a substrate of both neutral endopeptidase (NEP : CD 10) and aminopeptidase N (APN : CD 13), had an effect on cell growth. ³H-Thymidine incorporation and MTT assay showed that in cell lines of biphenotypic leukemia that had both activities of NEP and APN, ³H-thymidine uptake and cell growth increased with Enk, whereas acute lymphoblastic and non-lymphoblastic leukemia cell lines did not. Inhibition of APN activity suppressed proliferation. There was no Ca mobilization. These data suggest that Enk is one of the growth factors for some leukemias, that the cell growth pathway requires that it be cleaved by APN and that it is independent of Ca mobilization.

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A 5-year-old boy with no underlying diseases, was admitted to our hospital because of splenomegaly and pancytopenia as follows; RBC : 451×10⁴/μl (←500×10⁴/μl, 2 days before admission), WBC : 3, 000/μl (←10, 000/μl) (st 43%, sg 28%, ly 18%, mo 8%, eo 2%) and platelets : 6.8×10⁴/×l (←14.8×10⁴/μl). Bone marrow aspiration showed marked dyshematopoiesis such as Pelger-like anomaly, impaired segmentation of megakaryocytes, and giant pronormoblasts, which are reportedly specific to parvovirus B19 infection induced erythrocytopenia. Parvovirus B19 infection was confirmed by the presence of parvovirus B19 DNA in both his serum and bone marrow. This case suggests the probability that parvovirus B19 may cause transient dyshematopoiesis.

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A 2-month-old boy was hospitalized with severe cough, anemia, liver dysfunction and neutropenia. He was diagnosed as having Shwachman syndrome based on the laboratory findings of anemia, neutropenia, mild thrombocytopenia, and pancreatic insufficiency. Bone marrow examination showed a decrease in the counts of nuclear cells. During the clinical course, he developed sepsis, and was treated with antibiotics and recombinant human granulocyte colony-stimulating factor (rhG-CSF). As soon as the number of neutrophils improved, he became well. To maintain the number of neutrophils and to treat anemia, rhG-CSF (50μg/m², 3 times/week) and oxymetholone (2 mg/kg/day) were administered. Severe bacterial infection was prevented and anemia gradually improved without any other treatment.

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We reported a three-month-old female infant with cyclic neutropenia. Not only neutrophils, but also reticulocytes had their own oscillations with this patient. She also showed chronic anemia. The period of neutropenia was between 26 to 27 days. The period of variation of reticulocytes was 10 to 16. The administration of recombinant granulocyte colony-stimulating factor twice a week increased the number of neutrophils. However, while she was suffering recurrent pharyngitis and coxitis, she needed the daily administration of rhG-CSF. The number of neutrophils was maintained above 1, 000/μl after the rhG-CSF treatment for 8 month. She did not have any serious infectious disease. The oscillation of reticulocytes continued during the rhG-CSF treatment.

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We report a boy with a severe combined immunodeficiency with B cell (SCID with B) who died of intracranial hemorrhage during the course of persistent diarrhea after human leukocyte antigen (HLA) nonidentical bone marrow transplantation (BMT). At 123 days of age, he received HLA two-locus mismatch marrow cells from his mother without T-cell depletion. After BMT, grade 1 acute graft-versus-host disease (GVHD) appeared but it was controlled with steroid therapy, and immunologic reconstitution was observed. Three months after BMT, however, watery diarrhea occured and continued for several weeks. There were no other symptoms of GVHD. Despite the use of γ-globulin and antiviral drugs for viral enterocolitis, severe diarrhea continued. Steroid therapy was not effective. Finally, he died of intracranial hemorrhage due to Vitamin K deficiency. Several approaches including T-cell depletion and conditioning should be considered to improve HLA non-identical BMT in cases of immunodeficiency. In this case, enteral biopsy and viral studies were necessary to distinguish GVHD from viral infection.

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An eleven-year-old boy presented with severe back pain of 3 months' duration. He eventually developed fever and pancytopenia. He had been lying all day long when the diagnosis of acute lymphoblastic leukemia (ALL) was made with bone marrow puncture. Simple X-ray films of vertebral bones showed multiple compression fructures from Th7 to L2. T2-weighted MR imaging exhibited a high signal area in the vertebral bone, compatible with leukemic infiltration. The leukemia responded well to induction therapy of the TCCSG L92-13 PH regimen. In spite of the release of back pain, vertebral low density on X-ray films continued even after 5 months' chemotherapy. MRI, however, showed decreased T2-weighted signal intensity, compatible with a decrease in or the disappearance of leukemic infiltration. According to the literature, the ALL patients presenting with vertebral compression fractures have characteristic features as described below : (1) older age group, (2) long time until the correct diagnosis was made, (3) leukopenia at diagnosis, (4) low percentage of leukemic cells in the peripheral blood, (5) hyperdiploidy in chromosomal analysis, and (6) good prognosis.

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A 7-year-old girl was admitted to our department under the diagnosis of ALL. She was treated with a induction chemotherapy including prednisolone, vincristine, THP-adriamycin and L-asparaginase. In the course of the chemotherapy, a remarkable hyperlipidemia and liver dysfunction developed. While she was given reinforcement chemotherapy including L-asparaginase, she showed remarkable hyperlipidemia and liver dysfunction with fatty liver again. The levels of serum triglycerides, GOT and GPT increased to 727 mg/dl, 123 IU and 172 IU, respectively. These clinical findings strongly suggested that L-asparaginase could induce the type IV hyperlipidemia of Friedrickson classification and fatty liver. After discontinuation of L-asparaginase and treated with only supportive treatment, these laboratory data returned to normal.

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