Faculty Profiles - MURAMATSU, Hideki

Papers - MURAMATSU, Hideki

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Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia. Reviewed Open Access

Sakaguchi H, Muramatsu H, Okuno Y, Makishima H, Xu Y, Furukawa-Hibi Y, Wang X, Narita A, Yoshida K, Shiraishi Y, Doisaki S, Yoshida N, Hama A, Takahashi Y, Yamada K, Miyano S, Ogawa S, Maciejewski JP, Kojima S

PloS one Vol. 10 ( 12 ) page： e0145394 2015.12

Fulminant adenovirus hepatitis after hematopoietic stem cell transplant: Retrospective real-time PCR analysis for adenovirus DNA in two cases. Reviewed

Kawashima N, Muramatsu H, Okuno Y, Torii Y, Kawada J, Narita A, Nakanishi K, Hama A, Kitamura A, Asai N, Nakamura S, Takahashi Y, Ito Y, Kojima S

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy Vol. 21 ( 12 ) page： 857 - 863 2015.12

Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation. Reviewed

Hiramoto R, Imamura T, Muramatsu H, Wang X, Kanayama T, Zuiki M, Yoshida H, Moroto M, Fujiki A, Chiyonobu T, Osone S, Ishida H, Kojima S, Hosoi H

International journal of hematology Vol. 102 ( 6 ) page： 719 - 722 2015.12

Comparison of long-term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine Reviewed

Hama A., Takahashi Y., Muramatsu H., Ito M., Narita A., Kosaka Y., Tsuchida M., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

Haematologica Vol. 100 ( 11 ) page： 1426 - 1433 2015.10

Language：Japanese Publisher：Haematologica

The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood. However, it is unclear whether this morphological classification reflects clinical outcomes. We retrospectively reviewed bone marrow morphology in 186 children (median age 8 years; range 1-16 years) who were enrolled in the prospective study and received horse antithymocyte globulin and cyclosporine between July 1999 and November 2008. The median follow-up period was 87 months (range 1-146 months). Out of 186 patients, 62 (33%) were classified with aplastic anemia, 94 (49%) with refractory cytopenia of childhood, and 34 (18%) with refractory cytopenia with multilineage dysplasia. Aplastic anemia patients received granulocyte colony-stimulating factor more frequently and for longer durations than other patients (P<0.01). After six months, response rates to immunosuppressive therapy were not significantly different among the 3 groups. Acquisition of chromosomal abnormalities was observed in 5 patients with aplastic anemia, 4 patients with refractory cytopenia of childhood, and 3 patients with refractory cytopenia with multilineage dysplasia. Although the cumulative incidence of total clonal evolution at ten years was not significantly different among the 3 groups, the cumulative incidence of monosomy 7 development was significantly higher in aplastic anemia than in the other groups (P=0.02). Multivariate analysis revealed that only granulocyte colony-stimulating factor administration duration of 40 days or more was a significant risk factor for monosomy 7 development (P=0.02). These findings suggest that even the introduction of a strict morphological distinction from hypoplastic myelodysplastic syndrome cannot eradicate clonal evolution in children with aplastic anemia.

DOI： 10.3324/haematol.2015.128553

Scopus

GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies Reviewed

Wang X., Muramatsu H., Okuno Y., Sakaguchi H., Yoshida K., Kawashima N., Xu Y., Shiraishi Y., Chiba K., Tanaka H., Saito S., Nakazawa Y., Masunari T., Hirose T., Elmahdi S., Narita A., Doisaki S., Ismael O., Makishima H., Hama A., Miyano S., Takahashi Y., Ogawa S., Kojima S.

Haematologica Vol. 100 ( 10 ) page： e398 - e401 2015.10

Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia Reviewed

Kudo K., Muramatsu H., Yoshida N., Kobayashi R., Yabe H., Tabuchi K., Kato K., Koh K., Takahashi Y., Hashii Y., Kawano Y., Inoue M., Cho Y., Sakamaki H., Kawa K., Kato K., Suzuki R., Kojima S.

Bone Marrow Transplantation Vol. 50 ( 10 ) page： 1312 - 1315 2015.10

Language：Japanese Publisher：Bone Marrow Transplantation

The outcome of 55 children with severe aplastic anemia (SAA) who received a second hematopoietic stem cell transplantation (HSCT) was retrospectively analyzed using the registration data of the Japanese Society for Hematopoietic Cell Transplantation. The 5-year overall survival (OS) and failure-free survival (FFS) after the second transplantation were 82.9% (95% confidence interval (CI), 69.7-90.8)) and 81.2% (95% CI, 67.8-89.4), respectively. FFS was significantly better when the interval between the first and second transplantation was >60 days (88.9%; 95% CI, 73.0-95.7) than when it was ≤60 days (61.4%; 95% CI, 33.3-80.5; P=0.026). All 12 patients who were conditioned with regimens containing fludarabine and melphalan were alive with hematopoietic recovery. These findings justify the recommendation of a second HSCT for children with SAA who have experienced graft failure after first HSCT.

DOI： 10.1038/bmt.2015.153

Scopus

Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism. Reviewed

Okuno Y, Hoshino A, Muramatsu H, Kawashima N, Wang X, Yoshida K, Wada T, Gunji M, Toma T, Kato T, Shiraishi Y, Iwata A, Hori T, Kitoh T, Chiba K, Tanaka H, Sanada M, Takahashi Y, Nonoyama S, Ito M, Miyano S, Ogawa S, Kojima S, Kanegane H

Journal of clinical immunology Vol. 35 ( 7 ) page： 610 - 614 2015.9

Clinical and genetic features of dyskeratosis congenita, cryptic dyskeratosis congenita, and Hoyeraal-Hreidarsson syndrome in Japan. Reviewed

Yamaguchi H, Sakaguchi H, Yoshida K, Yabe M, Yabe H, Okuno Y, Muramatsu H, Takahashi Y, Yui S, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Inokuchi K, Ito E, Ogawa S, Kojima S

International journal of hematology Vol. 102 ( 5 ) page： 544 - 552 2015.9

Somatic Mosaicism for a NRAS Mutation Associates with Disparate Clinical Features in RAS-associated Leukoproliferative Disease: a Report of Two Cases Reviewed

Shiota M., Yang X., Kubokawa M., Morishima T., Tanaka K., Mikami M., Yoshida K., Kikuchi M., Izawa K., Nishikomori R., Okuno Y., Wang X., Sakaguchi H., Muramatsu H., Kojima S., Miyano S., Ogawa S., Takagi M., Hata D., Kanegane H.

Journal of Clinical Immunology Vol. 35 ( 5 ) page： 454 - 458 2015.7

Language：Japanese Publisher：Journal of Clinical Immunology

RAS-associated leukoproliferative disease (RALD) is a newly classified disease; thus its clinical features and management are not fully understood. The cases of two patients with characteristic features of RALD are described herein. Patient 1 was a 5-month-old female with clinical features typical of autoimmune lymphoproliferative syndrome (ALPS) and markedly elevated TCRαβ+CD4−CD8− T cell numbers. Genetic analyses failed to detect an ALPS-related gene mutation; however, whole exome sequencing and other genetic analyses revealed somatic mosaicism for the G13D NRAS mutation. These data were indivative of NRAS-associated RALD with highly elevated αβ-double-negative T cells. Patient 2 was a 12-month-old girl with recurrent fever who clearly met the diagnostic criteria for juvenile myelomonocytic leukemia (JMML). Genetic analyses revealed somatic mosaicism, again for the G13D NRAS mutation, suggesting RALD associated with somatic NRAS mosaicism. Notably, unlike most JMML cases, Patient 2 did not require steroids or hematopoietic stem cell transplantation. Genetic analysis of RAS should be performed in patients fulfilling the diagnostic criteria for ALPS in the absence of ALPS-related gene mutations if the patients have elevated αβ-double-negative-T cells and in JMML patients if autoimmunity is detected. These clinical and experimental data increase our understanding of RALD, ALPS, and JMML.

DOI： 10.1007/s10875-015-0163-3

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A Female Patient with Incomplete Hemophagocytic Lymphohistiocytosis Caused by a Heterozygous XIAP Mutation Associated with Non-Random X-Chromosome Inactivation Skewed Towards the Wild-Type XIAP Allele Reviewed

Yang X., Hoshino A., Taga T., Kunitsu T., Ikeda Y., Yasumi T., Yoshida K., Wada T., Miyake K., Kubota T., Okuno Y., Muramatsu H., Adachi Y., Miyano S., Ogawa S., Kojima S., Kanegane H.

Journal of Clinical Immunology Vol. 35 ( 3 ) page： 244 - 248 2015.3

Language：Japanese Publisher：Journal of Clinical Immunology

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI.

DOI： 10.1007/s10875-015-0144-6

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Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder Reviewed

Hyakuna N., Muramatsu H., Higa T., Chinen Y., Wang X., Kojima S.

Pediatric Blood and Cancer Vol. 62 ( 3 ) page： 542 - 544 2015.3

Language：Japanese Publisher：Pediatric Blood and Cancer

Germline mutations in CBL have been identified in patients with Noonan syndrome-like phenotypes, while juvenile myelomonocytic leukemia (JMML) harbors duplication of a germline CBL, resulting in acquired isodisomy. The association between moyamoya disease and Noonan syndrome carrying a PTPN11 mutation has recently been reported. We present a patient with JMML who developed moyamoya disease and neovascular glaucoma. Our patient exhibited a Noonan syndrome-like phenotype. Genetic analysis revealed acquired isodisomy and a germline heterozygous mutation in CBL. This is a rare case of CBL mutation associated with moyamoya disease. Prolonged RAS pathway signaling may cause disruption of cerebrovascular development.

DOI： 10.1002/pbc.25271

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Aldehyde dehydrogenase-2 polymorphism contributes to the progression of bone marrow failure in children with idiopathic aplastic anaemia Reviewed

Kawashima N., Narita A., Wang X., Xu Y., Sakaguchi H., Doisaki S., Muramatsu H., Hama A., Nakanishi K., Takahashi Y., Kojima S.

British Journal of Haematology Vol. 168 ( 3 ) page： 460 - 463 2015.2

Choreito Formula for BK Virus-associated Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation Reviewed

Kawashima N., Ito Y., Sekiya Y., Narita A., Okuno Y., Muramatsu H., Irie M., Hama A., Takahashi Y., Kojima S.

Biology of Blood and Marrow Transplantation Vol. 21 ( 2 ) page： 319 - 325 2015.2

Language：Japanese Publisher：Biology of Blood and Marrow Transplantation

Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (. P=.018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P=.037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P=.0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT.

DOI： 10.1016/j.bbmt.2014.10.018

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Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia Reviewed

Narita A., Muramatsu H., Sekiya Y., Okuno Y., Sakaguchi H., Nishio N., Yoshida N., Wang X., Xu Y., Kawashima N., Doisaki S., Hama A., Takahashi Y., Kudo K., Moritake H., Kobayashi M., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

Haematologica Vol. 100 ( 12 ) page： 1546 - 1552 2015

Language：Japanese Publisher：Haematologica

Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was −0.99 standard deviation (SD) (range −4.01–+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation.

DOI： 10.3324/haematol.2015.132530

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First-line treatment for severe aplastic anemia in children: Bone marrow transplantation from a matched family donor versus immunosuppressive therapy Reviewed

Yoshida N., Kobayashi R., Yabe H., Kosaka Y., Yagasaki H., Watanabe K.I., Kudo K., Morimoto A., Ohga S., Muramatsu H., Takahashi Y., Kato K., Suzuki R., Ohara A., Kojima S.

Haematologica Vol. 99 ( 12 ) page： 1784 - 1791 2014.12

Language：Japanese Publisher：Haematologica

The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86-90) versus 92% (90-94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54-59) versus 87% (85-90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992-1999 versus 2000-2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe aplastic anemia.

DOI： 10.3324/haematol.2014.109355

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Clinical course of juvenile myelomonocytic leukemia in the blast crisis phase treated by acute myeloid leukemia-oriented chemotherapy and allogeneic hematopoietic stem cell transplantation Reviewed

Ueda S., Sakata N., Muramatsu H., Sakaguchi H., Wang X., Xu Y., Kojima S., Yamaguchi T., Higa T., Takemura T.

International Journal of Hematology Vol. 100 ( 5 ) page： 502 - 506 2014.11

Language：Japanese Publisher：International Journal of Hematology

Juvenile myelomonocytic leukemia (JMML) is a mixed myeloproliferative and myelodysplastic disorder that occurs in early childhood. The clinical course of JMML is highly variable. A third of patients follow a relatively indolent course, although approximately 15 % cases are thought to develop acute myeloid leukemia, referred to as blast crisis. The etiology and clinical characteristics of blast crisis remain unclear. We document the case of a 27-month-old boy who presented with hepatosplenomegaly, skin rash, and lymphadenopathy. An initial diagnosis of acute erythroid leukemia was made according to the French–American–British classification. Following estimation of hypersensitivity to GM-CSF and genetic analysis of PTPN11, he was diagnosed with JMML in the blast crisis phase. Although he had several poor prognostic factors, including monosomy 7 and high HbF percentage, he achieved partial remission after treatment with acute myeloid leukemia-oriented chemotherapy followed by allogeneic hematopoietic stem cell transplantation. He has been in complete remission for over 6 years.

DOI： 10.1007/s12185-014-1638-3

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Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia Reviewed

Sakaguchi H., Nishio N., Hama A., Kawashima N., Wang X., Narita A., Doisaki S., Xu Y., Muramatsu H., Yoshida N., Takahashi Y., Kudo K., Moritake H., Nakamura K., Kobayashi R., Ito E., Yabe H., Ohga S., Ohara A., Kojima S.

Haematologica Vol. 99 ( 8 ) page： 1312 - 1316 2014.8

Language：Japanese Publisher：Haematologica

Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5-16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41-69%) and 97% (95%CI: 87-99%), respectively. Median telomere length in responders was -0.4 standard deviation (SD) (-2.7 to +3.0 SD) and -1.5 SD (-4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than -1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19-115; P<0.001), platelet count at diagnosis less than 25×109/L (HR: 13.9; 95%CI: 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia. © 2014 Ferrata Storti Foundation.

DOI： 10.3324/haematol.2013.091165

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Bloodstream Infection after Stem Cell Transplantation in Children with Idiopathic Aplastic Anemia Reviewed

Kobayashi R., Yabe H., Kikuchi A., Kudo K., Yoshida N., Watanabe K., Muramatsu H., Takahashi Y., Inoue M., Koh K., Inagaki J., Okamoto Y., Sakamaki H., Kawa K., Kato K., Suzuki R., Kojima S.

Biology of Blood and Marrow Transplantation Vol. 20 ( 8 ) page： 1145 - 1149 2014.8

Language：Japanese Publisher：Biology of Blood and Marrow Transplantation

Bloodstream infection (BSI) is the most common infectious complication of hematopoietic stem cell transplantation (HSCT) and can cause substantial morbidity and mortality. Identification of risk factors for BSI might be helpful in efforts to reduce transplantation-related death. This study analyzed the incidence of BSI and risk factors for BSI after HSCT in pediatric patients with aplastic anemia (AA). BSI occurred in 39 of the 351 patients with AA (11.1%). Onset of BSI occurred at a median of 8 days after HSCT (range, 0 to 92 days). The 5-year overall survival rate was lower in patients with BSI than in patients without BSI (63.32% ± 7.90% versus 93.35% ± 1.44%; P < .0001). Univariate analysis identified the following variables as associated with BSI: history of immunosuppressive therapy with antithymocyte globulin (ATG), transplantation from an unrelated donor, frequent blood transfusion before transplantation, major or major plus minor ABO type mismatch, graft-versus-host disease prophylaxis with tacrolimus and without cyclosporine, and long interval from diagnosis to transplantation. Among these factors, long interval from diagnosis to transplantation was the sole statistically significant risk factor for BSI on multivariate analysis. In patients who underwent HSCT from a related donor, age ≥14 years at transplantation was risk factor for BSI. In contrast, history of immunosuppressive therapy with ATG, frequent blood transfusion before HSCT, graft failure, and major or major plus minor ABO type mismatch were risk factors for BSI in patients who underwent HSCT from an unrelated donor. Because the overall 5-year survival rate without BSI was >90%, even in patients who were received a transplant from an unrelated donor, control of BSI is very important for successful HSCT in pediatric patients with AA. © 2014 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2014.04.006

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Whole-exome sequence analysis of ataxia telangiectasia-like phenotype Reviewed

Hasegawa S., Imai K., Yoshida K., Okuno Y., Muramatsu H., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Kojima S., Ogawa S., Morio T., Mizutani S., Takagi M.

Journal of the Neurological Sciences Vol. 340 ( 1-2 ) page： 86 - 90 2014.5

Language：Japanese Publisher：Journal of the Neurological Sciences

A number of diseases exhibit neurodegeneration with/without additional symptoms such as immunodeficiency, increased cancer risk, and microcephalus. Ataxia telangiectasia and Nijmegen breakage syndrome, for example, develop as a result of mutations in genes involved in the DNA damage response. However, such diseases can be difficult to diagnose as they are only rarely encountered by physicians. To overcome this challenge, nine patients with symptoms that resemble those of ataxia telangiectasia, including neurodegeneration, hypogammaglobulinemia, telangiectasia, and/or elevated serum α-fetoprotein, were subjected to whole-exome sequencing (WES) to identify the causative mutations. Molecular diagnosis was achieved in two patients: one displayed CD40 ligand (CD40LG) deficiency, while a second showed a homozygous SIL1 mutation, which has been linked to Marinesco-Sjögren syndrome (MSS). Typical features of CD40LG deficiency and MSS are distinct from the symptoms usually seen in ataxia telangiectasia. These dissociations between phenotype and genotype make it difficult to achieve molecular diagnosis of orphan diseases. Whole-exome sequencing analyses will assist in the molecular diagnosis of such cases and allow the identification of genotypes that would not be expected from the phenotype. © 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2014.02.033

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Immunosuppressive therapy with horse anti-thymocyte globulin and cyclosporine as treatment for fulminant aplastic anemia in children Reviewed

Yagasaki H., Shichino H., Ohara A., Kobayashi R., Yabe H., Ohga S., Hamamoto K., Ohtsuka Y., Shimada H., Inoue M., Muramatsu H., Takahashi Y., Kojima S.

Annals of Hematology Vol. 93 ( 5 ) page： 747 - 752 2014.5

Language：Japanese Publisher：Annals of Hematology

Patients with severe aplastic anemia (SAA) and an absolute neutrophil count (ANC) of 0 typically have fatal outcomes. We defined fulminant AA (FAA) as ANC=0 for at least 2 weeks prior to and after immunosuppressive therapy (IST). We analyzed the outcomes of 35 children with FAA among 288 children who enrolled in a prospective study for AA (AA-97 study). AA was classified as FAA (n=35), very SAA (vSAA; n=129), or SAA (n=124). All of the children received the IST with horse anti-thymocyte globulin (ATG) and cyclosporine (CsA). A significantly lower response rate at 6 months was seen in children with FAA when compared to those with vSAA or SAA (40.0, 63.6, and 63.7 %, respectively; p=0.027). Of 20 nonresponder patients in the FAA group, 11 were rescued by alternative donor transplantation, and 5 patients showed a late response after 6 months. Consequently, no significant difference was noted in overall survival when comparing the FAA, vSAA, and SAA groups (88.5, 95.8, and 96.8 %). These findings indicate that IST with ATG and CsA is justified as a first-line treatment for children with FAA who lack a human leukocyte antigen-matched sibling donor. © 2013 Springer-Verlag Berlin Heidelberg.

DOI： 10.1007/s00277-013-1984-x

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Papers - MURAMATSU, Hideki