研究者詳細 - 村松　秀城

An infant with generalized pustular psoriasis and geographic tongue had a heterozygous IL36RN mutation and IgG2 deficiency 査読有り

Oi R., Takeichi T., Okuno Y., Kojima D., Sugawara K., Kono M., Muramatsu H., Akiyama M.

Journal of Dermatological Science 90 巻 ( 2 ) 頁： 216 - 218 2018年5月

Integrated molecular profiling of juvenile myelomonocytic leukemia 査読有り

Murakami N., Okuno Y., Yoshida K., Shiraishi Y., Nagae G., Suzuki K., Narita A., Sakaguchi H., Kawashima N., Wang X., Xu Y., Chiba K., Tanaka H., Hama A., Sanada M., Ito M., Hirayama M., Watanabe A., Ueno T., Kojima S., Aburatani H., Mano H., Miyano S., Ogawa S., Takahashi Y., Muramatsu H.

Blood 131 巻 ( 14 ) 頁： 1576 - 1586 2018年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Blood

Juvenile myelomonocytic leukemia (JMML), a rare and aggressive myelodysplastic/ myeloproliferative neoplasm that occurs in infants and during early childhood, is characterized by excessive myelomonocytic cell proliferation. More than 80% of patients harbor germ line and somatic mutations in RAS pathway genes (eg, PTPN11, NF1, NRAS, KRAS, and CBL), and previous studies have identified several biomarkers associated with poor prognosis. However, the molecular pathogenesis of 10% to 20% of patients and the relationships among these biomarkers have not been well defined. To address these issues, we performed an integrated molecular analysis of samples from 150 JMML patients. RNA-sequencing identified ALK/ROS1 tyrosine kinase fusions (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1) in 3 of 16 patients (18%) who lacked canonical RAS pathway mutations. Crizotinib, an ALK/ROS1 inhibitor, markedly suppressed ALK/ROS1 fusion–positive JMML cell proliferation in vitro. Therefore, we administered crizotinib to a chemotherapy-resistant patient with the RANBP2-ALK fusion who subsequently achieved complete molecular remission. In addition, crizotinib also suppressed proliferation of JMML cells with canonical RAS pathway mutations. Genome-wide methylation analysis identified a hypermethylation profile resembling that of acute myeloid leukemia (AML), which correlated significantly with genetic markers with poor outcomes such as PTPN11/NF1 gene mutations, 2 or more genetic mutations, an AML-type expression profile, and LIN28B expression. In summary, we identified recurrent activated ALK/ROS1 fusions in JMML patients without canonical RAS pathway gene mutations and revealed the relationships among biomarkers for JMML. Crizotinib is a promising candidate drug for the treatment of JMML, particularly in patients with ALK/ROS1 fusions.

DOI： 10.1182/blood-2017-07-798157

Danaparoid reduces transplant-related mortality in stem cell transplantation for children 査読有り

Kato K., Sakaguchi H., Muramatsu H., Sekiya Y., Kawashima N., Narita A., Doisaki S., Watanabe N., Yoshida N., Matsumoto K.

Pediatric Transplantation 22 巻 ( 2 ) 2018年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Transplantation

In SCT, death from transplant-related complications is the major obstacle hindering improvement of transplant outcomes, and proper supportive care is essential to reduce TRM. The transplant outcomes of 210 pediatric patients with malignant and non-malignant disorders who consecutively underwent SCT in our institution from 2000 to 2013 were analyzed. The transplant years were divided into three periods: A (2000-2004), B (2005-2008), and C (2009-2013), and an improvement in 5-year OS and a decrease in 5-year TRM were observed over these time periods; that is, OS was 61.5%, 60.3%, and 79.5% (P =.062), and TRM was 19.9%, 7.9%, and 0.0% (P <.001) in periods A, B, and C, respectively. On multivariate analysis, the prognostic factor for TRM for all patients was administration of danaparoid (HR = 0.109, 95% CI = 0.033-0.363, P <.001), and for patients with hematological malignancies in allogeneic SCT, the prognostic factors were danaparoid (HR = 0.046, 95% CI = 0.006-0.326, P =.002) and advanced disease at SCT (HR = 4.802, 95% CI = 1.734-13.30, P =.003). A reduction in TRM after SCT was observed over the time periods, and supportive care with danaparoid was found to be significantly effective in reducing TRM in SCT for children.

DOI： 10.1111/petr.13099

Comprehensive genetic analysis of donor cell derived leukemia with KMT2A rearrangement 査読有り

Taniguchi R., Muramatsu H., Okuno Y., Suzuki K., Obu S., Nakatochi M., Shimamura T., Takahashi Y., Horikoshi Y., Watanabe K., Kojima S.

Pediatric Blood and Cancer 65 巻 ( 2 ) 2018年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Blood and Cancer

Background: Donor cell leukemia (DCL) occurs after allogeneic hematopoietic stem cell transplantation. Several mechanisms, including occult leukemic/preleukemic subclones in the donor graft and germline predisposition to leukemia, are proposed to be associated with DCL's molecular pathogenesis. We report a comprehensive genetic analysis of a patient with KMT2A-rearranged DCL after allogeneic bone marrow transplantation for refractory cytopenia of childhood. Procedure: We performed a whole-exome sequencing of the recipient's peripheral blood before transplant and the donor's peripheral blood and the recipient's bone marrow at the time of DCL diagnosis. RNA sequencing was also performed to detect fusion genes in DCL blasts. Results: There were no germline mutations that were associated with a predisposition to leukemia in the recipient and donor. Furthermore, there were no detectable somatic alterations except KMT2A-MLLT10 and other related gene fusions in DCL. KMT2A-MLLT10 was not detectable in the donor's bone marrow. Conclusion: We propose a novel pattern of the molecular pathogenesis of DCL solely involving a genetic mutation acquired after transplant with no identifiable genetic factor related to the donor and recipient.

DOI： 10.1002/pbc.26823

Biallelic mutations in SZT2 cause a discernible clinical entity with epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum 査読有り

Nakamura Y., Togawa Y., Okuno Y., Muramatsu H., Nakabayashi K., Kuroki Y., Ieda D., Hori I., Negishi Y., Togawa T., Hattori A., Kojima S., Saitoh S.

Brain and Development 40 巻 ( 2 ) 頁： 134 - 139 2018年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Brain and Development

Mutations in SZT2 were first reported in 2013 as a cause of early-onset epileptic encephalopathy. Because only five reports have been published to date, the clinical features associated with SZT2 remain unclear. We herein report an additional patient with biallelic mutations in SZT2. The proband, a four-year-old girl, showed developmental delay and seizures from two years of age. Her seizures were not intractable and readily controlled by valproate. She showed mildly dysmorphic facies with macrocephaly, high forehead, and hypertelorism, and also had pectus carinatum. An EEG showed epileptic discharges which rarely occurred. A brain MRI revealed a short and thick corpus callosum. Whole-exome sequencing detected compound heterozygous biallelic mutations (c.8596dup (p.Tyr2866Leufs∗42) and c.2930-17_2930-3delinsCTCGTG) in SZT2, both of which were novel and predicted to be truncating. This case suggested a broad phenotypic spectrum arises from SZT2 mutations, forming a continuum from epileptic encephalopathy and severe developmental delay to mild intellectual disability without epilepsy. The characteristic thick and short corpus callosum observed in 7/8 cases with epilepsy, including the proband, but not in three non-syndromic cases, appears to be specific, and thus useful for indicating the possibility of SZT2 mutations. This feature has the potential to make loss of SZT2 a clinically discernible disorder despite a wide clinical spectrum.

DOI： 10.1016/j.braindev.2017.08.003

Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation 査読有り

Takagi M., Hoshino A., Yoshida K., Ueno H., Imai K., Piao J., Kanegane H., Yamashita M., Okano T., Muramatsu H., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Ogawa S., Hayashi Y., Kojima S., Morio T.

Pediatric Blood and Cancer 65 巻 ( 2 ) 2018年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Blood and Cancer

Autoimmune diseases in children are rare and can be difficult to diagnose. Single causative genes have been identified for some pediatric autoimmune diseases. Such orphan diseases may not be diagnosed properly due to the variability of patients' phenotypes. Guidelines for the diagnostic process need to be developed. Fifteen patients with uncharacterized childhood autoimmune diseases with lymphoproliferation that had negative testing for autoimmune lymphoproliferative syndrome were subjected to whole-exome sequencing to identify genes associated with these conditions. Five causative genes, CTLA4, STAT3, TNFAIP3, IKZF1, and PSTPIP1, were identified. These genes should be considered as candidates for uncharacterized childhood autoimmune diseases with lymphoproliferation.

DOI： 10.1002/pbc.26831

Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial 査読有り

Ogawa C., Sato Y., Suzuki C., Mano A., Tashiro A., Niwa T., Hamazaki S., Tanahashi Y., Suzumura M., Hayano S., Hayakawa M., Tsuji T., Hoshino S., Sugiyama Y., Kidokoro H., Kawada J.i., Muramatsu H., Hirakawa A., Ando M., Natsume J., Kojima S.

PLoS ONE 13 巻 ( 2 ) 頁： e0192688 2018年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS ONE

Objective The aim of this prospective multicenter randomized controlled trial was to compare the efficacy of silver nitrate cauterization against that of topical steroid ointment in the treatment of neonatal umbilical granuloma. Methods An open-label, non-inferiority randomized controlled trial was conducted from January 2013 to January 2016. The primary endpoint for the silver nitrate cauterization and topical steroid ointment groups was the healing rate after 2 weeks of treatment, applying a non-inferiority margin of 10%. The healing rate was evaluated until completion of 3 weeks of treatment. Results Participants comprised 207 neonates with newly diagnosed umbilical granuloma, randomized to receive silver nitrate cauterization (n = 104) or topical steroid ointment (n = 103). Healing rates after 2 weeks of treatment were 87.5% (91/104) in the silver nitrate cauterization and 82% (82/100) in the topical steroid ointment group group. The difference between groups was -5.5% (95% confidence interval, -19.1%, 8.4%), indicating that the non-inferiority criterion was not met. After 3 weeks of treatment, the healing rate with topical steroid ointment treatment was almost identical to that of silver nitrate cauterization (94/104 [90.4%] vs. 91/100 [91.0%]; 0.6% [-13.2 to 14.3]). No major complications occurred in either group. Conclusions This study did not establish non-inferiority of topical steroid ointment treatment relative to silver nitrate cauterization, presumably due to lower healing rates than expected leading to an underpowered trial. However, considering that silver nitrate cauterization carries a distinct risk of chemical burns and that the overall efficacy of topical steroid ointment treatment is similar to that of silver nitrate cauterization, topical steroid ointment might be considered as a good alternative in the treatment of neonatal umbilical granuloma due to its safety and simplicity. To clarify non-inferiority, a larger study is needed.

DOI： 10.1371/journal.pone.0192688

Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders 査読有り

Slack J., Albert M.H., Balashov D., Belohradsky B.H., Bertaina A., Bleesing J., Booth C., Buechner J., Buckley R.H., Ouachée-Chardin M., Deripapa E., Drabko K., Eapen M., Feuchtinger T., Finocchi A., Gaspar H.B., Ghosh S., Gillio A., Gonzalez-Granado L.I., Grunebaum E., Güngör T., Heilmann C., Helminen M., Higuchi K., Imai K., Kalwak K., Kanazawa N., Karasu G., Kucuk Z.Y., Laberko A., Lange A., Mahlaoui N., Meisel R., Moshous D., Muramatsu H., Parikh S., Pasic S., Schmid I., Schuetz C., Schulz A., Schultz K.R., Shaw P.J., Slatter M.A., Sykora K.W., Tamura S., Taskinen M., Wawer A., Wolska-Kuśnierz B., Cowan M.J., Fischer A., Gennery A.R.

Journal of Allergy and Clinical Immunology 141 巻 ( 1 ) 頁： 322 - 328.e10 2018年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Allergy and Clinical Immunology

Background Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos–XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). Methods Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. Results Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P =.006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P =.45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. Conclusion RIC HCT resolves DNA repair disorder–associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

DOI： 10.1016/j.jaci.2017.02.036

Kudo K., Muramatsu H., Narita A., Yoshida N., Kobayashi R., Yabe H., Endo M., Inoue M., Hara J., Kounami S., Inagaki J., Hashii Y., Kato K., Tabuchi K., Kojima S.

Bone Marrow Transplantation 52 巻 ( 12 ) 頁： 1659 - 1661 2017年12月

Development of clinical paroxysmal nocturnal haemoglobinuria in children with aplastic anaemia 査読有り

Narita A., Muramatsu H., Okuno Y., Sekiya Y., Suzuki K., Hamada M., Kataoka S., Ichikawa D., Taniguchi R., Murakami N., Kojima D., Nishikawa E., Kawashima N., Nishio N., Hama A., Takahashi Y., Kojima S.

British Journal of Haematology 178 巻 ( 6 ) 頁： 954 - 958 2017年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：British Journal of Haematology

The clinical significance of paroxysmal nocturnal haemoglobinuria (PNH) in children with aplastic anaemia (AA) remains unclear. We retrospectively studied 57 children with AA between 1992 and 2010. During the follow-up, five patients developed clinical PNH, in whom somatic PIGA mutations were detected by targeted sequencing. The 10-year probability of clinical PNH development was 10·2% (95% confidence interval, 3·6–20·7%). Furthermore, the detection of minor PNH clones by flow cytometry at AA diagnosis was a risk factor for the subsequent development of clinical PNH. These patients with PNH clones at AA diagnosis should undergo periodic monitoring for potential clinical PNH development.

DOI： 10.1111/bjh.14790

Flow cytometric analysis as an additional predictive tool of treatment response in children with chronic-phase chronic myeloid leukemia treated with imatinib 査読有り

Shima H., Kiyokawa N., Miharu M., Tanizawa A., Kurosawa H., Watanabe A., Ito M., Tono C., Yuza Y., Muramatsu H., Hotta N., Okada M., Hamamoto K., Kajiwara R., Saito A.M., Horibe K., Mizutani S., Adachi S., Ishii E., Shimada H.

Pediatric Blood and Cancer 64 巻 ( 9 ) 2017年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Blood and Cancer

Bone marrow samples of newly diagnosed children with chronic-phase chronic myeloid leukemia (CML) were obtained at diagnosis and after imatinib initiation and stained with anti-human CD34, CD38, CD123, CD45RA, cMpl, and lineage antibodies. Flow cytometric analysis revealed that granulocyte macrophage progenitor predominance in CML progenitors at diagnosis and elevated cMpl expression in bone marrow progenitors at 3 months may predict poor outcome in children with chronic-phase CML treated with imatinib. We recommend flow cytometric analysis of bone marrow in the early phase of treatment, as it is a convenient tool that may predict treatment response and guide CML management.

DOI： 10.1002/pbc.26478

A case of GATA2-related myelodysplastic syndrome with unbalanced translocation der(1;7)(q10;p10) 査読有り

Kurata T., Shigemura T., Muramatsu H., Okuno Y., Nakazawa Y.

Pediatric Blood and Cancer 64 巻 ( 8 ) 2017年8月

Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes 査読有り

Muramatsu H., Okuno Y., Yoshida K., Shiraishi Y., Doisaki S., Narita A., Sakaguchi H., Kawashima N., Wang X., Xu Y., Chiba K., Tanaka H., Hama A., Sanada M., Takahashi Y., Kanno H., Yamaguchi H., Ohga S., Manabe A., Harigae H., Kunishima S., Ishii E., Kobayashi M., Koike K., Watanabe K., Ito E., Takata M., Yabe M., Ogawa S., Miyano S., Kojima S.

Genetics in Medicine 19 巻 ( 7 ) 頁： 796 - 802 2017年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Genetics in Medicine

Purpose:Precise genetic diagnosis of inherited bone marrow failure syndromes (IBMFS), a heterogeneous group of genetic disorders, is challenging but essential for precise clinical decision making.Methods:We analyzed 121 IBMFS patients using a targeted sequencing covering 184 associated genes and 250 IBMFS patients using whole-exome sequencing (WES).Results:We achieved successful genetic diagnoses for 53 of 121 patients (44%) using targeted sequencing and for 68 of 250 patients (27%) using WES. In the majority of cases (targeted sequencing: 45/53, 85%; WES: 63/68, 93%), the detected variants were concordant with, and therefore supported, the clinical diagnoses. However, in the remaining 13 cases (8 patients by target sequencing and 5 patients by WES), the clinical diagnoses were incompatible with the detected variants.Conclusion:Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS.Genet Med advance online publication 19 January 2017.

DOI： 10.1038/gim.2016.197

Common Variable Immunodeficiency Caused by FANC Mutations 査読有り

Sekinaka Y., Mitsuiki N., Imai K., Yabe M., Yabe H., Mitsui-Sekinaka K., Honma K., Takagi M., Arai A., Yoshida K., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Muramatsu H., Kojima S., Hira A., Takata M., Ohara O., Ogawa S., Morio T., Nonoyama S.

Journal of Clinical Immunology 37 巻 ( 5 ) 頁： 434 - 444 2017年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Immunology

Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4+ T cells were skewed toward CD45RO+ memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.

DOI： 10.1007/s10875-017-0396-4

Efficacy of neutrophil non-muscle myosin heavy chain-IIA immunofluorescence analysis in determining the pathogenicity of MYH9 variants 査読有り

Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm 査読有り

Suzuki K., Suzuki Y., Hama A., Muramatsu H., Nakatochi M., Gunji M., Ichikawa D., Hamada M., Taniguchi R., Kataoka S., Murakami N., Kojima D., Sekiya Y., Nishikawa E., Kawashima N., Narita A., Nishio N., Nakazawa Y., Iwafuchi H., Watanabe K.I., Takahashi Y., Ito M., Kojima S., Kato S., Okuno Y.

Leukemia 31 巻 ( 7 ) 頁： 1629 - 1633 2017年7月

Kunishima S., Yusuke O., Muramatsu H., Kojima D., Nagai N., Takahashi Y., Kojima S.

Annals of Hematology 96 巻 ( 6 ) 頁： 1065 - 1066 2017年6月

Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome 査読有り

Takagi M., Ogata S., Ueno H., Yoshida K., Yeh T., Hoshino A., Piao J., Yamashita M., Nanya M., Okano T., Kajiwara M., Kanegane H., Muramatsu H., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Bando Y., Kato M., Hayashi Y., Miyano S., Imai K., Ogawa S., Kojima S., Morio T.

Journal of Allergy and Clinical Immunology 139 巻 ( 6 ) 頁： 1914 - 1922 2017年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Allergy and Clinical Immunology

Background Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype. Objective The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype. Methods Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. Results A de novo heterozygous frameshift mutation of TNF-α–induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20). Conclusion Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

DOI： 10.1016/j.jaci.2016.09.038

Reticular dysgenesis: International survey on clinical presentation, transplantation, and outcome 査読有り

Hoenig M., Lagresle-Peyrou C., Pannicke U., Notarangelo L.D., Porta F., Gennery A.R., Slatter M., Cowan M.J., Stepensky P., Al-Mousa H., Al-Zahrani D., Pai S.Y., Al Herz W., Gaspar H.B., Veys P., Oshima K., Imai K., Yabe H., Noroski L.M., Wulffraat N.M., Sykora K.W., Soler-Palacin P., Muramatsu H., Al Hilali M., Moshous D., Debatin K.M., Schuetz C., Jacobsen E.M., Schulz A.S., Schwarz K., Fischer A., Friedrich W., Cavazzana M.

Blood 129 巻 ( 21 ) 頁： 2928 - 2938 2017年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Blood

Reticular dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis, and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease.Retrospective data on clinical presentation, genetics, and outcome of HSCT were collected from centers in Europe, Asia, and North America for a total of 32 patients born between 1982 and 2011.Age at presentationwas <4 weeks in 30 of 32 patients (94%). Grafts originated frommismatched family donors in 17 patients (55%), frommatched family donors in 6 patients (19%), and from unrelated marrow or umbilical cord blood donors in 8 patients (26%). Thirteen patients received secondary or tertiary transplants. After transplantation, 21 of 31 patients were reported alive at a mean follow-up of 7.9 years (range: 0.6-23.6 years). All patients who died beyond 6 months after HSCT had persistent or recurrent agranulocytosis due to failure of donor myeloid engraftment. In the absence of conditioning, HSCT was ineffective to overcome agranulocytosis, and inclusion of myeloablativecomponents in theconditioningregimenswasrequiredtoachievestable lymphomyeloidengraftment. Incomparisonwith other SCID entities, considerable differences were noted regarding age at presentation, onset, and type of infectious complications, as well as the requirement of conditioning prior toHSCT.Although long-termsurvival is possible in the presence ofmixed chimerism, highlevel donor myeloid engraftment should be targeted to avoid posttransplant neutropenia.

DOI： 10.1182/blood-2016-11-745638