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1.
J Dermatol ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31820501

RESUMO

Hermansky-Pudlak syndrome type 2 (HPS2) is an extremely rare autosomal recessive inherited disease characterized by partial oculocutaneous albinism (OCA), bleeding diathesis due to a storage pool deficiency and immunodeficiency. The disorder is caused by disruption of the adapter protein 3 complex, which is involved in impaired intracellular vesicle transport. Here, we report the first case of a 1-year-old girl with HPS2 in Asia. She had no specific symptoms other than OCA and neutropenia. We analyzed her platelet function using transmission electron microscopy and a platelet aggregation test, cytotoxic degranulation assay of her natural killer (NK) cells and bleeding time, the results of which led to the diagnosis of HPS2. Although her NK-cell cytotoxic degranulation was impaired, she had not developed signs of hemophagocytic lymphohistiocytosis (HLH) or fibrosing lung disease. Molecular genetic analyses showed novel heterozygous mutations (c.188T>A [p.M63K] and c.2546>A [p.L849X]) in AP3B1. When examining patients with OCA, blood tests should be performed to confirm neutrophil count, bleeding time and platelet agglutination. When HPS2 is suspected, detailed immunological tests should be considered, and attention should be paid to HLH and pulmonary lesions immediately and over the long term.

2.
Cell Rep ; 29(9): 2823-2834.e7, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31775048

RESUMO

Intestinal microfold cells (M cells) in Peyer's patches are a special subset of epithelial cells that initiate mucosal immune responses through uptake of luminal antigens. Although the cytokine receptor activator of nuclear factor-κB ligand (RANKL) expressed on mesenchymal cells triggers differentiation into M cells, other environmental cues remain unknown. Here, we show that the metastasis-promoting protein S100A4 is required for development of mature M cells. S100A4-producing cells are a heterogenous cell population including lysozyme-expressing dendritic cells and group 3 innate lymphoid cells. We found that in the absence of DOCK8, a Cdc42 activator critical for interstitial leukocyte migration, S100A4-producing cells are reduced in the subepithelial dome, resulting in a maturation defect of M cells. While S100A4 promotes differentiation into mature M cells in organoid culture, genetic inactivation of S100a4 prevents the development of mature M cells in mice. Thus, S100A4 is a key environmental cue that regulates M cell differentiation in collaboration with RANKL.

3.
Eur J Pediatr ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754776

RESUMO

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency disease that can be divided into two types: SAP deficiency (XLP1) and XIAP deficiency (XLP2), caused by mutations in the SH2D1A and XIAP genes, respectively. Few cases of XLP (particularly XIAP deficiency) have been reported in mainland China; hence, little is known about the characteristics of Chinese patients with XLP. We identified 13 and 7 patients with SAP and XIAP deficiency, respectively, in our center. Of our 20 patients, 19/20 (95%) presented with disease symptoms at a very early age: six in infancy and 13 in childhood. One XIAP- and three SAP-deficient patients died, while 3/7(42.9%) and 4/13(30.8%), respectively, developed hemophagocytic lymphohistiocytosis (HLH). Epstein-Barr virus (EBV) infection was significantly more common in SAP-deficient 10/13 (76.9%) than XIAP-deficient 2/7 (28.6%) patients, as was hypogammaglobulinemia (10/13 (76.9%) vs. 1/7 (14.3%)). None of the seven XIAP-deficient patients had colitis or lymphoma. Nine SAP-deficient patients and five XIAP-deficient patients showed markedly deficient SAP and XIAP expression, respectively, in lymphocytes. Significantly reduced levels of switched memory B cells were observed in six SAP-deficient patients with persistent hypogammaglobulinemia. One of 13 (7.7%) SAP-deficient patients and 1 of 7 (12.3%) XIAP-deficient patients have received HSCT treatment and are now alive and well; the other alive patients were waiting for HSCT. We also summarized clinical, genetic, and immunological characteristics of all 55 patients (including our 20 patients) reported in the literature in mainland China today.Conclusion: The overall characteristics of SAP deficiency in mainland China were consistent with those in previous reports, whereas manifestations of XIAP deficiency varied significantly. None of inflammatory bowel disease (IBD) has been reported among XIAP-deficient patients in our center; however, whether Chinese XIAP-deficient patients will develop colitis in the future warrants further investigation. HSCT is the only curative therapy for XLP and this therapy should be urgently considered.What is Known:• SAP and XIAP deficiencies share common clinical feature, HLH, whereas they also have their own specific manifestations.• IBD affects 25-30% of XIAP-deficient patients, which has been reported in other countries especially in European country and Japan.What is New:• This is the largest patient cohort study of XLP in China.• We firstly summarized the clinical features and outcomes of Chinese XIAP-deficient patients and found only 1 in 22 patients developed IBD and diet background may contribute to it; Asian SAP-deficient patients carrying SH2D1A R55X mutation were more prone to HLH.

4.
Int J Hematol ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758416

RESUMO

The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.

5.
J Dermatol ; 46(11): 1019-1023, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31456262

RESUMO

Prominent dermal infiltration by Langerhans cells (LC) is a rare finding in patients with Omenn syndrome (OS). Here, we report the case study of a 7-month-old boy with OS and with prominent dermal infiltration by LC, which is a rare histological manifestation of the skin. Striking erythroderma appeared in the patient 2 weeks after birth. We also noted alopecia, lymphadenopathy, hepatosplenomegaly, eosinophilia and an elevated serum immunoglobulin E level with hypogammaglobulinemia. Peripheral blood flow cytometry showed the Tlow NK+ B+ immunophenotype and genetic analysis, a novel mutation in the IL2RG gene (c.337_339delTCT, p.Ser113del). The final diagnosis was that of OS. He responded well to an allograft umbilical cord blood transplantation that was performed when the patient was 8 months of age. We speculate that the LC accumulated in the dermis will eventually migrate to the regional lymph node, then stimulate autoreactive T cells by overpresenting antigens, thus causing OS-specific skin symptoms.

6.
Pediatr Diabetes ; 20(7): 1035-1040, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322807

RESUMO

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T-(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic ß-cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16-year-old adolescent with late-onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin-dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC-peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal ß-cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D-associated IPEX syndrome improves Treg deficiency and prevents elimination of ß-cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue ß-cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.

7.
Rinsho Ketsueki ; 60(6): 708-715, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281164

RESUMO

Lymphoproliferative disorders (LPDs) are caused by dysregulated lymphocyte proliferation and include polyclonal benign and monoclonal malignant diseases. LPDs frequently occur in immunocompromized patients, particularly those with primary immunodeficiency disease (PID), a monogenic disease. PID-associated LPD corresponds to inherited LPD. Here, we describe inherited LPD and focus on IKZF1-associated diseases and Epstein-Barr virus-associated LPD, such as ZAP70 deficiency and X-linked lymphoproliferative syndrome type 1 with somatic reversion mosaicism. Disclosing the pathogenesis of inherited LPDs would lead to a broad understanding of LPDs and development of new treatment strategies.


Assuntos
Síndromes de Imunodeficiência/complicações , Transtornos Linfoproliferativos/genética , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Humanos , Fator de Transcrição Ikaros/genética
8.
Stem Cell Res Ther ; 10(1): 185, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234949

RESUMO

BACKGROUND: Disease modeling with patient-derived induced pluripotent stem cells (iPSCs) is a powerful tool for elucidating the mechanisms underlying disease pathogenesis and developing safe and effective treatments. Patient peripheral blood (PB) cells are used for iPSC generation in many cases since they can be collected with minimum invasiveness. To derive iPSCs that lack immunoreceptor gene rearrangements, hematopoietic stem and progenitor cells (HSPCs) are often targeted as the reprogramming source. However, the current protocols generally require HSPC mobilization and/or ex vivo expansion owing to their sparsity at the steady state and low reprogramming efficiencies, making the overall procedure costly, laborious, and time-consuming. METHODS: We have established a highly efficient method for generating iPSCs from non-mobilized PB-derived CD34+ HSPCs. The source PB mononuclear cells were obtained from 1 healthy donor and 15 patients and were kept frozen until the scheduled iPSC generation. CD34+ HSPC enrichment was done using immunomagnetic beads, with no ex vivo expansion culture. To reprogram the CD34+-rich cells to pluripotency, the Sendai virus vector SeVdp-302L was used to transfer four transcription factors: KLF4, OCT4, SOX2, and c-MYC. In this iPSC generation series, the reprogramming efficiencies, success rates of iPSC line establishment, and progression time were recorded. After generating the iPSC frozen stocks, the cell recovery and their residual transgenes, karyotypes, T cell receptor gene rearrangement, pluripotency markers, and differentiation capability were examined. RESULTS: We succeeded in establishing 223 iPSC lines with high reprogramming efficiencies from 15 patients with 8 different disease types. Our method allowed the rapid appearance of primary colonies (~ 8 days), all of which were expandable under feeder-free conditions, enabling robust establishment steps with less workload. After thawing, the established iPSC lines were verified to be pluripotency marker-positive and of non-T cell origin. A majority of the iPSC lines were confirmed to be transgene-free, with normal karyotypes. Their trilineage differentiation capability was also verified in a defined in vitro assay. CONCLUSION: This robust and highly efficient method enables the rapid and cost-effective establishment of transgene-free iPSC lines from a small volume of PB, thus facilitating the biobanking of patient-derived iPSCs and their use for the modeling of various diseases.

9.
World Allergy Organ J ; 12(3): 100018, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30937141

RESUMO

Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. Methods: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. Results: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. Conclusions: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.

10.
Clin Immunol ; 203: 9-13, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30951839

RESUMO

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is one of the inborn errors of immunity, characterized by impaired function of the regulatory T cells. Clinical manifestations of IPEX syndrome are characterized by various autoimmune diseases with autoantibodies. The comprehensive analysis for autoantibodies using human proteome microarrays in the four patients with IPEX syndrome was performed. The numbers of the highly expressed autoantibody showing relative log2 ratios greater than 1 were 1876, 513, 234 and 831 (mean: 864), respectively. Some novel autoantibodies which could explain the phenotypes of patients, adrenal dysfunction, muscular hypotonia, afibrinogenemia, enteropathy and pancytopenia were identified. Various kinds of autoantibodies targeting testis-specific antigens were also identified. Human proteome microarray is a powerful tool to understand the pathophysiology of IPEX syndrome. The larger cohort analysis using this method will provide further understanding of the impaired immune tolerance in humans.

12.
Int J Hematol ; 109(5): 603-611, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30850927

RESUMO

X-Linked severe combined immunodeficiency (X-SCID) is a severe form of primary immunodeficiency characterized by absence of T cells and NK cells. X-SCID is caused by a loss-of-function mutation in the IL2RG gene that encodes common gamma chain (γc), which plays an essential role in lymphocyte development. We report the first case of hypomorphic X-SCID caused by a synonymous mutation in the IL2RG gene leading to a splice anomaly, in a family including two patients with diffuse cutaneous warts, recurrent molluscum contagiosum, and mild respiratory infections. The mutation caused aberrant splicing of IL2RG mRNA, subsequently resulted in reduced γc expression. The leaky production of normally spliced IL2RG mRNA produced undamaged protein; thus, T cells and NK cells were generated in the patients. Functional assays of the patients' T cells and NK cells revealed diminished cytokine response in the T cells and absent cytokine response in the NK cells. In addition, the TCR repertoire in these patients was limited. These data suggest that a fine balance between aberrant splicing and leaky production of normally spliced IL2RG mRNA resulted in late-onset combined immunodeficiency in these patients.


Assuntos
Subunidade gama Comum de Receptores de Interleucina , Mutação , Sítios de Splice de RNA , Processamento de RNA , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Adolescente , Feminino , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Processamento de RNA/genética , Processamento de RNA/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/patologia
13.
Front Pediatr ; 7: 15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30778380

RESUMO

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is an EBV-associated lymphoproliferative disease characterized by repeated or sustainable infectious mononucleosis (IM)-like symptoms. EBV is usually detected in B cells in patients who have IM or Burkitt's lymphoma and even in patients with X-linked lymphoproliferative syndrome, which is confirmed to have vulnerability to EBV infection. In contrast, EBV infects T cells (CD4+ T, CD8+ T, and γδT) or NK cells mono- or oligoclonally in CAEBV patients. It is known that the CAEBV phenotypes differ depending on which cells are infected with EBV. CAEBV is postulated to be associated with a genetic immunological abnormality, although its cause remains undefined. Here we describe a case of EBV-related γδT-cell proliferation with underlying hypomorphic IL2RG mutation. The immunological phenotype consisted of γδT-cell proliferation in the peripheral blood. A presence of EBV-infected B cells and γδT cells mimicked γδT-cell-type CAEBV. Although the patient had normal expression of CD132 (common γ chain), the phosphorylation of STAT was partially defective, indicating impaired activation of the downstream signal of the JAK/STAT pathway. Although the patient was not diagnosed as having CAEBV, this observation shows that CAEBV might be associated with immunological abnormality.

14.
Int J Hematol ; 109(5): 612-617, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788725

RESUMO

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) is highly prevalent in Japan. To date, no standard treatment for EBV-HLH has been established owing to the diversity in treatment response and the difficulty in assessing prognostic factors. The present prospective study recruited 27 children with EBV-HLH who were also part of the HLH-2004 study. EBV load in the peripheral blood was monitored at diagnosis and 2, 4, and 8 weeks after treatment initiation. Additionally, T-cell receptor (TCR) clonality and other laboratory data were evaluated. TCR clonality was positive in 14 patients at diagnosis. Seven of 27 patients experienced recurrences after treatment. No correlation was noted among any clinical data at diagnosis of patients with and without recurrence. However, the recurrence rate was significantly higher in patients aged < 2 years and/or those with a high plasma EBV load of > 103 copies/mL 2 weeks after treatment than that in patients without these factors. These findings suggest that a younger age or a high EBV load in plasma at the early phase of treatment is a factor predicting a recurrence and helps guide the intensity of subsequent treatment phases for children with EBV-HLH.


Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4/metabolismo , Linfo-Histiocitose Hemofagocítica , Receptores de Antígenos de Linfócitos T/genética , Carga Viral , Adolescente , Fatores Etários , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Feminino , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/virologia , Masculino , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T/sangue , Recidiva
15.
Int J Hematol ; 109(4): 382-389, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30758723

RESUMO

Mutation in the gene encoding tRNA nucleotidyl transferase, CCA-adding 1 (TRNT1), an enzyme essential for the synthesis of the 3'-terminal CCA sequence in tRNA molecules, results in a disorder that features sideroblastic anemia, B-cell immunodeficiency, periodic fever, and developmental delay. Mutations in TRNT1 are also linked to phenotypes including retinitis pigmentosa, cataracts, and cardiomyopathy. To date, it has remained unclear how defective TRNT1 is linked to B-cell deficiency. Here we report the case of a 12-year-old boy without sideroblastic anemia who harbors novel compound heterozygous mutations in TRNT1. Immunophenotypic analysis revealed severely decreased levels of B cells and follicular helper T cells. In the bone marrow, B-cell maturation stopped at the CD19+CD10+CD20+/- pre-B-cell stage. Severe combined immunodeficiency mice transplanted with bone marrow hematopoietic stem cells from the patient showed largely normal B-cell engraftment and differentiation in the bone marrow and periphery at 24 weeks post-transplantation, comparable to those in mouse transplanted with healthy hematopoietic stem cells. Biochemical analysis revealed augmented endoplasmic reticulum (ER) stress response in activated T cells. Peripheral B-cell deficiency of TRNT1 deficiency may be associated with augmented ER stress in immature B cells in the bone marrow.


Assuntos
Heterozigoto , Síndromes de Imunodeficiência , Nucleotidiltransferases , Antígenos CD/sangue , Antígenos CD/genética , Linfócitos B/metabolismo , Linfócitos B/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Lactente , Masculino , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/patologia
16.
J Pediatr Hematol Oncol ; 41(8): e538-e541, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30676439

RESUMO

X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare congenital immunodeficiency disease. We report the case of an 18-year-old male who developed hemophagocytic lymphohistiocytosis (HLH) with neurologic complications after primary Epstein-Barr virus (EBV) infection and subsequently developed EBV-related central nervous system lymphoma (CNSL). Given the vulnerability to EBV, he was finally diagnosed with XLP1 and treated with whole-brain irradiation along with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation from a SH2D1A wild-type sibling donor. Although the prognosis for CNSL is generally dismal, reconstitution of the immune system from a normal donor contributed to the patient remaining in remission for 30 months.

17.
Hum Genome Var ; 6: 2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30622725

RESUMO

Biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene have been reported to cause two different clinical spectra: short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome and infantile liver failure syndrome 2 (ILFS2). Here, we describe a case of a 3-year-old Japanese boy who presented with fever-triggered recurrent acute liver failure (ALF). The clinical characteristics were considerable elevation of liver enzymes, severe coagulopathy, and acute renal failure. In addition to the liver phenotype, he had short stature and Pelger-Huët anomaly in the peripheral granulocytes. Whole-exome and Sanger sequencing of the patient and his parents revealed that he carried novel compound heterozygous missense mutations in NBAS, c.1018G>C (p.Gly340Arg) and c.2674 G>T (p.Val892Phe). Both mutations affect evolutionarily conserved amino acid residues and are predicted to be highly damaging. Immunoblot analysis of the patient's skin fibroblasts showed a normal NBAS protein level but a reduced protein level of its interaction partner, p31, involved in Golgi-to-endoplasmic reticulum retrograde vesicular trafficking. We recommend NBAS gene analysis in children with unexplained fever-triggered recurrent ALF or liver dysfunction. Early antipyretic therapy may prevent further episodes of ALF.

19.
Int J Hematol ; 109(2): 206-213, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535855

RESUMO

Recent advances in intensive chemo- and immunotherapy have contributed to the outcome of hemophagocytic lymphohistiocytosis (HLH); however, the prognosis of HLH in children differs by HLH subtype. In Japan, secondary HLH, particularly Epstein-Barr virus-associated HLH (EBV-HLH), is the most common HLH subtype. The prognosis of HLH has improved in recent years. We here conducted a prospective study of 73 patients who were treated with HLH-2004 protocol in Japan. EBV-HLH, familial HLH (FHL), and HLH of unknown etiology were seen in 41, 9, and 23 patients, respectively. Patients with resistant or relapsed disease after HLH-2004 treatment and those with FHL received hematopoietic stem cell transplantation (HSCT). The induction rate after initial therapy was 58.9%, and the 3-year overall survival (OS) rate of all patients was 73.9% and differed significantly among those with EBV-HLH, FHL, and HLH of unknown etiology. Of the 17 patients who received HSCT, the 3-year OS rates of those with and without complete resolution before HSCT were 83.3% and 54.5%, respectively. Outcomes in children with HLH who were treated with the same protocol differed among HLH subtypes. Appropriate strategy for each subtype should be established in future studies.


Assuntos
Linfo-Histiocitose Hemofagocítica/classificação , Linfo-Histiocitose Hemofagocítica/terapia , Adolescente , Criança , Pré-Escolar , Protocolos Clínicos , Feminino , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4 , Humanos , Japão , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/mortalidade , Masculino , Estudos Prospectivos , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento
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