RESUMEN
Noonan syndrome-related myeloproliferative disorder (NS/MPD) and juvenile myelomonocytic leukemia (JMML) are rare MPDs that occur in young children. We herein report a case of NS/MPD with neonatal onset. The patient had a characteristic appearance and high monocyte count in the peripheral blood and bone marrow. Genetic testing showed the E139D mutation in PTPN11 ; however, the patient did not meet all the diagnostic criteria for JMML, and we thus diagnosed him with NS/MPD. Eight other cases of NS/MPD with neonatal onset are also summarized. The initial presentation varied, and the prognosis was considered poor compared with previous reports of NS/MPD.
Asunto(s)
Leucemia Mielomonocítica Juvenil , Trastornos Mieloproliferativos , Síndrome de Noonan , Humanos , Recién Nacido , Masculino , Leucemia Mielomonocítica Juvenil/complicaciones , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/genética , Mutación , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/genética , Síndrome de Noonan/complicaciones , Síndrome de Noonan/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genéticaRESUMEN
Neuroblastoma is the most common extracranial solid tumor in children. When metastasis to the falx cerebri is present, it is classified as stage M; however, its behavior has not been well characterized. Here we present a case of stage M infantile neuroblastoma (NB) with involvement of the falx cerebri, and also summarize the clinical profiles of previously reported cases. Notably, all of the tumors resolved with low-dose chemotherapy alone. Although further study is needed to distinguish NBs presenting at these different intracranial locations, NB with metastasis to the falx cerebri may be categorized as MS when diagnosed at less than 18 months of age.
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Neoplasias Meníngeas , Neuroblastoma , Niño , Humanos , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Duramadre/patología , Neoplasias Meníngeas/patologíaRESUMEN
BACKGROUND: DNA replisome is a molecular complex that plays indispensable roles in normal DNA replication. IMAGE-I syndrome is a DNA replisome-associated genetic disease caused by biallelic mutations in the gene encoding DNA polymerase epsilon catalytic subunit 1 (POLE). However, the underlying molecular mechanisms remain largely unresolved. METHODS: The clinical manifestations in two patients with IMAGE-I syndrome were characterised. Whole-exome sequencing was performed and altered mRNA splicing and protein levels of POLE were determined. Subcellular localisation, cell cycle analysis and DNA replication stress were assessed using fibroblasts and peripheral blood from the patients and transfected cell lines to determine the functional significance of POLE mutations. RESULTS: Both patients presented with growth retardation, adrenal insufficiency, immunodeficiency and complicated diffuse large B-cell lymphoma. We identified three novel POLE mutations: namely, a deep intronic mutation, c.1226+234G>A, common in both patients, and missense (c.2593T>G) and in-frame deletion (c.711_713del) mutations in each patient. The unique deep intronic mutation produced aberrantly spliced mRNAs. All mutants showed significantly reduced, but not null, protein levels. Notably, the mutants showed severely diminished nuclear localisation, which was rescued by proteasome inhibitor treatment. Functional analysis revealed impairment of cell cycle progression and increase in the expression of phospho-H2A histone family member X in both patients. CONCLUSION: These findings provide new insights regarding the mechanism via which POLE mutants are highly susceptible to proteasome-dependent degradation in the nucleus, resulting in impaired DNA replication and cell cycle progression, a characteristic of DNA replisome-associated diseases.
RESUMEN
In this study, we performed a retrospective analysis of a cohort of Japanese paediatric patients with B-cell precursor (BCP)-acute lymphoblastic leukaemia (ALL) treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol, to clarify the incidence, clinical characteristics, and risk factors of osteonecrosis (ON) in comparison to the ALL-02 protocol. We identified a high frequency of ON with the BFM95-based protocol compared to the ALL-02 protocol. The incidence of symptomatic ON with the BFM95-based protocol is comparable to previous studies in Western countries. We believe that the type of treatment regimen has more impact on the incidence of symptomatic ON in paediatric ALL than ethnicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Osteonecrosis/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/efectos adversos , Asparaginasa/uso terapéutico , Niño , Preescolar , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Citarabina/efectos adversos , Citarabina/uso terapéutico , Daunorrubicina/efectos adversos , Daunorrubicina/uso terapéutico , Femenino , Humanos , Incidencia , Lactante , Japón/epidemiología , Masculino , Mercaptopurina/efectos adversos , Mercaptopurina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Prednisolona/efectos adversos , Prednisolona/uso terapéutico , Prednisona/efectos adversos , Prednisona/uso terapéutico , Estudios Retrospectivos , Vincristina/efectos adversos , Vincristina/uso terapéuticoRESUMEN
IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.
Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Herpesvirus Humano 6/fisiología , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Infecciones por Roseolovirus/diagnóstico , Infecciones por Roseolovirus/virología , Activación Viral , Alelos , Encefalitis Antirreceptor N-Metil-D-Aspartato/etiología , Autoinmunidad , Biomarcadores , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Genes Reporteros , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Lactante , Quinasas Asociadas a Receptores de Interleucina-1/inmunología , Imagen por Resonancia Magnética , Masculino , Mutación , Linaje , Enfermedades de Inmunodeficiencia Primaria/inmunología , Evaluación de SíntomasRESUMEN
Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.
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Candidiasis Mucocutánea Crónica/etiología , Mutación con Ganancia de Función , Predisposición Genética a la Enfermedad , Heterocigoto , Factor de Transcripción STAT1/genética , Adolescente , Adulto , Edad de Inicio , Alelos , Autoinmunidad , Candidiasis Mucocutánea Crónica/diagnóstico , Candidiasis Mucocutánea Crónica/metabolismo , Candidiasis Mucocutánea Crónica/terapia , Niño , Preescolar , Manejo de la Enfermedad , Estudios de Asociación Genética , Humanos , Lactante , Interferón Tipo I/metabolismo , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
The original version of our manuscript, entitled, " The IL1RN mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation" unfortunately contained mistakes in Fig. 1a and d legends. The text should read as follows.
RESUMEN
Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.
Asunto(s)
Infecciones Bacterianas/inmunología , Candidiasis/inmunología , Micosis/inmunología , Receptores de Interleucina-17/deficiencia , Receptores de Interleucina-17/genética , Alelos , Candida , Membrana Celular , Niño , Preescolar , Salud de la Familia , Femenino , Fibroblastos/metabolismo , Genes Recesivos , Estudio de Asociación del Genoma Completo , Células HEK293 , Homocigoto , Humanos , Inmunofenotipificación , Lactante , Recién Nacido , Interleucina-17/metabolismo , Masculino , Mutación , Sistemas de Lectura Abierta , Linaje , Receptores de Interleucina-17/metabolismo , Piel/microbiología , Linfocitos T/citologíaRESUMEN
BACKGROUND: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis. OBJECTIVE: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS: A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts. RESULTS: Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin ß receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS: IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.
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Displasia Ectodérmica/genética , Displasia Ectodérmica/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Genotipo , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Transducción de Señal , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Quimiocina CCL20/genética , Quimiocina CCL20/inmunología , Displasia Ectodérmica/patología , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Células HEK293 , Humanos , Síndromes de Inmunodeficiencia/patología , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Inhibidor NF-kappaB alfa/genética , Inhibidor NF-kappaB alfa/inmunología , Subunidad p52 de NF-kappa B/genética , Subunidad p52 de NF-kappa B/inmunología , Mutación Puntual , Enfermedades de Inmunodeficiencia Primaria , Proto-Oncogenes Mas , Transducción de Señal/genética , Transducción de Señal/inmunologíaAsunto(s)
Síndrome Antifosfolípido , Hipoprotrombinemias , Lupus Eritematoso Sistémico , Infecciones por Mycoplasma , Masculino , Humanos , Inhibidor de Coagulación del Lupus , Hipoprotrombinemias/complicaciones , Hipoprotrombinemias/diagnóstico , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/diagnóstico , Infecciones por Mycoplasma/complicaciones , Infecciones por Mycoplasma/diagnóstico , ProtrombinaRESUMEN
Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra-cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single-agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning-Feuerstein-Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most-druggable targets.
Asunto(s)
Adenoma de las Glándulas Sudoríparas/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de las Glándulas Sudoríparas/genética , Adenoma de las Glándulas Sudoríparas/tratamiento farmacológico , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Ojo/patología , Anomalías del Ojo/genética , Humanos , Indoles/uso terapéutico , Lactante , Mosaicismo , Nevo Sebáceo de Jadassohn/genética , Nacimiento Prematuro , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Neoplasias de las Glándulas Sudoríparas/tratamiento farmacológico , VemurafenibAsunto(s)
Mutación de Línea Germinal/genética , Osteosarcoma/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Esclerosis Tuberosa/genética , Proteína p53 Supresora de Tumor/genética , Angiofibroma/complicaciones , Angiomiolipoma/complicaciones , Astrocitoma/complicaciones , Niño , Femenino , Humanos , Mutación Missense/genética , Osteosarcoma/tratamiento farmacológicoRESUMEN
We report on a 24-year-old woman who was diagnosed as having Maffucci syndrome with anaplastic astrocytoma. We analyzed the IDH1 and IDH2 mutations of enchondroma, hemangioma and anaplastic astrocytoma tissues and the same somatic mosaic mutation in IDH2 gene was identified in all these tissues. In addition, we identified additional mutation of the TP53 gene in anaplastic astrocytoma tissue but not in other benign tumors. This is the first report of the detection of an identical IDH2 mutation in multiple tissues and TP53 mutation in anaplastic astrocytoma in a patient with Maffucci syndrome. This case is unique and supports the IDH2-dependent genetic pathway and second-hit model for gliomagenesis.
Asunto(s)
Astrocitoma/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico por imagen , Encondromatosis/genética , Isocitrato Deshidrogenasa/genética , Proteína p53 Supresora de Tumor/genética , Astrocitoma/genética , Astrocitoma/terapia , Secuencia de Bases , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Hemangioma/diagnóstico , Hemangioma/genética , Humanos , Mutación Missense , Radiografía , Adulto JovenRESUMEN
Notch1 mutations are found in more than 50% of human T cell acute lymphoblastic leukemia (T-ALL) cells. However, the functions of Notch1 for human T cell development and leukemogenesis are not well understood. To examine the role of Notch1, human hematopoietic stem cells (HSCs), which had been transduced with a constitutively active form of Notch1 (ICN1), were transplanted into severely immunodeficient NOD/Shi-scid-IL2rγ(null) (NOG) mice. We found that the great majority of the ICN1-expressing hematopoietic cells in the bone marrow expressed surface markers for T cells, such as CD3, CD4, and CD8, and that this T cell development was independent of the thymus. Accordingly, phenotypically mature CD8(+) single positive (SP) T cells were observed in the spleen. Furthermore, T-ALL developed in one NOG recipient mouse out of 26 that had been secondary transferred with the T cells developed in the first NOG mice. These results indicate that Notch1 signaling in HSCs promotes CD8(+) SP T cell development, and that T cell leukemogenesis may require additional oncogenic factors other than Notch1 activation.
Asunto(s)
Linfocitos T CD8-positivos/patología , Carcinogénesis , Células Madre Hematopoyéticas/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Receptor Notch1/metabolismo , Animales , Linfocitos T CD8-positivos/metabolismo , Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Humanos , Ratones , Ratones Endogámicos NOD , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/genética , Bazo/patologíaRESUMEN
Hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) is a vesicular sorting protein that functions as one of the endosomal-sorting proteins required for transport (ESCRT). Hrs, which binds to ubiquitinated proteins through its ubiquitin-interacting motif (UIM), contributes to the lysosomal transport and degradation of ubiquitinated membrane proteins. However, little is known about the relationship between B-cell functions and ESCRT proteins in vivo. Here we examined the immunological roles of Hrs in B-cell development and functions using B-cell-specific Hrs-deficient (Hrs(flox/flox);mb1(cre/)(+):Hrs-cKO) mice, which were generated using a cre-LoxP recombination system. Hrs deficiency in B-cells significantly reduced T-cell-dependent antibody production in vivo and impaired the proliferation of B-cells treated in vitro with an anti-IgM monoclonal antibody but not with LPS. Although early development of B-cells in the bone marrow was normal in Hrs-cKO mice, there was a significant decrease in the number of the peripheral transitional B-cells and marginal zone B-cells in the spleen of Hrs-cKO mice. These results indicate that Hrs plays important roles during peripheral development and physiological functions of B lymphocytes.
Asunto(s)
Linfocitos B/citología , Linfocitos B/fisiología , Endocitosis/fisiología , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Endosomas/enzimología , Factor de Crecimiento de Hepatocito/metabolismo , Fosfoproteínas/metabolismo , Animales , Proliferación Celular , Células Cultivadas , Activación Enzimática , Regulación Enzimológica de la Expresión Génica/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Especificidad por SustratoRESUMEN
Mesenchymal chondrosarcoma (MC) is an extremely rare subtype of chondrosarcoma that has a small round-cell sarcoma with focal cartilaginous differentiation, often with a pericytomatous vascular pattern. The non-cartilaginous components are usually dominant, and such lesions might be confused with other small round-cell tumors. Recently, a tumor-specific HEY1-NCOA2 fusion gene was identified in MC. Here we report the case of a 9-year-old boy who was diagnosed with MC by detection of HEY1-NCOA2 fusion signals in almost 50% of tumor cells in tissue sections on fluorescence in situ hybridization (FISH). In this way, the tumor was definitively diagnosed as MC. This case suggests that the detection of the HEY1-NCOA2 fusion gene on FISH is of diagnostic value for MC.