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We reported a dichorionic diamniotic placental twin (DD twin) with a family history of a congenital nephrotic syndrome of the Finnish type (CNF), of which the parent had heterozygous for the NPHS1 gene mutation. The DD twin was born at 36 weeks gestation, and their fused placenta weighed 1,340 g. Although the first-born child had heavy proteinuria and hypoalbuminemia and needed daily albumin replacement to manage severe edema, the second had only mild proteinuria after birth. Genetic testing performed 28 days after birth detected homozygous for the NPHS1 gene mutation in only the first-born child but not in the second, which resulted in performing invasive left nephrectomy and peritoneal dialysis (PD) to manage edema in the first. For DD twins with a family history of CNF, prenatal diagnosis of CNF may be difficult. Therefore, close postnatal clinical observation and early genetic testing are essential for the diagnosis of CNF.
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Human leukocyte antigen (HLA) mismatched unrelated donor transplantation is associated with an increased risk of graft-versus-host disease, graft failure, and infection, which increases post-transplant morbidity and mortality. In this single-center retrospective study, outcomes were evaluated in 30 consecutive children who underwent bone marrow transplantation (BMT) from HLA 1 allele-mismatched (HLA 7/8-matched) unrelated donors with rabbit anti-thymocyte globulin (rATG) as graft-versus-host disease (GVHD) prophylaxis. The 3-year overall survival (OS), event-free survival (EFS), and GVHD-relapse-free survival rates were 91.7% (95% CI 70.5%-91.9%), 88.3% (95% CI 67.5%-96.1%), and 73.9% (95% CI 52.4%-86.8%), respectively. Grade II-IV and III-IV acute GVHD occurred in 10 (33%) and 2 (7.0%) patients, respectively. The 3-year cumulative incidence of chronic GVHD was 7.8%. No fatal viral infections occurred. The study results show the feasibility of HLA 7/8-matched unrelated BMT with ATG to achieve favorable outcomes and acceptable GVHD, especially for patients who lack a fully matched donor.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Niño , Trasplante de Médula Ósea/efectos adversos , Suero Antilinfocítico/uso terapéutico , Estudios Retrospectivos , Trasplante Homólogo/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/genética , Donante no Emparentado , Antígenos de Histocompatibilidad Clase II , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
Melphalan is widely used for hematopoietic stem cell transplantation (HSCT) conditioning. However, the relationship between its pharmacokinetic (PK) and transplantation outcomes in children has not been thoroughly investigated. We prospectively analyzed the relationship between melphalan area under the curve (AUC) and transplantation outcome and examined the development of a predictive model for melphalan clearance in children. This study included 43 children aged 0 to 19 years who underwent HSCT following a melphalan-based conditioning regimen from 2017 to 2021. In univariable analysis, high-melphalan AUC resulted in a significantly lower cumulative incidence of acute graft-versus-host disease and a higher cumulative incidence of thrombotic microangiopathy, although no significant difference was observed in survival. Regression analysis of a randomly selected derivation cohort (n = 21) revealed the following covariate PK model: predicted melphalan clearance (mL/min) = 6.47 × 24-h urinary creatinine excretion rate (CER, g/day) × 24-h creatinine clearance rate (CCR, mL/min) + 92.8. In the validation cohort (n = 22), the measured melphalan clearance values were significantly correlated with those calculated based on the prediction equation (R2 = 0.663). These results indicate that melphalan exposure may be optimized by adjusting the melphalan dose according to CER and CCR.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Niño , Melfalán/farmacocinética , Creatinina , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a rare heterogeneous hematological malignancy of early childhood characterized by causative RAS pathway mutations. Classifying patients with JMML using global DNA methylation profiles is useful for risk stratification. We implemented machine learning algorithms (decision tree, support vector machine, and naïve Bayes) to produce a DNA methylation-based classification according to recent international consensus definitions using a well-characterized pooled cohort of patients with JMML (n = 128). DNA methylation was originally categorized into three subgroups: high methylation (HM), intermediate methylation (IM), and low methylation (LM), which is a trichotomized classification. We also dichotomized the subgroups as HM/IM and LM. The decision tree model showed high concordances with 450k-based methylation [82.3% (106/128) for the dichotomized and 83.6% (107/128) for the trichotomized subgroups, respectively]. With an independent cohort (n = 72), we confirmed that these models using both the dichotomized and trichotomized classifications were highly predictive of survival. Our study demonstrates that machine learning algorithms can generate clinical parameter-based models that predict the survival outcomes of patients with JMML and high accuracy. These models enabled us to rapidly and effectively identify candidates for augmented treatment following diagnosis.
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Leucemia Mielomonocítica Juvenil , Teorema de Bayes , Preescolar , Metilación de ADN , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patología , Mutación , PronósticoRESUMEN
Diamond-Blackfan anaemia (DBA) shares clinical features with two recently reported sporadic cases of dyserythropoietic anaemia with a cryptic GATA1 splicing mutation (c.871-24 C>T). We hypothesized that some patients clinically diagnosed with DBA but whose causative genes were unknown may carry the intronic GATA1 mutation. Here, we examined 79 patients in our DBA cohort, who had no detectable causative genes. The intronic GATA1 mutation was identified in two male patients sharing the same pedigree that included multiple cases with anaemia. Cosegregation of this mutation and disease in multiple family members provide evidence to support the pathogenicity of the intronic GATA1 mutation.
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Severe combined immunodeficiency (SCID) is an inborn error of immunity that occurs in approximately 1 in 50,000 births, mainly due to impaired lymphocyte differentiation. Without curative treatment, such as hematopoietic cell transplantation (HCT) or gene therapy, severe infection in the first year of life could make this condition fatal. The results of HCT are poor when patients have active infections, thus requiring early diagnosis before onset of infection. In five cases of SCID diagnosed in Japan, the oral rotavirus vaccine had been administered before diagnosis. In this study, we demonstrated that the rotavirus from their stools was a vaccine-derived strain. In some cases, severe gastroenteritis triggered the diagnosis of SCID. However, newborn screening for SCID is available before the first rotavirus vaccination using assays for the detection of T-cell receptor excision circles (TRECs). Therefore, to improve the prognosis of patients with SCID in Japan, we should establish a screening system of TRECs for newborns throughout Japan.
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Rotavirus , Inmunodeficiencia Combinada Grave , ADN , Humanos , Recién Nacido , Japón , Tamizaje Neonatal/métodos , Rotavirus/genética , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Vacunación/efectos adversosRESUMEN
BACKGROUND: Patients with primary refractory and relapsed neuroblastoma have a poor prognosis since safe and effective chemotherapies for these patients are currently limited. The development of new chemotherapy regimens for these patients is imperative to improve survival outcomes. METHODS: We retrospectively analyzed 40 patients with refractory (n = 36) or relapsed (n = 4) neuroblastoma who received irinotecan, etoposide, and carboplatin (IREC) as a second-line treatment. We evaluated their therapeutic response and the toxicity of IREC. We also assessed the impact of UGT1A1 gene polymorphisms, which are involved in irinotecan metabolism, on outcomes and toxicity. RESULTS: A total of 112 cycles of IREC were administered to 40 patients with a median of 2 cycles per patient (range, 1-9). Six (15%) patients (UGT1A1 wild-type [n = 2] and heterozygous [n = 4]) showed objective responses, including partial response (n = 1), tumor shrinkage (n = 4), and improved findings on their MIBG scan (n = 1). Grade 4 neutropenia, grade 4 leukopenia, and grades 3-4 gastrointestinal toxicity were observed in 110 (98%), 88 (79%), and 3 (3%) cycles, respectively. There was no IREC-related mortality. Patients with UGT1A1 polymorphisms showed a higher frequency of grade 4 leukopenia, but these patients did not have increased treatment-related mortality or non-hematologic toxicity. CONCLUSIONS: IREC showed an objective response rate of 15% including 1 case with partial response. IREC was well tolerated regardless of UGT1A1 genotype. This study suggests that IREC is a promising second-line chemotherapy for refractory or relapsed neuroblastoma.
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Neuroblastoma , Neutropenia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina , Carboplatino , Etopósido , Humanos , Irinotecán , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Neutropenia/inducido químicamente , Estudios RetrospectivosRESUMEN
We report the case of a child with a venous malformation (VM), in whom streptococcal toxic shock syndrome (STSS) developed from cellulitis. A six-year-old boy with VM of the left lower limb had a fever and left lower limb pain since the afternoon of the day before admission. He presented with swelling, redness, heat, and tenderness on an area extending from the sole of the foot to the lower leg on the left side. Disturbance of consciousness gradually appeared, and he was admitted to the intensive care unit. We administered intravenous antibiotics and an immunoglobulin. On day two of hospitalization, group A hemolytic streptococci were detected in the blood culture. We managed the patient in coordination with a plastic surgeon for consideration of surgical interventions. The local findings subsequently improved to change the antibiotics promptly without debridement, and he was discharged after 14 days of antibiotic therapy. In this case, the VM may have contributed to the worsening of the infection. In children with VM, soft tissue inflammation with local pain and fever must be treated promptly, with the expectation of prompt surgical intervention, because the condition can progress to sepsis and necrotizing fasciitis.
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Familial hemophagocytic lymphohistiocytosis (FHL) is a severe inborn error of immunity caused by a genetic defect that impairs the function of cytotoxic T and NK cells. There are only a few reported cases of FHL with diffuse swelling of the cerebellum and obstructive hydrocephalus. We report a case of FHL3 with neurological symptoms associated with cerebellar swelling and obstructive hydrocephalus. A male patient was hospitalized several times due to fever and decreased feeding, hepatosplenomegaly, and cytopenia since the first month of life. At 7 months of age, disturbance of consciousness was seen. Brain magnetic resonance imaging revealed signal intensity in the bilateral cerebellar hemispheres, diffusely increased periventricular white matter, and ventriculomegaly. Although he was treated with methylprednisolone pulse therapy, he was unresponsive to the treatment. He was then transferred to a local hospital after tracheotomy but died. Targeted clinical sequencing revealed a homozygous splice-site mutation in UNC13D. Pediatric hemophagocytic lymphohistiocytosis (HLH) includes some cases of central nervous symptom (CNS)-isolated HLH or CNS HLH preceding systemic lesions, which often do not initially meet the diagnostic criteria for FHL. Patients with FHL initiated by cerebellar symptoms may present with an atypical clinical course for HLH, leading to delayed diagnosis and poor outcomes. Despite the usefulness of a combination of a high percentage of lymphocytes in the peripheral leukocytes, a low lactate dehydrogenase level, and a high sIL-2R/ferritin ratio for identifying FHL, the diagnosis may be missed due to the absence of these results. Presymptomatic diagnosis of FHL by screening of newborns and subsequent early treatment of patients with a predicted poor prognosis may contribute to better outcomes.
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Microsatellite instability (MSI)-high status is associated with good responsiveness to immune checkpoint inhibitors. Although MSI-high status has been actively investigated in pediatric brain tumors, studies of other pediatric solid tumors are lacking. Among 334 consecutive pediatric patients with solid tumors, we retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues of 36 of 74 patients (49%) who died of disease. We assessed the MSI status in these tissues using five multiplexed markers. The results revealed that none of the patients had an MSI-high status. These results indicate that MSI-high status is a rare event in pediatric patients with refractory/relapsed solid tumors.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1998266.
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Inestabilidad de Microsatélites , Neoplasias , Niño , Reparación de la Incompatibilidad de ADN , Humanos , Neoplasias/genética , Estudios RetrospectivosRESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by heterozygous germline variants in the fumarate hydratase (FH) gene and is associated with increased susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). HLRCC-associated RCC usually occurs in the middle age, with the median age being 40-44 years. This report describes a seven-year-old (84-month-old) male who developed a large right kidney tumor with multiple cystic lesions that contained enhanced solid components. There was no evidence of distant metastasis. The male patient underwent right nephrectomy and has been recovering well without metastasis or recurrence. Pathological examination revealed that tumor cells with relatively prominent nucleoli and surrounded by halos, were located in a limited area. Immunohistochemical staining was negative for FH. Whole-exome sequencing identified his germline variant in the FH gene and its loss of heterozygosity in the tumor. At nine years (114 months) of age, the male patient showed no recurrence of the tumor. This was the youngest-onset case of HLRCC-associated RCC to date. This report may affect the starting age for future RCC-surveillance programs for patients with HLRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas , Neoplasias Uterinas , Adulto , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Niño , Femenino , Fumarato Hidratasa/genética , Humanos , Neoplasias Renales/genética , Leiomiomatosis/patología , Masculino , Síndromes Neoplásicos Hereditarios/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Uterinas/genéticaAsunto(s)
Anemia Aplásica , Enfermedades de la Médula Ósea , Anemia Aplásica/diagnóstico , Anemia Aplásica/genética , Enfermedades de la Médula Ósea/diagnóstico , Enfermedades de la Médula Ósea/genética , Trastornos de Fallo de la Médula Ósea , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Humanos , Telómero/genéticaRESUMEN
Context: With prolonged life expectancy, we often encounter patients with elderly-onset type 2 diabetes mellitus (eT2DM). Although the clinical features of eT2DM are suggested to be different from those in patients with middle-age-onset type 2 diabetes mellitus (mT2DM), the islet pathologic features in eT2DM have not been addressed. Objective: We attempted to characterize the pancreatic pathology in eT2DM and sought its clinical implications. Materials and Methods: Pancreata from 13 young nondiabetic (age, 20 to 29 years), 27 patients with mT2DM (age, 45 to 87 years), 22 middle-age subjects without T2DM, 15 subjects with eT2DM (age, 85 to 100 years), and 30 elderly subjects without T2DM were investigated. Together with conventional microscopic observations, morphometric analysis on the islet, islet endocrine cells, and amyloid deposition was conducted on immunostained sections. Results: The estimated age of diabetes onset was 80.8 ± 1.4 years (mean ± standard error) in the eT2DM group and that of the mT2DM group was 48.3 ± 2.4 years. The pancreatic weight was nearly 50% less in the eT2DM group than in the other groups, showing duct obstruction with epithelial hyperplasia, marked acinar atrophy, fibrosis, and amyloid deposition in the islet. The islet mass was significantly reduced in the eT2DM group. The amyloid volume density correlated inversely with the ß-cell volume density but not with the body mass index in the eT2DM group. Laboratory data showed mild elevation of serum amylase in the eT2DM group, although clinical signs and symptoms of pancreatitis were not apparent. Conclusions: eT2DM is distinct from mT2DM and characterized by pancreas atrophy, ductal lesions, and amyloid deposition.
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Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/patología , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Páncreas/patología , Adulto , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Apoptosis/fisiología , Atrofia/patología , Biopsia con Aguja , Estudios de Casos y Controles , Proliferación Celular/fisiología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Inmunohistoquímica , Islotes Pancreáticos/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
AIMS: Islet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear. METHODS: From 118 autopsy cases with type 2 diabetes, 26 cases with islet amyloid deposition (DA+) were selected. Twenty diabetic subjects without obvious amyloid deposition (DA-) matched for the age and diabetes duration and 20 non-diabetic subjects (ND) served for comparison. We examined the severity of amyloid deposition and its relationships with population of endocrine cells, expression of cell damage markers or macrophage infiltration. Correlation of clinical profile with islet pathology was also sought on the subset of the investigated patients. RESULTS: ß-Cell volume density was nearly 40% less in DA+ and 20% less in DA- when compared to ND. Severity of amyloid deposition correlated with reduced volume densities of ß-cell and α-cell, and increased body mass index (BMI), but not with duration of diabetes, age or HbA1c. Amyloid-rich islets contained an increased number of macrophages mixed with ß-cells with oxidative stress-related DNA damage, characterized by γH2AX expression, and suppressed (pro)insulin mRNA expression. CONCLUSIONS: In Japanese type 2 diabetic patients, islet amyloid was more common with severe ß-cell loss and high BMI, associated with macrophage infiltration.
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Diabetes Mellitus Tipo 2/patología , Células Secretoras de Glucagón/patología , Células Secretoras de Insulina/patología , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Macrófagos/patología , Anciano , Autopsia , Estudios de Casos y Controles , Movimiento Celular , Daño del ADN , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Expresión Génica , Células Secretoras de Glucagón/metabolismo , Hemoglobina Glucada/genética , Hemoglobina Glucada/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Japón , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Estrés Oxidativo , Proinsulina/deficiencia , Proinsulina/genéticaRESUMEN
OBJECTIVE: Deficits of ß-cells characterize the islet pathology in type 2 diabetes. It is yet to be clear how the ß-cell loss develops in type 2 diabetes. We explored the implication of oxidative stress, endoplasmic reticulum (ER)-induced stress, and autophagy deficit in the ß-cell decline in Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Pancreases from recent autopsy cases of 47 type 2 diabetic and 30 nondiabetic subjects were investigated on the islet structure with morphometric analysis. Volume densities of islet (Vi), ß-cell (Vß), and α-cell (Vα) were measured. To evaluate cell damage of endocrine cells, immunohistochemical expressions of oxidative stress-related DNA damage as expressed by γH2AX, ER stress-related cell damage as CCAAT/enhancer 1 binding protein-ß (C/EBP-ß), and autophagy deficit as P62 were semiquantified, and their correlations to islet changes were sought. RESULTS: Compared with nondiabetic subjects, Vß was reduced in diabetic subjects. Contrariwise, there was an increase in Vα. There was a significant link between reduced Vß and increased HbA1c levels (P < 0.01) and a trend of inverse correlation between Vß and duration of diabetes (P = 0.06). Expressions of γH2AX, P62, and C/EBP-ß were all enhanced in diabetic islets, and reduced Vß correlated with the intensity of γH2AX expression but not with C/EBP-ß or P62 expressions. Combined expressions of γH2AX, P62, and C/EBP-ß were associated with severe reduction of Vß. CONCLUSIONS: ß-Cell deficit in type 2 diabetes was associated with increased oxidative stress and may further be augmented by autophagic deficits and ER stress.
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Daño del ADN/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Estrés del Retículo Endoplásmico/fisiología , Estrés Oxidativo/fisiología , Anciano , Pueblo Asiatico , Autofagia/fisiología , Autopsia , Femenino , Humanos , Células Secretoras de Insulina/metabolismo , Japón , Masculino , Persona de Mediana Edad , Páncreas/patologíaRESUMEN
BACKGROUND: Previous studies have demonstrated essential roles for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) in learning, memory and long-term potentiation (LTP). However, previous studies have also shown that alpha-CaMKII (+/-) heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important not only for learning and memory but also for emotional behaviors. In this study, to understand the roles of alpha-CaMKII in emotional behavior, we generated transgenic mice overexpressing alpha-CaMKII in the forebrain and analyzed their behavioral phenotypes. RESULTS: We generated transgenic mice overexpressing alpha-CaMKII in the forebrain under the control of the alpha-CaMKII promoter. In contrast to alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in anxiety-like behaviors in open field, elevated zero maze, light-dark transition and social interaction tests, and a decrease in locomotor activity in their home cages and novel environments; these phenotypes were the opposite to those observed in alpha-CaMKII (+/-) heterozygous knockout mice. In addition, similarly with alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in aggression. However, in contrast to the increase in defensive aggression observed in alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in offensive aggression. CONCLUSION: Up-regulation of alpha-CaMKII expression in the forebrain leads to an increase in anxiety-like behaviors and offensive aggression. From the comparisons with previous findings, we suggest that the expression levels of alpha-CaMKII are associated with the state of emotion; the expression level of alpha-CaMKII positively correlates with the anxiety state and strongly affects aggressive behavior.
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Agresión , Ansiedad/enzimología , Conducta Animal , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Prosencéfalo/enzimología , Regulación hacia Arriba/genética , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Miedo , Regulación Enzimológica de la Expresión Génica , Hipocampo/enzimología , Hipocampo/patología , Ratones , Ratones Transgénicos , Actividad Motora , Prosencéfalo/patología , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Previous studies have suggested that calcium/calmodulin-dependent protein kinase IV (CaMKIV) functions as a positive regulator for memory formation and that age-related memory deficits are the result of dysfunctional signaling pathways mediated by cAMP response element-binding protein (CREB), the downstream transcription factor of CaMKIV. Little is known, however, about the effects of increased CaMKIV levels on the ability to form memory in adult and aged stages. We generated a transgenic mouse overexpressing CaMKIV in the forebrain and showed that the upregulation of CaMKIV led to an increase in learning-induced CREB activity, increased learning-related hippocampal potentiation, and enhanced consolidation of contextual fear and social memories. Importantly, we also observed reduced hippocampal CaMKIV expression with aging and a correlation between CaMKIV expression level and memory performance in aged mice. Genetic overexpression of CaMKIV was able to rescue associated memory deficits in aged mice. Our findings suggest that the level of CaMKIV expression correlates positively with the ability to form long-term memory and implicate the decline of CaMKIV signaling mechanisms in age-related memory deficits.