RESUMO
Monogenic diseases of immune dysregulation should be considered in the evaluation of children presenting with recurrent neutrophilic dermatoses in association with systemic signs of inflammation, autoimmune disease, hematologic abnormalities, and opportunistic or recurrent infections. We report the case of a 2-year-old boy presenting with a neutrophilic dermatosis, found to have a novel likely pathogenic germline variant of the IKAROS Family Zinc Finger 1 (IKZF1) gene; the mutation likely results in a loss of function dimerization defective protein based on reports and studies of similar variants. IKZF1 variants could potentially lead to aberrant neutrophil chemotaxis and development of neutrophilic dermatoses. Long-term surveillance is required to monitor the development of hematologic malignancy, autoimmunity, immunodeficiency, and infection in patients with pathogenic IKZF1 germline variants.
Assuntos
Fator de Transcrição Ikaros , Humanos , Masculino , Pré-Escolar , Fator de Transcrição Ikaros/genética , Síndrome de Sweet/genética , Síndrome de Sweet/diagnóstico , Neutrófilos , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Mutação em Linhagem GerminativaRESUMO
Despite availability of epidemiologic studies and national guidelines for the management of newly diagnosed pediatric immune thrombocytopenia (ITP), practice variation exists among and within hematology practices. We previously described the development of an ITP pathway guiding management based on bleeding symptoms. Over an 8-year period, integration of this iterative ITP pathway into management of newly diagnosed ITP increased observation rates in children with no or mild bleeding symptoms and improved consistency of laboratory evaluation and treatment strategies without increasing adverse outcomes. This quality improvement initiative has been sustainable, acceptable to providers, and increased adherence to guidelines.
Assuntos
Hematologia , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Criança , Humanos , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/terapia , Melhoria de Qualidade , HemorragiaRESUMO
BACKGROUND: Autoimmune hemolytic anemia (AIHA) after allogeneic hematopoietic stem cell transplant (HSCT) is a rare but complex and serious complication. Detailed descriptions of cases and management strategies are needed due to lack of prospective trials. OBJECTIVES: Describe the incidence, clinical characteristics, and management of AIHA after HSCT in a pediatric cohort. METHODS: This is a retrospective cohort study of 33 pediatric patients with AIHA after HSCT at an academic tertiary care center from 2003 to 2019. RESULTS: The overall incidence of AIHA after allogeneic HSCT was 3.8% (33/868). AIHA was significantly more common after transplant for nonmalignant versus malignant diagnoses (7.0% [26/370] vs. 1.4% [7/498], p < .0001). AIHA developed at a median of 4.7 months (range 1.0-29.7) after transplant. Sixteen of 33 patients (48.5%) required new AIHA-directed pharmacologic therapy; 17 (51.5%) were managed on their current immunosuppression and supportive care. Patients managed without additional therapy were significantly older, more likely to have a malignant diagnosis, and tended to develop AIHA at an earlier time point after transplant. Patients received a median of two red blood cell transfusions within the first 2 weeks of diagnosis and a median of one AIHA-directed medication (range one to four), most commonly corticosteroids and rituximab. CONCLUSIONS: AIHA after HSCT is rare but occurs more commonly in patients transplanted for nonmalignant diagnoses. While some pediatric patients who develop AIHA after transplant can be managed on current immunosuppression and supportive care, many require AIHA-directed therapy including second-line medications.
Assuntos
Anemia Hemolítica Autoimune , Transplante de Células-Tronco Hematopoéticas , Anemia Hemolítica Autoimune/epidemiologia , Anemia Hemolítica Autoimune/etiologia , Anemia Hemolítica Autoimune/terapia , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Estudos Retrospectivos , Transplante HomólogoRESUMO
BACKGROUND: Despite advances in supportive measures, myeloablative chemotherapy with stem cell rescue remains limited by toxicity and treatment-related mortality. The purpose of this study was to identify factors influencing the rate of hematopoietic recovery following autologous stem cell transplant in high-risk neuroblastoma. PROCEDURE: We retrospectively studied 54 patients with high-risk neuroblastoma who received a single autologous stem cell transplant between 2006 and 2016. Race, sex, conditioning regimen, chemotherapy delays and bone marrow involvement were analyzed using Kaplan-Meier Log-Rank test while the amount of cells infused, age, and length of hospital stay were analyzed using univariate Cox Proportional Hazards Regression. RESULTS: The conditioning regimen administered was significant (P=0.016) for time to engraftment of neutrophils, with busulfan/melphalan (Bu/Mel) at 16.6 days, and carboplatin/etoposide/melphalan at 12.1 days. A delay of chemotherapy during induction (n=24) was significant (P<0.001) for time to platelet engraftment of >75,000/µL. Female patients had a longer time to engraftment (P=0.029). CONCLUSION: Patients receiving Bu/Mel as a conditioning regimen, patients who had a delay in induction chemotherapy and patients of female sex were found to be significant for delayed engraftment of neutrophils, platelets, and hemoglobin, respectively, in patients with high-risk neuroblastoma undergoing autologous stem cell transplant. Knowing these factors may lead to new expectations and possible interventions to decrease the morbidity and mortality of treatment and recovery.
Assuntos
Neuroblastoma/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Quimioterapia de Indução/métodos , Lactente , Masculino , Transplante Autólogo/métodosRESUMO
There are no agreed upon terminology to define "refractory" pediatric Immune Thrombocytopenia (ITP). Guidelines are therefore limited to arbitrary and outdated definitions. The Pediatric ITP Consortium of North America held a meeting in 2023 to define this entity. With 100% agreement, the faculty established that pediatric ITP that is refractory to emergent therapy could be defined as no platelet response after treatment with all eligible emergent pharmacotherapies. With 100% agreement, the working group established that pediatric patients with ITP that continue to demonstrate high disease burden and/or no platelet response despite treatment with multiple classes of disease modifying therapies represent a challenging subset of ITP. These patients are at higher risk of ongoing disease burden and merit additional investigation as well as consideration for clinical trials or novel therapies. Future efforts to define disease burden and disease response will be completed in collaboration with the ITP International Working Group.
RESUMO
BACKGROUND: Osteoarthritis (OA) is an inflammatory disease of synovial joints involving the loss and degeneration of articular cartilage. The gold standard for evaluating cartilage loss in OA is the measurement of joint space width on standard radiographs. However, in most cases the diagnosis is made well after the onset of the disease, when the symptoms are well established. Identification of early biomarkers of OA can facilitate earlier diagnosis, improve disease monitoring and predict responses to therapeutic interventions. METHODS: This study describes the bioinformatic analysis of data generated from high throughput proteomics for identification of potential biomarkers of OA. The mass spectrometry data was generated using a canine explant model of articular cartilage treated with the pro-inflammatory cytokine interleukin 1 ß (IL-1ß). The bioinformatics analysis involved the application of machine learning and network analysis to the proteomic mass spectrometry data. A rule based machine learning technique, BioHEL, was used to create a model that classified the samples into their relevant treatment groups by identifying those proteins that separated samples into their respective groups. The proteins identified were considered to be potential biomarkers. Protein networks were also generated; from these networks, proteins pivotal to the classification were identified. RESULTS: BioHEL correctly classified eighteen out of twenty-three samples, giving a classification accuracy of 78.3% for the dataset. The dataset included the four classes of control, IL-1ß, carprofen, and IL-1ß and carprofen together. This exceeded the other machine learners that were used for a comparison, on the same dataset, with the exception of another rule-based method, JRip, which performed equally well. The proteins that were most frequently used in rules generated by BioHEL were found to include a number of relevant proteins including matrix metalloproteinase 3, interleukin 8 and matrix gla protein. CONCLUSIONS: Using this protocol, combining an in vitro model of OA with bioinformatics analysis, a number of relevant extracellular matrix proteins were identified, thereby supporting the application of these bioinformatics tools for analysis of proteomic data from in vitro models of cartilage degradation.
Assuntos
Cartilagem Articular/metabolismo , Proteínas/metabolismo , Animais , Inteligência Artificial , Cães , Interleucina-1beta , Masculino , Espectrometria de Massas , Osteoartrite/etiologia , ProteomaRESUMO
Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for maintenance of the red cell membrane and function. Heterogeneous clinical manifestations can result in significant morbidity and reduced health-related quality of life. Treatment options have historically been limited to supportive care, including red cell transfusions and splenectomy. Current disease-modifying treatment considerations include an oral allosteric PK activator, mitapivat, which was recently approved for adults with PK deficiency, and gene therapy, which is currently undergoing clinical trials. Studies evaluating the role of PK activators in other congenital hemolytic anemias are ongoing. The long-term effect of treatment with disease-modifying therapy in PK deficiency will require continued evaluation.
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Anemia Hemolítica Congênita não Esferocítica , Erros Inatos do Metabolismo dos Piruvatos , Adulto , Humanos , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Qualidade de Vida , Anemia Hemolítica Congênita não Esferocítica/genética , Anemia Hemolítica Congênita não Esferocítica/terapia , Erros Inatos do Metabolismo dos Piruvatos/genética , Erros Inatos do Metabolismo dos Piruvatos/terapiaRESUMO
Lupus anti-coagulant hypoprothrombinemia syndrome (LAHPS) is a rare condition that can be difficult to treat. It increases the risk of thrombosis and bleeding due to the presence of lupus anti-coagulant and factor II deficiency, respectively. There are a limited number of cases described in the literature. Herein we describe a case of LAHPS with bleeding symptoms as a first clinical manifestation of systemic lupus erythematosus (SLE) in an 8-year-old female. She has had multiple recurrences of her bleeding symptoms, requiring treatment with steroids, cyclophosphamide, mycophenolate mofetil, and rituximab. Her course was later complicated by development of arthritis and lupus nephritis. Her complicated course provides a new perspective on the clinical course and treatment of LAHPS. We also present a comprehensive literature review which demonstrates the difficulty in treating patients with LAHPS with underlying SLE and the variability of the clinical course and management of LAHPS depending on the age at presentation.
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Hipoprotrombinemias , Lúpus Eritematoso Sistêmico , Humanos , Feminino , Criança , Hipoprotrombinemias/complicações , Hipoprotrombinemias/diagnóstico , Hipoprotrombinemias/tratamento farmacológico , Inibidor de Coagulação do Lúpus , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Hemorragia/complicações , Progressão da DoençaRESUMO
BACKGROUND: Venous thromboembolism is a significant cause of postoperative death and morbidity. While prophylactic and treatment regimens exist, they usually come with some risk of clinically relevant bleeding and, thus, must be considered carefully for each individual patient. METHODS: This special topic article represents a review of current evidence regarding venous thromboembolism risk, biology, and prevention in plastic surgery patients. The specific types and duration of available prophylaxis are also reviewed. The balance of venous thromboembolism risk must be weighed against the risk of hemorrhage. RESULTS: Though alternatives exist, the most validated risk assessment tool is the 2005 modification of the Caprini Risk Assessment Model. Controversies remain regarding recommendations for outpatient and low risk cosmetic patients. The authors additionally make recommendations for high-risk patients regarding the use of tranexamic acid, estrogen therapy, anesthesia, and prophylaxis regimens. CONCLUSION: Our profession has made great strides in understanding the science behind venous thromboembolism, risk stratification for patients, and prophylactic regimens; yet, continued studies and definitive data are needed.
Assuntos
Procedimentos de Cirurgia Plástica/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Tromboembolia Venosa/epidemiologia , Anticoagulantes/administração & dosagem , Humanos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controleRESUMO
BACKGROUND: Rituximab is a monoclonal anti-CD20 antibody used as a second-line treatment for immune thrombocytopenia (ITP). As additional treatments for ITP emerge, identifying the most appropriate patients and optimal timing for rituximab are important but challenging without established predictors of response to therapy. OBJECTIVES: The purpose of this study was to describe demographic, clinical, and laboratory characteristics of pediatric and adult patients with ITP to identify differences in evaluation before rituximab administration and correlates of platelet response. METHODS: This is a retrospective cohort study describing the characteristics of patients with ITP treated with rituximab from 2010 to 2020 at two academic tertiary care centers. RESULTS: A total of 64 patients met criteria for inclusion. Complete rituximab response (56%) was not significantly different between children (58%, n = 24) and adults (55%, n = 40). Response rate was similar in those with primary versus secondary ITP (53% vs 62%). Among patients treated with rituximab, Evans Syndrome was more common in children than adults (42% vs 18%). Immunologic labs assessed before rituximab varied by age and were more commonly evaluated in children (lymphocyte subsets 88% vs 22%). Immunologic markers, including antinuclear antibody, direct antiglobulin testing, immunoglobulin levels, and lymphocyte subsets, did not predict response to rituximab in pediatric or adult patients with ITP. CONCLUSIONS: Pre-rituximab immunologic evaluation varied significantly between adults and children, which could represent institution-specific practice patterns or a more general practice difference. If the latter, underlying immunodeficiency in adults with ITP may be underrecognized. Standardized guidance for pre-rituximab immunologic evaluation is needed.
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Medullary thyroid carcinoma (MTC) is most commonly associated with RET gene mutations. ALK fusions have rarely been described, although not previously in pediatrics and not previously partnered with CCDC6 in MTC or any other cancer. A 10-year-old boy with progressive stridor was found to have metastatic MTC, including lung, lymph node, and adrenal metastases. Baseline calcitonin was 6703 pg/mL. While molecular testing was pending, he was treated empirically with the investigational selective RET inhibitor, LOXO-292, without improvement. Molecular testing revealed a novel CCDC6-ALK fusion. His therapy was changed to crizotinib and then to alectinib for improved tolerability. Calcitonin decreased to 663 pg/mL after 6 days of ALK inhibition. He remains on alectinib with ongoing response. A novel CCDC6-ALK fusion has now been implicated in a pediatric case of metastatic MTC. This fusion has profound clinical sensitivity to ALK inhibitors. This report expands the spectrum of ALK fusions seen in MTC, including the first pediatric case of ALK translocated MTC. This novel fusion with CCDC6 has not previously been reported in other human cancers. Given the dramatic response to ALK inhibition in this case, identifying patients with ALK fusion MTC has important therapeutic implications.
Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Neuroendócrino/genética , Fusão Gênica/genética , Neoplasias da Glândula Tireoide/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Calcitonina/metabolismo , Carbazóis/uso terapêutico , Criança , Proteínas do Citoesqueleto/genética , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Metástase Neoplásica , Piperidinas/uso terapêutico , Resultado do TratamentoRESUMO
A 3-week-old boy, former 39-week term infant, presented to the emergency department with a rash. One week before presentation, he developed dark, purple papules on his forehead, which then spread to the abdomen and inguinal regions. Throughout this time, he was eating well, gaining weight, developing appropriately, and was afebrile without cough, congestion, or rhinorrhea. On presentation, the patient was well appearing with normal vital signs. His weight was 4.83 kg (86th percentile for age), his length was 56 cm (47th percentile for age), and his head circumference was 37 cm (62nd percentile for age). On skin examination, there were scattered purpuric papules and macules on the scalp, forehead, trunk, abdomen, and inguinal region. Initial laboratory studies were remarkable only for mild anemia. Our expert panel examines the case, offers a differential for a child with a "blueberry muffin" rash, and makes diagnostic considerations.
Assuntos
Exantema/diagnóstico , Pele/patologia , Mirtilos Azuis (Planta) , Diagnóstico Diferencial , Humanos , Recém-Nascido , MasculinoRESUMO
OBJECTIVES: To examine the effects of early formula feeding or breast-feeding on hypoglycemia in infants born to 303 A1-A2 and 88 Class B-RF diabetics. METHODS: Infants with hypoglycemia (blood glucose < 40 mg/dL) were breast-fed or formula-fed, and those with recurrences were given intravenous dextrose. RESULTS: Of 293 infants admitted to the well-baby nursery, 87 (30%) had hypoglycemia, corrected by early feeding in 75 (86%), while 12 (14%) required intravenous dextrose. In all, 98 infants were admitted to the newborn intensive care unit for respiratory distress (40%), prematurity (33%) or prevention of hypoglycemia (27%). Although all newborn intensive care unit patients received intravenous dextrose, 22 (22%) had hypoglycemia. Of 109 hypoglycemia episodes, 89 (82%) were single low occurrences. At discharge, 56% of well-baby nursery and 43% of newborn intensive care unit infants initiated breast-feeding. CONCLUSIONS: Hypoglycemia among infants of diabetic mothers can be corrected by early breast-feeding or formula feeding.