RESUMEN
The association between individual-level poverty and relapse in children receiving maintenance treatment for acute lymphoblastic leukemia (ALL) remains unclear. In a secondary analysis of COG-AALL03N1, we used data from US Census Bureau to categorize patients living below year-specific federal poverty thresholds, calculated using self-reported annual household income and size of household. Participants with federal poverty thresholds above 120% of their yearly household income were categorized as living in extreme poverty. Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression for patients living in extreme poverty while receiving ALL maintenance therapy after adjusting for relevant predictors. Among 592 patients in this analysis, 12.3% of the patients were living in extreme poverty. After a median follow-up of 7.9 years, the cumulative incidence of relapse at 3 years from study enrollment among those living in extreme poverty was significantly higher (14.3%) than those not living in extreme poverty (7.6%). Multivariable analysis demonstrated that children living in extreme poverty had a 1.95-fold greater hazard of relapse than those not living in extreme poverty; this association was mitigated after the inclusion of race/ethnicity in the model, likely because of collinearity between race/ethnicity and poverty. A greater proportion of children living in extreme poverty were nonadherent to mercaptopurine (57.1% vs 40.9%); however, poor adherence did not completely explain the association between poverty and relapse risk. Future studies need to understand the mechanisms underlying the association between extreme poverty and relapse risk. This trial was registered at www.clinicaltrials.gov as #NCT00268528.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Mercaptopurina , Recurrencia , Pobreza , IncidenciaRESUMEN
Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14+/- CD16+ ) monocytes, associated with a systemic inflammatory cytokine profile, in the two affected brothers. Importantly, despite normal expression of cognate receptors, monocytes from PN patients did not respond to M-CSF or IL-34 in vitro, as determined by cytokine secretion or CD16 expression. RNAseq of monocytes showed 293 differentially expressed genes, including significant downregulation of GATA2, AKAP6 and PDE4DIP that are associated with leucocyte differentiation and cyclic adenosine monophosphate (cAMP) signalling. Notably, the plasma cAMP was significantly low in the PN patients. Our study revealed a novel association of PN with a lack of non-classical monocyte population. The defects in monocyte plasticity may contribute to disease manifestations in PN and a defective cAMP signalling may be the primary effect of the splicing errors caused by USB1 mutation.
Asunto(s)
Neutropenia , Anomalías Cutáneas , Masculino , Niño , Humanos , Monocitos/metabolismo , Anomalías Cutáneas/genética , Anomalías Cutáneas/metabolismo , Neutropenia/genética , Citocinas , Receptores de IgG , Hidrolasas Diéster Fosfóricas/genéticaRESUMEN
BACKGROUND: Obesity at diagnosis of childhood acute lymphoblastic leukemia (ALL) is associated with greater risk of relapse; whether this association extends to obesity during maintenance is unstudied. METHODS: This study used data from AALL03N1 to calculate median body mass index (BMI) for 676 children over 6 consecutive months during maintenance therapy; BMI percentile (BMI%ile) were operationalized as normal/underweight (<85%ile), overweight/obese (85%-98%ile), and extreme obesity (≥99%ile). Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression after adjusting for all relevant demographic and clinical predictors. RESULTS: Median age at study enrollment was 6 years and median length of follow-up was 7.9 years. Overall, 43.3% of the cohort was underweight/normal weight, 44.8% was overweight/obese, and 11.8% had extreme obesity. Cumulative incidence of relapse at 4 years from study enrollment was higher among those with extreme obesity (13.6% ± 4.5%) compared to those with underweight/normal weight (9.0% ± 2.1%). Multivariable analysis revealed that children with extreme obesity had a 2.4-fold (95% confidence interval [CI], 1.1-5.0; p = .01) greater hazard of relapse compared to those who were underweight/normal weight. Overweight/obese patients were at comparable risk to those who were underweight/normal weight (hazard ratio, 0.8; 95% CI, 0.4-1.6). Erythrocyte thioguanine nucleotide (TGN) levels were significantly lower among children with extreme obesity compared to those with underweight/normal weight (141.6 vs. 168.8 pmol/8 × 108 erythrocytes; p = .0002), however, the difference in TGN levels did not explain the greater hazard of relapse among those with extreme obesity. CONCLUSIONS: Extreme obesity during maintenance therapy is associated with greater hazard of relapse in children with ALL. Underlying mechanisms of this association needs further investigation. LAY SUMMARY: Findings from this study demonstrate that extreme obesity during maintenance therapy is associated with a greater hazard of relapse among children with acute lymphoblastic leukemia. We show that children with obesity have lower levels of erythrocyte thioguanine nucleotides even after adjusting for adherence to oral chemotherapy. However, these lower levels do not explain the greater hazard of relapse, paving the way for future studies to explore this association.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Índice de Masa Corporal , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Sobrepeso/complicaciones , Sobrepeso/epidemiología , Delgadez/complicaciones , Obesidad/complicaciones , Obesidad/epidemiología , Tioguanina , RecurrenciaRESUMEN
Duffy-null phenotype-associated neutropenia was present in 77.7% of leukopenia/neutropenia referrals to our center in Detroit with a high prevalence in Yemeni (96.6%), African American (91%), and non-Yemeni Middle Eastern (52.9%) patients. Greater availability of Duffy typing in patients with neutropenia but without recurrent/frequent/serious infections may lessen the need for additional consultations and investigations.
Asunto(s)
Sistema del Grupo Sanguíneo Duffy , Neutropenia , Humanos , Niño , Sistema del Grupo Sanguíneo Duffy/genética , Neutropenia/genética , Fenotipo , Derivación y Consulta , HospitalesRESUMEN
BACKGROUND: Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODS: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTS: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONS: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica/tratamiento farmacológico , Hemoglobinas/metabolismo , Piperazinas/administración & dosificación , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato/tratamiento farmacológico , Quinolinas/administración & dosificación , Administración Oral , Adolescente , Adulto , Anemia Hemolítica Congénita no Esferocítica/sangre , Anemia Hemolítica Congénita no Esferocítica/genética , Catecoles , Esquema de Medicación , Femenino , Estudios de Seguimiento , Cefalea/inducido químicamente , Humanos , Masculino , Mutación , Piperazinas/efectos adversos , Piruvato Quinasa/sangre , Piruvato Quinasa/genética , Errores Innatos del Metabolismo del Piruvato/sangre , Errores Innatos del Metabolismo del Piruvato/genética , Quinolinas/efectos adversos , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Tirfostinos , Adulto JovenRESUMEN
Diagnosis of pyruvate kinase deficiency (PKD), the most common cause of hereditary non-spherocytic haemolytic anaemia, remains challenging in routine practice and no biomarkers for clinical severity have been characterised. This prospective study enrolled 41 patients with molecularly confirmed PKD from nine North American centres to evaluate the diagnostic sensitivity of pyruvate kinase (PK) enzyme activity and PK:hexokinase (HK) enzyme activity ratio, and evaluate the erythrocyte PK (PK-R) protein level and erythrocyte metabolites as biomarkers for clinical severity. In this population not transfused for ≥90 days before sampling, the diagnostic sensitivity of the PK enzyme assay was 90% [95% confidence interval (CI) 77-97%], whereas the PK:HK ratio sensitivity was 98% (95% CI 87-100%). There was no correlation between PK enzyme activity and clinical severity. Transfusion requirements correlated with normalised erythrocyte ATP levels (r = 0·527, P = 0·0016) and PK-R protein levels (r = -0·527, P = 0·0028). PK-R protein levels were significantly higher in the never transfused [median (range) 40·1 (9·8-73·9)%] versus ever transfused [median (range) 7·7 (0·4-15·1)%] patients (P = 0·0014). The PK:HK ratio had excellent sensitivity for PK diagnosis, superior to PKLR exon sequencing. Given that the number of PKLR variants and genotype combinations limits prognostication based on molecular findings, PK-R protein level may be a useful prognostic biomarker of disease severity and merits further study.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica/sangre , Eritrocitos/enzimología , Hexoquinasa/sangre , Piruvato Quinasa/sangre , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato/sangre , Adolescente , Adulto , Anemia Hemolítica Congénita no Esferocítica/genética , Biomarcadores/sangre , Niño , Preescolar , Femenino , Hexoquinasa/genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Piruvato Quinasa/genética , Errores Innatos del Metabolismo del Piruvato/genética , Índice de Severidad de la EnfermedadRESUMEN
Children with Down syndrome (DS) are at an increased risk of developing transient abnormal myelopoiesis (TAM) and acute leukemia. Aberrant expression of CD56 has been observed on myeloid leukemic blasts in DS patients. In general, CD56 expression in acute myeloid leukemia (AML) is considered a promoter of leukemogenesis. We did a retrospective flow cytometric study to investigate mature myelomonocytic cell CD56 expression patterns in TAM, non-TAM, and leukemia cases with DS. Flow cytometric analysis showed that granulocyte and monocyte aberrant/dysplastic CD56 expression is an inherent characteristic of most DS patients irrespective of the presence of TAM or leukemia. Increased CD56 expression in monocyte and granulocyte populations in DS could be multifactorial; greater expression of RUNX1 secondary to the gene dose effect of trisomy 21 along with the maturational state of the cells are the potential contributors. Unlike AML seen in non-DS patients, CD56 overexpression in DS AML cases does not appear to play a role in leukemogenesis.
Asunto(s)
Antígeno CD56/biosíntesis , Síndrome de Down/genética , Granulocitos/metabolismo , Monocitos/metabolismo , Mielopoyesis , Antígenos CD/análisis , Antígeno CD56/genética , Transformación Celular Neoplásica , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal/biosíntesis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Síndrome de Down/metabolismo , Síndrome de Down/fisiopatología , Citometría de Flujo , Regulación de la Expresión Génica , Humanos , Lactante , Leucemia Mieloide , Leucocitosis/etiología , Estudios Retrospectivos , Trombocitopenia/etiologíaRESUMEN
BACKGROUND: Pyruvate kinase deficiency (PKD) is a rare, autosomal recessive red blood cell enzyme disorder, which leads to lifelong hemolytic anemia and associated complications from the disease and its management. METHODS: An international, multicenter registry enrolled 124 individuals younger than 18 years old with molecularly confirmed PKD from 29 centers. Retrospective and prospective clinical data were collected. RESULTS: There was a wide range in the age at diagnosis from 0 to 16 years. Presentation in the newborn period ranged from asymptomatic to neonatal jaundice to fulminant presentations of fetal distress, myocardial depression, and/or liver failure. Children <5 years old were significantly more likely to be transfused than children >12 to <18 years (53% vs. 14%, p = .0006), which correlated with the timing of splenectomy. Regular transfusions were most common in children with two severe PKLR variants. In regularly transfused children, the nadir hemoglobin goal varied considerably. Impact on quality of life was a common reason for treatment with regular blood transfusions and splenectomy. Splenectomy increased the hemoglobin and decreased transfusion burden in most children but was associated with infection or sepsis (12%) and thrombosis (1.3%) even during childhood. Complication rates were high, including iron overload (48%), perinatal complications (31%), and gallstones (20%). CONCLUSIONS: There is a high burden of disease in children with PKD, with wide practice variation in monitoring and treatment. Clinicians must recognize the spectrum of the manifestations of PKD for early diagnostic testing, close monitoring, and management to avoid serious complications in childhood.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato , Adolescente , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/terapia , Niño , Preescolar , Humanos , Estudios Prospectivos , Errores Innatos del Metabolismo del Piruvato/diagnóstico , Errores Innatos del Metabolismo del Piruvato/genética , Errores Innatos del Metabolismo del Piruvato/terapia , Calidad de Vida , Estudios RetrospectivosRESUMEN
Data on preservation of vaccine immunity following allogeneic HSCT in children is limited. We investigated vaccine titers and sought correlations with patient characteristics in this study. Twenty-eight cases were retrospectively analyzed. Antibody concentrations against hepatitis A, hepatitis B, 3 poliovirus serotypes, tetanus, diphtheria, measles, mumps, rubella, varicella, and 13 pneumococcus serotypes were measured as part of planned monitoring following HSCT. Protective antibody levels were found for hepatitis A in 79% of the recipients, measles in 54%, all poliovirus serotypes in 50%, tetanus in 50%, rubella in 50%, varicella in 46%, hepatitis B in 46%, mumps in 43%, diphtheria in 29%, and ≥7/13 pneumococcus serotypes in 46%; lowest level observed for diphtheria and highest for hepatitis A prior to starting post-HSCT immunizations. In univariate analysis, patients with non-malignant diseases (P = .03) and without GvHD (P = .04) had more protective titers. A significant positive association was found among vaccine titers against the microorganisms or the serotypes of the same microorganism, which were administered together in the same product, including polio serotypes, diphtheria and tetanus, mumps, measles, and rubella. Higher degrees of sero-positivity are likely to be due to lack of prior chemotherapy in non-malignant disease cases and lesser immunosuppression in patients without GvHD. Monitoring long-term vaccine titers and administering vaccines accordingly could be evaluated for post-HSCT re-immunization practice.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunidad Humoral , Vacunas/inmunología , Adolescente , Aloinjertos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
RUNX1 associated familial platelet disorder (FPD) is a rare autosomal dominant hematologic disorder characterized by thrombocytopenia and/or altered platelet function. There is an increased propensity to develop myeloid malignancy (MM) - acute myeloid leukemia, myeloproliferative neoplasms or myelodysplastic syndrome often in association with secondary somatic variants in other genes. To date, 23 FPD-MM pediatric cases have been reported worldwide. Here, we present two new kindreds with novel RUNX1 pathogenic variants in which children are probands. The first family is a daughter/mother diad, sharing a heterozygous frameshift variant in RUNX1 gene (c.501delT p.Ser167Argfs*9). The daughter, age 13 years, presented with features resembling juvenile myelomonocytic leukemia - severe anemia, thrombocytopenia, high white cell count with blast cells, monocytosis, increased nucleated red cells and had somatic mutations with high allele burden in CUX1, PHF6, and SH2B3 genes. She also had increased fetal hemoglobin and increased LIN28B expression. The mother, who had a long history of hypoplastic anemia, had different somatic mutations- a non-coding mutation in CUX1 but none in PHF6 or SH2B3. Her fetal hemoglobin and LIN28B expression were normal. In the second kindred, the proband, now 4 years old with thrombocytopenia alone, was investigated at 3 months of age for persistent neonatal thrombocytopenia with large platelets. Molecular testing identified a heterozygous intragenic deletion in RUNX1 encompassing exon 5. His father is known to have increased bruising for several years but is unavailable for testing. These two cases illustrate the significance of secondary mutations in the development and progression of RUNX1-FPD to MM.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Hemoglobina Fetal/genética , Leucemia Mieloide Aguda/genética , Adolescente , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Fenotipo , Estudios RetrospectivosRESUMEN
An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Estudios de Asociación Genética , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato/diagnóstico , Adolescente , Adulto , Anemia Hemolítica Congénita no Esferocítica/etiología , Anemia Hemolítica Congénita no Esferocítica/metabolismo , Anemia Hemolítica Congénita no Esferocítica/terapia , Transfusión Sanguínea , Niño , Preescolar , Colecistectomía/efectos adversos , Colecistectomía/métodos , Terapia Combinada , Activación Enzimática , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Piruvato Quinasa/metabolismo , Errores Innatos del Metabolismo del Piruvato/etiología , Errores Innatos del Metabolismo del Piruvato/metabolismo , Errores Innatos del Metabolismo del Piruvato/terapia , Esplenectomía/efectos adversos , Esplenectomía/métodos , Evaluación de Síntomas , Resultado del Tratamiento , Adulto JovenRESUMEN
Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica/genética , Estudios de Asociación Genética/métodos , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Piruvato Quinasa/genética , Adulto JovenRESUMEN
Monocyte subset analysis by flow cytometry has been shown to be a useful diagnostic tool in chronic myelomonocytic leukemia in adults. An increase in the classical monocyte fraction (CD14++/CD16-) greater than 94.0% of total monocytes is considered highly sensitive and specific in distinguishing chronic myelomonocytic leukemia from other myeloproliferative disorders. In a pilot study of juvenile myelomonocytic leukemia cases, we noted that CD14++/CD16- monocyte fraction was >95% in de novo juvenile myelomonocytic leukemia (JMML) with somatic PTPN11 mutations but normal in those with monosomy 7 or Noonan syndrome. Monocyte subgroup profiling by itself is not diagnostic of JMML but may distinguish molecular subgroups within JMML.
Asunto(s)
Leucemia Mielomonocítica Juvenil/metabolismo , Leucemia Mielomonocítica Juvenil/patología , Receptores de Lipopolisacáridos/metabolismo , Monocitos/metabolismo , Receptores de IgG/metabolismo , Preescolar , Femenino , Estudios de Seguimiento , Proteínas Ligadas a GPI/metabolismo , Humanos , Lactante , Masculino , Proyectos Piloto , Pronóstico , Estudios RetrospectivosRESUMEN
Evans syndrome is defined by bilineal autoimmune cytopenia, typically coombs positive hemolytic anemia and thrombocytopenia. Corticosteroids are the mainstay of treatment, with rituximab and/or mycophenolate mofetil often used in steroid-refractory cases. However, no treatment methodology has ever evaluated by a randomized clinical trial. We present a 15-year-old boy with Evans syndrome and common variable immunodeficiency who experienced a severe, refractory flare 16 months postsplenectomy. After failing to respond to multiple other agents, he achieved a durable response to a bortezomib-based regimen. Bortezomib may be a reasonable second or third line option, especially before high-morbidity therapies such as splenectomy or stem cell transplantation.
Asunto(s)
Anemia Hemolítica Autoinmune/cirugía , Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Complicaciones Posoperatorias/tratamiento farmacológico , Esplenectomía/efectos adversos , Trombocitopenia/cirugía , Adolescente , Anemia Hemolítica Autoinmune/patología , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/patología , Pronóstico , Recurrencia , Trombocitopenia/patologíaRESUMEN
Severe veno-occlusive disease (VOD) following hematopoietic stem cell transplantation has a high mortality rate. The clinical course of VOD, role of preemptive and aggressive supportive care, and outcomes were investigated in a retrospective study from 2007 to 2014. Defibrotide was not available in all but one case with VOD at our center during the study. Forty-nine allogeneic transplants with intravenous busulfan-based or total body irradiation-based myeloablative conditioning were included. The median after hematopoietic stem cell transplantation day for suspicion of developing VOD (pre-VOD phase) was 6 due to weight gain, hepatomegaly, and/or mild increase in total bilirubin without fulfilling the modified Seattle criteria in 22 cases (45%). Despite fluid restriction, aggressive diuresis, and fresh frozen plasma infusions, 16 patients (33%) developed VOD by +10 days. Five cases (31%) had severe, 9 (56%) moderate, and 2 (13%) mild VOD. Eight cases (50%) required transfer to intensive care. One patient was given defibrotide, which was later discontinued due to concerns of adverse effects. Day +100 survival was 100% with complete resolution of VOD. Preemptive and aggressive supportive care could help achieve favorable outcomes in VOD and may have ameliorated the severity. This approach may be combined with other measures in the prevention/treatment of VOD.
Asunto(s)
Enfermedades Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Agonistas Mieloablativos/uso terapéutico , Cuidados Paliativos/métodos , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Enfermedades Hematológicas/patología , Enfermedades Hematológicas/terapia , Humanos , Lactante , Masculino , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Adulto JovenRESUMEN
Acquired pure red cell aplasia and acquired amegakaryocytic thrombocytopenic purpura are rare in children. Similarly, clonal expansion of T-cell large granular lymphocytes is infrequently seen in pediatrics. Lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency is a recently described immunodeficiency syndrome that has been associated with inflammatory bowel disease and autoimmune phenomena such as Evans syndrome. Here, we describe a patient with LRBA deficiency who developed acquired pure red cell aplasia and acquired amegakaryocytic thrombocytopenic purpura associated with expansion of clonal T-cell large granular lymphocytes. This has not been described in the literature previously and adds to the knowledge on the spectrum of manifestations of LRBA deficiency.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/deficiencia , Aplasia Pura de Células Rojas , Linfocitos T , Adolescente , Enfermedades de la Médula Ósea/complicaciones , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/metabolismo , Enfermedades de la Médula Ósea/patología , Humanos , Masculino , Púrpura Trombocitopénica/complicaciones , Púrpura Trombocitopénica/genética , Púrpura Trombocitopénica/metabolismo , Púrpura Trombocitopénica/patología , Aplasia Pura de Células Rojas/complicaciones , Aplasia Pura de Células Rojas/genética , Aplasia Pura de Células Rojas/metabolismo , Aplasia Pura de Células Rojas/patología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
The human phosphoglycerate kinase-1 enzyme is the first of two energy generating steps in the glycolysis. Since its discovery in 1968, many pathologically mutated forms of PGK1 have been described. PGK1 is expressed in all tissues. The clinical manifestations of PGK1 deficiency are some combination of anemia, central nervous system and/or musculoskeletal manifestations. We describe a case of PGK1 in an African-American child, which to our knowledge, has never been described to date. The manifestations of PGK1-Detroit (c.1105A > C (p.Thr369Pro)) include hematologic and central nervous manifestations.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/genética , Errores Innatos del Metabolismo/genética , Mutación Missense , Fosfoglicerato Quinasa/deficiencia , Negro o Afroamericano , Sustitución de Aminoácidos , Preescolar , Humanos , Masculino , Fosfoglicerato Quinasa/genéticaRESUMEN
Piezo1, encoded by the gene PIEZO1, is an erythrocytic cellular membrane mechanoactivated cation channel. Mutations have been implicated in erythrocyte volume disorders (EVDs)-especially hereditary xerocytosis (HX)/dehydrated stomatocytosis (DHS). We identified three patients, all with novel PIEZO1 mutations, but only one displaying the HX/DHS phenotype. Retrospective review of three cases. Osmotic gradient red cell deformability (Osmoscan) was assessed via the Technicon Ektacytometer. Red cell band 3 content was estimated using Eosin-5'-Maleimide staining. Patient 1 was evaluated for polycythemia. Osmoscans suggested mild spherocytosis; a novel PIEZO1 mutation (p.Thr1589Ile, exon 35) was identified, causing mild erythrocytosis without hemolytic anemia. Patient 2 was evaluated for macrocytosis/reticulocytosis, normal-to-high hemoglobin, and indirect hyperbilirubinemia. Osmoscans suggested increased cellular hydration; a second novel PIEZO1 mutation (p.Arg1728Cys, exon 37) was identified, resulting in overhydrated stomatocytosis with well-compensated hemolysis. Patient 3 was evaluated for indirect hyperbilirubinemia only. Osmoscans suggested dehydrated stomatocytosis (DHS, xerocytosis); a third novel PIEZO1 mutation (p.Arg2279Cys, exon 47) was identified. All three patients' blood smears demonstrated stomatocytes and spherocytes. EVDs may be underdiagnosed due to the lack of "expected" anemia in a hemolytic disorder; two of three patients had high hemoglobin and red cell counts and one had high normal values for both parameters and the presence of stomatocytes/dehydrated cells lead to identification of causative PIEZO1 mutations. PIEZO1-associated EVDs may be more common than previously suspected and should be included in the diagnostic algorithms for mild erythrocytosis/unexplained jaundice.
Asunto(s)
Anemia Hemolítica Congénita/genética , Exones , Hidropesía Fetal/genética , Canales Iónicos/genética , Mutación Missense , Policitemia/genética , Esferocitosis Hereditaria/genética , Adolescente , Sustitución de Aminoácidos , Volumen de Eritrocitos , Humanos , MasculinoRESUMEN
Some cancer predisposing germline mutations cause overt birth defects and congenital anomalies. Others are clinically silent and can only be suspected by the presence of increased cancer incidence in family members. A new study shows that long-term monitoring of families may be needed to discover previously unsuspected underlying cancer predisposing mutations.