Evidence of spatial clustering of childhood acute lymphoblastic leukemia cases in Greater Mexico City: report from the Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia.

Background: A heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC). Methods: A population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff's spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained. Results: A total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed. Conclusions: The identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL.

North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.

Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico.

Introduction: The inherited bone marrow failure syndromes (IBMFSs) are a group of rare disorders characterized by bone marrow failure (BMF), physical abnormalities, and an increased risk of neoplasia. The National Institute of Pediatrics (INP) is a major medical institution in Mexico, where patients with BMF receive a complete approach that includes paraclinical tests. Readily recognizable features, such as the hematological and distinctive physical phenotypes, identified by clinical dysmorphologists, remain crucial for the diagnosis and management of these patients, particularly in circumstances where next-generation sequencing (NGS) is not easily available. Here, we describe a group of Mexican patients with a high clinical suspicion of an IBMFS. Methods: We performed a systematic retrospective analysis of the medical records of patients who had a high IBMFS suspicion at our institution from January 2018 to July 2021. An initial assessment included first ruling out acquired causes of BMF by the Hematology Department and referral of the patient to the Department of Human Genetics for physical examination to search for specific phenotypes suggesting an IBMFS. Patients with high suspicion of having an IBMFS were classified into two main groups: 1) specific IBMFS, including dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), thrombocytopenia with absent radii (TAR), and severe congenital neutropenia (SCN); 2) undefined IBMFS (UI). Results: We established a high suspicion of having an IBMFS in 48 patients. At initial evaluation, the most common hematologic features were bicytopenia (20%) and aplastic anemia (16%); three patients received hematopoietic stem cell transplantation. Among patients with a suspicion of an IBMFS, the most common physical abnormality was minor craniofacial features in 83% of patients and neurodevelopmental disorders in 52%. The specific suspicions that we built were DBA (31%), SDS (18%), DC (14%), TAR (4%), and SCN (4%), whereas 27% of cases remained as undefined IBMFS. SDS, TAR, and SCN were more commonly suspected at an earlier age (<1 year), followed by DBA (2 years) and DC (5 years). Conclusions: Thorough examination of reported clinical data allowed us to highly suspect a specific IBMFS in approximately 70% of patients; however, an important number of patients remained with suspicion of an undefined IBMFS. Implementation of NGS and telomere length measurement are forthcoming measures to improve IBMFS diagnosis in Mexico.

Maternal diet in pregnancy and acute leukemia in infants: a case-control study in Mexico City.

Introduction: Epidemiological studies around the world on acute leukemia (AL) and risk factors in infants are scarce. Infant AL has been proposed to originate in utero, which facilitates its study by establishing a short exposure time in pregnant women to environmental and dietary factors that could contribute to the risk of or protection against leukemia. We hypothesized that maternal diet during pregnancy may be an important factor involved in AL in offspring. Methods: We conducted a hospital-based case-control study from 2010 to 2019 on maternal diet during pregnancy in nine high-specialty public hospitals of different health institutions that diagnose and offer treatment to children with AL in Mexico City. Cases (n=109) were children ≤24 months of age with de novo diagnosis of AL, and controls (n=252) were children obtained in hospitals from second-level medical care matched for age, sex, and health institution. Maternal diet during pregnancy was obtained by a semiquantitative food frequency questionnaire. Unconditional logistic regression models were used to assess the association between food groups and infant AL. Potential confounders were assessed by constructing directed acyclic graphs (DAGs) with Dagitty software in which adjusted options were identified for the construction of unconditional logistic regression models. Results: Cases were slightly predominantly female (52.3%). The years of education of the mother in cases and controls was 0-9 on average, and those who reported smoking cigarettes and consuming alcohol during pregnancy did so at a low frequency. Regarding the mother's diet, the main findings were that the consumption of allium vegetables during pregnancy was inversely associated with AL for medium and high consumption (OR=0.26, 95% CI 0.14-0.46; P-trend< 0.001). In contrast, the high consumption of high-fat dairy products had a positive association with AL (OR=2.37, 95% CI 1.30-4.34; P-trend<0.001). No association was found between consumption of topoisomerase II inhibitor foods during pregnancy and AL. Conclusion: The results suggest that maternal intake during pregnancy of allium vegetables, specifically garlic, is inversely associated with the development of AL in children ≤24 months old. On the other hand, consumption of high-fat dairy products is positively associated with AL in children ≤24 months old.

Persistently high incidence rates of childhood acute leukemias from 2010 to 2017 in Mexico City: A population study from the MIGICCL.

Introduction: Over the years, the Hispanic population living in the United States has consistently shown high incidence rates of childhood acute leukemias (AL). Similarly, high AL incidence was previously observed in Mexico City (MC). Here, we estimated the AL incidence rates among children under 15 years of age in MC during the period 2010-2017. Methods: The Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia conducted a study gathering clinical and epidemiological information regarding children newly diagnosed with AL at public health institutions of MC. Crude age incidence rates (cAIR) were obtained. Age-standardized incidence rates worldwide (ASIRw) and by municipalities (ASIRm) were calculated by the direct and indirect methods, respectively. These were reported per million population <15 years of age; stratified by age group, sex, AL subtypes, immunophenotype and gene rearrangements. Results: A total of 903 AL cases were registered. The ASIRw was 63.3 (cases per million) for AL, 53.1 for acute lymphoblastic leukemia (ALL), and 9.4 for acute myeloblastic leukemia. The highest cAIR for AL was observed in the age group between 1 and 4 years (male: 102.34 and female: 82.73). By immunophenotype, the ASIRw was 47.3 for B-cell and 3.7 for T-cell. The incidence did not show any significant trends during the study period. The ASIRm for ALL were 68.6, 66.6 and 62.8 at Iztacalco, Venustiano Carranza and Benito Juárez, respectively, whereas, other municipalities exhibited null values mainly for AML. Conclusion: The ASIRw for childhood AL in MC is among the highest reported worldwide. We observed spatial heterogeneity of rates by municipalities. The elevated AL incidence observed in Mexican children may be explained by a combination of genetic background and exposure to environmental risk factors.

Blood cytology in children with down syndrome.

INTRODUCTION: Down syndrome is associated with various congenital anomalies and metabolic alterations such as hematological alterations. Values for the major hematological indicators vary with age and sex, but these values have not been described for Mexican children with Down syndrome. OBJECTIVE: To describe the complete blood count (CBC) values of pediatric patients with Down syndrome in México and report the most common non-malignant hematological alterations. MATERIALS AND METHODS: The analysis includes data from 450 patients with Down syndrome, 55.5% ware males, aged 0-18 years who were patients at the Mexican National Institute of Pediatrics and whose clinical charts included CBC panel results for the period January 2008 through March 2018. RESULTS: A total of 3438 CBC panels were analyzed with descriptive statistics to find the values and statistical dispersion of the major indicators, with percentiles, and reported separately by sex and age group. The most common non-malignant hematological alterations found were macrocytic anemia, leukopenia, lymphopenia, and thrombocytosis. There were differences in values in all three series. CONCLUSIONS: The CBC panels and hematological alterations are summarized for patients with Down syndrome.

High occurrence of CRLF2 abnormalities in Mexican children with B-cell acute lymphoblastic leukemia.

The P2RY8-CRLF2 and IGH-CRLF2 rearrangements induce the overexpression of cytokine receptor-like factor 2 (CRLF2) and have been associated with relapse and poor prognosis in B-cell acute lymphoblastic leukemia (B-ALL). Additionally, they are frequently documented in high-risk Hispanic populations. To better understand the potential causes of the adverse prognosis of childhood B-ALL in Mexico, we analyzed these rearrangements and the CRLF2 mRNA and protein levels in 133 Mexican children with B-ALL. We collected bone marrow samples at diagnosis and evaluated the CRLF2 gene expression by qRT-PCR and the total CRLF2 protein by flow cytometry. P2RY8-CRLF2 and IGH-CRLF2 were detected by RT-PCR and FISH, respectively. The median time of follow-up to determine the prognostic significance of the CRLF2 abnormalities was three years. In 82% of the participants, the mRNA levels correlated with the cell-surface and intracellular CRLF2 protein levels. The P2RY8-CRLF2 rearrangement was present in 31.5% (42/133) of the patients, while the IGH-CRLF2 rearrangement was detected in 13.5% (9/67) of patients with high expression of CRLF2 (6.8% of the total sample). CRLF2 copy number variations (gain) were also detected in 7.5% (5/67) of patients with high protein levels. The overall survival (OS) presented significantly lower rates in patients with high white blood cell count (≥50x109/L) regardless of CRLF2 expression, but high levels of CRLF2 gene expression appears to contribute to the reduction of OS within this group of patients. In conclusion, in our cohort, a high occurrence of CRLF2 abnormalities was documented, particularly the P2RY8-CRLF2 rearrangement, which might represent a characteristic of the Mexican population. Targeted therapy to treat this group of patients could improve OS.

Bilateral Ischemic Retinopathy Associated With Upshaw-Schulman Syndrome: A Case Report.

Purpose: This is the first report to our knowledge of ischemic retinopathy in a pediatric patient with Upshaw-Schulman syndrome (USS). Methods: A 6-year-old girl previously diagnosed with USS was referred to our clinic with exodeviation of the left eye and a 2-month-long decrease in vision of both eyes. A dilated fundus examination showed a total vitreous hemorrhage in both eyes. The first course of action was conservative treatment, with the patient experiencing visual-acuity improvement in her right eye. Results: An ischemic retina and optic nerve atrophy was found once the left eye was cleared of the hemorrhage. Conclusions: We present a case of a vitreous hemorrhage, possibly secondary to an episode of severe thrombocytopenia. Following USS diagnosis, providers should perform dilated ophthalmologic examinations as part of initial and follow-up general evaluations. This case exemplifies that, in understudied and underdescribed pediatric retinal diseases, extreme therapeutic decisions-such as surgery-should not be rushed.

Primary cutaneous blastic plasmacytoid dendritic cell neoplasm in a child: A challenging diagnosis and management.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive malignancy of the skin and hematopoietic system. There are few pediatric cases reported in the literature. Management of primary cutaneous BPDCN is challenging because, despite an apparently indolent clinical presentation, rapid dissemination with high mortality can occur. We describe a child with isolated cutaneous involvement who had a good response to chemotherapy as first-line treatment of BPDCN.

COVID-19 en el paciente pediátrico / COVID-19 in the pediatric patient

Resumen Este documento fue preparado (en junio de 2020) por y para los profesionales médicos (clínicos y proveedores de salud), y está disponible públicamente para propósitos de recomendaciones relacionada con pacientes pediátricos y enfermedad por coronavirus 2019 (COVID-19). Según datos disponibles hasta la fecha, los niños de todas las edades pueden contraer la COVID-19; sin embargo, tienen mejor pronóstico que los adultos, siendo pocos los casos graves reportados, y los casos leves se recuperan en 1-2 semanas después del inicio de la enfermedad. El objetivo de este documento es aportar peculiaridades que consideramos importantes para el diagnóstico y tratamiento. Debido a los cambios en la actual situación epidemiológica se pueden modificar algunos conceptos y acciones, por lo que la información aquí contenida debe ser adaptada a cada paciente, basada en el juicio clínico, necesidades del paciente y recursos disponibles.

Abstract This document was prepared (June 2020) by and for medical professionals (clinicians and health providers), and it is available as a guideline for pediatric patients with coronavirus disease 2019 (COVID-19). So far, according to available data although children of all ages can acquire COVID-19, they have better outcome than adults, with a little proportion of severe disease, and in mild cases they have a 1 to 2-week recovery after the beginning of the infection. The objective of this document is to provide particularities that we consider important for diagnosis and treatment. Owe to the changing epidemiological situation some concepts and actions can change, so this information must be adapted to each specific case, based on the clinical judgement according to patient requirements and available resources.

Linfohistiocitosis hemofagocítica secundaria a infección crónica activa por virus de Epstein-Barr en un hospital pediátrico en México: series de casos y revisión de la literatura / Hemophagocytic lymphohistiocytosis secondary to chronic active Epstein-Barr virus infection in a pediatric hospital in Mexico: case series and literature review

INTRODUCCIÓN: La linfohistiocitosis hemofagocitica (HLH) secundario está asociada a enfermedades malignas, genéticas o autoinmunes, pero también a infecciones principalmente EBV hasta en un 70%, sin embargo hay poca información. Esta entidad se caracteriza por un curso variable y recurrente que conlleva a una alta morbimortalidad con complicaciones potencialmente mortales. OBJETIVO: Describir las características clínicas y evolución de los pacientes pediátricos con diagnóstico de HLH secundario a CAEBV. RESULTADOS: Se incluyeron 7 pacientes, edad media al diagnóstico fue 52 meses con predilección al sexo masculino. Todos los pacientes fueron tratados con un régimen quimioterapéutico multiagente, que incluye corticosteroide, etopósido y Ciclosporina. Después del tratamiento 6 pacientes presentaron remisión y uno de ellos reactivación. La media de seguimiento fue 19 meses y la supervivencia libre de enfermedad (SLE) 16 meses. CONCLUSIÓN: Podemos observar que el curso clínico es variable en ocasiones fulminantes y con pobre respuesta al tratamiento. Un diagnóstico temprano, así como detectar los factores pronóstico podría ayudar a adaptar estrategias de tratamiento que cambiaría la evolución clínica.

INTRODUCTION: Secondary hemophagocytic lymphohistiocytosis (HLH) is associated with malignant, genetic or autoimmune diseases but also with infections mainly EBV in up to 70%, however there is little information. This entity is characterized by a variable and recurrent course that leads to high morbidty and mortality with life-threatening complications. OBJECTIVE: To describe the clinical characteristics and evolution of pediatric patients with a diagnosis of HLH secondary to CAEBV. RESULTS: 7 patients were included, mean age at diagnosis was 52 months with a predilection for males. All patients were treated with a multiagent chemotherapeutic regimen, including corticosteroid, etoposide, and cyclosporine. After treatment, 6 patients presented remission and one of them had reactivation. The mean follow-up was 19 months and disease-free survival (DFS) 16 months. CONCLUSION: We can observe that the clinical course is variable, sometimes fulminant and with poor response to treatment. An early diagnosis as well as detecting prognostic factors could help to adapt treatment strategies that would change the clinical course.

Spatial distribution of manganese concentration and load in street dust in Mexico City / Distribución espacial de las concentraciones y carga de manganeso en el polvo urbano de la Ciudad de México

Abstract: Objective: To obtain a first indication of the distribution and extent of manganese (Mn) contamination in Mexico City. Mn concentration and load in street dust were analyzed in order to reveal the most contaminated areas. Materials and methods: 482 samples of street dust were analyzed through inductively coupled plasma-optical emission spectroscopy. The contamination factor (CF), the geoaccumulation index (Igeo) and the spatial interpolations of the kriging indicator were calculated. Results: A slight influence of anthropogenic activities is detected on the Mn content of street dust. The highest levels of pollution by concentration (Igeo=uncontaminatedtomoderately contaminated) are grouped towards the city's north (industrial) and center (commercial and high traffic) areas. The areas with the highest Mn load were located towards the east and northwest areas (Igeo=moderately contaminated). Conclusions: These findings will serve as a baseline to assess future variations in Mn content in Mexico City's environment.

Resumen: Objetivo: Obtener una primera aproximación sobre la distribución espacial de la contaminación por manganeso (Mn) en la Ciudad de México. Se analizó la concentración y carga de Mn en el polvo de la calle para identificar las áreas más contaminadas. Material y métodos: 482 muestras de polvo de la calle fueron analizadas con espectroscopía de emisión por plasma de acoplamiento inductivo. Se calculó el factor de contaminación, índice de geoacumulación, y las interpolaciones espaciales del indicador kriging. Resultados: Existe una ligera influencia de actividades antropogénicas en el contenido de Mn del polvo de la calle. Los niveles más altos de contaminación por concentración (Igeo=no contaminado a moderadamente contaminado) se agruparon en el norte (industrial) y centro (comercial y de alto tráfico) de la ciudad. Las áreas con las cargas de Mn más altas estuvieron al este y noroeste (Igeo=moderadamente contaminado), donde había más polvo. Conclusiones: Estos resultados servirán como punto de referencia para evaluar variaciones futuras en el contenido de Mn en la Ciudad de México.

Variants in ARID5B gene are associated with the development of acute lymphoblastic leukemia in Mexican children.

A high impact of ARID5B SNPs on acute lymphoblastic leukemia (ALL) susceptibility has been described in Hispanic children; therefore, it is relevant to know if they influence the high incidence of childhood-ALL in Mexicans. Seven SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, rs4948488) of ARID5B were analyzed in 384 controls and 298 ALL children using genomic DNA and TaqMan probes. The SNPs were analyzed for deviation of Hardy-Weinberg equilibrium; Fisher's exact test was used to compare the genotypic and allelic frequencies between controls and patients. The association between SNPs and ALL susceptibility was calculated, and haplotype and ancestry analyses were conducted. All SNPs were associated with ALL, pre-B ALL, and hyperdiploid-ALL susceptibility (p < 0.05). No association with T-ALL and gene fusions was found (p > 0.05). The seven SNPs were associated with risk of pre-B ALL in younger children; however, rs2393732, rs2393782, rs2893881, and rs4948488 were not associated with susceptibility in older children and adolescents. The CAG haplotype (rs10821936, rs10994982, rs7089424) was strongly associated with ALL risk in our population (p < 0.00001). The frequency of all risk alleles in our ALL, pre-B, and hyperdiploid-ALL patients was higher than that in Hispanic children reported. This is the first report showing the association between rs2393732, rs2393782, and rs4948488 with pre-B hyperdiploid-ALL children. The G allele at rs2893881 confers major risk for pre-B hyperdiploid-ALL in Mexican (OR, 2.29) than in Hispanic children (OR, 1.71). The genetic background of our population could influence the susceptibility to ALL and explain its high incidence in Mexico.

A greater birthweight increases the risk of acute leukemias in Mexican children-experience from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL).

In Mexico, due to the high rates of diabetes, overweight, and obesity, there has also been noted an increased newborn weight, which may be contributing to the elevated incidence rate of childhood acute leukemia (AL). We conducted a case-control study in public hospitals of Mexico City aimed to know whether a greater weight at birth is associated with a higher risk of developing leukemia. We included incident cases with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) diagnosed between 2010 and 2015. Controls were frequency-matched to the cases by age, sex, and health institution. Logistic regression analysis was performed adjusting risks by child's sex, overcrowding index, birth order, and mother's age at the time of pregnancy. Adjusted odds ratios (aORs) and 95% confidence intervals were calculated. A total of 1455 cases and 1455 controls were included. An evident association between ALL and child's birthweight ≥2500 g was found (aOR 2.06; 95% CI: 1.59, 2.66) and also, in those with birthweight ≥3500 g (aOR 1.19; 95% CI: 1.00, 1.41). In AML patients with birthweight ≥2500 g and ≥3500 g, an aOR of 1.77 (95% CI: 1.07, 2.94) and 1.42 (95% CI: 1.03-1.95) was observed, respectively. No association was noticed with either type of AL and a birthweight ≥4000 g. To sum up, we found a moderate association between not having a low birthweight and an increased risk of acute leukemias. Birthweight ≥3500 g was also a risk factor for both types of leukemia. This suggests that a greater birthweight may increase the risk of acute leukemias in Mexican children.

Parental Exposure to Workplace Carcinogens and the Risk of Development of Acute Leukemia in Infants. Case-Control Study.

BACKGROUND AND AIMS: Occupational exposure of parents to carcinogens is of great interest in the etiology of leukemias. Evidence of the impact of such exposure on infants or small children is scarce. Here we estimated whether occupational exposure of parents to carcinogens could be a risk factor for leukemias in their children. METHODS: Cases of acute leukemia (AL) in infants ≤24 months old diagnosed in Mexico City (1998-2013) were included in a population-based, case-control study. Each of the 195 cases was matched with at least one healthy child (n = 369). For each of four exposure windows studied, the degree of exposure to carcinogens was determined for both parents by using a validated occupational exposure index. An unconditional logistic regression was carried out. RESULTS: Odds ratios (OR) and the 95% confidence intervals (CI) of the overall occupational exposure for parents during the four exposure windows indicated no association with risk of AL in their children. Pre-conception, the OR by the father 0.77 (0.49-1.21), by the mother 1.03 (0.50-2.11); during pregnancy, father 0.66 (0.38-1.15), mother 1.79 (0.46-6.90); during breastfeeding, father 0.75 (0.43-1.30), mother 0.96 (0.21-4.30); and after birth, father 0.74 (0.45-1.22), mother 0.90 (0.24-3.32). The statistical power of the sample size to identify an OR ≥2 and an exposure of ≥10% among controls was 78%. CONCLUSIONS: These data support the idea that parents' occupational exposure during any of the periods studied was not a risk factor contributing to the etiology of AL in infants ≤24 months of age.

Significance of CASP8AP2 and H2AFZ expression in survival and risk of relapse in children with acute lymphoblastic leukemia.

Novel biomarkers for risk refinement and stratification in childhood acute lymphoblastic leukemia (ALL) are needed to optimize treatment results. We studied the expression of CASP8AP2 and H2AFZ associated with relapse and survival in bone marrow samples from newly diagnosed children with ALL. We found: (a) an increased risk for early relapse in those patients with low expression of CASP8AP2 (odds ratio [OR] 3.93, 95% confidence interval [CI] 1.40-11.02, p < 0.05) confirming its usefulness as a predictive risk marker, although H2AFZ did not present the same effect; (b) patients with low expressions of CASP8AP2 and H2AFZ had inferior survival rates (p < 0.001); (c) the predictive values regarding low expressions of H2AFZ and CASP8AP2 and high white blood cell count suggest that these features could help to identify more accurately patients at greater risk of relapse.

Síndrome de Hermansky-Pudlak: Expresión clínica variable en dos casos clínicos / Hermansky-Pudlak syndrome: variable clinical expression in two cases

Introducción. El síndrome de Hermansky-Pudlak es un padecimiento genético caracterizado por albinismo y hemorragias, en grado variable, por alteraciones en la estructura de las plaquetas. Puede presentar alteraciones pulmonares, intestinales o renales. En la literatura se han reportado varias alteraciones genéticas relacionadas a este síndrome. Casos clínicos. Se presentan dos casos. El primero se trató de un adolescente de sexo masculino con albinismo mucocutáneo y afección a nivel renal. Los episodios de sangrado iniciaron después de ser sometido a venopunciones y estudios invasivos. Desarrolló, incluso, un hematoma perirrenal. Después de una sepsis de foco abdominal, presentó hemoperitoneo y hemorragia pulmonar, que precipitó su muerte; el diagnóstico se realizó post mórtem. El segundo caso se trató de una paciente de sexo femenino en quien, desde el periodo de lactancia, se identificó el síndrome por el albinismo mucocutáneo, los episodios de sangrado y los datos de fibrosis pulmonar progresiva, lo que ha limitado su capacidad vital. Conclusiones. El diagnóstico del síndrome, así como el abordaje correcto y temprano pueden evitar el desarrollo de complicaciones o limitar su evolución. Aún es materia de debate si las alteraciones genéticas descritas se asocian a la expresión de alguna manifestación clínica particular.

Background. Hermansky-Pudlak syndrome is a genetic disorder characterized by albinism and bleeding of varying degrees due to alteration in the structure of the platelets. The disorder may be accompanied by pulmonary, intestinal or kidney involvement. Identification of several genetic alterations in this syndrome has been reported. Case reports. We present two cases: the first of an adolescent male with mucocutaneous albinism and renal involvement. Bleeding episodes started after being subjected to invasive studies and venipunctures, developing a perinephric hematoma. After severe sepsis, the patient developed hemoperitoneum and pulmonary hemorrhage, which precipitated the patient's death. Diagnosis was made postmortem. In the second case, a female patient was diagnosed during infancy due to albinism and bleeding episodes, with progressive pulmonary fibrosis that to date has limited her vital lung capacity. Conclusions. Early diagnosis of the syndrome as well as the correct approach may prevent the development of complications or limit the evolution. It is still under debate whether the genetic alterations described are associated with the expression of any particular clinical manifestation.

Sobrecarga de hierro en pacientes pediátricos / Iron overload in pediatric patients

En pediatría, las anemias crónicas hereditarias, como la anemia drepanocítica y los síndromes talasémicos, y en menor grado la anemia aplásica, la aplasia pura de serie roja y los síndromes mielodisplásicos y diseritropoyéticos, cursan con requerimientos transfusionales elevados y consecuentemente, con el peligro potencial de desarrollar sobrecarga de hierro. El hierro de la sangre transfundida es procesado inicialmente por los macrófagos, que digieren los eritrocitos senescentes y retornan el hierro a la transferrina del plasma. Esta carga de hierro transfusional puede saturar la transferrina y llevar a la formación de "hierro no unido a transferrina" en el plasma; éste es tomado por las células del parénquima hepático y depositado como ferritina y hemosiderina. El hierro puede ser reducido de férrico (Fe+3) a ferroso (Fe2+), y en esta forma catalizar la formación de radicales hidroxilo (altamente reactivos), que pueden causar daño oxidativo y afectar lípidos, proteínas y moléculas de ADN y llevar a la muerte celular o fibrosis. Diagnóstico. La medición del índice de saturación de la transferrina y las mediciones seriadas de ferritina sérica son métodos confiables y sencillos para evaluar la tendencia de la sobrecarga de hierro y la eficacia de la terapia de quelación. Un método no invasivo para esta evaluación es el Dispositivo de Interferencia Cuántica de Superconducción (SQUID). Este dispositivo no está disponible en nuestro país, y sólo cuentan con él cinco centros de todo el mundo. La resonancia magnética puede usarse para valorar la carga de hierro en el hígado, corazón y páncreas, y puede sustituir procedimientos invasivos como la biopsia cardiaca y hepática. Tratamiento. En la actualidad, la terapia de quelación de hierro se realiza con deferoxamina, deferiprona o deferasirox. Cuando la deferoxamina se administra por vía subcutánea se recomiendan 20-40 mg/kg/día en infusión continua de 10-12 horas, de preferencia nocturna, con bomba de infusión, durante 5 días a la semana, hasta lograr niveles de ferritina sérica ≤500 µg/L. Igualmente, para la vía intravenosa se utilizan de 20-40 mg/ kg/día, administrados durante 12-14 horas en infusión continua. No se recomienda la administración intramuscular por su baja acción quelante. La dosis usual de deferiprona es de 75 mg/kg/día. El deferasirox en dosis de 20-40 mg/kg puede producir una tasa de excreción de hierro de 0.3 mg/kg/día, que permite mantener el equilibrio férrico en pacientes con transfusiones; posee una potencia comparable a la deferoxamina. Aunque no existe evidencia categórica de que todos los pacientes anémicos politransfundidos desarrollarán sobrecarga de hierro, se recomienda realizar programas integrales de vigilancia para establecer un tratamiento temprano cuando se estime necesario.

In pediatrics, chronic genetic anemias such as sickle cell disease, thalassemic syndromes and, to a lesser degree, aplastic anemia, pure red cell aplasia, myelodysplastic syndromes and dyserythropoietic syndromes, are characterized by high transfusional requirements and, consequently, a potential risk to develop iron overload. Iron transfusional loading is initially processed by macrophages after the breakdown of senescent erythrocytes and the iron released to plasma transferrin. This transfusional iron load can saturate the transferrin and result in the emergency of toxic "plasma nontransferrin bound iron" that is taken up by the parenchymal hepatic cells and stored as ferritin and hemosiderin. The iron can be reduced from ferric (Fe3+) to ferrous (Fe2+) ions and catalyze the formation of free hydroxyl radicals (highly reactive) that may produce oxidative damage that may also affect lipids, proteins and DNA molecules and finally result in cellular death and/or fibrosis. Transferrin saturation index and serum ferritin serial measurements have shown to be simple and reliable techniques for efficiently evaluating iron overload and chelation therapy. The SQUID (Superconducting Quantum Interference Device) constitutes a noninvasive method for evaluating iron overload; however, this device is not available in México and only five medical centers worldwide have this equipment. Magnetic resonance imaging can be used to evaluate iron load in liver, heart, and pancreas and may replace invasive procedures such as heart or hepatic biopsies. Deferoxamine, deferiprone and deferasirox are currently used in the treatment of transfusional iron overload. Deferoxamine is infused SC (20-40 mg/kg/day) in a continuous infusion connected to a portable pump for 10-12 h, 5x/week, mainly at night, and IV 20-40 mg/kg/day in a continuous infusion for 1214 h. Intramuscular administration is not recommended due to the low chelation action. A daily dose of 75 mg/ kg of deferiprone is recommended. Deferasirox is safe, orally administered and is as effective as deferoxamine. The effective oral dose is 20-40 mg/kg. Iron balance is obtained with 0.3 mg/kg/day urinary iron excretion in transfusion-dependent patients. Even though there is no conclusive evidence that all anemic polytransfused patients will develop iron overload, it is recommended to carry out integral surveillance programs to establish early iron chelation therapies.

Biology, clinical, and hematologic features of acute megakaryoblastic leukemia in children.

To assess the incidence, clinical features at presentation, hematologic, immunophenotypic, and cytogenetic characteristics of AMKL in children we prospectively studied 834 consecutive non selected children with newly diagnosed acute leukemia (AL) admitted to the Hematology Department at the Instituto Nacional de Pediatría (INP), Mexico, D.F. We found 682 cases (81.8%) with a typical ALL immunophenotype, and the remaining 152 (18.2%) were considered to have AML. In 29 of the 152 patients with AML studied, a diagnosis of AMKL was established. These 29 cases represented 19.1% of the cases of AML and 3.48% of the total cases of AL during the time span covered by the study. Twenty-four percent of the cases occurred in infants 2 years old or younger and 41.4% occurred in children 41 months of age or younger. In contrast, in only 18.6% of the patients with AML (M0-M6), the diagnosis was established before 42 months of age and in 17% before their second year of life. Clinical presentation was not strikingly different than that observed in patients with other types of AML, and the time interval from onset of symptoms to diagnosis was also similar, though in a small subset of patients, the clinical course was characterized by a chronic slowly progressive disorder extending over weeks or months resembling smoldering leukemia or chronic myelofibrosis with agnogenic myeloid metaplasia. Bone marrow (BM) fibrosis was a constant features in our patients; 75% of the patients studied showed this complication at the time of diagnosis. Some rather unusual findings in this study were intense skeletal pains from multiple osteolytic lesions, the presence of soft-tissue tumor, and the presence of cohesive scanty clusters of primitive-looking blast cells in BM aspirates. Several interesting cytogenetic findings in our study were t(1;22)(p13;q13) in a 14-year-old boy, t(9;22)(q34;q11) in one patient, and monosomy 7 in two patients. Another important finding in our study was the clinical association with colonic adenocarcinoma in one patient, an association that to our knowledge has not been reported previously. In conclusion, our data suggest that the incidence of AMKL in Mexico might be higher than those reported in Caucasian white pediatric population, and that biologic and cytogenetic profile may differ from those of western countries, but more studies are needed to corroborate cytogenetic heterogeneity, ethnic and geographic diversity. Early onset of the disease, low WBC counts, slight thrombocytopenia or normal platelet counts, and BM fibrosis were characteristic distinctive features of at least half of the patients with this subtype of AML.

Neumonía eosinofílica secundaria a larva migrans visceral en un niño / Eosinophilic pneumonia secondary to visceral larva migrans in children

La infección por larvas de Toxocara sp puede presentarse en niños como un cuadro clínico de larva migrans visceral. La neumonía eosinofílica constituye una manifestación clínica de la enfermedad sistémica. Para el diagnóstico de laboratorio es de utilidad la presencia de hiperleucocitosis con eosinofilia elevada y la detección de anticuerpos anti-toxocara mediante ELISA. Se presenta el caso de un paciente de dos y medio años de edad con antecedentes de geofagia intensa que cursó con un cuadro caracterizado por fiebre, tos, polipnea, hepatomegalia, lesiones dérmicas, infiltrados pulmonares e hiperleucocitosis con eosinofilia en el que el diagnóstico de larva migrans visceral fue confirmado mediante ELISA. El paciente fue manejado con albendazol y esteroides con evolución satisfactoria. Se sugiere que como parte del diagnóstico de larva migrans visceral se busquen antecedentes de geofagia intensa, convivencia estrecha con perros o gatos, búsqueda específica de manifestaciones clínicas sistémicas o localizadas, radiodiagnóstico, ELISA y estudio de fondo de ojo.