RESUMEN
Sideroblastic anaemias are a diverse group of congenital and acquired bone marrow failure disorders marked by the presence of ring sideroblasts, ineffective erythropoiesis, and systemic iron overload. Congenital Sideroblastic anaemia (CSA) is mainly caused by gene mutations associated with heme synthesis, iron-sulfur [Fe-S] cluster, and mitochondrial protein synthesis pathways. The most prevalent form of CSA is caused by mutations in the erythroid-specific -amino levulinate synthase (ALAS2) gene, which encodes the first enzyme in the heme synthesis pathway in red blood cells. The second most prevalent form of CSA is caused by a mutation in the Solute carrier family 25 member 38 (SLC25A38) gene, which codes for an erythroid-specific protein of the inner mitochondrial membrane. Additionally, 15-20 genes are altogether associated with CSA. In this study, we aim to identify the CSA patients, understand their genetics and establish genotype-phenotype correlation. We have identified fifteen cases of CSA using our targeted NGS (t-NGS) panel. The major clinical findings in our cohort were microcytic anaemia, ring sideroblasts, and dyserythropoiesis in the bone marrow. Currently, two patients are responsive to pyridoxine, while the rest are on blood transfusion support. We have identified ten variants in three different genes of CSA (ALAS2, SLC25A38 & HSPA9). Five patients harbour four hemizygous variants- p.Ala282Ser, p.Arg170Cys, p.Arg204Gln and exon 2 duplication in the ALAS2 gene. In seven patients, we have identified three homozygous mutations - p.Pro190Arg, p.Arg187Gln and p.Arg134Cys in the SLC25A38 gene. These mutations have been predominantly identified in the European population. Three patients revealed three heterozygous variants p. Thr463Ile, D326Tyr, and Arg284Trp in the HSPA9 gene. PyMoL was used to evaluate the functional effects of these variations and understand their effect on the structure of the protein. We believe that by combining a bone marrow examination with genetic sequencing, CSA patients can acquire a definitive diagnosis.
RESUMEN
In 2024, the World Health Organization (WHO) has proposed revised hemoglobin cutoffs for diagnosing anemia in children aged 6-23 months, pregnant women in the second trimester and those residing in elevated areas with the aim of increasing the sensitivity and ensuring uniformity in diagnosis. There are no major changes in other domains.
Asunto(s)
Anemia , Hemoglobinas , Femenino , Humanos , Lactante , Embarazo , Anemia/diagnóstico , Anemia/sangre , Hemoglobinas/análisis , Guías de Práctica Clínica como Asunto , Valores de Referencia , Organización Mundial de la SaludRESUMEN
Although graft T cells assist in engraftment, mediate antiviral immune-reconstitution, and cause graft-versus-host disease, graft size is not determined by T-cell content of the graft. The conventional method of graft size determination based on CD34+ cells with alemtuzumab serotherapy is associated with delayed immune reconstitution, contributing to an increased risk of viral infections and graft failure. Alemtuzumab, a long half-life anti-CD52 monoclonal antibody is a robust T-cell depleting serotherapy, and relatively spares memory-effector T cells compared to naïve T cells. We therefore hypothesized that graft size based on T-cell content in patients receiving peripheral blood stem cell graft with alemtuzumab serotherapy would facilitate immune-reconstitution without increasing the risk of graft-versus-host disease. We retrospectively analysed twenty-six consecutive patients with non-malignant disorders grafted using alemtuzumab serotherapy and capping of graft T cells to a maximum of 600 million/kg. The graft T-cell capping protocol resulted in early immune-reconstitution without increasing the risk of severe graft-versus-host disease. Graft T-cell content correlated with CD4+ T-cell reconstitution and acute graft-versus-host disease. The course of CMV viraemia was predictable without recurrence and associated with early T-cell recovery. No patient developed chronic graft-versus-host disease. Overall survival at one year was 100% and disease-free survival was 96% at a median of 899 days (range: 243-1562). Graft size determined by peripheral blood stem cell graft T-cell content in patients receiving alemtuzumab serotherapy for non-malignant disorders is safe and leads to early T-cell immune-reconstitution with excellent survival outcomes.
Asunto(s)
Enfermedad Injerto contra Huésped , Humanos , Alemtuzumab/uso terapéutico , Estudios Retrospectivos , Inmunización Pasiva , Tamaño de la CélulaRESUMEN
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, genetic, autosomal recessive disorder characterized by severe thrombocytopenia, due to inefficient bone marrow megakaryopoiesis eventually leading to aplasia. Majority of the cases are due to homozygous or compound heterozygous mutations in MPL gene encoding for thrombopoietin (THPO) receptor protein. CAMT can be diagnosed at early phase of life, with major complication of transfusion dependency and hematopoietic transplantation as only curative treatment. We have investigated the sequence variations in MPL gene of 7 bone marrow failure (BMF) subjects, who presented with clinically diverse phenotypes, through next generation sequencing (NGS). Plasma THPO levels were estimated using ELISA. Insilico sequence and structure-based analyses were performed to understand the structural and functional implications of mutations, identified through NGS. We studied 7 CAMT subjects suspected of BMF, who presented with severe thrombocytopenia followed by pancytopenia, bleeding manifestation and physical anomalies. The plasma THPO levels were significantly elevated (p<0.05) in all the cases. Molecular analysis by NGS identified 9 genomic mutations in MPL gene. These included 7 non-synonymous substitution, 1 nonsense substitution and 1 in-del mutations, of which 4 are novel mutations. Insilico analysis predicted damaging effects on THPO-R and its reduced affinity for THPO for all the identified mutations. CAMT is a rare disorder with diverse clinical phenotypes and diagnosis is challenging. The elevated plasma THPO levels should be considered for the primary diagnosis and prognosis of the disease. However, molecular analysis of MPL gene is important for the diagnosis and management of the disease through genetic counselling. Though the cytokines, THPO-R agonist are used for the treatment of CAMT, HSCT is the only curative therapy.
Asunto(s)
Pancitopenia , Trombocitopenia , Humanos , Trombocitopenia/diagnóstico , Pancitopenia/etiología , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Genómica , Trombopoyetina/genética , Receptores de Trombopoyetina/genéticaRESUMEN
Immature platelet fraction (IPF) is a quantification of immature platelets in the circulation reflecting the state of thrombopoiesis in the marrow. Normal reference range for IPF has been established in adults. Reference intervals in neonates are highly dependent on gestational age of the neonate. Complete blood counts (CBC) with IPF of all neonates admitted in neonatal intensive care unit (NICU) were analyzed using Mindray BC-6800 Auto Hematology analyzer. Platelet count of less than 150 × 10^9/L was assigned as thrombocytopenia. Neonates were divided into four groups as per the corrected gestational age (CGA) on the day of CBC analysis: 28-32 weeks, 32-34 weeks, 34-37 weeks, and >37 weeks according to World Health Organization (WHO) classification. Mean, standard deviation, and 95% confidence interval for IPF was calculated in each group and reference range for IPF was derived. Mean IPF in neonates with normal platelet count was term--3.58 (95% CI 3.29 to 3.87), late preterm Neonates (34-37 weeks)--4.14 (95% CI 3.82 to 5.0), moderate preterm neonates (32-34 weeks)--4.14 (95% CI 3.46 to 4.82), and in Very Preterm neonates (28-32 weeks)--IPF of 5.51 (95% CI 3.95 to 7.07). We aimed to establish a reference range for IPF in neonates of different gestational age groups. The IPF values in neonates were comparable between hematology analyzers in neonates with normal platelet counts.
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Plaquetas/citología , Plaquetas/fisiología , Trombocitopenia/diagnóstico , Edad Gestacional , Humanos , Lactante , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Recuento de Plaquetas , Estándares de Referencia , Valores de Referencia , Trombopoyesis/fisiologíaAsunto(s)
COVID-19 , Huésped Inmunocomprometido , Leucemia Mieloide Aguda , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica , COVID-19/sangre , COVID-19/inmunología , COVID-19/patología , Preescolar , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/patologíaRESUMEN
To study the clinical course of patients with sickle cell anemia and coinherited hematological disorders. Retrospective analysis of clinical data of patients enrolled at our hospital over last 7 years was performed. Eighty four patients of symptomatic sickling disorders were registered during this period, comprising of HbSS (n = 49), HbS-ß thalassemia (n = 28), HbS-HbD disease (n = 5), HbS-ß thalassemia with G6PD deficiency (n = 1) and HbS-hemophilia A (n = 1). Among HbS-ß thalassemia, 18% suffered from occasional pain crises and 27% required occasional blood transfusion. 40% patients with HbS-HbD disease required occasional blood transfusions, one patient was transfusion dependent, while none suffered from crisis episodes. Patient with HbS-ß thalassemia with G6PD deficiency had increased transfusion requirement during first 3 years of life, which decreased after that. Patient with HbS and severe hemophilia A had only one episode of severe bleeding, suffered from 1 crisis episode. In conclusion, HbA reduces severity of HbS in HbS-ß + thalassemia. HbS-HbD disease can manifest as a transfusion dependent illness. HbSS reduces severity of G6PD deficiency after first few years of life. HbSS and hemophilia coinheritance ameliorates symptoms of hemophilia.
RESUMEN
Hypercalcemia is a rare presentation of childhood acute lymphoblastic leukemia (ALL), and presents with nonspecific symptoms. A 11-year old boy developed severe hypercalcemia during initial presentation and relapse of ALL. Both times, he subsequently developed transient symptomatic hypocalcemia, associated with hypomagnesemia and renal tubulopathy. Disturbances in calcium homeostasis may rarely be the sole presenting feature of ALL in children, as a paraneoplastic syndrome, or may arise as a consequence of the malignancy and its treatment. Along with other measures, early recognition of malignancy and initiation of treatment play a key role in correcting calcium disturbances.
Asunto(s)
Hipercalciuria/patología , Hipocalcemia/patología , Enfermedades Renales/patología , Nefrocalcinosis/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Defectos Congénitos del Transporte Tubular Renal/patología , Niño , Homeostasis , Humanos , Hipercalciuria/etiología , Hipocalcemia/etiología , Enfermedades Renales/etiología , Masculino , Nefrocalcinosis/etiología , Pronóstico , Defectos Congénitos del Transporte Tubular Renal/etiologíaRESUMEN
Peripherally inserted central catheter (PICCs) are popular means of long-term intravenous access in oncology patients. Fracture and embolization are rare but potentially serious complications. Here we present an unusual fracture of the PICC line in a 9-year-old boy with Ewing's sarcoma with embolization to the right ventricle (RV) and right pulmonary artery (RPA) which was retrieved percutaneously by trans-catheter snare assisted retrieval. Adequate care and precautions like handling by trained nursing staff/parental education must be undertaken to prevent such complications.