RESUMEN
Diamond-Blackfan anaemia (DBA) is a rare and heterogeneous disease characterised by hypoplastic anaemia, congenital anomalies and a predisposition for malignancies. The aim of this paper is to report the findings from the Italian DBA Registry, and to discuss the Registry's future challenges in tackling this disease. Our 20-year long work allowed the connection of 50 Italian Association of Paediatric Haematology and Oncology (AIEOP) centres and the recruitment of 283 cases. Almost all patients have been characterised at a molecular level (96%, 271/283), finding a causative mutation in 68% (184/271). We confirm the importance of determination of erythrocyte adenosine deaminase activity (eADA) and of ribosomal RNA assay in the diagnostic pipeline and characterisation of a remission state. Patients with mutations in large ribosomal subunit protein (RPL) genes had a significant correlation with the incidence of malformations, higher eADA levels and more severe outcomes, compared to patients with mutations in small ribosomal subunit protein (RPS) genes. Furthermore, as a consequence of our findings, particularly the incidence of malignancies and the high percentage of patients aged >18 years, we stress the importance of collaboration with adult clinicians to guarantee regular multi-specialist follow-up. In conclusion, this study highlights the importance of national registries to increase our understanding and improve management of this complex disease.
Asunto(s)
Anemia de Diamond-Blackfan/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Sistema de Registros , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms. OBJECTIVE: Aim of this study is to provide clinical-immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation. METHODS: We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0-18 years at onset of immune cytopenias and/or immune-dysregulation. The cohort was divided into two groups (IEI+ and IEI-), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19). RESULTS: IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naÑve T-cells%, switched memory B-cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T-cells% and CD21low B-cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn. CONCLUSION: The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI-related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted-gene variants responsible for IEI phenotype.
Asunto(s)
Anemia Hemolítica Autoinmune , Inmunodeficiencia Variable Común , Púrpura Trombocitopénica Idiopática , Trombocitopenia , Anemia Hemolítica Autoinmune/diagnóstico , Niño , Humanos , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/genética , Estudios RetrospectivosAsunto(s)
Proteínas Portadoras/genética , Codón sin Sentido , Exoma/genética , Síndrome de Hermanski-Pudlak/genética , Síndromes de Inmunodeficiencia/genética , Lectinas/genética , Adolescente , Codón sin Sentido/genética , Análisis Mutacional de ADN , Femenino , Síndrome de Hermanski-Pudlak/inmunología , Humanos , Síndromes de Inmunodeficiencia/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/fisiología , Análisis de Secuencia de ADNRESUMEN
Pearson syndrome (PS) is a very rare and often fatal multisystemic mitochondrial disorder involving the liver, kidney, pancreas, and hematopoietic and central nervous system. It is characterized principally by a transfusion-dependent anemia that usually improves over time, a tendency to develop severe infections, and a high mortality rate. We describe a group of 11 PS patients diagnosed in Italy in the period 1993-2014. The analysis of this reasonably sized cohort of patients contributes to the clinical profile of the disease and highlights a rough incidence of 1 case/million newborns. Furthermore, it seems that some biochemical parameters like increased serum alanine and urinary fumaric acid can help to address an early diagnosis.