Are all cases of paediatric essential thrombocythaemia really myeloproliferative neoplasms? Analysis of a large cohort

Sporadic essential thrombocythaemia (ET) is rare in paediatrics, and the diagnostic and clinical approach to paediatric cases cannot be simply copied from experience with adults. Here, we assessed 89 children with a clinical diagnosis of ET and found that 23 patients (258%) had a clonal disease. The JAK2 V617F mutation was identified in 14 children, 1 child had the MPL W515L mutation, and 6 had CALR mutations. The monoclonal X-chromosome inactivation pattern was seen in six patients (two with JAK2 V617F and two with CALR mutations). The other 66 patients (742%) had persistent thrombocytosis with no clonality. There were no clinical or haematological differences between the clonal and non-clonal patients. The relative proportion of ET-specific mutations in the clonal children was much the same as in adults. The higher prevalence of nonclonal cases suggests that some patients may not have myeloproliferative neoplasms, with significant implications for their treatment

First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected

Acute differentiated dendritic cell leukemia: a variant form of pediatric acute myeloid leukemia with MLL translocation

Dendritic cells (DCs) are the primary antigen-presenting cells (APCs) for eliciting T-cell response.1 The immunophenotype and function of DCs are heterogeneous in vivo.1 DCs can be generated in vitro from cord blood or bone marrow CD34+ progenitors,1 and from peripheral blood or cord blood monocytes in the presence of tumor necrosis factor (TNF) and IL-4.1, 2, 3 Induction of DC differentiation in vitro from acute or chronic leukemia cells has been described using a combination of cytokines.2, 3 Primitive DC neoplasms are rare and remain unclassified according to the French–American–British (FAB) system.4 The recent World Health Organization (WHO) classification of hematological malignancies introduced a distinct category among the DC neoplasm but not in myeloid neoplasms.5 In the present study, we identified three pediatric cases of acute myeloid leukemia (AML) with features of well-differentiated DCs. We performed a morphological, immunological and molecular characterization of these cases using well-established methodologies. Detailed information regarding Materials and methods are reported in Supplementary Materials and methods. Demographic and clinical features of all three patients are listed in Table 1. They were admitted in three different children's hospitals in Italy (Catania for case 1; Padova for case 2; Catanzaro for case 3). They presented with fever, pallor, abdominal and joint pain, cervical adenopathy and mild hepatosplenomegaly. In all three cases, the white blood cell count was normal. There was no involvement of the central nervous system. Morphologic evaluation of the bone marrow aspirates was similar in the three cases. The marrows were completely replaced with large blasts in a percentage of 85, 80 and 85% for cases 1, 2 and 3, respectively. The blasts were characterized by irregular nuclei, slightly basophilic cytoplasm and prominent cytoplasmic projections. There were no cytoplasmatic granules and no evidence of phagocytosis (Figure 1a–c). Myeloperoxidase (MPO) and alpha naphthyl acetate esterase (NAE) reactions were negative (Figure 1d). Additional morphological features are shown in Supplementary Figure 1A (for case 1), 1B (case 2) and 1C (case 3). We provided several images of blasts in order to demonstrate the DC nature of this form of leukemia

Retrospective evaluation of 90 children with essential thrombocythemia: the AIEOP experience

We report 90 children affected by ETevaluated over many years in the Units of Italian Association for Hemato-Oncolog