Francesco Arcioni

NPM1 Deletion Is Associated with Gross Chromosomal Rearrangements in Leukemia

Background NPM1 gene at chromosome 5q35 is involved in recurrent translocations in leukemia and lymphoma. It also undergoes mutations in 60% of adult acute myeloid leukemia (AML) cases with normal karyotype. The incidence and significance of NPM1 deletion in human leukemia have not been elucidated. Methodology and Principal Findings Bone marrow samples from 145 patients with myelodysplastic syndromes (MDS) and AML were included in this study. Cytogenetically 43 cases had isolated 5q-, 84 cases had 5q- plus other changes and 18 cases had complex karyotype without 5q deletion. FISH and direct sequencing investigated the NPM1 gene. NPM1 deletion was an uncommon event in the “5q- syndrome” but occurred in over 40% of cases with high risk MDS/AML with complex karyotypes and 5q loss. It originated from large 5q chromosome deletions. Simultaneous exon 12 mutations were never found. NPM1 gene status was related to the pattern of complex cytogenetic aberrations. NPM1 haploinsufficiency was significantly associated with monosomies (p<0.001) and gross chromosomal rearrangements, i.e., markers, rings, and double minutes (p<0.001), while NPM1 disomy was associated with structural changes (p = 0.013). Interestingly, in complex karyotypes with 5q- TP53 deletion and/or mutations are not specifically associated with NPM1 deletion. Conclusions and Significance NPM1/5q35 deletion is a consistent event in MDS/AML with a 5q-/-5 in complex karyotypes. NPM1 deletion and NPM1 exon 12 mutations appear to be mutually exclusive and are associated with two distinct cytogenetic subsets of MDS and AML.

MN1-ETV6 fusion gene arising from MDS with 5q-.

An isolated 5q− Myelodysplastic Syndrome (MDS), “5q− synrome”, is characterized by a favorable prognosis whereas a eletion of chromosome 5q associated with one additional abnorality seems to confer a shorter median survival even though the rognostic impact of diverse aberrations in addition to 5q− has not een established [1]. Translocation t(12;22)(p13;q11)/MN1-ETV6 has been found in nly 2 cases of MDS [2,3]. The putative MN1-ETV6 transcription facor has transforming activity in vitro and may induce Acute Myeloid eukemia (AML) in mice [4,5]. Here we report the first case of MDS with 5q− and trisomy 21 t diagnosis which developed into secondary MN1-ETV6 positive ML.

Wernicke Encephalopathy in Pediatric Neuro-oncology: Presentation of 2 Cases and Review of Literature

Wernicke encephalopathy represents a well-known entity characterized by a set of cognitive and neurologic alterations. Wernicke encephalopathy is rare and under-recognized in childhood and may be fatal. Few cases have been documented in pediatric oncology. We report on 2 Wernicke encephalopathy cases that occurred in children having a brain tumor. The diagnosis of Wernicke encephalopathy was suggested by clinical manifestations associated with the typical radiologic findings and a laboratory evidence of thiamine deficiency. No large series have been published to support the evidence that pediatric malignancies represent a demonstrated factor of increased risk to develop a Wernicke encephalopathy. Moreover, the diagnosis may be even more difficult in brain tumors, considering the overlapping symptoms and the risk of encephalopathy related to both the disease and the treatment. Wernicke encephalopathy should be considered in all children with cancer presenting a neurologic deterioration, mainly in brain tumors. An early diagnosis is imperative for a prompt therapy that might prevent or minimize the irreversible brain damage related to this condition.

The hereditary hyperferritinemia-cataract syndrome in 2 italian families.

Two 8- and 9-year-old brothers were referred to the Pediatric Oncology Unit, Perugia General Hospital, because of hyperferritinemia. Both had a history of bilateral cataract and epilepsy. Genetic investigation revealed two distinct mutations in iron haemostasis genes; homozygosity for the HFE gene H63D mutation in the younger and heterozygosity in the elder. Both displayed heterozygosity for C33T mutation in the ferritin light chain iron response element. A 7-year-old boy from another family was referred to our unit because of hyperferritinemia. Genetic analyses did not reveal HFE gene mutations. Family history showed that his mother was also affected by hyperferritinemia without HFE gene mutations. Magnetic resonance imaging in the mother was positive for iron overload in the spleen. Cataract was diagnosed in mother and child. Further genetic investigation revealed the C29G mutation of the ferritin light chain iron response element. C33T and C29G mutations in the ferritin light chain iron response element underlie the Hereditary Hyperferritinemia-Cataract Syndrome (HHCS). The HFE gene H63D mutation underlies Hereditary Haemochromatosis (HH), which needs treatment to prevent organ damages by iron overload. HHCS was definitively diagnosed in all three children. HHCS is an autosomal dominant disease characterized by increased L-ferritin production. L-Ferritin aggregates accumulate preferentially in the lens, provoking bilateral cataract since childhood, as unique known organ damage. Epilepsy in one case and the spleen iron overload in another could suggest the misleading diagnosis of HH. Consequently, the differential diagnosis between alterations of iron storage system was essential, particularly in children, and required further genetic investigation.

Sirolimus-Based Immunosuppression as GvHD Prophylaxis after Bone Marrow Transplantation for Severe Aplastic Anaemia: A Case Report and Review of the Literature

Congenital or acquired severe aplastic anaemia (SAA) is cured by bone marrow transplantation (BMT) from a histocompatible leukocyte antigen- (HLA-) identical sibling. The best conditioning regimen is cyclophosphamide (CTX) with or without antithymocyte globulin (ATG), followed by short-term methotrexate (MTX) and cyclosporine A (CsA) to prevent graft-versus-host disease (GvHD). In our pediatric oncology-hematology unit, a 5-year-old girl with SAA was treated with two BMT from the same HLA-identical sibling donor. Severe CsA-induced adverse events (severe hypertension and PRES) after the first BMT led necessarily to CSA withdrawal. Alternative immunosuppressive treatment for GvHD prevention as tacrolimus and mycophenolate were not tolerated by our patient because toxicity > grade II. For this reason we decided to administrate sirolimus alone as GvHD prophylaxis and to prevent disease relapse after the rescue BMT. Here we report the successful use of sirolimus alone for GvHD prophylaxis after the second transplant in a pediatric BMT setting for SAA.

Lenalidomide treatment of myelodysplastic syndromes with chromosome 5q deletion: Results from the National Registry of the Italian Drug Agency

The most typical cytogenetic aberration in myelodysplastic syndromes is del(5q), which, when isolated, is associated with refractory anaemia and good prognosis. Based on high rates of erythroid response and transfusion independence, Lenalidomide (LEN) became the standard treatment. This multi‐centre study was designed to supplement Italian Registry data on LEN by addressing prescription, administration appropriateness, haematological and cytogenetic responses and disease evolution.

The Molecular Spectrum of β- and α-Thalassemia Mutations in Non-Endemic Umbria, Central Italy

Abstract The aim of this study was to describe the mutational spectrum of hemoglobinopathies during the period 1988–2015 in Umbria, Central Italy, which has never been considered endemic for these conditions. Twenty-four different β-globin gene mutations were identified in 188 patients and eight different α-globin gene mutations in 74 patients. Sixty percent β-thalassemia (β-thal), 85.0% sickle cell disease, 44.0% Hb S (HBB: c.20A>T)/β-thal and 85.0% compound heterozygotes for hemoglobin (Hb) variant-carrying patients were diagnosed or molecularly characterized in the last 3 years. Moreover, most homozygous or compound heterozygous patients (84.5%) came from foreign countries, while only 15.5% were of Italian origin. These data are in accordance with the increasing foreign resident population in Umbria, which has nearly doubled in 10 years (2004–2014). Different from β-globin gene variations, no increasing trend in α defects was observed in our study cohort. Consistently, 58.0% of patients have an Italian origin, suggesting no broad influence of foreign migration in the α-globin genes genetic background. As few defects are prevalent in each country of origin or ethnic group, their knowledge may provide a proper strategy for the identification of mutations in immigrant individuals in a non-endemic region and be important for carrier identification and prenatal screening.

Prospective changes of cardiac iron and function in low and intermediate-1 risk mds patients

while one showed cardiac iron (global heart T2*=12.3 ms). Due mainly to technical reasons, biventricular function was assesses at both baseline and FU MRIs in 22 patients. At baseline 6 patients showed a reduced left ventricular ejection fraction (LVEF) and 4 of them recovered at the FU. All patients had a baseline global heart T2*>20 ms (one with 2 segmental T2* values<20 ms). At baseline 5 patients showed a reduced right ventricular EF (RV EF) and all recovered at the FU. One patient with normal LV EF at baseline showed pathological LV EF at the and 2 patients with normal RV EF at baseline showed reduced RV EF at the FU (one patient suffered from pulmonary hypertension). At the FU we detected a significant increase in the LV end-diastolic volume index (EDVI) (mean difference: 6.5±11.3 ml/m2; P=0.015) as well as in the RV EDVI (mean difference: 7.8±9.3 ml/m2; P=0.002).