Ferritin is a multimeric protein composed of light (L-ferritin) and heavy (H-ferritin) subunits that binds and stores iron inside the cell. A variety of mutations have been reported in the L-ferritin subunit gene (FTL gene) that cause the following five diseases: (1) hereditary hyperferritinemia with cataract syndrome (HHCS), (2) neuroferritinopathy, a subtype of neurodegeneration with brain iron accumulation (NBIA), (3) benign hyperferritinemia, (4) L-ferritin deficiency with autosomal dominant inheritance, and (5) L-ferritin deficiency with autosomal recessive inheritance. Defects in the FTL gene lead to abnormally high levels of serum ferritin (hyperferritinemia) in HHCS and benign hyperferritinemia, while low levels (hypoferritinemia) are present in neuroferritinopathy and in autosomal dominant and recessive L-ferritin deficiency. Iron disturbances as well as neuromuscular and cognitive deficits are present in some, but not all, of these diseases. Here, we identified two novel FTL variants that cause dominant L-ferritin deficiency and HHCS (c.375+2T > A and 36_42delCAACAGT, respectively), and one previously reported variant (Met1Val) that causes dominant L-ferritin deficiency. Globally, genetic changes in the FTL gene are responsible for multiple phenotypes and an accurate diagnosis is useful for appropriate treatment. To help in this goal, we included a diagnostic algorithm for the detection of diseases caused by defects in FTL gene.

Given the rarity of spinal FCM, there are no guidelines about its management. However, treatment of this neoplasm seems to be mainly surgical aiming at total removal of the lesion, if feasible, as FCM may recur locally.

Background Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients. Methods This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes. Results Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT , TERC , RTEL1 , CTC1 and ACD . In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening. Conclusion Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed. Electronic supplementary material The online version of this article (10.1186/s13023-019-1046-0) contains supplementary material, which is available to authorized users.

Background T‐cell lymphoblastic lymphoma (T‐LBL) is an aggressive neoplasm closely related to T‐cell acute lymphoblastic leukaemia (T‐ALL). Despite their similarities, and contrary to T‐ALL, studies on paediatric T‐LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T‐LBL and to evaluate novel molecular markers differentiating this entity from T‐ALL. Procedure Thirty‐three paediatric T‐LBL patients were analyzed using an integrated approach, including targeted next‐generation sequencing, RNA‐sequencing transcriptome analysis and copy‐number arrays. Results Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24‐q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T‐ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T‐LBL. Additionally, we identified novel gene fusions in paediatric T‐LBL, including NOTCH1–IKZF2, RNGTT–SNAP91 and DDX3X–MLLT10, the last being the only one previously described in T‐ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. Conclusions In summary, the genomic landscape of paediatric T‐LBL is similar to that observed in T‐ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.

Background The administration of triple intrathecal therapy with methotrexate, cytarabine and a corticosteroid for the prophylaxis and treatment of neoplastic cell infiltration in the central nervous system in hematological malignancies is a widespread practice. There is limited information available about its toxicity profile. Several factors related to intrathecal preparation can affect toxicity. Thus, it was decided to standardize intrathecal chemotherapy, trying to obtain the best toxicity profile. Objective To assess the toxicity of a standardized triple intrathecal chemotherapy in oncohematological pediatric patients and to establish risk factors of toxicity. Setting Oncohematological pediatric unit from a tertiary hospital in Spain. Methods Prospective, descriptive and observational study in which all the administrations of standardized triple intrathecal chemotherapy in pediatric patients were registered. Main outcome measure Toxicity of the intrathecal therapy was recorded and possible risk factors were assessed. Results A total of 269 administrations of triple intrathecal chemotherapy were registered in 41 patients (mean age = 6.6 ± 3.9 years). In 16.7% of the procedures, an adverse event was reported (total number of adverse events = 61). 47.5% were grade 1, 47.5% grade 2 and 4.9% grade 3. The administration of intrathecal chemotherapy inpatient and patient age ≥3 years were risk factors of toxicity in the multivariate analysis. Conclusions The administration of standardized triple intrathecal chemotherapy is related to a low frequency of toxicity and most of the adverse events registered were mild/moderate. The detection of adverse effects was significantly greater in children with age greater than or equal to three years and in hospitalized patients.