New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.

Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the SLC11A2 gene. DMT1 has a vital role in iron homeostasis by mediating iron uptake in the intestine and kidneys and by recovering iron from recycling endosomes after transferrin endocytosis. Mutations in SLC11A2 cause an ultra-rare hypochromic microcytic anemia with iron overload (AHMIO1), which has been described in eight patients so far. Here, we report two novel cases of this disease. The first proband is homozygous for a new SLC11A2 splicing variant (c.762 + 35A > G), becoming the first ever patient reported with a SLC11A2 splicing mutation in homozygosity. Splicing studies performed in this work confirm its pathogenicity. The second proband harbors the previously reported DMT1 G75R mutation in homozygosis. Functional studies with the G75R mutation in HuTu 80 cells demonstrate that this mutation results in improper DMT1 accumulation in lysosomes, which correlates with a significant decrease in DMT1 levels in patient-derived lymphoblast cell lines (LCLs). We also suggest that recombinant erythropoietin would be an adequate therapeutic approach for AHMIO1 patients as it improves their anemic state and may possibly contribute to mobilizing excessive hepatic iron.

Prevention and Treatment of Oral Complications in Hematologic Childhood Cancer Patients: An Update.

Cancers have a highly negative impact on the quality of life of paediatric patients and require an individualised oral treatment program for the phases of the disease. The aim of this study was to update existing research on oral care in children diagnosed with cancer. We carried out a literature search (in English, Spanish and Portuguese) in the Pubmed, Cochrane Library, EBSCO, WOS, SciELO, Lilacs, ProQuest, and SCOPUS databases and the websites of hospitals that treat childhood cancers. We found 114 articles and two hospital protocols. After review, we describe the interventions necessary to maintain oral health in children with cancer, divided into: phase I, before initiation of cancer treatment (review of medical record and oral history, planning of preventive strategies and dental treatments); phase II, from initiation of chemo-radiotherapy to 30-45 days post-therapy (maintenance of oral hygiene, reinforcement of parent/patient education in oral care, prevention and treatment of complications derived from cancer treatment); phase III, from 1 year to lifetime (periodic check-ups, maintenance, and reinforcement of oral hygiene, dental treatments, symptomatic care of the effects of long-term cancer treatment). The use of standardised protocols can avoid or minimise oral cancer complications and the side effects of cancer therapies.

Eficacia del Equipo de Cuidados Paliativos Pediátricos de Murcia según la experiencia de los padres / Efficacy of the Paediatrics Palliative Care Team of Murcia according to the experience of the parents

INTRODUCCIÓN: La atención al final de la vida de los niños debe ser sensible a las necesidades del niño y de su familia. Necesitamos entender la enfermedad desde la perspectiva de los padres que se enfrentan a la muerte de su hijo, para poder mejorar la calidad y guiar el desarrollo de la atención al final de la vida en Pediatría. MÉTODO: Estudio observacional retrospectivo a través de cuestionario, para evaluar las necesidades, experiencias y satisfacción con la atención recibida, de una muestra de padres que perdieron un hijo por una causa previsible, entre junio de 2014 y junio de 2017. Diferenciamos tres grupos de estudio en función del equipo responsable de la atención al final de la vida, y las diferencias entre el grupo atendido por el equipo de cuidados paliativos pediátricos, el grupo atendido por pediatras no paliativistas y el grupo neonatal, son analizadas. RESULTADOS: De las 80 familias elegibles, 64 pudieron ser contactadas y 28 (43,8%) finalmente completaron el cuestionario. Nuestro estudio muestra experiencias positivas y alta satisfacción de los padres con la atención recibida al final de la vida de su hijo. Las puntuaciones más altas tanto en experiencias como en satisfacción, fueron otorgadas por los padres de los niños atendidos por el equipo de cuidados paliativos pediátricos con diferencias estadísticamente significativas en apoyo a la familia, comunicación, toma de decisiones compartida y atención en torno a la muerte (p < 0,05). CONCLUSIONES: Los padres están satisfechos con la atención recibida al final de la vida de sus hijos, pero la intervención de un equipo específico de cuidados paliativos pediátricos mejora la calidad de la atención al final de la vida en pediatría

INTRODUCTION: The care at the end of children's lives must be sensitive to the needs of the child and their family. An understanding of the illness is required from the perspective of parents faced with the death of their child, in order to improve quality and guide the development of end-of-life care in Paediatrics. METHOD: A retrospective observational study was conducted between June 2014 and June 2017 using a questionnaire, to assess the needs, experiences, and satisfaction with the care received, from a sample of parents who lost a child due to a foreseeable cause. Three different study groups were formed based on the team responsible for end-of-life care, and an analysis was carried out on the differences between the group treated by the paediatric palliative care team, the roup attended by non-palliative paediatricians, and the neonatal group. RESULTS: Of the 80 eligible families, 64 could be contacted, and 28 (43.8%) finally completed the questionnaire. Our study shows positive experiences and high satisfaction of parents with the care received at the end of their child's life. The highest scores in experiences and satisfaction were given by the parents of the children served by the paediatric palliative care team, with statistically significant differences in family support, communication, shared decision making, and bereavement support (P < .05). CONCLUSIONS: Parents are satisfied with the care received at the end of their children's lives, but the intervention of a specific paediatric palliative care team improves the quality of care at the end of life in paediatrics

[Efficacy of the Paediatrics Palliative Care Team of Murcia according to the experience of the parents]. / Eficacia del Equipo de Cuidados Paliativos Pediátricos de Murcia según la experiencia de los padres.

INTRODUCTION: The care at the end of children's lives must be sensitive to the needs of the child and their family. An understanding of the illness is required from the perspective of parents faced with the death of their child, in order to improve quality and guide the development of end-of-life care in Paediatrics. METHOD: A retrospective observational study was conducted between June 2014 and June 2017 using a questionnaire, to assess the needs, experiences, and satisfaction with the care received, from a sample of parents who lost a child due to a foreseeable cause. Three different study groups were formed based on the team responsible for end-of-life care, and an analysis was carried out on the differences between the group treated by the paediatric palliative care team, the group attended by non-palliative paediatricians, and the neonatal group. RESULTS: Of the 80 eligible families, 64 could be contacted, and 28 (43.8%) finally completed the questionnaire. Our study shows positive experiences and high satisfaction of parents with the care received at the end of their child's life. The highest scores in experiences and satisfaction were given by the parents of the children served by the paediatric palliative care team, with statistically significant differences in family support, communication, shared decision making, and bereavement support (P<.05). CONCLUSIONS: Parents are satisfied with the care received at the end of their children's lives, but the intervention of a specific paediatric palliative care team improves the quality of care at the end of life in paediatrics.

Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.

PURPOSE: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies. METHODS: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test FANCA missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies. RESULTS: We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two FANCA variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes.

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.

Type III pleuropulmonary blastoma in a dicer1 germline mutation carrier: The management of residual lung cystic lesions.

Pleuropulmonary blastoma (PPB) is a rare malignancy of childhood. It often represents a manifestation of a hereditary tumor predisposition syndrome (DICER1 syndrome). Because of its malignant potential, surgical resection of cystic lung lesions is recommended in germline DICER1 mutation carriers. We present a case of a 3-year-old male child with type III PPB successfully managed with ifosfamide, vincristine, actinomycin-D, and doxorubicin (IVADo) chemotherapy and surgery. A heterozygous germline pR688X mutation of DICER1 gene was demonstrated. Six years after primary diagnosis, several small lung cysts remained stable without further therapy. The management of residual asymptomatic lung cysts represents a clinical challenge in these patients.

Evaluation of standardized triple intrathecal therapy toxicity in oncohematological pediatric patients.

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.

Fibrocartilaginous mesenchymoma of the spine in a child: a case report.

BACKGROUND: Originally described by Dahlin et al. in 1984, fibrocartilaginous mesenchymoma (FCM) constitutes a rare bone tumor of children and adolescents that mainly affects the long bones. A spinal location of this tumor is exceptional. Only two previous instances of vertebral FCM have been reported in the current literature, and both occurred in young adults. REPORT OF THE CASE: We report the case of a 9-year-old boy with backache caused by a neoplasm that involved the Th12 vertebra treated with tumor excision. Histopathological diagnosis was confirmatory of FCM. During a follow-up period of 2 years, there was no evidence of disease progression. Our patient, thus, represents the first case of FCM occurring in a child. CONCLUSIONS: 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.