Germline mutations in the transcription factor IKZF5 cause thrombocytopenia.

To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13 037 individuals enrolled in the National Institute for Health Research (NIHR) BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor-encoding gene IKZF5 and thrombocytopenia. We report 5 causal missense variants in or near IKZF5 zinc fingers, of which 2 occurred de novo and 3 co-segregated in 3 pedigrees. A canonical DNA-zinc finger binding model predicts that 3 of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared with wild-type IKZF5, and electron microscopy revealed a reduced quantity of α granules in normally sized platelets. Proplatelet formation was reduced in megakaryocytes from 7 cases relative to 6 controls. Comparison of RNA-sequencing data from platelets, monocytes, neutrophils, and CD4+ T cells from 3 cases and 14 healthy controls showed 1194 differentially expressed genes in platelets but only 4 differentially expressed genes in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.

Fatigue, executive function and psychological effects in children with immune thrombocytopenia: a cross-sectional study.

Childhood ITP is often considered to be a relatively mild haematological disorder, with only a minority of patients requiring treatment for troublesome bleeding. Over recent years, wider effects of the condition have been identified in some adults, particularly relating to fatigue and cognitive impairment. In this study, we sought to investigate such effects in a group of children with ITP and further our understanding of their psychological profile. Children attending routine haematology outpatient clinics and their parents were asked to complete standardised questionnaires designed to assess a range of psychological and cognitive factors. Although the majority of children had some scores within the normal range, a significantly high proportion had difficulties with fatigue (70·6%), emotional and behavioural symptoms (25·7%) or executive functioning (19·4%). Quality of life and subjective evaluation of the illness (appraisal) correlated significantly with each of these domains, but bleeding severity and platelet count did not. Our findings provide valuable insight into the broader impact of childhood ITP, which could aid in providing holistic care, potentially contribute to decisions regarding medical treatment, and guide future research.

Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by antibodies against ADAMTS13. From the United Kingdom TTP registry, we undertook a prospective study investigating the impact of the presenting anti-ADAMTS13 IgG antibody and ADAMTS13 antigen on mortality. A total of 312 episodes involving 292 patients over 87 months were included; 68% were female, median age 46 (range, 11-88 years), and median presenting ADAMTS13 of <5% (range, <5%-18%). The mortality rate was 10.3% (n = 32); 68% of patients had a raised troponin at presentation conferring a sixfold increase in mortality compared with those with normal troponin levels (12.1% vs 2.0%, P = .04). Twenty-four percent had a reduced Glasgow Coma Score (GCS) at presentation with a ninefold increase in mortality (20% vs 2.2% for normal GCS at presentation, P < .0001). Mortality increased with higher anti-ADAMTS13 antibody levels and lower ADAMTS13 antigen levels. Those with antibody levels in the upper quartile (antibody >77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody <20%) (P = .004). Those with an antigen level in the lowest quartile (antigen <1.5%) had a mortality of 18% compared with 3.8% for the highest quartile (antigen >11%) (P = .005). The synergistic effect of anti-ADAMTS13 IgG antibody in the upper quartile and ADAMTS13 antigen in the lowest quartile had the highest mortality of 27.3%. We conclude that both anti-ADAMTS13 IgG antibody and ADAMTS13 antigen levels correlate with outcome in TTP with increased cardiac and neurological involvement and increased mortality.

An 11-year experience of acquired von Willebrand syndrome in children diagnosed with Wilms tumour in a tertiary referral centre.

Wilms tumour (WT) is the commonest primary malignant renal tumour of childhood. Acquired von Willebrand syndrome (avWS) is a well-described paraneoplastic phenomenon, but it is uncommon and may not be detected until clinically significant bleeding is encountered during interventional procedures. Previous studies on small cohorts of patients have determined an incidence of between 4 and 8%. We have performed a retrospective study on cases of WT presenting over an 11.5-year period to a paediatric haematology/oncology unit in a tertiary referral centre to review the incidence of avWS, bleeding phenotype, management, and response to treatment of the primary pathology.

Strategies to Prevent and Manage Thrombotic Complications of Acute Lymphoblastic Leukemia in Children and Young People Vary Between Centers in the United Kingdom.

There is a lack of evidence-based guidance for the prevention and management of thrombosis in children and young people treated for acute lymphoblastic leukemia. To determine current UK practice, a survey was sent to 28 centers participating in the Medical Research Council UKALL 2011 trial. Marked variation in practice was noted. In total, 43% of centers defer central venous access device insertion until end of induction for treatment of low-risk disease. Central venous access devices are removed at the end of intensive blocks in 38% and end of treatment in 42%. Duration of anticoagulation for line-associated thrombosis is 6 weeks in 43% and 3 months in 33% and for cerebral sinovenous thrombosis is 3 months in 71% and 6 months in 24%. Platelet transfusion to maintain platelet count >50×10/L, in preference to interrupting therapeutic anticoagulation, is used by 50% for line-associated thrombosis and 73% for cerebral sinovenous thrombosis. Conformity of practice was seen in some areas. In total, 70% treat thrombosis with twice-daily low-molecular weight heparin and 86% monitor antifactor Xa activity levels. In total, 91% reexpose individuals to asparaginase following a thrombotic event. Given this variation in practice, in the absence of high-quality evidence, consensus guidelines may be helpful.

A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations.

Nuclear-encoded disorders of mitochondrial translation are clinically and genetically heterogeneous. Genetic causes include defects of mitochondrial aminoacyl-tRNA synthetases, and factors required for initiation, elongation and termination of protein synthesis as well as ribosome recycling. We report on a new case of myopathy, lactic acidosis and sideroblastic anemia (MLASA) syndrome caused by defective mitochondrial tyrosyl aminoacylation. The patient presented at 1 year with anemia initially attributed to iron deficiency. Bone marrow aspirate at 5 years revealed ringed sideroblasts but transfusion dependency did not occur until 11 years. Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support. Long-range PCR excluded mitochondrial DNA rearrangements. Clinical diagnosis of MLASA prompted direct sequence analysis of the YARS2 gene encoding the mitochondrial tyrosyl-tRNA synthetase, which revealed homozygosity for a known pathogenic mutation, c.156C>G;p.F52L. Comparison with four previously reported cases demonstrated remarkable clinical homogeneity. First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy. Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy. Reasons for segregation of specific clinical phenotypes with particular mitochondrial aminoacyl tRNA-synthetase defects remain unknown.

Rituximab in combination with CODOX-M/IVAC: a retrospective analysis of 23 cases of non-HIV related B-cell non-Hodgkin lymphoma with proliferation index >95%.

The safety and efficacy of rituximab with CODOX-M/IVAC (cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine) was retrospectively analysed in 23 patients with non-human immunodeficiency virus-related B-cell non-Hodgkin lymphoma with proliferation index >95% [14 with classical Burkitt lymphoma (BL), five with B-cell lymphoma unclassifiable, with features intermediate between diffuse large B cell lymphoma (DLBCL) and BL, and four with DLBCL]. Six (26%) low-risk (LR) patients received three cycles of CODOX-M and 17 (74%) high-risk (HR) cases were assigned to four cycles of alternating CODOX-M/IVAC. Rituximab 375 mg/m² was infused on days 1 and 10 of each cycle. Toxicity was comparable to that reported with CODOX-M/IVAC, with no treatment-related death. Two patients developed grade 3 rituximab-induced delayed neutropenia, with no adverse outcome. After completing treatment, 83% LR patients and 71% HR patients achieved CR by positron emission tomography-computerized tomography (PET-CT). Three (13%) patients received salvage treatment. At a median follow-up of 34 months (range = 18-75), 19 (83%) patients (100% LR and 74% HR) were alive, including one case undergoing salvage for late relapse. Four HR patients (17%) had died, three from primary progressive disease and one from treatment-refractory relapse 2 months after achieving CR. These results with R-CODOX-M/R-IVAC compare favourably with existing data using CODOX-M/IVAC and warrant further prospective studies. The potential pitfalls of PET-CT to assess response are highlighted.

Early UK experience in the use of clofarabine in the treatment of relapsed and refractory paediatric acute lymphoblastic leukaemia.

Clofarabine is a second-generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine-based chemotherapy regimes were effective and well-tolerated in this heavily pre-treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics.

Rituximab Unveils Hypogammaglobulinemia and Immunodeficiency in Children with Autoimmune Cytopenia.

BACKGROUND: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. OBJECTIVE: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. METHODS: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. RESULTS: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P < .05), and 6 of 17 (35%) patients had unresolved B-cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs 116 months; P < .01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9 of 17 [53%]) were eventually diagnosed with a PID. CONCLUSIONS: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In-depth investigation for PID is therefore recommended in these patients.

Systemic juvenile xanthogranulomatosis imitating a malignant abdominal wall tumor with lung metastases.

Juvenile xanthogranulomatosis (JXG) is a rare benign condition, which usually presents with characteristic skin lesions and can be diagnosed clinically. However, systemic JXG may involve a wide range of extracutaneous sites and may pose a diagnostic dilemma for the clinician, radiologist, and pathologist. In particular it may simulate malignancy. Here, we report a case of systemic JXG within the abdominal wall musculature and lungs, which imitated a sarcoma with pulmonary metastases on computerized tomography. To the best of our knowledge, this is the first such reported case. In particular, systemic disease presenting without skin lesions is unusual.