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Mutations of several genes have been implicated in autosomal recessive osteopetrosis ( OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies ( SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5′ region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease. [ABSTRACT FROM AUTHOR]

Background Non-stimulatory, meal-mediated electrical stimulation of the stomach ( TANTALUS- DIAMOND) improves glycaemic control and causes modest weight loss in patients with Type 2 diabetes who are inadequately controlled on oral anti-diabetic medications. The magnitude of the glycaemic response in clinical studies has been variable. A preliminary analysis of data from patients who had completed 6 months of treatment indicated that the glycaemic response to the electrical stimulation was inversely related to the baseline fasting plasma triglyceride level. Method An analysis of 40 patients who had had detailed longitudinal studies for 12 months. Results Twenty-two patients with fasting plasma triglycerides ≤ 1.7 mmol/l had mean decreases in HbA1c after 3, 6 and 12 months of gastric contraction modulation treatment of −15 ± 2.1 mmol/mol (−1.39 ± 0.20%), −16 ± 2.2 mmol/mol (−1.48 ± 0.20%) and −14 ± 3.0 mmol/mol (−1.31 ± 0.26%), respectively. In contrast, 18 patients with fasting plasma triglyceride > 1.7 mmol/l had mean decreases in HbA1c of −7 ± 1.7 mmol/mol (−0.66 ± 0.16%), −5 ± 1.6 mmol/mol (−0.44 ± 0.18%) and −5 ± 1.7 mmol/mol (−0.42 ± 0.16%), respectively. Pearson's correlation coefficient between fasting plasma triglyceride and decreases in HbA1c at 12 months of treatment was 0.34 ( P < 0.05). Homeostasis model assessment of insulin resistance was unchanged during 12 months of treatment in patients with high baseline fasting triglycerides, while it progressively improved in patients with low fasting plasma triglycerides. Patients with low fasting plasma triglycerides had a tendency to lose more weight than those with high fasting plasma triglycerides, but this did not achieve statistical significance. Conclusions The data presented suggest the existence of a triglyceride lipotoxic mechanism that interferes with gastric/neural mediated pathways that can regulate glycaemic control in patients with type 2 diabetes. The data suggest the existence of a triglyceride lipotoxic pathway that interferes with gastric/neural mediated pathways that can regulate glycaemic control. [ABSTRACT FROM AUTHOR]

Klein T, Yaniv I, Stein J, Narinsky R, Finkelstein Y, Garty BZ. Extended family studies for the identification of allogenic stem cell transplant donors in Jewish and Arabic patients in Israel.Pediatr Transplantation 2004.© 2004 Blackwell MunksgaardHLA-identified donors are the best source of allogeneic hematopoietic stem cell transplants, and are available in approximately 40% of cases. If no HLA-identical core family member is found, an extended family search may be performed. The aim of the study was to summarize the 10-year (1990–1999) experience of our tertiary care center with extended family donor search. During this period, 356 patients and 2659 of their family members were tissue-typed; 239 patients were Jewish (67%) and 117 were Arabic (33%). An HLA-identical core-family donor was identified for 168 patients (47%): 95 Jewish (40%) and 73 Arabic (62%) (p < 0.0001); 49 patients (14%) had more than one potential donor. An extended family search (grandmother/grandfather, aunts, uncles, etc.) was performed in 38 of the remaining families, which were found to be consanguineous: five Jewish and 33 Arabic. One HLA match was found in the Jewish families (20%) and 21 in the Arabic families (64%). The odds ratio for an Arabic patient to find a donor in the extended family search was 8.75, as opposed to a Jewish patient. Overall, HLA-matched donors were found by core and extended family search for 53% of the patients. The rate for Arabic patients was 80% and for Jewish patients, 40% (p < 0.001). This difference may be explained by the greater number of siblings and higher rate of consanguinity in the Arabic population. In conclusion, an extended family search for potential HLA-matched donors is worthwhile, especially in distinct ethnic populations with high consanguinity, such as Israeli Arabs. [ABSTRACT FROM AUTHOR]

The importance of environment in the regulation of brain, behaviour and physiology has long been recognized in biological, social and medical sciences. Animals maintained under enriched conditions have clearly been shown to have better learning abilities than those maintained under standard conditions. However, the effects of environmental enrichment (EE) on immunity and emotionality have been less documented and remain questionable. Therefore, we investigated the effect of FE on natural killer (NK) cell activity, psychological stress responses and behavioural parameters. Male C3H mice were housed either in enriched or standard conditions for 6 weeks. Behaviour was then examined by the grip-strength test, staircase and elevated plus maze, and corticosterone levels and NK cell activity were measured. Furthermore, animals exposed to the stress paradigm, achieved by electric shock with reminders, were tested for freezing time in each reminder. Corticosterone levels were also measured. The FE mice showed decreased anxiety- like behaviour and higher activity compared to standard mice, as revealed by a greater percentage of time spent in the open arms of the elevated plus maze, and a higher rate of climbing the staircase. A shorter freezing time in the stress paradigm and no corticosterone level reactivity were measured in FE mice. In addition, NK cell activity in spleens of FE mice was higher than that demonstrated in those of standard mice. Thus, FE has a beneficial effect on anxiety-like behaviour, stress response and NK cell activity. The effect on NK cell activity is promising, due to the role of NK cells in host resistance. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Familial thrombocytopenia is a relatively rare and heterogeneous group of clinical and genetic syndromes of unknown etiology. Recently, mutations in a few hematopoietic transcription factors were implicated in dysmegakaryopoiesis with and without dyserythropoietic anemia. The aim of the present study was to describe the clinical and hematologic picture of members of a Bedouin family with severe congenital thrombocytopenia associated with neutropenia and anemia and to determine the possible involvement of hematopoietic transcription factor genes in their disease. Patients and methods: Four members of a Bedouin family presented with severe bleeding tendency, including intracranial hemorrhage in three. Three of the four were successfully treated with allogenic human leukocyte antigen (HLA)-matched bone marrow transplants. Measurements of serum erythropoietin and thrombopoietin levels, bone marrow electron microscopy, and megakaryocytic colony were grown for each patient in addition to DNA amplification and single-strand conformation polymorphism of each exon of the NF-E2 , Fli-1 , FOG-1 , and Gfi-1b in genes. Results: Bone marrow studies revealed dysmegakaryopoiesis and mild dyserythropoiesis. A low number of bone marrow megakaryocyte colony-forming units was found, as well as a slightly elevated serum thrombopoietin level. No mutation was identified in any of the transcription factor genes examined. Conclusions: A unique autosomal recessive bone marrow disorder with prominent involvement of megakaryocytes is described. Defects were not identified in transcription factors affecting the common myeloid progenitor. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: In patients with thalassemia major (TM) who are non-compliant with long-term deferoxamine (DFO) chelation, survival is limited mainly because of cardiac complications of transfusional siderosis. It was recently shown in a small group of TM patients with established cardiac damage that continuous 24-h DFO infusion via an indwelling intravenous (i.v.) catheter is effective in reversing cardiac toxicity. The aim of the present study was to evaluate the results with intermittent daily (8–10 h) i.v. DFO. Patients: Eight TM patients with cardiac complications treated with intensive intermittent DFO were retrospectively evaluated by the mean annual serum ferritin, radionucleated ventriculography and 24-h electrocardiography recordings. Results: The median age at diagnosis of cardiac disease was 17.5 yr (range 14–21), and the median follow-up time was 84 months (range, 36–120). In the majority of patients (seven of eight) high-dose DFO (mean 95 ± 18.3 mg/kg/d) was administered via a central venous line. During follow-up, there was a significant decrease in the mean ferritin levels (5828 ± 2016 ng/mL to 1585 ± 1849 ng/mL, P < 0.001). Both cardiac failure (mean ejection fraction 32 ± 5) and cardiac arrhythmias were resolved in four of five patients. One non-compliant patient died during the follow-up. Following discontinuation of the i.v. therapy, compliance with conventional DFO therapy improved. The complications of this regimen, mainly catheter-related infections and catheter-related thrombosis, were similar to those described earlier. Conclusions: These results with the longest follow-up period in the literature suggest that i.v. high-dose DFO for 8–10 h daily may be as effective as continuous 24-h infusion for the reversal of established cardiac disease in TM. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Congenital dyserythropoietic anemia (CDA) type I is a rare autosomal recessive macrocytic anemia whose natural history is not well documented. The aim of the present study was to evaluate the clinical picture of the disease in young adults. Methods: The study sample consisted of 17 patients of mean age 11.9±5.4 yr (range 18–33 yr) and one older patient (age 44 yr), all Israeli Bedouins. The degree of anemia was evaluated as well as the extent of development of gallstones and iron overload. In each subject we determined the hemochromatosis gene mutations and the uridine dyphosphate-glucoronosyltransferase (UGT-1A) gene polymorphism associated with Gilbert's syndrome. Results: The patients were found to have moderate anemia, with the women displaying lower mean hemoglobin levels than the men (8.2±0.9 g dL-1 vs. 10±1.3 g dL-1 ; P =0.0059). The majority of patients (59%) had received at least one blood transfusion, with the women having a significantly higher transfusion requirement. Although delayed puberty was noted, final height and weight were within normal limits, and eight patients had progeny. Biliary stones were found in three of 16 patients, two of whom were homozygous for UGT-1A gene polymorphism. None of the patients carried the common hemochromatosis gene mutation, although serum ferritin levels were moderately elevated (788±332 ng mL-1 ). Conclusions: CDA type I in young adults is characterized by moderate macrocytic anemia, more severe in women, and a tendency to cholelithiasis and secondary progressive iron overload. We suggest that iron overload in this patient population should be monitored and chelation therapy initiated when indicated to prevent organ damage. [ABSTRACT FROM AUTHOR]

Fanconi anaemia (FA) is a genetically heterogeneous disease with at least eight complementation groups (A–H). In the present study, we investigated the molecular basis of the disease in 13 unrelated Israeli Jewish (non-Ashkenazi) patients with FA. All 43 exons of the Fanconi anaemia A (FANCA) gene were amplified from genomic DNA and screened for mutations by single-strand conformation polymorphism and DNA sequencing. We identified four ethnic-specific mutations: (1) 2172–2173insG (exon 24), the first ‘Moroccan mutation’; (2) 4275delT (exon 43), the second ‘Moroccan mutation’; (3) 890–893del (exon 10), the ‘Tunisian mutation’; and (4) 2574C > G (S858R), the ‘Indian mutation’. The tetranucleotide CCTG motif, previously identified as a mutation hotspot in FANCA and other human genes, was found in the vicinity of 2172–2173insG and 890–893del. According to our study, the four mutations account for the majority (88%) of the FANCA alleles in the Israeli Jewish (non-Ashkenazi) FA population. A screening of 300 Moroccan Jews identified three carriers of the first ‘Moroccan mutation’, but we did not find any carrier of the second ‘Moroccan mutation’ among 140 Moroccan Jews, nor any carrier of the ‘Tunisian mutation’ among 50 Tunisian Jews. Two ‘Indian mutation’ carriers were identified among 53 Indian Jews. All carriers within each ethnic group had the same haplotype, suggesting a common founder for each mutation. [ABSTRACT FROM AUTHOR]

Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but contemporary data in children are lacking. We conducted a nationwide multicentre study to investigate the characteristics of mucormycosis in children with haematological malignancies. The cohort included 39 children with mucormycosis: 25 of 1136 children (incidence 2·2%) with acute leukaemias prospectively enrolled in a centralized clinical registry in 2004-2017, and an additional 14 children with haematological malignancies identified by retrospective search of the databases of seven paediatric haematology centres. Ninety-two percent of mucormycosis cases occurred in patients with acute leukaemias. Mucormycosis was significantly associated with high-risk acute lymphoblastic leukaemia (OR 3·75; 95% CI 1·51-9·37; P = 0·004) and with increasing age (OR 3·58; 95% CI 1·24-9·77; P = 0·01). Fifteen patients (38%) died of mucormycosis. Rhinocerebral pattern was independently associated with improved 12-week survival (OR 9·43; 95% CI 1·47-60·66; P = 0·02) and relapsed underlying malignancy was associated with increased 12-week mortality (OR 6·42; 95% CI, 1·01-40·94; P = 0·05). In patients receiving frontline therapy for their malignancy (n = 24), one-year cumulative mucormycosis-related mortality was 21 ± 8% and five-year overall survival was 70 ± 8%. This largest paediatric population-based study of mucormycosis demonstrates that children receiving frontline therapy for their haematological malignancy are often salvageable., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7·7 months; median follow-up from relapse after allo-SCT until last follow-up was 3·4 years. The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo-SCT hold promise to improve outcome in children with post allo-SCT relapse., (© 2017 John Wiley & Sons Ltd.)

Chromosomal rearrangements involving the MECOM (MDS1 and EVI1 complex) locus are recurrent genetic events in myeloid leukaemia and are associated with poor prognosis. In this study, we assessed the role of MECOM locus protein EVI1 in the transcriptional regulation of microRNAs (miRNAs) involved in the leukaemic phenotype. For this, we profiled expression of 366 miRNAs in 38 MECOM-rearranged patient samples, normal bone marrow controls and MECOM (EVI1) knock down/re-expression models. Cross-comparison of these miRNA expression profiling data showed that MECOM rearranged leukaemias are characterized by down regulation of MIR449A. Reconstitution of MIR449A expression in MECOM-rearranged cell line models induced apoptosis resulting in a strong decrease in cell viability. These effects might be mediated in part by MIR449A regulation of NOTCH1 and BCL2, which are shown here to be bona fide MIR449A targets. Finally, we confirmed that MIR449A repression is mediated through direct promoter occupation of the EVI1 transcriptional repressor. In conclusion, this study reveals MIR449A as a crucial direct target of the MECOM locus protein EVI1 involved in the pathogenesis of MECOM-rearranged leukaemias and unravels NOTCH1 and BCL2 as important novel targets of MIR449A. This EVI1-MIR449A-NOTCH1/BCL2 regulatory axis might open new possibilities for the development of therapeutic strategies in this poor prognostic leukaemia subgroup., (© 2011 Blackwell Publishing Ltd.)

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders - medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1-18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin-Frankfurt-Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 +/- 5.9% and the INS 98 (n = 43), 83.7 +/- 5.6% (P = 0.12); the cumulative incidence (CI) of any CNS relapse was 5.0 +/- 2.8% and 2.3 +/- 2.3% (P = 0.50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) >or=100 x 10(9)/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61.9 +/- 5.3% in INS 89 and 72.9 +/- 5.8% in INS 98, (P = 0.21); the CI of any CNS relapse was 7.1 +/- 2.8% and 1.7 +/- 1.7% (P = 0.142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.

We report for the first time a child with chronic granulomatous disease (CGD) who developed acute lymphoblastic leukemia (ALL). The diagnosis of CGD was made at the age of 4 months, by studies of his neutrophil functions. The superoxide production of the cells was negligible, as was the bactericidal activity. He was found to have a deficiency of the gp91(phox) subunit of the leukocyte NADPH oxidase, with the X-linked inheritance of the disease. DNA analysis revealed a C nucleotide insertion between C1028 and T1029. This insertion has not been described before and causes a frameshift and a premature stop codon at amino-acid position 347. The mother was found to be a carrier of this mutation. At the age of 16 months, the patient developed T-cell ALL. He was treated for 2 years, and today, 10 years since the diagnosis, he is disease-free. During the course of ALL and later, he suffered from recurrent severe pyogenic infections, but careful detection of the etiological agent and promptly instituted specific treatment resulted in his complete recovery. Although primary immune deficiencies have been reported to have an increased tendency to develop malignancies, until now there have been no reports of CGD patients with ALL., (Copyright 2005 Wiley-Liss, Inc.)

Congenital dyserythropoietic anaemia (CDA) type I is a rare, inherited disorder characterised by ineffective erythropoiesis and macrocytic anaemia. Complex bone disease has only occasionally been associated with this disease. CDA I is caused by mutations in the CDAN1 gene encoding for codanin-1. Our aim was to characterise the CDAN1 mutation in eight unrelated patients with sporadic CDA I, three of whom had complex bone disease. Six novel mutations in the CDAN1 gene were identified. In two patients, one mutation and in another, both mutations were elusive. No patient was homozygous for a null-type mutation. However, one patient with complex bone disease was homozygous for a splice-site mutation (IVS-12+5G>A). Western blotting revealed that codanin-1 synthesis was 65% less than the control. Five single nucleotide polymorphisms (SNPs) previously unreported in the literature or the SNP database were also identified. Although the absence of codanin-1 is probably lethal, the presence of 35% of the protein was compatible with life but was associated with severe clinical manifestations. However, in most patients studied, no correlation could be established between the expected levels of codanin-1 or the nature of the mutation and the severity of the clinical manifestations.

The incidence of cytogenetic abnormalities in childhood de novo acute myeloid leukaemia (AML) and its prognostic significance was assessed in an Israeli paediatric referral centre. Cytogenetic analysis was successful in 86 of 97 children (< 20 years of age) diagnosed between 1988 and 2002 with de novo AML. Fluorescence in situ hybridization analysis detected new information in 11 of them, leading to reassignment in cytogenetic group classification. The incidence of the various cytogenetic subgroups was as follows: normal - 9%; t(11q23) - 22%; t(8;21) - 13%; t(15;17) - 8%; inv(16) - 3.4%; abn(3q) - 4.6%; 7/7q-(sole or main) - 5.8%; del(9q)(sole) and +21(sole) - 4.6% each; t(8;16) - 2.3%; t(6;9), t(1;22), +8(sole) - 1.1% each; and miscellaneous - 18%. The overall survival (OS) and event-free survival (EFS) (4 years) for 94 patients treated with the modified Berlin-Frankfürt-Münster (BFM) AML protocols (non-irradiated) were 59.9% (SE = 5%) and 55.7% (SE = 5%), respectively, and for the favourable t(8;21), t(15;17) and inv(16), OS was 60% (SE = 15%), 83% (SE = 15%) and 100% respectively. For the normal group it was 62% (SE = 17%), miscellaneous 64% (SE = 12%), t(11q23) 44.6% (SE = 11%) and of the -7/7q-, del(9q)(sole) or t(6;9), none had survived at 4 years. The incidence of cytogenetic subgroups in the Israeli childhood AML population and their outcome were similar to other recently reported paediatric series. Cytogenetic abnormalities still carry clinical relevance for treatment stratification in the context of modern chemotherapy., (Copyright 2004 Blackwell Publishing Ltd)

Objective: Venous sinus thrombosis (VST) is the second most common intracranial complication of acute otitis media (AOM). There is some evidence that hereditary and acquired prothrombotic disorders are risk factors for VST. The aim of the present study was to evaluate whether children with AOM complicated VST have a prothrombotic tendency, which might have important therapeutic and preventive implications., Study Design: Retrospective., Methods: The files of children hospitalized at Schneider Children's Medical Center of Israel, a tertiary referral center, from 1999 to 2002, because of AOM complicated by acute mastoiditis and VST were reviewed. All children underwent laboratory work-up for hypercoagulability., Results: Seven children met the study criteria. Of these, five had prothrombotic disorders, namely elevated levels of lipoprotein apolipoprotein (Lp[a]) (n = 4), antibodies to beta 2-glycoprotein and to cardiolipin (markers of antiphospholipid syndrome) (n = 4), and heterozygosity for factor V Leiden mutation (n = 1). One child had three abnormalities, two children had two abnormalities, and two children had one abnormality., Conclusions: A prothrombotic tendency may exist in children with AOM complicated by mastoiditis and VST. Further studies are needed to evaluate its extent.

An intrauterine origin of childhood acute lymphoblastic leukaemia (ALL) was proven by the identical clonotypic gene rearrangement in the concordant leukaemias of monozygotic twins, arising from a single clonogenic progeny. The monozygotic twins, presented at the age of 22 months with acute megakaryoblastic leukaemia (AML-M7) in one and myelodysplasia transformed to AML-M7 in the other. Leukaemic cells in both twins carried trisomy 21 and additional different clonal evolution changes of del(20q) in the first twin and trisomy 8 in the second. AML-M7 of late infancy with trisomy 21 may be included in the leukaemias of intrauterine origin, possibly a result of genotoxic insult.