Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants - identification of 11 novel mutations in CYBB.

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910 , X91- or X91+ ), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910 -CGD and two X91- -CGD). One X910 -CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91- -CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91- -CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91- -CGD patients correlates with mild clinical forms of CGD, whereas X910 -CGD and X91+ -CGD cases remain the most clinically severe forms.

Effectiveness of antibacterial prophylaxis in children with acute leukemia: A report from a single institution over a 20-year period.

BACKGROUND: Infection is the major cause of treatment-related mortality in childhood acute leukemia, mainly due to bacterial translocation across the intestinal mucosa. Only a few studies have reported the impact of different antibacterial prophylaxis treatments on digestive tract flora and infection-related mortality. PROCEDURES: We performed a retrospective analysis of two different digestive tract decontamination modalities (selective or total digestive decontamination) in a large single-center series of 323 children during the induction treatment of acute leukemia between January 1995 and December 2014. We examined the impact of antibiotic prophylaxis and food regimen (sterile or selected) on the digestive tract flora during the period of antibacterial prophylaxis, on the frequency of bacteremia, and on antibiotic sensitivity. RESULTS: Only one Gram-negative (Klebsiella pneumonia) translocation occurred in the SDD group. No infection-related death occurred. Extended-spectrum beta-lactamase (ESBL) bacteria were observed in seven of 170 (4%) patients in the SDD group. The faecal-flora total suppression and faecal-flora Gram-negative bacilli suppression was 67 and 77%, respectively, in the TDD group with sterile food, 0 and 58%, respectively, in the SDD group with sterile food, and 6 and 63%, respectively, in the SDD group with selective food. CONCLUSIONS: This study gives a rationale not to use antibacterial prophylaxis systematically in children who receive induction treatment for acute leukemia; additionally, antibiotics should only be used in case of stool contamination by highly pathogenic bacteria with a high potential of translocation.

Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?

Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.

[Good's syndrome and congenital toxoplasmosis due to maternal reactivation during pregnancy]. / Syndrome de Good et toxoplasmose congénitale secondaire à une réactivation maternelle pendant la grossesse.

INTRODUCTION: Good syndrome is a rare condition in which thymoma is associated with hypogammaglobulinemia. It is characterized by an increased susceptibility to infections. CASE REPORT: We report a woman with Good's syndrome diagnosed after severe congenital toxoplasmosis in her daughter, even though she was immunized against this infection during pregnancy. CONCLUSION: This presentation is very unusual by its early diagnosis and to our knowledge is the first report of parasitic infection in this syndrome.

[Treatment of febrile neutropenia episodes in children, with a piperacillin-tazobactam and netilmicin combination]. / Traitement des épisodes de neutropénie fébrile chimio-induite de l'enfant par l'association pipéracilline-tazobactam et nétilmicine.

OBJECTIVES: The authors had for aim to assess the effectiveness and toxicity of a piperacillin-tazobactam-netilmicin combination, and the possibility of avoiding using glycopeptide, in children with febrile neutropenic episodes induced by chemotherapy. METHODS: A retrospective study was made, including children treated for a febrile neutropenic episode (absolute neutrophile count < 0.5 x 10(9)/l) by a piperacillin-tazobactam-netilmicin combination. If fever persisted 48 hours after the beginning of antibiotic therapy, a glycopeptide could be added. The responses to the treatment were defined as follows: 1) total success (no fever or documented infection) at 48 hours and at 72 hours following the beginning of treatment; 2) partial success (apyrexia beyond 72 hours without any therapeutic change); 3) failure (persistent infectious signs 48 hours after the introduction of glycopeptide). RESULTS: Sixty-nine episodes were assessable, corresponding to 41 patients, treated for a solid tumour (29), an acute leukaemia in remission (11), or a metabolic disease (1). The febrile episodes were divided into fever of unknown origin (71%), microbiologically documented fever (12%), and clinically documented fever (17%). No death occurred, no toxicity was reported. With this antibiotic therapy, total success at 72 hours was observed in 72% in case of fever of unknown origin and 45% in case of documented infections. The success rate reached 84% when a glycopeptide was added (30% of the cases). CONCLUSION: The piperacillin-tazobactam-netilmicin combination is very effective and well tolerated in probabilistic treatment of febrile neutropenia induced by chemotherapy, but does not allow to decreasing the frequency of glycopeptide administration.