Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel.

BACKGROUND: Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. OBJECTIVE: To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. METHODS: We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing. RESULTS: Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman-Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation. CONCLUSIONS: The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.

Comparison Between Peripheral and Central Blood Cultures in Pediatric Oncology Patients With Blood Stream Infections.

BACKGROUND: Current guidelines for fever in children with cancer recommend obtaining blood cultures from all lumens of the central venous catheter (CVC) and to consider a concurrent peripheral blood culture. We assessed the characteristics of blood stream infections (BSI) in oncology children and compared central and peripheral pathogen growth. METHODS: A prospective, computerized surveillance of BSI in children treated at the oncology unit between May 2014 and July 2020. The growth of the same organism within a month was considered a single episode, ≥2 organisms in the same culture were defined as different episodes. Only children with concomitant cultures, drawn at presentation before initiation of antibiotics were included in the comparison between CVC and peripheral cultures. RESULTS: A total of 139 episodes in 81 children (with implanted Port-A-catheters) were considered true BSI. Of the 94/139 (67.6%) cases where a central and peripheral culture were concomitantly obtained, 52/94 (55.3%) had positive central/peripheral cultures that grew the same organism, 31/94 (33.0%) had positive central cultures only, and 11/94 (11.7%) had positive peripheral cultures only. In 3/94 cases, the organisms that grew from the CVC were not identical to those from the peripheral site. Four of 52 (7.7%) of the same positive central/peripheral pathogens had different susceptibility testing results. Higher CVC removal rates were observed when both peripheral and CVC cultures were positive ( P =0.044). CONCLUSIONS: Overall, 11.7% of BSI episodes were identified only by peripheral culture and 7.7% of paired organisms did not share the same susceptibility test results which emphasizes the importance of a peripheral culture in managing fever in oncology children.

SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma.

Increased susceptibility to develop severe forms of Epstein-Barr virus (EBV) infection in early age is a significant hallmark of an underlying primary immunodeficiency (PID). Here, we present immunologic and genetic evaluations of a 3-year-old child who was born to first-cousins parents and presented with recurrent infections, failure to thrive, and severe EBV-related infection and proliferation. A diagnosis of diffuse large B cell lymphoma was made and the immunological workup was suggestive of T cell immunodeficiency. Unfortunately, the patient succumbed to EBV-related lymphoma. Whole-exome sequencing revealed a novel homozygous mutation, c.991del.C; p. Q331Sfs*6 in the SLP76 gene. The SLP76 protein, a TCR signaling molecule, was recently linked to a human disease of the immune system. In order to examine the effect of this new SLP76 mutation on T cell signaling, a SLP76-deficient Jurkat-derived T cell line was transduced either with wild-type (WT), or with the specific SLP76 mutant, or with a mock vector. Downstream TCR signaling events, including ERK1/2 phosphorylation, CD69 expression, and Ca2 + mobilization, were reduced in cells harboring the reported mutation, linking this novel mutation to the expected immunological outcome. SLP76 deficiency should be added to the growing list of monogenetic diseases that predispose affected individuals to acquire severe and uncontrolled EBV infections and to develop substantial complications. This case further links mutations in the SLP76 gene to a significant human immunodeficiency and extends its clinical phenotype.

Ethnic and socioeconomic disparities in survival of children and adolescents with CNS tumors in Southern Israel.

Background: This study sought to evaluate survival of pediatric and adolescent patients with central nervous system (CNS) cancer in southern Israel, outline disparities between ethnic and socioeconomic groups (Bedouin Arabs compared to Jews) and evaluate the role of socioeconomic status (SES) in ethnic disparities. Methods: A retrospective study was conducted among 91 patients aged one to 20 years, who were diagnosed with CNS tumors between 2001 and 2017, and followed-up through 2020. Ethnic differences in survival were measured by age, sex, stage, histology and SES. One and 3-year survival rates were calculated. Multivariable regression analysis was used to estimate adjusted ethnic differences in survival rates. Results: Ethnic differences in survival existed within all studied variables. All Bedouin patients lived in low SES settlements (All Bedouin settlement in Southern Israel are ranked in lower socioeconomic deciles). Twenty-eight patients had medulloblastoma. Seven (25%) presented with leptomeningeal disease or distant metastases. Medulloblastoma molecular subgroups were not assessed for logistic reasons. Three-year overall survival of Bedouins was 50% compared to 92.3% for Jews. Adjusted risk of death at 3 years was significantly higher for Bedouin patients (aHR 3.36, 95% CI 1.41-7.98, P = .006). Conclusions: We conclude that Bedouin children with CNS tumors have significantly lower survival rates compared to Jewish children, and SES seems to play a major part in these disparities. Factors influencing these disparities should be addressed and public health interventions to eliminate these disparities should be developed.

Severe Pneumonia Caused by Methicillin-Resistant Staphylococcus pseudintermedius in an Oncology Patient: Case Report and Literature Review.

Staphylococcus pseudintermedius is usually a commensal bacterium of microbiota of dogs and cats that can become pathogenic in these animals. In the past two decades, an increasing number of human infections caused by this pathogen was reported; only two pediatric cases were due to methicillin-susceptible isolates. We describe the first case of methicillin-resistant S. pseudintermedius diagnosed in a 12-year-old immunocompromised girl with refractory anaplastic ependymoma, presented with life-threatening pneumonia and bacteremia. The girl had close contact with her two pet dogs. This case emphasizes that immunocompromised children should be advised on proper handling of household pets to minimize the risk of infection, which could be life threatening.

Factor VII Deficiency in Patients Receiving Chronic Packed Cell Transfusions.

Acquired factor VII deficiency is a rare coagulopathy that has not been reported in transfusion-dependent patients so far. In this study, we reviewed files of 26 transfusion-dependent patients for coagulation profiles, factor V levels, factor VII levels, possible environmental factors influencing factor VII levels, and bleeding history. In 26 of 29 patients (89.6%), we found mild factor VII deficiency (<60%) with levels ranging between 35% and 56%. Bleeding history was unremarkable. We concluded that transfusion-dependent patients may have mild factor VII deficiency with no bleeding tendency under physiologic conditions.

Hepatic and cardiac iron load as determined by MRI T2* in patients with congenital dyserythropoietic anemia type I.

Iron overload comprises one of the main complications of congenital dyserythropoietic anemia type I (CDA-I). When analyzing magnetic resonance imaging T2* (MRI T2*) results in CDA patients, two previous studies reported discordant results regarding iron load in these patients. To further understand iron loading pattern in this group of patients, we analyzed MRI T2* findings in 46 CDA-I patients. Mild to moderate hepatic iron overload was detected in 28/46 (60.8%) patients. A significant correlation was found between serum ferritin and liver iron concentration (LIC). A significant correlation (p value = 0.02) was also found between the patient's age and LIC, reflecting increased iron loading over time, even in the absence of transfusion therapy. Notably, no cardiac iron overload was detected in any patient. Transfusion-naive patients had better LIC and better cardiac T2* values. These results demonstrate that a high percentage of CDA-I patients have liver iron concentration above the normal values, risking them with significant morbidity and mortality, and emphasize the importance of periodic MRI T2* studies for direct assessment of tissue iron concentration in these patients, taking age and transfusional burden into consideration.

Treatment of transfusion-dependent congenital dyserythropoietic anemia Type I patients with pegylated interferon alpha-2a.

OBJECTIVE: Pegylated IFN-α2a has been reported in two case reports as being efficacious in treating CDA-I patients. This study aims to assess its efficacy on a series of CDA-I patients. METHODS: Study sample consisted of seven CDA type 1 transfusion-dependent patients. They received pegylated interferon alpha-2a at an initial dose of 90-180 µg once a week, tapered according to clinical response and side effects. Good response was defined as Hb ≥ 10 g/dL for ≥3 months, partial response was defined as 7 ≤ Hb<10 g/dL for ≥3 months, and no response was defined as HB < 7 g/dL for over 3 months on treatment. Time to response was defined as the time needed to achieve hemoglobin levels ≥ 10 g/dL without transfusion. Patients were evaluated periodically by abdominal ultrasounds to rule out liver adenomas. RESULTS: Five patients (71%) had a good response to treatment. One patient stopped treatment due to side effects. One patient had partial response. One patient, with more severe phenotype and poor compliance, had poor response to treatment. No abnormal findings were found in ultrasound examination. No effect on serum ferritin level could be established. CONCLUSION: Pegylated interferon α2a therapy is efficacious in CDA-I patients with a reasonable safety profile.