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.

Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population.

Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hundred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no significant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and follow-up programs.

Craniofacial Deformities in Patients With Beta-Thalassemia: Orthodontic Versus Surgical Correction-A Systematic Review.

Rapid blood cell turnover and bone marrow expansion caused by beta-thalassemia (ßT) result in craniofacial and dentoalveolar anomalies. This report presents a systematic review of the literature over the past 50 years on orthodontic and surgical considerations in the management of ßT-affected patients. Seventeen publications encompassed 24 patients, 11 male individuals and 13 female individuals, 7 to 43 years of age. Eleven patients underwent only surgical treatment, eleven combined orthodontic-surgical treatment, and 2 orthodontic treatment. Surgical treatment primarily addressed typical maxillary overgrowth by maxillary reshaping, premaxillary segmental repositioning, or complete Le Fort I impaction and set back osteotomy. In severe maxilla-mandibular discrepancy and/or increased lower facial height, a bilateral sagittal split mandibular osteotomy is the treatment of choice. Although surgery involves risks of excessive bleeding, morbidity, and impaired nasal esthetics, little attention is given to the orthodontic modality. In conclusion, the current literature recommends early interceptive orthodontics aimed to decrease dentoskeletal deformities, severe malocclusion, and soft tissue imbalance. Treatment includes maxillo-mandibular orthopedic and functional manipulation with dentoalveolar treatment, which might either prevent orthosurgical procedures later or reduce its extent. This suggested a multidisciplinary approach comprising a hematologist, a pediatrician, a pediatric dentist, and an orthodontist, which might also significantly improve the patient's quality of life.

Targeted next generation sequencing for the diagnosis of patients with rare congenital anemias.

BACKGROUND: Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes. OBJECTIVE: We aimed to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing. METHODS: Genetic diagnosis was performed by gene capture followed by next-generation sequencing of 76 genes known to cause anemia syndromes. RESULTS: Genetic diagnosis was achieved in 13 out of 21 patients (62%). Six patients were diagnosed with pyruvate kinase deficiency, 4 with dehydrated hereditary stomatocytosis, 2 with sideroblastic anemia, and 1 with CDA type IV. Eight novel mutations were found. In 7 patients, the genetic diagnosis differed from the pretest presumed diagnosis. The mean lag time from presentation to diagnosis was over 13 years. CONCLUSIONS: Targeted next-generation sequencing led to an accurate diagnosis in over 60% of patients with rare anemias. These patients do not need further diagnostic workup. Earlier incorporation of this method into the workup of patients with congenital anemia may improve patients' care and enable genetic counseling.

Syncytial variant of nodular sclerosing Hodgkin lymphoma in children: A prognostic factor?

Nodular sclerosing Hodgkin lymphoma (HL) has an excellent prognosis in children. The syncytial variant (SV) of HL in adults represents a clinic pathologic entity with a worse outcome. We report the clinical features and the course of the disease of three children with refractory HL. The three patients with SV were analyzed in a retrospective multi-institutional study conducted in Israel in 51 children diagnosed with refractory or recurrent HL between 1997 and 2014. All the three children developed multiple recurrences soon after diagnosis. All three received at least three different chemotherapy combinations with autologous bone marrow transplantation for two patients, allogenic bone marrow transplantation in one, and immunotherapy in one. One patient died of disease, one is in complete response of the disease but developed a second metastatic malignancy, and one is alive without disease. This retrospective study shows that SV histology may be a prognostic factor for poor outcome in children diagnosed with HL.

Surgical Treatment of Neuroblastoma.

BACKGROUND: Neuroblastoma is the most common non-central nervous system (CNS) solid malignant tumor in children. The surgical treatment of high-risk neuroblastoma presents a challenge, and the benefits of aggressive surgical resection have been called into question. OBJECTIVES: To examine our experience with surgical resection of neuroblastoma. METHODS: We report on a retrospective chart review of our preliminary surgical experience in 25 patients with neuroblastoma who underwent surgery performed by a single surgeon at two institutions over a 3 year period. Demographic data, including stage of tumor and risk stratification, were recorded. Primary outcome was total gross resection. Patients were followed for 3 years after surgery. RESULTS: We found that 80% of the patients, including those with high-risk neuroblastoma tumors, had total gross resection of their tumor with minimal operative morbidity and no mortality; 88% had greater than 90% resection of their tumor. Overall, 3 year survival was 84% (21/25). CONCLUSIONS: Resection of neuroblastoma, even large, high-risk, bilateral tumors, was possible when performed by surgical teams with considerable experience.

Quantitation of bleeding symptoms in a national registry of patients with inherited platelet disorders.

BACKGROUND: Inherited platelet deficiency and/or dysfunction may be more common in the general population than has previously been appreciated. In 2013 the Israeli Inherited Platelet Disorder (IPD) Registry was established. METHODS: Clinical and laboratory data were collected to pre-specified registration forms. The study protocol was approved by the local hospital ethics committees. RESULTS: To date we have included in the registry 89 patients (male 52%) from 79 families. Most patients (74%) have a not-yet specified inherited thrombocytopenia (n=39) or non-specific platelet function disorder (n=27). Full clinical data were available for 81 (91%) patients. The median (range) age at presentation and time of follow-up were 1.8years (1day-17.8years) and 4.7 (0-26) years, respectively. The Pediatric Bleeding Questionnaire was available for 78patients; abnormal bleeding score (≥2) was recorded in 47 (52.8%, 95% CI 42%-63.5%) patients and was less frequent in patients followed for isolated thrombocytopenia. Abnormal score was associated with a longer time of follow-up, OR 1.19 (95% CI 1.04-1.36). CONCLUSION: Long term follow-up of patients with IPDs is important as bleeding risks may increase with time. We expect that clinical and laboratory information of patients/families with IPDs gathered in a systemic format will allow for better diagnosis and treatment of these patients.

Orthodontic Consideration in Patients with Beta-Thalassemia Major: Case Report and Literature Review.

OBJECTIVE: Beta Thalassemia (ßT) patients present a unique facial appearance and specific craniofacial, jaw and dental patterns. Although this anomaly often requires orthodontic management, ßT patients have received scant attention in the orthodontic and dental literature over the past 50 years. The aim of this article is to review the characteristic craniofacial and dental manifestation pattern of ßT patients and to emphasize their preferred orthodontic management protocol by presenting a ßT orthodontic treated patient. CASE REPORT: A 10 year old patient presented with a complaint of severe esthetic and functional disorders due to her diagnosis of ßT. We initiated orthodontic treatment including a combined orthopedic and functional treatment modality to improve facial appearance. RESULTS: Maxillary restraint and increased mandibular size during treatment along with an increase in the vertical dimension were achieved. The patient presented with Angle class I molar relationship, with reduction of the excessive overjet and deep overbite. CONCLUSION: Orthodontic treatment comprised of maxillary orthopedic treatment directed especially toward premaxilla with light forces, and mandibular modification by functional appliance along with fixed orthodontic treatment is recommended in ßT patients.

'Becoming a Physician'-medical students get acquainted with disadvantaged populations, and practise sensitive and effective communication.

BACKGROUND: The three-year pre-medical programme 'Becoming a Physician' focuses on different aspects of medical professionalism. Objectives are to increase awareness and sensitivity to disadvantaged populations, and practise sensitive effective communication skills. METHODS: The curriculum includes: (1) Visits to treatment centres for people with special needs, mental illnesses, substance abuse issues, physically or sexually abused, and prisoners. Students tour the facility, hold discussions with residents, and discuss ethical professional interrelations to the medical world. Students then write 'reflective diaries' summarizing their thoughts and emotions. (2) Participation in a communication course that focuses on learning by practising patient-oriented communication. Qualitative data were collected from three sources: reflective diaries, students' course evaluations, and interviews with the students' tutors. RESULTS: Data indicated that the students were very satisfied with the programme. They indicated an increase in awareness of the special needs of diverse populations, and in the sense of efficacy for conducting interviews tailored to patients' needs. Tutors reported a sense of 'personal growth' following their role as mentors. REFLECTIONS: Interactions of medical students with diverse populations, when accompanied by appropriate feedback mechanisms and strengthening of communication skills, can improve awareness and sensitivity to patients' special needs. This could help students become more sensitive and thoughtful physicians.

Genetic analysis and clinical picture of severe congenital neutropenia in Israel.

BACKGROUND: The relative frequency of mutated genes among patients with severe congenital neutropenia (SCN) may differ between various ethnic groups. To date, few population-based genetic studies have been reported. This study describes the genetic analysis of 32 Israeli patients with SCN. PROCEDURES: Clinical data were retrieved from the prospective Israeli Inherited Bone Marrow Failure Registry. Recruitment included living and deceased patients who were diagnosed between 1982 and 2012, for whom molecular diagnosis was performed. ELANE, HAX1 and G6PC3 genes were sequenced in all patients, and GFI-1 and WAS genes were sequenced if other genes were wildtype. RESULTS: Eleven patients (34%) had heterozygous mutations in ELANE (10 kindreds), eight (25%) had homozygous mutations in G6PC3 (5 kindreds) and 13 (41%) had no detected mutations. No patients had mutations in HAX1 or WAS. Four of the eight patients with G6PC3 mutations had congenital anomalies. The probability of survival for all patients was 50% at age of 18. Deaths were mainly due to sepsis (5 patients, 4/5 not responding to G-CSF, none with G6PC3 mutation). Two patients developed acute myelogenous leukemia (AML) and one myelodysplastic syndrome (MDS), none with G6PC3 mutation. CONCLUSIONS: We found a unique pattern of SCN mutations in Israel with homozygous G6PC3 mutations in eight (25%) patients, the highest frequency described so far. HAX1 mutations, reported mainly in Sweden and Iran, were absent. Patients with G6PC3 mutations had congenital anomalies, appeared to have a better response to G-CSF, and so far have not developed AML or MDS.

Mycobacterium phocaicum bacteremia: an emerging infection in pediatric hematology-oncology patients.

Nontuberculous mycobacteria may cause central venous catheter-associated bacteremia. Between March 2011 and October 2013, 6 cases of Mycobacterium phocaicum bacteremia were found in the pediatric hematology-oncology department. All patients recovered. No positive blood culture was documented after removal of the central venous catheter. All 4 patients with pulsed field gel electrophoresis had the same pattern, different from the water sample, suggesting a common water source.

Characterizing bone marrow involvement in Hodgkin's lymphoma by FDG-PET/CT.

PURPOSE: Fluoro-deoxyglucose positron emmission tomography combined with computed tomography (FDG-PET/CT) is superior to iliac bone marrow biopsy (iBMB) for detection of bone marrow involvement (BMI) in staging of Hodgkin's lymphoma (HL). The present study aims to characterize the patterns and distribution of BMI in HL as determined by FDG-PET/CT. METHODS: Reports of FDG-PET/CT studies performed for staging of HL were reviewed. BMI was defined as positive iBMB and/or foci of pathological FDG uptake in the skeleton that behaved in concordance with other sites of lymphoma in studies following chemotherapy. Number of FDG uptake foci, their specific location in the skeleton and the presence of corresponding lesions in the CT component of the study, and stage according to the Ann Arbor staging system, were recorded. RESULTS: The study included 473 patients. iBMB was performed in 336 patients. Nine patients had positive iBMB (9/336, 3%). Seventy-three patients (73/473, 15%) had FDG-PET/CT-defined BMI. The BM was the only extranodal site of HL in 52/473 patients (11 %). Forty-five patients had three or more foci of pathological skeletal FDG uptake (45/73, 62 %). Sixty-four patients (64/73, 88%) had at least one uptake focus in the pelvis or vertebrae. In 60 patients (60/73, 82%), the number of skeletal FDG uptake foci without corresponding CT lesions was equal to or higher than the number of foci with morphological abnormalities. CONCLUSION: FDG-PET/CT demonstrated BMI in 15% of patients with newly diagnosed HL. Diagnosis of BMI in HL by FDG-PET/CT was more sensitive than iBMB with potential upstage in 11% of patients. The most common pattern of FDG-PET/CT BMI was multifocal (at least three foci) skeletal FDG uptake, with at least one focus in the pelvis or vertebrae and no corresponding CT lesions.

Targeted therapy with low doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma.

BACKGROUND: Palliative treatment ore remains a significant clinical problem. OBJECTIVES: To retrospectively determine the clinical response to 131I-MIBG therapy at low doses in patients with refractory neuroblastoma. METHODS: We performed a retrospective chart review of 10 patients with neuroblastoma treated with 1311-MIBG at Rambam Health Care Campus from 1994 to 2012. Clinical data, number of 131I-MIBG courses delivered, toxicities, and clinical responses were reviewed. MIBG scan was performed after each course. RESULTS: Twenty-one courses of 131I-MIBG were delivered to 10 patients (3 girls, 7 boys). Their mean age was 3.8 years (range 1.5-6 years). All patients received several protocols of chemotherapy including the high dose form. Three patients received three courses of 131I-MIBG with a minimum of 6 weeks between each course, five patients received two courses, and two patients received only one course. An objective response to the first course was obtained in nine patients and to the second course in six of eight, and in three children who underwent the third course the pain decreased. One patient has no evidence of disease, four are alive with disease, and five died of the disease. No unanticipated toxicities were observed. CONCLUSIONS: Low dose 131I-MIBG is an effective and relatively non-toxic treatment in neuroblastoma disease palliation. Rapid and reproducible pain relief with 131I-MIBG was obtained in most of the children. Treatment with systemic radiotherapy in the form of low dose 131I-MIBG was easy to perform and effective in cases of disseminated neuroblastoma, demonstrating that this primary therapy can be used for palliative purposes.

Early interim FDG PET/CT prediction of treatment response and prognosis in pediatric Hodgkin disease-added value of low-dose CT.

BACKGROUND: Interim 18F-FDG PET helps predict outcome and tailor treatment in adults with Hodgkin disease (HD). OBJECTIVE: The purpose of this study was to assess predictive values of interim 18F-FDG PET/CT in children with HD and to define the potential added value to interim PET of low-dose CT. MATERIALS AND METHODS: Children were prospectively enrolled August 2002-April 2007. PET/low-dose CT was performed at staging, after 2 cycles, at the end of treatment and during follow-up (mean 45 months). Treatment was unchanged regardless of interim results. PET and low-dose CT were read independently. RESULTS: Of 34 enrolled children (ages 3-17 years), 27 achieved complete response, 4 had progressive disease and 3 had relapse. Interim PET alone had positive and negative predictive values of 67% and 89%, respectively. Interim low-dose CT alone had positive and negative predictive values of 35% and 100%, respectively. Interim PET/CT had positive and negative predictive values of 75% and 96%, respectively. CONCLUSIONS: Early interim PET/CT was a good predictor of outcome. Integrated PET and low-dose CT improved the predictive value in children with HD.

Treatment of T cell lymphoblastic lymphoma in children and adolescents: Israel Society of Pediatric Hematology Oncology retrospective study.

BACKGROUND: Survival in T cell lymphoblastic lymphoma has improved over the past 30 years, largely due to treatment protocols derived from regimens designed for children with acute lymphoblastic leukemia. OBJECTIVES: To assess the outcome of the NHL-BFM-95 protocol in children and adolescents hospitalized during the period 1999-2006. METHODS: We conducted a retrospective multi-institutional, non-randomized study of children and adolescents up to age 21 with T cell lymphoma admitted to pediatric departments in six hospitals in Israel, with regard to prevalence, clinical characteristics, pathological characteristics, prognostic factors, overall survival (OS) and event-free survival (EFS). All patients had a minimal follow-up of one year after diagnosis. The study was based on the NHL-BFM-95 protocol. RESULTS: At a median follow-up of 4 years (range 1-9 years), OS and EFS for all patients was 86.5% and 83.8%, respectively. OS was 86.7% and 83.3% for patients with stage III and stage IV, respectively, and EFS was 83.3% and 83.3%, respectively. EFS was 62.5% for Arab patients and 89.7% for Jewish patients (P = 0.014). Patients who did not express CD45 antigen showed superior survival (P = 0.028). Five patients (13.5%) relapsed, four of whom died of their disease. Death as a consequence of therapy toxicity was documented in one patient while on the re-induction protocol (protocol IIA). CONCLUSIONS: Our study shows that OS and EFS for all patients was 86.5% and 83.8%, respectively.

An outbreak of Mycobacterium mucogenicum bacteremia in pediatric hematology-oncology patients.

BACKGROUND AND AIMS: Mycobacterium mucogenicum (MM) is a rapidly growing nontuberculous mycobacterium that is commonly identified in tap water that can rarely cause bacteremia. We describe an outbreak of MM bacteremia among pediatric hematology-oncology patients. METHODS: Charts of children with MM bacteremia were retrospectively reviewed. Demographic data, underlying conditions, central venous catheter (CVC) type, duration of bacteremia, and treatment were retrieved. Epidemiologic investigation was conducted during the outbreak including environmental sampling. RESULTS: During an 8-month period (September 2005-May 2006), 8 patients aged 1.5 to 17 years had MM bacteremia. Seven patients had underlying malignancy and 1 with thalassemia major had bone marrow transplantation. The mean number of positive blood cultures was 4.2 (1-11) per patient. Two patients received antibiotic treatment in addition to removal of CVC. All patients were cured. Almost 60 environmental samples were obtained from surfaces, ice, and municipal water supply. All were negative and no source was documented. Infection control measures included emphasis on guidelines for prevention of CVC-associated infections. No cases occurred before and after this outbreak. CONCLUSIONS: MM is a rare agent of CVC-associated bacteremia. Removal of the CVC may be sufficient for management of bacteremia. In the absence of definite source identification, reinforcement of standard infection control measures can be successful in containing outbreaks.

Delayed spontaneous remission in a child with primary acquired chronic pure red cell aplasia.

The acquired form of pure red cell aplasia (PRCA) presents either as an acute self-limited disease, predominantly seen in children, or as a chronic illness more frequently seen in adults with rare spontaneous remissions. A 14-year-old boy presented with pallor, without hepatosplenomegaly, jaundice, lymphadenopathy, petechiae, or any other apparent abnormalities. Isolated anemia in the presence of normal white cell and platelet counts with a marrow of normal cellularity and absence of erythroblasts but normal myeloid cells and megakaryocytes revealed the diagnosis of PRCA. All possible investigations excluded secondary causes of PRCA. The patient required packed red cell transfusions every 2 to 3 weeks. He failed therapy with intravenous immunoglobulin, corticosteroids, cyclosporine A plus corticosteroids, antithymocyte globulin, anti-CD 20 (rituximab), and erythropoietin (EPO). He showed a severe, resistant, and transfusion-dependent PRCA. Spontaneous remission with normal hemoglobin and reticulocyte levels was dramatic 6.5 years after the diagnosis of PRCA and 3.6 years after his last treatment.

Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry.

BACKGROUND: Inherited bone marrow failure syndromes are rare genetic disorders characterized by bone marrow failure, congenital anomalies, and cancer predisposition. Available single disease registries provide reliable information regarding natural history, efficacy and side effects of treatments, and contribute to the discovery of the causative genes. However, these registries could not shed light on the true incidence of the various syndromes. We, therefore, established an Israeli national registry in order to investigate the relative frequency of each of these syndromes and their complications. DESIGN AND METHODS: Patients were registered by their hematologists in all 16 medical centers in Israel. We included patients with Fanconi anemia, severe congenital neutropenia, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii. RESULTS: One hundred and twenty-seven patients diagnosed between 1966 and 2007 were registered. Fifty-two percent were found to have Fanconi anemia, 17% severe congenital neutropenia, 14% Diamond-Blackfan anemia, 6% congenital amegakaryocytic thrombocytopenia, 5% dyskeratosis congenita, 2% Shwachman-Diamond syndrome, and 2% thrombocytopenia with absent radii. No specific diagnosis was made in only 2 patients. Of the thirty patients (24%) developing severe bone marrow failure, 80% had Fanconi anemia. Seven of 9 patients with leukemia had Fanconi anemia, as did all 6 with solid tumors. Thirty-four patients died from their disease; 25 (74%) had Fanconi anemia and 6 (17%) had severe congenital neutropenia. CONCLUSIONS: This is the first comprehensive population-based study evaluating the incidence and complications of the different inherited bone marrow failure syndromes. By far the most common disease was Fanconi anemia, followed by severe congenital neutropenia and Diamond-Blackfan anemia. Fanconi anemia carried the worst prognosis, with severe bone marrow failure and cancer susceptibility. Diamond-Blackfan anemia had the best prognosis. The data presented provide a rational basis for prevention programs and longitudinal surveillance of the complications of inherited bone marrow failure syndromes.