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.

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.

Magnesium homeostasis and hypomagnesemia in children with malignancy.

Hypomagnesemia is not uncommon among children with malignancies. It is especially seen in association with certain medications and can be further complicated by the presence of diarrhea and malnutrition. Severe hypomagnesemia may cause disturbances in the neuromuscular and cardiovascular systems. All patients with hypomagnesemia should be supplemented with the mineral, and urgent treatment is indicated when serum magnesium decreases below 1.0 mg/dl, a level under which symptoms may develop. This review addresses the essentials of magnesium physiology, and pathophysiology of hypomagnesemia, its etiologies, clinical manifestations and ways to treat it, with an emphasis on the child with hematologic/oncologic disorders.

The correlation between dose of folinic acid and neurotoxicity in children and adolescents treated for osteosarcoma with high-dose methotrexate (HDMTX): a neuropsychological and psychosocial study.

BACKGROUND: This study has been performed to examine the currently used doses of folinic acid (FA) and to determine the importance of the dose of FA in preventing subtle neurotoxicity. Thirty osteosarcoma patients were an appropriate population studied as they have no intrinsic neurological involvement. The neuropsychological and psychosocial status was tested in 2 groups of patients treated with similar protocols containing repeated doses of high-dose methotrexate, but different doses of FA. The patients received 300 to 600 mg/m or 120 to 250 mg/m FA in their protocols. METHODS: Eighteen tests or subtests of neuropsychological assessment were tested. RESULTS: Eleven of 18 tests were significant at the P=0.025 level favoring the group treated with high dose of FA. There were no clear results in the psychosocial measures with only a single measure of self-esteem (understanding) being significantly higher (P=0.024) in the group treated with high dose of FA, other measures had no statistical significance. CONCLUSIONS: A correlation between a higher dose of FA after high-dose methotrexate and a better neuropsychological status was clearly shown. The doses of FA used in the low FA group, 120 to 250 mg/m, were similar to those used by several groups treating children with leukemia; some have used even lower doses and report gross neurotoxicity.

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.

Detection of anti-neutrophil antibodies in autoimmune neutropenia of infancy: a multicenter study.

BACKGROUND: Autoimmune neutropenia of infancy is caused by neutrophil-specific autoantibodies. Primary AIN is characterized by neutrophil count < 500 ml and a benign self-limiting course. Detecting specific antibodies against the polymorphic human neutrophil antigen usually confirms the diagnosis. Current available tests, however, are expensive and inapplicable in many laboratories as they require the use of isolated and fixed granulocytes obtained from donors pretyped for their distinct HNA alloform. OBJECTIVES: To assess the performance of a modified test to identify by FACS-analysis granulocyte-specific antibodies in the sera of neutropenic children. METHODS: We evaluated 120 children with a clinical suspicion of AIN, whose sera were analyzed by flow cytometry for the presence of autoantibodies using the indirect granulocyte immunofluorescence test. In contrast to the traditional tests, the sera were tested against randomly selected untyped neutrophils derived from a batch of 10 anonymous healthy subjects, presumably including the common HNA alloforms. Control sera samples were from patients with chemotherapy-induced, familial or congenital neutropenias. To further assure the quality of the new test, we retested six samples previously tested by the gold standard method. All medical files were screened and clinical outcomes were recorded. RESULTS: Our method showed specificity of 85%, sensitivity of 62.5%, and a positive predictive value of 91.8%, values quite similar to those obtained by more traditional methods. CONCLUSIONS: The new method showed high specificity for detection of anti-neutrophil antibodies in the appropriate clinical setting and could be an effective tool for clinical decision making.

Hemostasis and thrombosis in critically ill children.

Patients in the pediatric intensive care unit (PICU) often suffer from a variety of pathophysiologic conditions that are associated with abnormal hemostasis. Bleeding is a major complication of any surgery or trauma, thus patients with inherited or acquired coagulopathies or those experiencing massive trauma or undergoing major (especially cardiac) operations present a special challenge to the ICU experts as well as to the hematologist. Awareness of thromboembolic events in the pediatric population has been increasing in the past few years mainly due to improvement in diagnostic tools, advances in new therapy and procedures, together with an increased index of suspicion. Young infants are at greater risk for either bleeding or thromboembolic events, due to lower concentration of vitamin K-dependent procoagulant clotting factors, reduced thrombin potential, and altered fibrinolytic pathway with low levels of the coagulation inhibitors. The combination of infection, hypotension, acidosis, and release of activated substances, such as tumor necrosis factor, is common after severe trauma or in seriously ill ICU patients and often leads to disseminated intravascular coagulation, which may be complicated either by bleeding or thrombosis. The conditions, risk factors, and therapeutic options available for critically ill PICU patients are discussed in this review.

Combined analysis of morphology and fluorescence in situ hybridization in follow-up of minimal residual disease in a child with Philadelphia-positive acute lymphoblastic leukemia.

The past decade has brought new technologies to the study of minimal residual disease (MRD) in leukemia. Each of them has limitations and is far from being accurate. Recently, a new multiparametric cell scanning system (Duet) was introduced to the field of MRD detection. This system has the advantage of automatically scanning large numbers of cells and performing combined analysis of morphology and fluorescence in situ hybridization (FISH) on the same cell. We used this system to characterize the lineage and degree of maturation of the cells carrying the minor m-BCR/ABL fusion, in a follow-up of an 8-year-old boy with Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL). The boy was treated using a high-risk protocol and was closely monitored with FISH analysis for cells carrying the m-BCR/ABL fusion. Consecutive analysis along 2.5 years from remission showed 0.2-4.5% m-BCR/ALB(+) cells in the peripheral blood (PB), which is within the accepted background range for this method. The combined analysis found that all the m-BCR/ABL(+) cells were mature lymphocytes. Because mature lymphocytes have a long life span in the circulation, this finding supports the fact that the patient is in remission. Moreover, since mature differentiated cells have a low proliferative capacity, there is a low risk for relapse.

Post-splenectomy antibiotic prophylaxis--unfinished story: to treat or not to treat?

Overwhelming infection in asplenic patients is a well documented occurrence in the literature. The introduction of immunization with polyvalent pneumococcal, Hemophilus Influenza and meningococcal vaccines significantly cut down the incidence of post-splenectomy sepsis and mortality. However, the issue of prophylactic antibiotic therapy in these patients remains inconclusive. There are contradictory reports bouncing between life-long treatment to no treatment. There are also more flexible approaches emerging from patient difficulties complying with a prolonged therapy. This debate calls for developing a better predictive approach based on genetic profiling of patients with different susceptibility to infectious pathogens, host-pathogens interactions as well as to identify the impact of factors such as age, on immunological competence.

Prospective evaluation of clinical and laboratory effects of intrathecal chemotherapy on children with acute leukemia.

The objective of this prospective 18-month study was to evaluate the clinical and laboratory effects of repeated intrathecal injections of chemotherapy in children with acute leukemia. All procedures were performed under general anesthesia, and complications were prospectively recorded. Laboratory measurements included lumbar puncture opening pressure, cerebrospinal fluid (CSF) chemistry, and cell count and morphology. Central venous pressure and ophthalmologic examinations were also performed. Forty-seven children underwent 247 intrathecal injections of chemotherapy. Adverse effects (13.7% of the procedures) included nausea and vomiting, back pain, and headache. One child each had transient cauda equina syndrome, transient communicating hydrocephalus, and persistent sacral plexus injury. The mean lumbar puncture opening pressure was significantly higher after intrathecal therapy than before (22 +/- 8 vs. 15 +/- 9 cm H2O, P = 0.02) and higher than reported in age-matched children without leukemia. All CSF chemistries, cell count, and morphology were normal. The overall incidence of complications was 13.7%. Most were mild and resolved quickly, but significant neurologic complications did occur. Lumbar puncture opening pressure was significantly higher in children with acute leukemia after intrathecal chemotherapy.