Severe congenital neutropenia (Kostmann Syndrome)

Severe congenital neutropenia (SCN), Kostmann syndrome is a heterogenous disorder of myelopoiesis characterized by severe chronic neutropenia, absolute neutrophil count (ANC) persistently below 0.50 x 109/L, with maturation arrest of neutrophil precursors in the bone marrow; and associated with serious recurrent bacterial infections from early infancy. Sepsis mortality is reduced by an advent of granulocyte colony stimulating factor (G-CSF) therapy. More than 90% of patients respond to G-CSF therapy. However, hematopoietic stem cell transplantation has shown promise in the treatment of non-responders. About 60-80% of SCN cases are associated with constitutive mutations in one copy of the gene encoding neutrophil elastase ELA2. Myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported. The hazard of MDS/AML increases significantly overtime. Approximately 10% of patients with severe congenital neutropenia develop AML. This is not thought to be the direct result of G-CSF therapy but related to the underlying disease itself.Key Words: Myeloid leukemia, congenital neutropenia, kostmann’s syndrome, myelodysplastic syndrome

Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Jeddah, Kingdom of Saudi Arabia

International audienceABSTRACT: BACKGROUND: The development of polymerase chain reaction (PCR)-based methods for the detection of known mutations has facilitated detecting specific red blood cell (RBC) enzyme deficiencies. We carried out a study on glucose-6-phosphate dehydrogenase (G6PD) deficient subjects in Jeddah to evaluate the molecular characteristics of this enzyme deficiency and the frequency of nucleotide1311 and IVS-XI-93 polymorphisms in the glucose-6-phosphate dehydrogenase gene. RESULTS: A total of 1584 unrelated Saudis (984 neonates and 600 adults) were screened for glucose-6-phosphate dehydrogenase deficiency. The prevalence of glucose-6-phosphate dehydrogenase deficiency was 6.9% (n=110). G6PD Mediterranean mutation was observed in 98 (89.1%) cases, G6PD Aures in 11 (10.0%) cases, and G6PD Chatham in 1 (0.9%) case. None of the samples showed G6PD A mutation. Samples from 29 deficient subjects (25 males and 4 females) were examined for polymorphism. The association of two polymorphisms of exon/intron 11 (c.1311T/IVS XI 93C) was observed in 14 (42.4%) of 33 chromosomes studied. This association was found in 9 (31.0%) carriers of G6PD Mediterranean and in 4 (13.8%) carriers of G6PD Aures. CONCLUSIONS: The majority of mutations were G6PD Mediterranean, followed by G6PD Aures and <1% G6PD Chatham. We conclude that 1311T is a frequent polymorphism in subjects with G6PD Mediterranean and Aures variants in Jeddah

Prevalence and molecular characterization of Glucose-6-Phosphate dehydrogenase deficient variants among the Kurdish population of Northern Iraq

<p>Abstract</p> <p>Background</p> <p>Glucose-6-Phosphate dehydrogenase (G6PD) is a key enzyme of the pentose monophosphate pathway, and its deficiency is the most common inherited enzymopathy worldwide. G6PD deficiency is common among Iraqis, including those of the Kurdish ethnic group, however no study of significance has ever addressed the molecular basis of this disorder in this population. The aim of this study is to determine the prevalence of this enzymopathy and its molecular basis among Iraqi Kurds.</p> <p>Methods</p> <p>A total of 580 healthy male Kurdish Iraqis randomly selected from a main regional premarital screening center in Northern Iraq were screened for G6PD deficiency using methemoglobin reduction test. The results were confirmed by quantitative enzyme assay for the cases that showed G6PD deficiency. DNA analysis was performed on 115 G6PD deficient subjects, 50 from the premarital screening group and 65 unrelated Kurdish male patients with documented acute hemolytic episodes due to G6PD deficiency. Analysis was performed using polymerase chain reaction/restriction fragment length polymorphism for five deficient molecular variants, namely G6PD Mediterranean (563 C→T), G6PD Chatham (1003 G→A), G6PD A- (202 G→A), G6PD Aures (143 T→C) and G6PD Cosenza (1376 G→C), as well as the silent 1311 (C→T) mutation.</p> <p>Results</p> <p>Among 580 random Iraqi male Kurds, 63 (10.9%) had documented G6PD deficiency. Molecular studies performed on a total of 115 G6PD deficient males revealed that 101 (87.8%) had the G6PD Mediterranean variant and 10 (8.7%) had the G6PD Chatham variant. No cases of G6PD A-, G6PD Aures or G6PD Cosenza were identified, leaving 4 cases (3.5%) uncharacterized. Further molecular screening revealed that the silent mutation 1311 was present in 93/95 of the Mediterranean and 1/10 of the Chatham cases.</p> <p>Conclusions</p> <p>The current study revealed a high prevalence of G6PD deficiency among Iraqi Kurdish population of Northern Iraq with most cases being due to the G6PD Mediterranean and Chatham variants. These results are similar to those reported from neighboring Iran and Turkey and to lesser extent other Mediterranean countries.</p

Molecular characterization of glucose-6-phosphate dehydrogenase deficient variants in Baghdad city - Iraq

Background: Although G6PD deficiency is the most common genetically determined blood disorder among Iraqis, its molecular basis has only recently been studied among the Kurds in North Iraq, while studies focusing on Arabs in other parts of Iraq are still absent. Methods: A total of 1810 apparently healthy adult male blood donors were randomly recruited from the national blood transfusion center in Baghdad. They were classified into G6PD deficient and non-deficient individuals based on the results of methemoglobin reduction test (MHRT), with confirmation of deficiency by subsequent enzyme assays. DNA from deficient individuals was studied using a polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) for four deficient molecular variants, namely G6PD Mediterranean (563 C®T), Chatham (1003 G®A), A- (202 G®A) and Aures (143 T®C). A subset of those with the Mediterranean variant, were further investigated for the 1311 (C®T) silent mutation. Results: G6PD deficiency was detected in 109 of the 1810 screened male individuals (6.0%). Among 101 G6PD deficient males molecularly studied, the Mediterranean mutation was detected in 75 cases (74.3%), G6PD Chatham in 5 cases (5.0%), G6PD A- in two cases (2.0%), and G6PD Aures in none. The 1311 silent mutation was detected in 48 out of the 51 G6PD deficient males with the Mediterranean variant studied (94.1%). Conclusions: Three polymorphic variants namely: the Mediterranean, Chatham and A-, constituted more than 80% of G6PD deficient variants among males in Baghdad. Iraq. This observation is to some extent comparable to othe

Saudi SCD patients’ symptoms and quality of life relative to the number of ED visits

Background Individuals living with sickle cell disease (SCD) have significantly increased emergency department (ED) use compared to the general population. In Saudi Arabia, health care is free for all individuals and therefore has no bearing on increased ED visits. However, little is known about the relationship between quality of life (QoL) and frequency of acute care utilization in this patient population. Methods A cross-sectional study was conducted on 366 patients with SCD who attended the outpatient department at King Fahad Hospital, Hofuf, Saudi Arabia. Data were collected through self-administered surveys, which included: demographics, SCD-related ED visits, clinical issues, and QoL levels. We assessed the ED use by asking for the number of SCD-related ED visits within a 6-month period. Results The self-report survey of ED visits was completed by 308 SCD patients. The median number of SCD-related ED visits within a 6-month time period (IQR) was four (2-7 visits). According to the unadjusted negative binomial model, the rate of SCD-related ED visits increased by (46, 39.3, 40, and 53.5 %) for patients with fever, skin redness with itching, swelling, and blood transfusion, respectively. Poor QoL tends to increase the rate of SCD-related ED visits. Well education and poor general health positively influenced the rate of SCD-related ED visits. Well education tends to increase the rate of SCD-related ED visits by 50.2 %. The rate of SCD-related ED visits decreased by 1.4 % for every point increase in general health. Conclusion Saudi patients with sickle cell disease reported a wide range of SCD-related ED visits. It was estimated that six of 10 SCD patients had at least three ED visits within a 6-month period. Well education and poor general health resulted in an increase in the rate of SCD-related ED visits

Lifetime cost-utility analyses of deferasirox in beta-thalassaemia patients with chronic iron overload: A UK perspective

Background and objectivesRegular blood transfusions for beta-thalassaemia patients lead to the accumulation of iron deposits in the body. In order to remove such deposits, iron chelation therapy is required. Subcutaneously administered deferoxamine has been the gold standard chelation therapy for over 40 years. Deferasirox is a newer chelation therapy that is taken orally once daily. The objective of this study was to estimate the long-term costs and quality-adjusted life-years (QALYs) associated with deferoxamine and deferasirox in a cohort of transfusion-dependent beta-thalassaemia patients from a UK health service perspective.MethodsA 50-year annual cycle state transition model comprised three core health states: alive without cardiac complications, alive with cardiac complications, and dead, as well as representing other chronic complications of iron overload: diabetes, hypogonadism, hypoparathyroidism and hypothyroidism. The model was calibrated to identify sets of convergent input parameter values that predicted observed overall survival by mean lifetime compliance with chelation therapy. A pivotal non-inferiority trial informed the main estimates of the effectiveness of deferasirox, which were applied to the calibrated model. Using cost values for the year 2011, costs and utilities were summed over patients' lifetimes to estimate lifetime costs and QALY gains.ResultsMean lifetime treatment costs for patients receiving deferoxamine were £70,000 higher than deferasirox. Drug acquisition costs were £100,000 higher for deferasirox, but administration costs associated with deferoxamine were £170,000 higher. Higher compliance associated with oral deferasirox administration led to fewer complications. Combined with the quality-of-life effects of an oral mode of administration, an average gain of 4.85 QALYs for deferasirox was estimated. In the base case, deferasirox dominates deferoxamine, i.e., costs less and patients gain more QALYs. The key parameter is the proportion of deferoxamine patients using balloon infusers. Sensitivity analyses showed that even when the proportion of patients using balloon infusers is decreased from 79 to 25 %, the incremental cost per QALY gained remains well under £20,000.ConclusionHigher drug acquisition costs for deferasirox are offset by the avoidance of infusion-related equipment costs. Combined with health benefits derived from an oral mode of administration and improved compliance, deferasirox has a high probability of being a cost-effective intervention compared with deferoxamine.Jonathan Karnon, Keith Tolley, Joao Vieira, David Chandiwan

Perioperative care of children with sickle cell disease: a systematic review and clinical recommendations.

Children with sickle cell disease (SCD) require specific perioperative care, and clinical practice in this area remains poorly defined. We aimed to a) conduct a systematic, PRISMA-based review of the literature and any available clinical guidelines, practice recommendations, and extract any valuable information for the "best of available-evidence"-based prevention of perioperative adverse events in children with SCD, b) highlight the most urgent priorities in clinical research. As data sources, US National Library of Medicine, Medline, National Guideline Clearinghouse, International Guideline Network, TRIP databases were searched for any content until January 2019. We also included institutional, consortia and expert group guidelines. Included were reports/guidelines in English, French, German, Italian. Excluded were reports on obstetrical and fetal management. We identified 202 reports/guidelines fulfilling the criteria outlined above. A majority focused on visceral, cardiovascular and orthopedic surgery procedures, and only five were multicenter randomized controlled trials and two prospective randomized studies. After grading of quality of evidence, the extracted data was summarized into clinical recommendations for daily practice. Additionally, we designed a risk-grading algorithm to identify contexts likely to be associated with adverse outcomes. In conclusion, we provide a systematic PRISMA-based review of the existing literature and any ancillary practice and delineate a set of clinical recommendations and priorities for research. This article is protected by copyright. All rights reserved