Erythrocytosis is a rare disorder characterized by increased red cell mass and elevated hemoglobin concentration and hematocrit. Several genetic variants have been identified as causes for ...erythrocytosis in genes belonging to different pathways including oxygen sensing, erythropoiesis and oxygen transport. However, despite clinical investigation and screening for these mutations, the cause of disease cannot be found in a considerable number of patients, who are classified as having idiopathic erythrocytosis. In this study, we developed a targeted next-generation sequencing panel encompassing the exonic regions of 21 genes from relevant pathways (~79 Kb) and sequenced 125 patients with idiopathic erythrocytosis. The panel effectively screened 97% of coding regions of these genes, with an average coverage of 450×. It identified 51 different rare variants, all leading to alterations of protein sequence, with 57 out of 125 cases (45.6%) having at least one of these variants. Ten of these were known erythrocytosis-causing variants, which had been missed following existing diagnostic algorithms. Twenty-two were novel variants in erythrocytosis-associated genes (EGLN1, EPAS1, VHL, BPGM, JAK2, SH2B3) and in novel genes included in the panel (e.g. EPO, EGLN2, HIF3A, OS9), some with a high likelihood of functionality, for which future segregation, functional and replication studies will be useful to provide further evidence for causality. The rest were classified as polymorphisms. Overall, these results demonstrate the benefits of using a gene panel rather than existing methods in which focused genetic screening is performed depending on biochemical measurements: the gene panel improves diagnostic accuracy and provides the opportunity for discovery of novel variants.
Reference intervals for laboratory test results have to be appropriate for the population in which they are used to be clinically useful. While sex and age are established partitioning criteria, ...patients' origin also influences laboratory test results, but is not commonly considered when creating or applying reference intervals. In the German population, stratification for ethnicity is rarely performed, and no ethnicity-specific hematology reference intervals have been reported yet. In this retrospective study, we investigated whether specific reference intervals are warranted for the numerically largest group of non-German descent, individuals originating from Turkey. To this end, we analyzed 1,314,754 test results from 167,294 patients from six German centers. Using a name-based algorithm, 1.9% of patients were identified as originating from Turkey, in line with census data and the algorithm's sensitivity. Reference intervals and their confidence intervals were calculated using an indirect data mining approach, and Turkish and non-Turkish reference limits overlapped completely or partially in nearly all analytes, regardless of age and sex, and only 5/144 (3.5%) subgroups' reference limits showed no overlap. We therefore conclude that the current practice of using common reference intervals is appropriate and allows correct clinical decision-making in patients originating from Turkey.
Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia ...vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation. We report here that JAK2V617F-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 × 10−16; essential thrombocythemia, n = 78, P = 8.2 × 10−9 and myelofibrosis, n = 41, P = 8.0 × 10−5). Furthermore, JAK2V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2V617F-associated MPNs (OR = 3.7; 95% CI = 3.1-4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Iron deficiency anemia has a high prevalence in children and has repeatedly been implicated as a risk factor for arterial and venous thrombosis. As an effective therapy for iron deficiency anemia is ...available, understanding the association between this form of anemia and the potentially severe thrombosis phenotype is of major clinical interest. Recent findings shed light on pathophysiology of hypercoagulability resulting from iron-restricted erythropoiesis. Specifically, an animal model of induced iron deficiency allowed identifying multiple mechanisms, by which iron deficiency anemia results in increased thrombus formation and thrombus progression both in arterial and venous thrombosis. These findings complement and support conclusions derived from clinical data. The purpose of this mini review is to summarize current evidence on the association of iron deficiency anemia and thrombosis. We want to increase the awareness of iron deficiency as a risk factor for thrombosis in the pediatric population. We discuss how novel pathophysiological concepts can be translated into the clinical settings and suggest clinical studies on prevention and treatment strategies in high-risk patient groups.
Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile ...charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity.
We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC's photometric method.
We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems.
The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.
We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and ...all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin (THPO): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family. Both mutations result in a lack of THPO in the patients' serum. For the 2 surviving patients, improvement in trilineage hematopoiesis was achieved following treatment with a THPO receptor agonist. These studies demonstrate that biallelic loss-of-function mutations in THPO cause BMF, which is unresponsive to transplant due to a hematopoietic cell-extrinsic mechanism. These studies provide further support for the critical role of the MPL-THPO pathway in hematopoiesis and highlight the importance of accurate genetic diagnosis to inform treatment decisions for BMF.
•Germ line biallelic loss-of-function THPO mutations cause BMF.•Marrow failure due to THPO mutations is characterized by poor graft function after transplantation but responds to THPO receptor agonists.
This monocentric study conducted at the Pediatric and Adult Hemoglobinopathy Outpatient Units of the University Hospital of Essen summarizes the results of hemoglobinopathies diagnosed between August ...2018 and September 2021, prior to the introduction of a general newborn screening (NBS) for SCD in Germany (October 2021). In total, 339 patients (pts.), 182 pediatric 50.5% males (92/182) and 157 adult pts. 75.8% females (119/157) were diagnosed by molecular analysis. The most common (parental) descent among affected pts. were the Middle Eastern and North African/Turkey (Turkey: 19.8%, Syria: 11.8%, and Iraq: 5.9%), and the sub-Saharan African region (21.3%). Median age at diagnosis in pediatric carriers N = 157; 54.1% males (85/157) was 6.2 yrs. (range 1 (months) mos.-17.8 yrs.) and 31 yrs. (range 18-65 yrs.) in adults N = 53; 75.2% females (115/153). Median age at diagnosis of homozygous or compound-heterozygous disease in pediatric pts. (72% (18/25) females) was 3.7 yrs., range 4 mos.-17 yrs. (HbSS (N = 13): 2.5 yrs., range 5 mos.-7.8 yrs.; HbS/C disease (N = 5): 8 yrs., range 1-8 yrs.; homozygous/compound heterozygous β-thalassemia (N = 5): 8 yrs., range 3-13 yrs.), in contrast to HbH disease (N = 5): 18 yrs. (median), range 12-40 yrs. Hemoglobinopathies represent a relevant health problem in Germany due to immigration and late diagnosis of second/third generation migrants. SCD-NBS will accelerate diagnosis and might result in reduction of disease-associated morbidity. However, diagnosis of carriers and/or disease-states (i.e. thalassemic syndromes) in newly immigrated and undiagnosed patients will further be delayed. A first major step has been taken, but further steps are required.
The course of sickle cell disease (SCD) is modified by polymorphisms boosting fetal hemoglobin (HbF) synthesis. However, it has remained an open question how these polymorphisms affect patients who ...are treated with the HbF-inducing drug hydroxyurea/ hydroxycarbamide. The German SCD registry offers the opportunity to answer this question, because >90% of patients are treated according to national guidelines recommending the use of hydroxyurea in all patients above 2 years of age. We analyzed the modifying effect of HbF-related genetic polymorphisms in 417 patients with homozygous SCD >2 years old who received hydroxyurea. HbF levels were correlated with higher total hemoglobin levels, lower rates of hemolysis, a lower frequency of painful crises and of red blood cell transfusions. The minor alleles of the polymorphisms in the γ-globin promoter (rs7482144), BCL11A (rs1427407) and HMIP (rs66650371) were strongly associated with increased HbF levels. However, these associations did not translate into lower frequencies of vaso-occlusive events which did not differ between patients either carrying or not carrying the HMIP and BCL11A polymorphisms. Patients on hydroxyurea carrying the γ-globin promoter polymorphism demonstrated substantially higher hemoglobin levels (P<10-4) but also higher frequencies of painful crises and hospitalizations (P<0.01) when compared to patients without this polymorphism. Taken together, these data indicate that the γ-globin, HMIP and BCL11A polymorphisms correlate with increased HbF in SCD patients on hydroxyurea. While HbF is negatively correlated with the frequency of painful crises and hospitalizations, this was not observed for the presence of known HbF-boosting alleles.
Introduction: Pearson syndrome (PS) was originally reported as a sideroblastic anemia in infancy with vacuolization of marrow precursors and exocrine pancreas dysfunction. It is now recognized as a ...fatal multisystem mitochondrial disorder caused by single mitochondrial DNA deletions (SLSMDs) presenting with anemia. PS, Kearns-Sayre Syndrome (KSS) and progressive external ophthalmoplegia (PEO) form a continuous spectrum of disease associated with SLSMDs. There have been only a few systematic studies on PS.
Methods: We retrospectively reviewed hematological features and clinical course of 25 children with PS diagnosed between 1987 and 2019.
Results: Patients presented with normo/macrocytic transfusion-dependent anemia (n=25), failure to thrive (n=3), diarrhea (n=1), acidosis (n=1) and/or omphalocele/esophageal atresia (n=1) at a median age of 5 (0-31) months. A median hemoglobin, platelet count and neutrophil count were 6.5 (1.9-9.8) g/dl, 104 (31-300) G/L, and 0.9 (0.1-2.4) G/L, respectively. Bone marrow (n=24) was normo- (n=15) or hypocellular (n=9). Vacuoles in erythroid and myeloid precursors were observed in all patients, but ring sideroblasts were present in only 16 of 23 patients examined. Morphology can resemble Diamond-Blackfan anemia (DBA) because of erythroid hypoplasia (15/21). Dysplastic features are often observed including micromegakaryocytes. Lactic acid was elevated in most patients examined (14/18). Exocrine pancreas insufficiency at diagnosis was documented in 5 patients only. The detection of SLSMDs confirmed the diagnosis of PS in all patients.
The median age at the time of the last follow-up was 47 (7 - 183) months. Among 11 patients with hematological follow-up for more than 3 years after diagnosis, 8 had spontaneous resolution of anemia at a median age of 28 (12-67) months, and 3 died at the age of 3, 6 or 8 years without hematological recovery. Clinical course was highly heterogeneous and various organ dysfunctions appeared. Renal tubulopathy/Fanconi syndrome (n=7) and cardiomyopathy/arrhythmia (n=5) were often fatal complications which developed at the median age of 32 and 45 months, respectively. Failure to thrive/short stature (n=13) and muscle hypotonia (n=9) were commonly observed. Other complications included pancreas insufficiency (n=7), liver dysfunction (n=4), endocrine dysfunctions (n=7), hearing loss (n=1), ophthalmoplegia (n=1), retinitis pigmentosa (n=1), cataract (n=1), ataxia (n=2) and encephalopathy (n=1). Thirteen patients died of acute metabolic acidosis with/without other complications (n=7), arrhythmia (n=2), respiratory failure (n=3) and liver/renal failure (n=1) at the median age of 50 (14-183) months. Two patients developed KSS and PEO-like phenotypes at the age 92 months and 19 months, respectively.
Summary: Anemia is generally the only presenting syndrome of PS. While the bone marrow morphology can resemble DBA or myelodysplastic syndrome, recognition of vacuolated myeloid/erythroid precursors lead to the correct diagnosis of PS in all cases. Other classical signs of PS, ring-sideroblasts and pancreas insufficiency, are often missing. Anemia spontaneously resolves in most patients surviving early childhood. However, PS is unexceptionally fatal (Figure), most patients succumb to metabolic acidosis and various forms of multi-organ failure. Since there is no effective therapy, the diagnosis of PS is one of the saddest news that pediatric hematologists have to break to parents of an anemic infant.
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Niemeyer:Celgene: Consultancy.
Introduction/Objectives
Fertility preservation is a major concern for adolescent cancer patients; yet, educational gaps remain. Our intervention study examined whether specially designed educational ...materials regarding fertility preservation increase knowledge and empowerment of patients and parents.
Methods
Eleven paediatric‐oncological centres in four European countries agreed to enrol all eligible patients and parents in a questionnaire survey at 3 and 6 months after diagnosis. Treating physicians were surveyed on their medical consultation regarding fertility.
Results
Educational intervention increased knowledge in both patients (n = 113 and n = 101 in the control and intervention groups, respectively) and parents (n = 111 and n = 99 in the control and intervention groups, respectively), but the difference did not achieve statistical significance (knowledge difference patients: 5.6% (t0)/13.1% (t1); parents: 6.4% (t0)/3.8% (t1)). Parents of older patients (OR = 1.3, 95%CI = 1.1‐1.7) and higher educational groups (OR = 6.2, 95%CI = 2.1‐18.3) in the intervention group (OR = 1.9, 95%CI = 1.03‐3.7) achieved higher knowledge levels. Empowerment was significantly improved in both patients (p = 0.046, d = 0.27) and parents (p = 0.046, d = 0.48) in the intervention group.
Discussion/Conclusions
In our study, the use of specifically prepared flyers and brochures successfully raised the level of fertility preservation knowledge in parents of older patients as well as parents with higher educational levels. Overall, the intervention improved patient and parent empowerment. Subsequent projects will include simpler information and digital material to particularly reach out to younger and less educated individuals.
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