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1
Gaggiano, Carla, Donato Rigante, Antonio Vitale, Orso Maria Lucherini, Alessandra Fabbiani, Giovanna Capozio, Chiara Marzo, et al. "Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases." Mediators of Inflammation 2019 (December 31, 2019): 1–29. http://dx.doi.org/10.1155/2019/3293145.
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Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.
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Spinner, Michael A., Lauren A. Sanchez, Amy P. Hsu, Pamela A. Shaw, Christa S. Zerbe, Katherine R. Calvo, Diane C. Arthur, et al. "GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity." Blood 123, no. 6 (February 6, 2014): 809–21. http://dx.doi.org/10.1182/blood-2013-07-515528.
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Abstract Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.
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Das, Reena, Manu Jamwal, Anu Aggarwal, Prashant Sharma, Arindam Maitra, Deepak Bansal, and Pankaj Malhotra. "Phenotype-Genotype Spectrum of Stomatocytic Disorders Encountered in India Using Next Generation Sequencing." Blood 132, Supplement 1 (November 29, 2018): 2326. http://dx.doi.org/10.1182/blood-2018-99-114554.
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Abstract Introduction Stomatocytes in peripheral blood are pathognomonic findings in multiple conditions along with hemolysis and reticulocytosis, often suggestive of erythrocyte membrane transport defects. These uncommon disorders are usually difficult to diagnose due to a wide range of overlapping phenotypes and a perception of stomatocytes being artefacts. Genes involved in these disorders are multiple (RHAG,SLC4A1, ABCG5, ABCG8, PIEZO1,KCNN4, ABCB6, SLC2A1 etc) rendering Sanger sequencing costly and labor intensive. Phenotypes vary from transfusion-dependent anemia to compensated hemolysis. Methods Seventeen patients were encountered in 12 families and enrolled in this study. Majority of the cases showed the presence of significant numbers of red blood cells showing stomatocytes with or without thrombocytopenia. Various hematological, biochemical and molecular tests were used to exclude thalassemia syndromes and hemoglobinopathies, glucose-6-phosphate dehydrogenase (G6PD) deficiency, autoimmune hemolytic anemia, hereditary spherocytosis (HS) and pyruvate kinase deficiency. Genomic DNA was extracted by the QIAamp DNA Blood Midi Kit and quantified on NanoDrop 2000 spectrophotometer and QubitFluorometer. DNA libraries were prepared using Illumina's custom panels (TruSight One Sequencing Panel and TruSeq Custom Amplicon v1.5) and sequenced on a MiSeq Sequencing System. MiSeq Reporter and VariantStudio were used for analysis, classification, and reporting of variants. Variants which were predicted pathogenic by in silico analysis using PolyPhen-2, SIFT, PROVEAN (http://provean.jcvi.org/), Mutpred (http://mutpred.mutdb.org/) and Human Splicing Finder as indicated, were subjected to Sanger sequencing in the patient and family members (where available). Results Of these 17 patients, 10 patients in 6 families were diagnosed to have Mediterranean stomatocytosis/ macrothrombocytopenia. All had the presence of stomatocytes along with macrothrombocytopenia, short stature, continuous abdominal discomfort and marked pleiotropic effects in different cases. This is a syndromic form of stomatocytosis and defects in ABCG5/ABCG8 genes were found and showed an autosomal recessive inheritance pattern. One case did not show any mutation. This number of cases suggests that this disorder is not rare in India and is probably underdiagnosed as patients have mild or moderate anemia and are often misdiagnosed as cases with HS. One of the patients also had coinheritance of G6PD deficiency (G6PD Kerela Kalyan). Patients with Mediterranean stomatocytosis/macrothrombocytopenia are advised to take sterol-absorption inhibitor 'ezetimibe' to reduce sterol accumulation. We also found 2 unrelated patients with stomatocytosis, reticulocytosis and splenomegaly with overhydrated hereditary stomatocytosis (OHSt) and pathogenic mutation in RHAG gene was found in both of them. The pattern of inheritance is sporadic or autosomal dominant. Splenectomy was deferred in a patient with OHSt as postsplenectomy thrombotic complications are known to occur and is contraindicated. Four patients in 3 families were found to have mutations in PIEZO1 gene which translates to red cell membrane mechanosensitive cation channel protein, causing xerocytosis/dehydrated hereditary stomatocytosis and 3 patients had severe anemia and were transfusion dependent. One patient showed the presence of stomatocytes and macrothrombocytopenia was found to have probably disease causing variant in SLC2A1 gene. She was incidentally undergoing treatment for infertility when the stomatocytosis was noted. Conclusions Stomatocytic disorders appear to be underdiagnosed in India which is compounded by the protean clinical manifestations, milder phenotypes, low index of suspicion and non-availability of molecular confirmation. Astute phenotype characterization is critical as it will help in establishing the causality of the variants identified and appropriate genetic counseling. Recently NGS for hemolytic anemias has led to rapid molecular characterization and accurate phenotypic correlation. Disclosures No relevant conflicts of interest to declare.
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Sabio, Hernan, Natalia Dixon, Ferdane Kutlar, Niren Patel, Hanfang Zhang, Lina Zhuang, and Abdullah Kutlar. "Homozygous Expression of a Novel Senegalese-Type Partial Deletion of the Beta and Delta Genes Causes a Delta0 Beta+ Thalassemia." Blood 120, no. 21 (November 16, 2012): 2128. http://dx.doi.org/10.1182/blood.v120.21.2128.2128.
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Abstract Abstract 2128 Clinical phenotype in β-thalassemia syndromes is determined by the degree of chain imbalance. An increase in γ-globin production will compensate for the absent or deficient β-globin synthesis and will result in the amelioration of the chain imbalance, and hence an improvement in clinical features. The known genotypes of δβ-thalassemia are associated with an increase in Hb F production, which results in the amelioration of the clinical presentation. Most δβ-thalassemias result from deletions that remove the δ- and β-globin genes, (δβ)0 with a compensatory increase in γ-globin (Hb F) expression. We report an unusual case of homozygous δ0β+ thalassemia that provides interesting insights into increased γ-globin expression and the regulation of β-globin gene expression. An 8-year old boy of African ancestry presented with lifelong jaundice and pallor. He also experienced episodes of worsening symptoms. He exhibited frontal bossing, pale mucosa, scleral icterus, and moderate splenomegaly. He was known to have G6PD deficiency and was suspected of having additional erythrocyte pathology. The CBC revealed a Hb of 8.7, Hct 26.4, MCV 64.7, WBC 10,700, platelets 283,000, reticulocytes 2.2%, and total bilirubin 5.3. Hemoglobin analysis by HPLC and IEF revealed HbA 13.4%, Hb F 86.6%, and no additional components. Alpha thalassemia −3.7kb deletion was not detected. Globin chain analysis revealed α, β, Gγ and AγI chains. DNA analysis revealed a novel Senegalese-type deletion of the beta and delta genes, resulting in a delta0 beta+ thalassemia. The subject's parents who were both from the same small village in Niger had normal hematology values. Their hemoglobin analyses revealed Hb A 94. 8%, Hb A2 2.0%, Hb F 3.2% and Hb A 93.5%, Hb A2 2.1%, Hb F 4.5% in the father and mother, respectively. They were both heterozygous for the delta-beta deletion identified in their son. DNA analysis revealed a breakpoint in the delta gene at nucleotides 54755–54760 and a breakpoint in the beta gene at nucleotides 62153– 62158 [GenBank Ref ID: HUMHBB] with a 5 nucleotide “CAACA” bp region overlapping area. The subject, who is homozygous for the identified deletions, has a clinical phenotype of thalassemia intermedia. He has not yet required red cell transfusions. This is the first instance of a Senegalese-type deletion occurring in the homozygous state. The genotype provides insights into regulation of globin gene expression. While the ∼7 Kb deletion in the δβ-intergenic region may be responsible for the increased expression of the γ-globin gene similar to Hb Lepore deletions, the continued low level expression of the β-globin gene is most probably the result of the juxtaposition of the inefficient δ-globin promoter brought in the vicinity of the β-globin gene. Disclosures: No relevant conflicts of interest to declare.
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Bernaudin, Francoise, Cecile Arnaud, Annie Kamdem, Elodie Fauveau, Anne Le Roux, Nadia Medejel, Isabelle Hau, Fouad Madhi, Ketty Lee, and Christophe Delacourt. "Prevalence and Risk Factors of Elevated Tricuspid Regurgitant Jet Velocity in Children with Sickle Cell Disease: Association with Age, Hemolysis, Oxygen Saturation and CD36 Deficiency." Blood 114, no. 22 (November 20, 2009): 1536. http://dx.doi.org/10.1182/blood.v114.22.1536.1536.
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Abstract Abstract 1536 Poster Board I-559 Background Pulmonary hypertension (PHT) is a widely recognized complication of sickle cell disease (SCD). It affects 32% of adults with SCD and is associated with an increased risk for early mortality. Screening of children with SCD by Doppler echocardiography has been recommended, using tricuspid regurgitant jet velocity (TRJV) to estimate pulmonary artery systolic pressure. However, the prevalence and risk factors of elevated TRJV in children with SCD at steady state have not been extensively defined. Methods SCD patients of the CHIC-cohort were prospectively assessed : alpha and beta genotype, G6PD, platelet-CD36 expression were determined; baseline blood parameters between 1 and 3 years of age were recorded and re-assessed every year at steady state with clinical data, TCD screening, abdominal sonography and every two years by Doppler echocardiography, evaluation of lung function and cerebral MRI/MRA. Pulmonary hypertension was defined as a TRJV ≥2.5 m/s. Univariate and multivariate logistic regression analyses were performed to evaluate risk factors for elevated TRJV. Results A total of 662 echocardiograms with available measure of TRJV were performed away from vaso-occlusive crises (VOC) and acute chest syndromes (ACS) in 320 SCD-patients (268 SS, 1 SDPunjab, 7 Sb0; 14 Sb+, 30 SC) between 12/98 and 07/09 and were included in the analyzes: 127/662 were performed in patients on hydroxurea (HU) therapy, 121 on transfusion program (TP) and 63 after stem cell transplantation (SCT). In SS/Sb0 patients, TRJV did not correlate with fractional shortening, ejection fraction, TCD velocities, systemic and diastolic blood pressure, cumulative number of VOC and ACS, LDH and SpO2, but correlated with age (r=0.258,p<0.001), height (SD) (r=-0.119, p=0.008), Hct (r=-0.091, p=0.028), MCV (r=0.109, p=0.009) and bilirubin (r=0.235, p<0.001). Elevated TRJV ≥2.5 m/s was found in 5/44 SC/Sb+ (11%) at the mean age of 12.6 ± 2.1 yr and in 57/276 SS/Sb0 (21%) (p=NS) at the mean age of 12.6 ± 4.5 yr (range 3.5-20). Univariate logistic regression analysis of the data from SS/Sb0 patients showed no significant association between elevated TRJV ≥2.5 m/s and the following variables: gender, alpha-thalassemia, G6PD deficiency, height and weight (SD), baseline blood parameters (recorded between 1 and 3 years of age), systolic/diastolic -blood pressure, cardiac rate, WBC and platelet count, HbF%, LDH, AST/ALT, history of abnormal TCD, overt and silent strokes and ongoing HU therapy and TP or a history of SCT. In contrast, CD36 deficiency (OR=4.55;CI95%:1.73-11.97,p=0.002), age (OR=1.087;CI95%:1.03-1.15,p=0.005), low SpO2 (OR=1.17;CI95%:1.05-1.32,p=0.005), Hb (OR=1.27;CI95%:1.07-1.51,p=0.007), high MCV (OR=1.03; CI95%: 1.01-1.05, p=0.008) and total bilirubin (OR=1.008; CI95%:1.002-1.014,p=0.006) were significantly associated with TRJV ≥2.5 m/s. After adjustment for age, SpO2, Hb, MCV, total bilirubin and CD36 deficiency remained significant risk factors. Conclusion In this pediatric cohort, early assessed by TCD and transfused in case of abnormal occurrence, no association was found between cerebral vasculopathy and elevated TRJV, which could be the result of early initiation of transfusion programs as soon as TCD became abnormal. The data also confirm the link between pulmonary hypertension, low oxygen saturation and hemolysis, previously reported by others. In addition, we show for the first time that CD36 deficiency is a risk factor for elevated TRJV in SCD patients. CD36 deficiency has been shown to be a common occurrence in subjects of African descent. The CD36 scavenger receptor is a multifunctional receptor, which is expressed on the surface of various cell types, and is involved in immunity, metabolism and angiogenesis. Previous studies suggested that CD36 deficiency did not modify the clinical course of SCD patients but echocardiograms had not been analyzed. Recent studies showed that hypoxia increases CD36 expression via its HIF-1 responsive promoter element and activation of the PI3K pathway, suggesting that CD36 deficient SCD patients could have an abnormal response to hypoxia. Additional studies will be needed to understand the relationship between PHT and CD36 deficiency and the role of hypoxia in these patients. Disclosures No relevant conflicts of interest to declare.
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Garçon, Loïc, Gérard Tertian, Audrey Boutron, Françoise Driss, Stéphane Giraudier, William Vainchenker, Michel Goossens, Frederic Galacteros, Gil Tchernia, and Claude Préhu. "A Somatic Mutation in the G6PD Gene in Hematopoietic Cells Causes a Chronic Haemolytic Anemia." Blood 114, no. 22 (November 20, 2009): 4033. http://dx.doi.org/10.1182/blood.v114.22.4033.4033.
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Abstract Abstract 4033 Poster Board III-969 G6PD deficiency is the more common human enzyme defect, leading typically to an acute intravascular hemolysis occurring when red cells are exposed to an oxidative stress. However, in rare patients, very low enzymatic level induces the class I G6PD deficiency according to the WHO classification, i.e. a chronic non-spherocytic hemolytic anemia. These cases are all sporadic, occur worldwide, and almost all arise from de novo independent mutations. These mutations are found at the genomic level in both hematopoietic and non hematopoietic cells and occur recurrently in “hot spots”: most of them are located in the exon 10 of the G6PD gene, implicated in the dimer formation and the stability of the active enzyme. No null or frameshift mutations have been reported yet, probably because such mutations would be lethal; indeed, a minimal residual G6PD activity is essential during embryogenesis. We report here the case of 65 years-old Caucasian man referred in 1993 for hemolytic anemia. No personal or familial history of anemia was noted. Nine and five years before, the hemoglobin (Hb) level and the mean corpuscular volume (MCV) were normal. At diagnosis, the anemia was moderate (Hb: 11.9 g/dL), macrocytic (MCV: 104 fL) and regenerative (reticulocyte count: 550G/L) with hemolytic features. Platelets and leucocytes counts were normal. No clinical or ultrasound spleen enlargement was noted. The screening tests ruled out all the classical causes of acquired hemolytic anemia. Red cells half life after Cr51 labelling was shortened with autologous (5 days) but not with allogenous red cells confirming the corpuscular mechanism of the hemolysis. Dosage of erythocyte G6PD activity revealed a very low level (from 0.6 to 1.5 UI/g of Hb, normal range 5.3-7.9). Pyruvate kinase, pyrimidine 5'-nucleotidase and hexokinase enzymatic activities were increased in agreement with the reticulocytosis. With a follow-up of 16 years, evolution was marked by a progressive worsening of the anemia, requiring 8 to 16 packed red cell transfusions per year in parallel with an iron chelation and folic acid therapy. Concomittantly, the macrocytosis increased up to 144 fL. At the molecular level, sequencing of the genomic DNA of the G6PD gene revealed presence of a single nucleotide mutation that altered the IVS 10 nucleotide 1 G>A from donor consensus sequence, leading to an impaired splicing between exon 10 and exon 11. The missplicing creates a premature termination codon giving theorically a truncated protein (464 versus 514 amino-acid). This severe genotype was discordant with the normal hemoglobin level five years before the diagnosis. Moreover, such a mutation at the germinal level would be expected to be lethal; therefore, we hypothesized that it arised at the somatic level in an hematopoietic stem cell; we measured the G6PD activity in hematopoietic and non hematopoietic cells and observed that it was decreased in red cells, polymorphonuclear cells and lymphocytes from blood, but was normal in skin fibroblasts; molecular analysis confirmed that the mutation was present in blood mononuclear cells but was absent in the fibroblasts. Bone marrow CD34+ cells were then sorted and plated at one cell per dish in the presence of a cocktail of cytokines including EPO and the different clones were harvested at day 10 for genomic analysis of the G6PD gene. Out of the 44 tested clones, we found that most of them carried the mutation (61%), but we were still able to detect a few unmutated clones (7%), reflecting the persistence of a minor polyclonal unmutated hematopoiesis. Surprisingly, we detect in the rest of the clones both the normal and mutated genotypes; at this time, we have no clear explanation to this finding. Acquired modifications of structure or expression of genes implicated in red cell physiology have been long recognized, occurring principally in myeloid malignancies such as myelodysplastic syndromes (MDS). This includes genes implicated in the red cell membrane skeleton or in haemoglobin synthesis or structure. However, our patient presented no MDS features on repeated bone marrow examination and on cytogenetic analysis. Regardless to all our data, we concluded that our patient present the first case ever reported of chronic non spherocytic anemia related to an acquired somatic mutation of the G6PD gene at the level of a hematopoietic pluripotent cell. Disclosures: No relevant conflicts of interest to declare.
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Kreins, Alexandra Y., Michael J. Ciancanelli, Satoshi Okada, Xiao-Fei Kong, Noé Ramírez-Alejo, Sara Sebnem Kilic, Jamila El Baghdadi, et al. "Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome." Journal of Experimental Medicine 212, no. 10 (August 24, 2015): 1641–62. http://dx.doi.org/10.1084/jem.20140280.
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Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17+ T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
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Boztug, Kaan, Philip S. Rosenberg, Marie Böhm, Thomas Moulton, Julie Curtin, Nima Rezaei, John Corns, et al. "Extended Molecular and Clinical Phenotype of Human G6PC3 Deficiency." Blood 116, no. 21 (November 19, 2010): 1495. http://dx.doi.org/10.1182/blood.v116.21.1495.1495.
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Abstract Abstract 1495 Severe congenital neutropenia (SCN) is a heterogenous group of disorders characterized by an increased susceptibility to bacterial infections. Recently, our discovery of G6PC3 deficiency in 12 patients with SCN and various developmental features highlighted the role of glucose metabolism in the viability of neutrophil granulocytes. To further delineate the molecular and clinical phenotype of this complex syndrome, we analyzed a second cohort of 23 SCN patients referred to us for molecular analysis of G6PC3 mutations. All patients had at least one syndromic feature in addition to congenital neutropenia such as such as congenital heart defects, urogenital malformations or increased venous marking. Among these 23 patients, we identified 14 patients with biallelic mutations in G6PC3. 10 patients had novel mutations in G6PC3. A comprehensive review of the clinical characteristics of these patients underlined the phenotypic variability of G6PC3 deficiency. In addition to known manifestations including cardiac (14/14) and urogenital malformations such as cryptorchidism (3/14), novel features such as facial dysmorphy (11/14) or malformation of the outer genitalia (4/14) were found. No obvious genotype-phenotype correlations could be established. All patients except one had a good response to treatment with G-CSF characterized by increased peripheral neutrophil counts and decreased frequency and severity of infections. To assess the risk of leukemogenesis, we performed a meta-analysis comparing the 14 G6PC3-deficient SCN patients combined with the 12 patients in the original publication with a cohort of 374 patients SCN patients bearing mutations in ELANE or HAX1, in which 61 developed MDS or AML. The rate of MDS/AML was found to be significantly lower in G6PC3-deficient patients (p=0.02). Our analysis suggests that the risk of transition to MDS/AML may be lower in G6PC3-deficient SCN compared with other genetically defined SCN subgroups. Disclosures: No relevant conflicts of interest to declare.
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Salzer, Ulrich, Chiara Bacchelli, Sylvie Buckridge, Qiang Pan-Hammarström, Stephanie Jennings, Vassilis Lougaris, Astrid Bergbreiter, et al. "Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes." Blood 113, no. 9 (February 26, 2009): 1967–76. http://dx.doi.org/10.1182/blood-2008-02-141937.
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Abstract TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell– specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n = 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n = 41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P <.001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD−CD27+ B cells (P = .019), benign lymphoproliferation (P < .001), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.
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Bhamidipati, Sameera, Venee N. Tubman, Norma Estrada, and Charles Minard. "Unswitched Memory B Cell Deficiency Is Associated with Acute Chest Syndrome and Stroke in Sickle Cell Disease." Blood 134, Supplement_1 (November 13, 2019): 1010. http://dx.doi.org/10.1182/blood-2019-128575.
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Background: The spleen is among the first organs negatively affected by sickle cell disease (SCD). Unswitched memory B cells (UMBCs) from the spleen, including the marginal zone B cells, circulate in peripheral blood and have been used as a measure of splenic function in non-hematologic disorders associated with functional asplenia. UMBC deficiency has been associated with adverse infectious and inflammatory outcomes in models of stroke and cardiovascular disease. The role of UMBCs has not been assessed in pediatric SCD. In this study, we sought to test he hypothesis that low UMBC is associated with significant infectious and inflammatory complications of SCD. Design/Method: Children seen at the Texas Children's Cancer and Hematology Centers from March - December 2018 were recruited for participation. Participants were 18 months -18 years of age. Samples were collected for complete blood count, serum analysis, and B cell subset by flow cytometry. For B cell subset quantification, whole blood samples were stained with fluorescent-labelled CD45, CD19, IgD, and CD27. The samples were analyzed by flow cytometry using the BD LSR Fortessa or LSR II (BD Biosciences, USA). In each sample, at least 2500 CD19+ events were captured. Data were analyzed using FlowJo X.V. Clinical data was abstracted from the electronic medical record into an online study database. Statistical analyses were performed using STATA. This study was approved by the Baylor College of Medicine IRB. Results: We enrolled 234 subjects. Among these, 169 had an evaluable UMBC. Those with UMBC data included 114 (67.4%) Hb SS and Hb S/b0-thalassemia, 14 (8.3%) Hb SC, Hb b+-thalassemia, and HbS/other, and 41 (24.2%) controls without SCD. There was no difference in the mean age at sampling between children with SCD and controls without SCD (8.74 vs 8.39 years, P=0.70). The geometric mean UMBC was 5.75% of all CD19+ (B) cells for controls, 4.24 % for HbSS-like group, and 5.29% for SCD patients with any other genotype. UMBC declined by 2.97% per year among all SCD subjects (P<0.01). UMBC declined 0.82% per year among all controls, although the rate of decline was not significant, P= 0.62). The change per year did not significantly differ between cohorts (P=0.26). To determine whether UMBC is associated with clinical complications of SCD, we reviewed the EMR of 127 subjects to identify any lifetime episodes of acute chest syndrome, bacteremia, blood transfusion, dactylitis, or stroke. Patients with any history of acute chest syndrome had significantly lower UMBC than those who have not had acute chest syndrome (median 4.3 vs. 6.2; P< 0.01). Patients with any history of stroke had significantly lower UMBC than those who have not had stroke (median 2.9 vs. 4.7; P=0.04). No significant difference was detected between groups with and without a history of bacteremia, blood transfusion, or dactylitis. Conclusion: We have demonstrated that children with SCD are deficient in UMBCs and that UMBC deficiency worsens with age. UMBC deficiency is associated with history of acute chest syndrome and stroke. Additional studies are needed to establish the mechanisms of UMBC deficiency and the role of UMBCs in the clinical outcomes for children with SCD. Table Disclosures Tubman: Novartis Pharmceuticals: Honoraria.
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Leung, Lawrence L., Zhifei Shao, Toshihiko Nishimura, Qin Zhou, Laura Gigliello, Peter Castro, John Higgins, and John Morser. "Deficiency of Either Carboxypeptidase B2 or Carboxypeptidase N Exacerbated Disease Activity in a Mouse Model of Hemolytic Uremic Syndrome." Blood 128, no. 22 (December 2, 2016): 3758. http://dx.doi.org/10.1182/blood.v128.22.3758.3758.
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Abstract Two different basic carboxypeptidases circulate in blood - carboxypeptidase N (CPN) and proCPB2. CPN is constitutively active, while proCPB2 is a zymogen, (also termed thrombin activatable fibrinolysis inhibitor, TAFI), and is activated by the endothelial thrombin/thrombomodulin complex to CPB2. Their kinetics of substrate cleavage are distinct but both can efficiently inactivate the complement anaphylatoxins, C3a and C5a. Hemolytic uremic syndrome (HUS) is caused by Shiga toxin (stx) producing strains of E. coli and is characterized by the triad of hemolysis, thrombocytopenia and uremia. We hypothesized that in a mouse model of HUS, Cpb2-/- and Cpn-/- mice would have prolonged C5a anaphylatoxin activity thus causing disease exacerbation. HUS was induced by stx2 and LPS administration in WT, Cpn-/- and Cpb2-/- mice. In Cpb2-/- mice, median time to death was earlier (60 hours, n=15) than in WT mice (96 hours: n=42, p<0.0001), and had greater kidney and liver damage shown by increases in ALT, AST, BUN and creatinine levels at 48 hours (creatinine Cpb2-/-: 1.01 mg/dL, WT: 0.25 mg/dL; Cpb2-/- control: 0.20 mg/dL and WT control: 0.19 mg/dL; Cpb2-/- p<0.0001 vs. all other groups, n>9). An increase in hemolysis was demonstrated by reduced RBC count and hemoglobin level plus an increase in total bilirubin and LDH. Profound thrombocytopenia (Cpb2-/-: 121,000/μL vs. WT: 217,000/μL; p=ns) developed in both genotypes (control Cpb2-/-: 1,001,000/μL vs. control WT: 1,141,000/μL; p=ns but vs. either Cpb2-/- or WT with HUS, p<0.0001) and thus the HUS clinical triad was present. Histology showed tubular epithelial necrosis in the kidney ante-mortem. Administration of either toxin separately caused milder disease without the characteristics of HUS and with no observed mortality. Induction of the disease depended on co-administration of both toxins. Treatment with anti-murine C5 antibody (0.75 mg every 24 hours from 3 hours before disease initiation) improved survival of both WT and Cpb2-/- mice with a median survival time of 168 hours for both genotypes (n=11, p=0.003 and <0.0001 respectively) and normalized the outcomes between the genotypes. Cpn-/- mice also died sooner (median time to survival 81.5 hours, n=28) than WT mice (96 hours, n=42, p=0.0002). The median survival time between Cpb2-/- and Cpn-/- mice was also significantly different (60 vs. 81.5 hours, p=0.0083). This is a first direct comparison of the role of CPN vs. CPB2 in regulating C5a activity in a disease relevant mouse model. Our study suggests that both CPB2 and CPN protect against HUS by inactivation of C5a with CPB2 having a greater effect than CPN. When Cpb2+/-/Cpn+/- mice are crossed, all expected genotypes are recovered in the expected Mendelian ratios including double deficient Cpb2-/-/Cpn-/- mice. Thus absence of both plasma basic carboxypeptidases is not essential for murine life. We are currently evaluating the Cpb2-/-/Cpn-/- mice in our HUS model. Disclosures No relevant conflicts of interest to declare.
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Balta, Gunay, Aytemiz Gurgey, Fatma Gumruk, Yahya Buyukasik, Meral Beksac, and Cigdem Altay. "Pyrimidine 5′ Nucleotidase-1 (P5N-1) Deficiency Associated with 4 Novel Mutations in 5 New Turkish Families: Genotype-Phenotype Analysis." Blood 108, no. 11 (November 16, 2006): 3743. http://dx.doi.org/10.1182/blood.v108.11.3743.3743.
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Abstract In the present study, molecular pathologies of 8 patients from unrelated 4 consanguineous and one non-consanguineous families were characterized; 4 novel and 1 previously reported homozygous mutations were identified in the P5N-1 gene. 1) A frameshift 700–701InsA mutation in exon 9 was identified in a 40 years old patient who has been followed as hereditary spherocytosis (HS) for many years because of marked spherocytes and highly increased osmotic fragility. He underwent splenectomy (11yr) and cholecystectomy (26yr). Afterwards, Hb level stayed between 8.5–11g/dl. Co-existence of Gilbert syndrome 7/7 TATA repeat genotype accounts for very high serum bilirubin level (18–28mg/dl). 2) A splicing mutation (IVS8+1 G>A) was found in a 30 years old patient who was followed as HS due to associated spherocytosis and slightly increased osmotic fragility. She received blood transfusions regularly, underwent splenectomy and cholecystectomy (14yr). Afterwards Hb stayed at 9.6–10.5 g/dl. Co-existence of Gilbert 7/7 genotype accounts for the high bilirubin (15mg/dl). 3) A splicing (IVS7+1 G>A) and a silent (T275C in exon 6) mutations were detected in 2 siblings. Despite non-consanguinity, identification of two homozygous mutations indicated the presence of a common ancestor. The girl received transfusion several times, underwent splenectomy and cholecystectomy(18yr). The boy, diagnosed in family survey (2yr) and underwent splenectomy (10yr), currently has highly increased osmotic fragility. Both had few acanthocytic spherocytes. After splenectomy Hb stayed around 11 gr/dl, bilirubin around 5–6 gr/dl in both. 4) A missense T220C mutation in exon 5 (C74R) was identified in 24 and 21 years old sisters. The elder had iron deficiency anemia and the younger diagnosed in a family survey had retinitis pigmentosa. Hb were around 10g/dl, bilirubin around 2.5–6 mg/dl, few acontocytic spherocytes observed in both. 5) A nonsense T543G mutation (Y181X) in exon 8 was detected in 14 and 7 years old brothers. The mutation was reported previously in another Turkish family, however, haplotype analysis failed to indicate founder effect. The older required blood transfusions while hospitalized several times due to recurrent attacks of cerebral infarcts. Hb fluctuated between 6.5–10 g/dl, bilirubin was around 3 mg/dl. He underwent splenectomy recently (17yr). The younger had iron deficiency anemia, Hb was between 7.2–9.9 gr/dl. Few aconthocytic spherocytes were observed in both. All mutations were screened in at least 100 individuals from a healthy Turkish population and no mutation was detected. In conclusion: 1- The mutation spectrum of P5N-1 gene is quite heterogeneous in Turkish population (7 different mutations in 9 unrelated families so far). 2- P5N-1 deficiency is classified as non-spherocytic hemolytic anemia, however, all patients of this study more or less had spherocyte in the peripheral blood smear. In addition, some patients even had increased erythrocyte osmotic fragility emerging as confounding factor in diagnosis. Taken together, there is a reason to suggest that the possibility of P5N-1 deficiency should be considered in at least some of the patients diagnosed as HS. 3- The co-existence of Gilbert disease could modify the clinical presentation of the disease. This study was supported by Hacettepe University Research Fund (02G116).
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Zakarija, Anaadriana, Hau C. Kwaan, Nicholas Banderanko, Dilip K. Pandey, John F. Cursio, Ivy M. Weiss, Thanh Ha Luu, et al. "Distinct Clinical Syndromes Are Defined by ADAMTS13 Activity in Idiopathic TTP: Results of the SERF-TTP Study." Blood 110, no. 11 (November 16, 2007): 1320. http://dx.doi.org/10.1182/blood.v110.11.1320.1320.
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Abstract Background: The Surveillance, Epidemiology & Risk Factors for TTP (SERF-TTP) study is the largest prospective cohort of idiopathic TTP cases to date. Methods: Patients with first episode of idiopathic TTP were enrolled at 11 sites in the US. Exclusion criteria include solid organ or allogeneic stem cell transplant, anti-neoplastic therapy or malignancy. All patients underwent therapeutic plasma exchange (TPE). Remission is defined as platelet count >150,000/mm3. ADAMTS13 activity was measured by fluorescence resonance energy transfer assay (FRETS-vWF73, Peptides Int.). ADAMTS13 inhibitor was assessed by ELISA (Technozym ADAMTS13 INH ELISA, Technoclone) and functional inhibition of normal ADAMTS13 activity (modified FRETS). Differences between the groups was evaluated by Chi-square test, t-test or Fisher’s exact test. Results: Complete data is available for 57 cases. 84% were female & median age was 42. ADAMTS13 was severely deficient (<10%) in 53%, moderate (10–50%) in 8%, & normal (>50%) in 39%. Adverse events were frequent & most commonly include citrate toxicity and allergic reactions. Long-term followup was available for 56 patients, and overall relapse rate was 25% with median time to relapse of 11 months. The relapse rate was 41% in patients with severe ADAMST13 deficiency & 0% in patients with normal ADAMTS13 activity (p=0.0077). Conclusions: Severe ADAMTS13 deficiency does not define all cases of idiopathic TTP, yet is associated with a unique syndrome characterized by severe thrombocytopenia, normal renal function, presence of ADAMTS13 neutralizing autoantibodies & high risk of relapse. Non-ADAMTS13 deficient idiopathic TTP has clinical features similar to thrombotic microangiopathies associated with stem cell transplant or drugs such as quinine, yet has a better than expected overall survival after TPE. There is likely an alternate disease mechanism for this cohort, possibly immunologic, which may be responsive to TPE and warrants further study. ADAMTS13 < 10% n=30 ADAMTS13 > 50% n=22 p-value * t-test, ** Fisher’s Exact Test, # Chi-Square Test Presenting Labs Hemoglobin (mean) 8.5 9.2 0.22* Platelet count (mean x10^9/L) 19 57 <0.0005* Serum creatinine (mean) 1.33 3.9 0.0012* ADAMTS13 antibody (neutralizing & non-neutralizing) % 100 63.6 0.0004** ADAMTS13 neutralizing antibody % 83 35 .0003# Presenting Symptoms Neurologic symptoms present 45 52.4 0.23# Diarrhea 23 30.4 0.79# Infection 40 43.5 0.79# Past Medical History Connective Tissue Disease % 10 8.5 0.28# Family history of TTP % 0 4.6 0.11# Remission Labs Hemoglobin (mean) 12.2 8.5 0.16* Platelet count (mean x10^9/L)) 169 152 0.15* Serum creatinine (mean) 1.02 3.7 0.0009* Outcomes Therapy-related Adverse events % 71 55 0.24# Time (days) to remission (plt > 150,000) 9.7 9.2 0.89* Early remission (< 8 days) % 73 57 0.20# 30 day Exacerbation rate % 35 28 0.63# 30 day Survival % 96.6 90.0 0.56** Long-term Relapse % 41 0 0.0077**
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Delaporta, Polyxeni, Christalena Sofocleous, Stavros Doudounakis, Marina Economou, Emmanouil Kanavakis, and Antonios Kattamis. "Variable Clinical Phenotype and Course In Greek Patients with Shwachman-Diamond Syndrome Carrying Identical SBDS Mutations." Blood 116, no. 21 (November 19, 2010): 4431. http://dx.doi.org/10.1182/blood.v116.21.4431.4431.
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Abstract Abstract 4431 Introduction-Background: Shwachman-Diamond syndrome (SDS) is a rare multi-system genetic disorder mainly characterized by exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Approximately 90% of patients meeting the clinical diagnostic criteria for SDS have mutations in the SBDS gene, located in chromosome 7q11. No genotype-phenotype correlations have been observed in patients with SDS. Patients and Method: Greek patients with similar SBDS mutations are included in this report. They were selected from the series of patients referred to our unit for SBDS gene molecular analysis due to pancreatic insufficiency and impaired hematopoiesis. Patient 1 presented at birth with respiratory difficulties, hypotonia, anemia, neutropenia and thrombocytopenia. She has congenital anomalies including thoracic dystrophy, digit abnormalities, open foramen ovale and hypertelorism. She was found to have myelodysplasia with a bone marrow clone carrying i(7q) chromosomal abnormality in around 32% of the bone marrow cells. Pancreatic insufficiency was clinically evident even at the age of 5 months. Patient 2 has chronic thrombocytopenia ranging between 40.000/μ L to 147.000/μ L, first presenting at the age of 7 years old. She has metaphyseal dysostosis, flared anterior end of ribs, open foramen ovale and growth hormone deficiency. Her pancreatic insufficiency is present from the age of 16 months. Patient 3 (sister of patient 2) has borderline neutropenia, short stature, metaphyseal dysostosis, open foramen ovale and mild pancreatic insufficiency. Patient 4 has thrombocytopenia since the age of 19 years old. She has stable clonal erythropoesis with a clone carrying the 46,X,del(X)(q24→qter) in 45% of the bone marrow cells. She presents recurrent bacterial infections, particularly bartholinitis. She has mild pancreatic insufficiency. Patient 5 presented with chronic neutropenia and decreaced IgA since the age of 2 months. At the age of 12 months she presented hepatomegaly and elevated liver enzymes. Pancreatic insufficiency initially presented in infancy but improved gradually. Genomic DNA was extracted from peripheral blood lymphocytes and molecular analysis with ECMA (Enzymatic Cleavage Mismatch Analysis), RFLPS and direct sequencing was performed allowing detection and characterization of disease causing mutations. PCR primers were specifically designed to amplify the whole coding region (five exons) and the flanking intron/exon junctions of SBDS gene but not the SBDSP pseudogene. RFLPs used the Bsu36I and AciI enzymes for the detection of the two most common c.183-184 TA>CT and 258+2 T>C mutations respectively. Result: All five patients were compound heterozygotes for 183–184 TA>CT and 258+2 T>C, which are the two most common mutations of SDS. One of those (patient 3) was found to be a mosaic which seems to explain the very mild phenotype, and another (patient 5) presented homozygosity for the 258+2 T>C while carrying the 183–184 TA>CT mutation as well. Patient 1 was successfully transplanted by her HLA-identical sister at the age of 12 months. Her pancreatic insufficiency has not improved and she is still on pancreatic enzyme supplementation. Patient 2 is receiving pancreatic enzyme supplementation and also is currently on growth hormone supplementation. Patients 3 and 4 are not receiving pancreatic enzyme supplementation or granulocyte colony-stimulating factor. Patient 5 is currently receiving only granulocyte colony-stimulating factor. Conclusion: Extreme variability ranging from severe clinical phenotype apparent at birth to close-to- normal phenotype in early adulthood was noted in this small series of Greek patients, carrying similar SBDS mutations. Moreover, gene conversion seems to be a frequent event in the SBDS gene. Further studies to evaluate the heterogeneity and the factors affecting the phenotype/genotype relationship in SDS are warranted. Disclosures: No relevant conflicts of interest to declare.
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Feng, Shuju, Stephen J. Eyler, Yuzhou Zhang, Tara K. Maga, Michael H. Kroll, Richard J. H. Smith, and Vahid Afshar-Kharghan. "ADAMTS13 Variants in Atypical Hemolytic Uremic Syndrome." Blood 120, no. 21 (November 16, 2012): 490. http://dx.doi.org/10.1182/blood.v120.21.490.490.
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Abstract Abstract 490 Atypical hemolytic uremic syndrome (aHUS) is a clinically defined thrombotic microangiopathic anemia (TMA) characterized by the symptom triad of renal failure, thrombocytopenia and microangiopathic hemolytic anemia in the absence of Shiga-toxin-producing bacteria as a triggering factor. Its pathogenesis is linked to dysregulation of the alternative pathway of the complement cascade, with loss-of-function mutations reported in complement regulators like factor H (CFH), membrane cofactor protein (MCP), factor I (CHI) and thrombomodulin (THBD), and gain-of-function mutations in complement activators like factor B (CFB) and complement component 3 (C3). In nearly 40% of patients, however, mutations are not identified in these genes raising the possibility of unrecognized contributory genetic causes. Genetic variants in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs) have been causally related to thrombotic thrombocytopenic purpura (TTP), another TMA characterized by the pentad of neurologic symptoms, fever, kidney failure, thrombocytopenia and microangiopathichemolytic anemia. The phenotypic similarities between aHUS and TTP can at times lead to difficulty in their clinical distinction. On this basis, we hypothesized that partial deficiency in ADAMTS13 function may coexist with abnormalities in the alternative complement pathway in patients with aHUS. To test this hypothesis, we measured ADAMTS13 functional activity in 26 patients with aHUS by fluorescence resonance energy transfer substrate-von Willebrandfactor 73mer (FRETS-VWF73) and recombinant VWF A2 domain cleavage assay. We also genotyped all patients for ADAMTS13 and alternative complement pathway genes. We transiently expressed 10 different ADAMTS13 missense variants in HEK293 cells to analyze activity and secretion of each recombinant protein. The ADAMTS13 functional activity was partially reduced (< 60%) in serum from 20 patients (77%) as measured by FRETS-VWF73 and recombinant VWF A2 cleavage assays. Genetic variants in ADAMTS13 were identified in 21 patients (81%) and included R386C, Q448E, A900V, V832M, R1060W, R7W/Q448E, A900V/Q448E, R1096H/A747V, R7W/A1033T, R7W/P618A/Q448E, R7W/P618A/A900V/Q448E, R7W/P618A/A732V/Q448E. The coexistence of both ADAMTS13 deficiency and excessive complement functional activity was present in 13 patients (50%). Activity of recombinant ADAMTS13 proteins containing the following variants was normal: R386C, Q448E, P618A, A732V, A747V, V832M, A900V, A1033T and R1060H. The R1096H variant of ADAMTS13 was associated with a reduction in functional activity by 50%. The secretion of recombinant proteins with the following variants was severely reduced: P618A, R1060H (<1%), R386C, R1096H (<10%), and A1033T (<50%) (Figures 1 and 2). This study implicates ADAMTS13 in the pathogenesis of aHUS and mandates the evaluation of ADAMTS13 in aHUS patients. Defining the role of ADAMTS13 in aHUS may aid in the development of new treatments and/or assist in clarifying whether long-term treatment with currently available anti-complement therapy is required for this disease. Disclosures: Kroll: Aplagon: Membership on an entity's Board of Directors or advisory committees; Optimer: Consultancy; Leo: Honoraria, Travel Expenses, Travel Expenses Other.
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Fujimura, Yoshihiro, Masanori Matsumoto, Koichi Kokame, Hideo Yagi, Ayami Isonishi, Tomomi Matsuyama, Seiji Kato, et al. "Natural History of 33 Patients with Upshaw-Schulman Syndrome Has Revealed That All the Gravida Develop Thrombocytopenia, Often Followed by Thrombotic Microangiopathy with Stillbirth." Blood 110, no. 11 (November 16, 2007): 3211. http://dx.doi.org/10.1182/blood.v110.11.3211.3211.
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Abstract Upshaw-Schulman syndrome (USS) is a congenital deficiency of the activity of von Willebrand factor (VWF)-cleaving protease or ADAMTS13 due to its gene mutations. USS is a complex thrombo-hemorrhagic disease, but its hallmark is severe neonatal jaundice soon after birth that often requires for exchange blood transfusion, and subsequently during childhood they have repeated episodes of chronic thrombocytopenia and hemolytic anemia that are reversed by infusions of fresh frozen plasma. However, after a discovery of ADAMTS13, the presence of two phenotype expression on USS-patients was described; one is the early-onset type as abovementioned, and the other is the late-onset type which is asymptomatic during childhood and the first bout develops after adolescent or during adulthood, in association with infections or pregnancy. During the past 8 years, we diagnosed 33 patients with USS. Through analyzing the natural history and the phenotype-genotype expression in these patients, and more specifically to 9 USS-patients who had their first bout at pregnancy, we found that two clinical phenotypes of USS are mostly attributable to misdiagnosis or overlook of thrombocytopenia during childhood, and excluded a possibility of the concern on a trace amount of ADAMTS13 activity which has not been evaluated by the previous methods. Further, in vitro studies we have clearly shown that platelet aggregation or thrombi formation under high shear stress is tremendously up-regulated in the absence of ADAMTS13, that occurs proportionally to the amount of high VWF multimers, that in part is assumed to be an in vitro reflection of the circulation in USS-gravida. Figure Figure
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Puck, Jennifer. "Diagnostic Challenges in the Era of Genomic Sequencing and Newborn Screening." Blood 130, Suppl_1 (December 7, 2017): SCI—30—SCI—30. http://dx.doi.org/10.1182/blood.v130.suppl_1.sci-30.sci-30.
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Abstract Early diagnosis of rare immune disorders is important for clinical care and of great interest for the study of immune pathways. Severe combined immunodeficiency (SCID) is a collective term for the most profound inherited defects of T cell development combined with B cell defects or dysfunction. While fatal without treatment, SCID is treatable by allogeneic hematopoietic cell transplantation, or in certain genotypes by enzyme or gene therapy. Avoidance of life-threatening infections to provide optimal treatment and outcomes for affected infants has led to population-based SCID newborn screening (NBS). Infants with SCID fail to generate a diverse repertoire of functional T cells, and consequently have very low numbers of T cells and T cell receptor excision circles (TRECs), DNA byproducts of T cell receptor gene rearrangement. TRECs are readily measured in DNA isolated from newborn dried blood spots (DBS) collected for population based screening. Thus newborn screening for insufficient TRECs identifies SCID before infections occur. As SCID NBS has become widespread, new disease definitions are required for healthy-appearing affected infants without failure to thrive or opportunistic infections. Typical SCID cases have <300 autologous T cells/uL, <10% of the lower range of normal proliferation to the mitogen phytohemmaglutinin A, and/or detectable maternal T cell engraftment, most often with deleterious mutations in recognized SCID genes. One fourth of all SCID cases are "leaky" due to hypomorphic SCID gene mutations; these cases are also detected by TREC testing; they may have >300 T cells/uL, but have impaired T cell function and lack naïve CD4 T cells expressing CD45RA. A subset of infants with leaky SCID have Omenn syndrome, with expansion of oligoclonal, dysregulated T cells leading to adenopathy, erythroderma, hepatosplenomegaly, eosinophilia, and elevated IgE. In addition to these primary target disorders of population screening for SCID, the TREC test identifies infants with additional conditions due to either impaired production or increased loss of T cells. Non-SCID congenital syndromes with variable degrees of T cell lymphopenia (TCL) include DiGeorge syndrome/22q11.2 deletion, CHARGE syndrome, trisomy 21, and ataxia telangiectasia, among others. TREC NBS also finds infants with secondary TCL, in which T cell generating capacity is intrinsically normal, but circulating T cells are diminished as a consequence of other factors, including hydrops, congenital heart disease, chylothorax, neonatal leukemia, maternal immunosuppressive medications taken during pregnancy, or extreme preterm birth. The T cells of these infants normalize once their primary problems resolve. A particularly challenging group of infants are those with abnormal TREC screen results and non-SCID TCL, but no immediate diagnosis. About half of these have syndromes, such as DiGeorge/22q deletion, but with mild or initially unapparent features; others experience resolution of TCL over time, while still others prove to have previously unknown immune disorders that may be diagnosed after deep sequencing and research functional studies. It is important to remember that many serious disorders of T cells are not identified by TREC screening if the block in T cell development or function occurs at a later stage than T cell receptor rearrangement; combined immunodeficiencies (CIDs) with TRECs that are often normal include Zap-70 deficiency and MHC class I and II non-expression. Thus, while virtually completely sensitive and highly specific for the intended target, SCID, population based TREC screening leaves us with both diagnostic dilemmas presented by non-symptomatic infants with low T cells and inability to capture individuals with the >300 non-SCID primary immunodeficiency disorders that would also benefit from early intervention. Deep sequencing is not yet clinically useful, not only due to cost, turnaround time and technical limitations, but primarily due to problems of interpretation, given the extraordinary number of genomic variants of uncertain significance. Disclosures Puck: InVitae, a clinical DNA sequencing company: Other: Spouse employment and stock options; UpToDate: Patents & Royalties: Recieve royalties to write and edit entries on primary immune disorders.
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Doshi, Bhavya, Aditi Kamdar, Kim Smith-Whitley, Michele P. Lambert, and Amrom Obstfeld. "Incidence of Hemolytic Events after Exposure to Triggering Medications in Pediatric Patients with G6PD Deficiency." Blood 128, no. 22 (December 2, 2016): 4810. http://dx.doi.org/10.1182/blood.v128.22.4810.4810.
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Abstract Background: Glucose 6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder that occurs in approximately 400 million people worldwide. It is characterized by varying degrees of hemolysis most often triggered by infections, drugs, or certain foods. However, most people with G6PD deficiency do not have a clinically significant phenotype. Some medications thought to trigger hemolytic crises in patients with G6PD deficiency can be life-saving (e.g. rasburicase in severe tumor lysis syndrome). Thus, the ability to stratify patients according to risk of hemolysis may have significant clinical implications. In December 2014, our reference lab increased the lower limit of normal of the G6PD enzymatic assay from 7 units/g Hb to 9.9 units/g Hb, which increased the number of patients diagnosed with G6PD deficiency. However, it remains unknown if patients with intermediate levels (between 7 and 11 units/g Hb) experience hemolysis when exposed to triggers compared to patients with levels below 7 units/g Hb. Methods: We conducted a retrospective cohort analysis of patients with G6PD enzymatic levels between 2014 and 2016 to determine risk of hemolysis in patients with low or intermediate levels upon exposure to hemolysis-triggering medications (rasburicase, dapsone, nitrofurantoin, primaquine, cotrimoxazole, methylene blue, probenecid, phenazopyridine, moxifloxacin and aspirin). Hemolysis was defined by clinical documentation and further characterized by need for transfusion after drug exposure as well as a decrease in pre-exposure hemoglobin after exposure. Inclusion criteria were patients 0-21 years of age at time of G6PD assay, G6PD assay level less than 11 units/g Hb, exposure to one of the listed medications, and those with peri-exposure hemoglobin and transfusion data available. Patients were excluded if G6PD assay level was ≥ 11 units/g Hb, they were over 21 years of age at time of assay, or were not exposed to the listed medications. Results: We identified 704 patients who had available G6PD assays during the study period. Assay levels in this cohort ranged from 0.3 to 270 units/g Hb with 291 having G6PD assay levels less than 11 units/g Hb. Of these patients, 39 had both qualifying G6PD levels and documented exposure to one or more of the triggering medications; 5 patients had low G6PD levels (<7 units/g Hb), 14 patients had intermediate levels (7-10 units/g Hb) and 20 patients had high intermediate G6PD levels (10-11 units/g Hb). The distribution of hemolysis-triggering medication exposure was as follows: cotrimoxazole (n=35), rasburicase (n=5), dapsone (n=1), primaquine (n=1), methylene blue (n=1), moxifloxacin (n=1), aspirin (n=1), nitrofurantoin (n=0), probenecid (n=0), and phenazopyridine (n=0). Of the triggering medications we identified, rasburicase is the only medication with a known black box warning against its use in patients with G6PD deficiency. There were two patients amongst those in the study who had significant hemolytic events associated with anemia warranting blood transfusion. One patient (a male) with a low G6PD assay level (2.4 units/g Hb) had clinically significant hemolysis in the setting of rasburicase exposure. The other patient (a female) with a high intermediate G6PD assay (10.8 units/g Hb) had clinically significant hemolysis in the setting of cotrimoxazole exposure, but had a complicated clinical course making it difficult to attribute causality of hemolysis definitively to cotrimoxazole. Of note, no patients with intermediate G6PD assay levels (between 7 and 10 units/g Hb) had significant hemolysis despite exposure to a triggering medication. Conclusions: Our results indicate that there was no clear association between G6PD assay levels above 7 units/g Hb and the incidence of hemolysis. Despite a general avoidance of cotrimoxazole exposure in patients with known G6PD deficiency, our study did not reveal a significant correlation between drug exposure and hemolytic events in this population. Importantly, the only patient with significant hemolysis in the setting of rasburicase exposure had a very low G6PD level. Further correlation with genotype and G6PD assay level may have significant clinical implications to predict one's risk of clinically significant hemolysis. Disclosures Smith-Whitley: Pfizer: Membership on an entity's Board of Directors or advisory committees. Lambert:Novartis: Consultancy.
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Beckman, Joan, Karen L. Smith, Samuel T. Hester, Ofri Leitner, and Raj S. Kasthuri. "Effect of Genotype and Antifibrinolytic Therapy on the Severity of Epistaxis in Hereditary Hemorrhagic Telangiectasia." Blood 124, no. 21 (December 6, 2014): 1515. http://dx.doi.org/10.1182/blood.v124.21.1515.1515.
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Abstract Background: Hereditary Hemorrhagic Telangiectasia (HHT, or Osler Weber Rendu syndrome) is an inherited multiorgan disorder characterized by the development of abnormal blood vessels, resulting in the formation of telangiectasias on mucocutaneous surfaces (skin, lips, nasal and buccal mucosa, gastrointestinal mucosa) and arteriovenous malformations (AVMs) in certain visceral organs (brain, lungs, spinal cord and liver). Over 90% of affected individuals develop epistaxis, often leading to complications, such as iron-deficiency anemia and the need for oral and parenteral iron supplementation, blood transfusions, and associated decrease in quality of life. The management of epistaxis in HHT has consisted predominantly of invasive approaches like cautery, laser photocoagulation, and septodermopasty. Antifibrinolytic agents [aminocaproic acid and tranexamic acid] are frequently used in the management of patients with inherited and acquired mucocutaneous bleeding disorders; however data on the use of antifibrinolytics for the treatment of epistaxis in HHT have been limited to case reports. We hypothesize that antifibrinolytic therapy is effective for the treatment of moderate to severe HHT-related epistaxis. Methods: The medical records of patients with HHT evaluated at University of North Carolina from 2009 to October 31, 2013 were retrospectively reviewed. Patients with epistaxis requiring pharmacologic therapy in whom the epistaxis severity score (ESS) was available were included. The ESS is a clinical scoring system that utilizes six factors associated with self-reported epistaxis severity (frequency, duration, intensity, need for medical attention, anemia, and need for transfusion) to generate a clinical score. The response to antifibrinolytic therapy was evaluated by comparing pre-post ESS. Demographic data and HHT mutation status were also noted and the impact of genotype on the severity of epistaxis was analyzed. All statistical analyses were performed with SigmaStat 2.0 for Windows (SYSTAT Inc, Chicago, IL) using analysis of variance. Values are reported as +/- standard error of means. The study was approved by the Institutional Review Board. Results: Two hundred and twenty two patient records were reviewed. Of these, 126 were adults with epistaxis and were eligible for study evaluation. Seventy-one of these patients underwent genetic testing and 34 (47.9%) had an ACVRL1 (ALK-1 mutation while 22 (30.99%) had an ENG mutation. Five patients (7%) had a variant of uncertain significance (VUS), while no mutation was identified in 10 patients (14%) with a clinical diagnosis of HHT as per Curacao criteria. There was a correlation between the ESS and HHT genotype. Patients with an ACVRL1 (ALK-1) mutation (n=34) had significantly higher ESS (4.32 ± 0.455, p<0.05) compared to patients without mutations (2.08 ± 0.672). There was no significant difference in ESS between patients with an ENG mutation (n=22, ESS= 3.379 ± 0.455) or with a VUS (n=5, ESS= 5.5 ± 1.049) compared to those with negative genetic testing. Forty-nine HHT patients with moderate to severe ESS were started on an oral antifibrinolytic agent (aminocaproic acid 6 grams per day or tranexamic acid 3.9 grams per day). Patients were allowed to titrate the dose of medication down based on response. Follow-up over an average of 15 months (range 3-39 months) was available on 16 of the 49 patients. Of the 16 patients with follow up data, the average pre-treatment ESS score was 5.7 ± 0.466 and decreased to 4.8 ± 0.321 with antifibrinolytic therapy (p<0.05). All the 16 patients tolerated antifibrinolytic therapy well and without significant adverse effects. Conclusion: This study demonstrates for the first time that the severity of epistaxis in patients with HHT correlates with the HHT genotype. Epistaxis is more severe in patients with ACVRL1 (ALK-1) mutations. We also show that antifibrinolytic therapy is effective in improving the severity of epistaxis in individuals with HHT and that their chronic use is well tolerated in this population. We are currently in the process of expanding assessments of our study cohort. Larger, multicenter, randomized control trials are needed to study durability of treatment response and safety of these agents with long-term, continuous use. Disclosures Off Label Use: off-label use of aminocaproic acid and tranexamic acid in patients with inherited and acquired mucocutaneous bleeding disorders.
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Edwards, Donna, Elizabeth Sierra Potchanant, Xinxin Huang, Zejin Sun, Maegan Capitano, Caroline Miller, Ying He, Hal E. Broxmeyer, and Grzegorz Nalepa. "Patient-Tailored Mouse Genome Editing Recapitulates Hematopoietic and Systemic Manifestations of Barth Syndrome." Blood 130, Suppl_1 (December 7, 2017): 775. http://dx.doi.org/10.1182/blood.v130.suppl_1.775.775.
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Abstract Barth syndrome (BTHS; OMIM# 302060) is an X-linked disorder of neutropenia, cardiomyopathy and muscular weakness due to mitochondrial dysfunction secondary to inherited tafazzin (TAZ) mutations. Neutropenia occurs in the majority of BTHS patients, leading to high risk of recurrent life-threatening bacterial infections. The etiology of the G-CSF-responsive neutropenia in BTHS is incompletely understood and appears to reflect impaired granulopoiesis. Long-term risk of myelodysplasia (MDS) in BTHS individuals requiring chronic G-CSF therapy is unknown due to the rarity of the disorder; further, genotype-phenotype correlations between the severity of neutropenia and TAZ mutations remain to be elucidated. Genetic Taz knockout is embryonic lethal in the mouse. Therefore, a genetic BTHS mouse model is urgently needed to improve our mechanistic understanding of this disease and develop clinical studies based on preclinical evidence. We employed CRISPR/Cas system to edit our BTHS patient's tafazzin point mutation (D75H) into the endogenous murine Taz gene. The resulting mice recapitulated hematopoietic and systemic manifestations of Barth syndrome. TazD75H males are born at less than expected Mendelian frequencies (p<0.0001) and suffer from perinatal lethality and failure to thrive with 69% decrease of body size at postnatal day 29 compared to age-matched wt males (p<0.0001). TazD75H males have neutropenia at 1 month of age evidenced by complete blood counts and independent manual peripheral smear analysis (p=0.04). Young TazD75H mice had mildly decreased bone marrow cellularity per femur (p=0.01675) accompanied by deficient functional bone marrow colony-forming ability compared to age- and sex-matched wt mice (approximately 3.5-fold decrease in CFU-GM, p=0.0002, and CFU-GEMM, p=0.0041), consistent with a functional hematopoietic defect. Similar to BTHS patients, TazD75H mice develop prenatal cardiomyopathy, with echocardiograms of surviving mice demonstrating left ventricular non-compaction (p=0.0339) and decreased ejection fraction (p=0.038). Further, TazD75H mice recapitulate the Barth syndrome phenotype of impaired skeletal muscle strength as shown by decreased ability to lift weights and perform hanging exercise (p=0.0072). Interestingly, TazD75H males developed infertility due to profound spermatogenesis arrest (p<0.0001). These data indicate that TazD75H mice recapitulate all crucial clinical findings in Barth syndrome. Given the role of tafazzin in mitochondrial cardiolipin metabolism, we examined the structure and function of mitochondria in TazD75H mice. Strikingly, transmission electron microscopy revealed accumulation of swollen mitochondria with fractured cristae in TazD75H hematopoietic cells, cardiomyocytes and skeletal muscle, reflecting the mitochondrial phenotype of BTHS patients. Total mitochondrial mass quantified by MitoTracker flow was unchanged in TazD75H hematopoietic cells, but flow cytometry using the JC-1 mitochondrial membrane potential probe revealed disrupted mitochondrial potential during live TazD75H hematopoiesis in multi-potential progenitors (MPPs, p=0.0025), Lin- Sca-1+ c-kit+ cells (p<0.0001), Lin- Sca-1- c-kit- (p=0.0036), lineage-negative (p<0.0001) and lineage-positive (p=0.0211) hematopoietic cells. Quantitative Seahorse metabolic profiling revealed impaired mitochondrial respiration in live TazD75H hematopoietic cells, confirming functional mitochondrial deficiency. In summary, our work demonstrates that impaired hematopoiesis in Barth syndrome, which is embryonic lethal in the mouse, can be recapitulated in vivo through editing a patient-specific hypomorphic tafazzin mutation into the murine genome. The precision-medicine TazD75H mouse model recapitulates clinical hallmarks of BTHS in hematopoietic and non-hematopoietic tissues, accompanied by structural and functional mitochondrial defects. This work enables in vivo studies to enhance our mechanistic understanding and treatment of hematopoetic and other defects in Barth syndrome. Figure Figure. Disclosures No relevant conflicts of interest to declare.
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Aldenhoven, Mieke, Maria Escolar, Robert Wynn, Ed Wraith, Anne O'Meara, Paul Veys, Nizar Mahlaoui, et al. "Long Term Outcomes of Hematopoietic Stem Cell Transplantation in Patients with Severe Phenotype Hurler Syndrome: an International Multi-Center Study." Blood 120, no. 21 (November 16, 2012): 1958. http://dx.doi.org/10.1182/blood.v120.21.1958.1958.
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Abstract Abstract 1958 Background: Hurler syndrome (HS), the most severe phenotype in the spectrum of Mucopolysaccharidosis type I, is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase. HS is clinically characterized by a progressive and ultimately fatal multi-system deterioration with involvement of the central nervous system. At present, hematopoietic stem cell transplantation (HSCT) is the only treatment that prevents disease progression in the central nervous system and is therefore considered the treatment of choice in HS. Long-term follow-up of outcomes of HSCT for HS are sparse and risk factors for favorable long-term outcomes are still largely unknown. Therefore, an international multicenter study was initiated to describe the long-term outcomes of successfully transplanted HS patients. Methods: HS-patients transplanted between 1980 and 2007 within the leading transplantation centers in Europe and the United States were include in this study. Patient, donor, and transplantation-related variables which may influence long-term outcome were analyzed. Patients who were ‘alive and engrafted (donor-chimerism >10%)’ with a follow up of at least three years after HSCT were included. The functional outcomes assessed for the various organ systems - orthopedic, cardiac, ophthalmologic, respiratory and audiologic - were analyzed using multivariate Cox proportional hazards and logistic regression models. Results: 197 Hurler patients were included from 8 different transplant centers. This is estimated to be about 70–80% of the successfully transplanted HS patients worldwide during that time period. These patients had a median age of 16 (2–80) months at HSCT with a median follow up of 88 (36–258) months after successful HSCT. Seventy-nine % of the patients received a graft from an unaffected (non-carrier) donor. Seventy-two % of the patients achieved full (>95%)-donor-chimerism and 28% mixed-chimerism. After HSCT, normal enzyme-levels (EL; according to the local reference range) were found in 75% of the patients while 25% had EL below lower limit of normal; either due to mixed-chimerism or carrier-donorship). Multivariate analyses (table 1) showed having a “normal EL” after HSCT and younger (below the median age of 16mths) “age at transplantation” were associated with less serious orthopedic complications requiring surgical interventions; e.g. cord compression, genu-valgum surgery, carpal tunnel surgery. Genotype (double non-sense vs. any other genotype) was associated with a lower probability of requiring hip dysplasia surgery as well as with the occurrence of retinopathy. For other endpoints; e.g progression valve insufficiency, progression corneal clouding and development of retinopathy and the need for hearing aids having a normal EL as well as age at HSCT (<16mths) were predictors for better outcome. Furthermore, growth at the age of 60mths was influenced by EL (−1.93 SDS vs. −1,09 SDS; p=0.042). Conclusion: The long-term outcome of clinical manifestations in HS-patients after successful HSCT is promising although residual disease burden remains. Predictors, favorably influencing the long-term outcomes are suggested to be 1) enzyme level (normal vs. below LLN) after HSCT, 2) genotype and 3) age at HSCT. Achieving normal enzyme levels at an early age might significantly impact the prognosis of Hurler syndrome patients. Newborn screening (resulting in early HSCT), the use of non-carrier donors and achieving full-donor chimerism may be crucial in optimizing long-term outcomes. Disclosures: No relevant conflicts of interest to declare.
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King, Stephanie, Manuela Germeshausen, Gabriele Strauss, Karl Welte, and Matthias Ballmaier. "Congenital Amegakaryocytic Thrombocytopenia (CAMT): A Detailed Clinical Analysis of 21 Cases Reveals Different Types of CAMT." Blood 104, no. 11 (November 16, 2004): 740. http://dx.doi.org/10.1182/blood.v104.11.740.740.
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Abstract CAMT is a rare disease characterized by thrombocytopenia in infancy due to ineffective megakaryopoiesis. We retrospectively analyzed clinical parameters of 21 patients diagnosed with CAMT, characterized by severe thrombocytopenia at birth, normal bone marrow cellularity and severely reduced numbers of megakaryocytes. 18 children developed postnatal bleeding symptoms with a median platelet count of 21/nl. 2 children suffered from a postnatal cerebral bleeding and intrauterine cerebral bleeding was suspected in 4 more children. We observed differences in the course of disease: 12 children formed a homogeneous group regarding the hematological parameters. Their platelet counts remained on a very low level, bone marrow cellularity decreased during the first year of life and they developed severe aplastic anemia in early infancy (2 to 53 months). 7 children also presented with physical anomalies like strabismus (2), nystagmus (2), motor and mental retardation (2), growth retardation (2) and cardiac defects (2). In 5 of 7 patients the parents were cousins of first degree. Sequence analysis of the c-mpl gene in 5 children revealed nonsense mutations with a complete loss of the thrombopoietin receptor. This group we classified as CAMT Type I. In contrast, 6 children formed a more heterogeneous group with delayed bone marrow failure. Their platelet counts at birth were slightly increased compared to those of type I patients (median 35/nl). In all children the number of platelets rose during early infancy and achieved a median maximum of 132/nl. At a median age of 4 9/12 years (range 3 to 6 10/12years) 4 children developed aplastic anemia. In one girl bone marrow morphology revealed refractory anemia with excess blasts at the age of 7 1/12 years. She received two bone marrow transplantations (BMT) and finally died from acute myeloid leukemia. Another girl feels well at the age of 14 years without signs of pancytopenia. One girl presented with growth retardation and a second with a small apical ventricular septal defect. Sequence analysis in 3 children revealed different forms of amino acid exchanges in the extracellular domain of c-Mpl. This might correspond to a residual function of c-Mpl. This group we classified as CAMT Type II. Altogether 18 children received BMT. 3 patients with type II CAMT required a second BMT due to primary graft failure, secondary graft failure and relapse of MDS. BMT with a matched unrelated donor (MUD) was performed in 5 patients, all with a fatal outcome. 8 children died at a mean age of 4 2/12 years: 2 due to bleeding complications and 6 following BMT. We conclude, that c-Mpl deficiency is the main reason for CAMT and can be associated with described physical anomalies. As exemplified the prognosis for patients is poor. Clinical differences can be seen between a total lack and a residual function of the c-Mpl receptor. Besides CAMT due to c-Mpl deficiency the incidence of congenital forms of ineffective megakaryopoiesis was described for other diseases with no defects in the c-mpl gene. (e.g. CAMT with radio-ulnar synostosis, Hoyeraal-Hreidarsson-Syndrome). This heterogeneous group of diseases with normal c-Mpl function we classified as CAMT Type III. Further clinical studies have to be performed to understand the relationship between genotype and clinical phenotype in terms of bone marrow failure, leukemia development and overall survival to better predict the clinical outcome.
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Bastida, Jose Maria, Sara Morais, Veronica Palma-Barqueros, Rocio Benito, Nuria Bermejo, Mutlu Karkucak, Maria Trapero-Marugan, et al. "Ten New Cases of Hermansky-Pudlak Syndrome in the Iberian Peninsula: Identification of Novel Genetic Variants in HPS3, HPS4, HPS6 and DTNBP1 Associated with Significant Clinical Complications." Blood 132, Supplement 1 (November 29, 2018): 1147. http://dx.doi.org/10.1182/blood-2018-99-112968.
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Abstract Introduction Hermansky-Pudlak syndrome (HPS) is an inherited platelet disorder characterized by bleeding diathesis, oculocutaneous albinism (OCA) and, sometimes, serious clinical complicationssuch as immunodeficiency, granulomatous colitis, and/or pulmonary fibrosis. Heterogeneous clinical symptoms and a large number of possible genetic culprits (10 HPS genes, >120 exons) complicate an unequivocal diagnosis of HPS. This study aimed to assess the clinical and platelet phenotype in ten patients with suspected HPS, and to identify the underlying genetic defects. Methods Ten patients from six families (F1 and F3 were Spanish, F2 was Turkish and F4, F5 and F6 were Portuguese) presenting with OCA (confirmed by skin biopsy) and bleeding diathesiswere included. Bleeding was evaluated by ISTH-BAT score. Phenotyping included, in patients with fresh blood samples available, platelet aggregation and ATP release, flow cytometry (FC), 14C-serotonin uptake and whole-mount electron microscopy (EM). Patients DNA was analyzed using two different targeted panels by high throughput sequencing (HTS). Sequence variants classification was performed according to ACMP recommendations. Results Patient characteristics are summarized in table 1. In F1, that had no history of consanguinity, there were two affected sisters. Patients 1 (P1) had several episodes of gastrointestinal bleeding (GI), which was attributed to granulomatous colitis. F2 is a consanguineous Turkish family, were P3 had severe rectal bleeding, requiring colectomy combined with ileostomy surgery. Pathological examination of the colon was reported as non-granulomatous colitis. Her older sister (P4) had exhibited dyspnea and shortness according to diffuse bilateral pulmonary fibrosis (BPF) diagnosis. In F3, P5 had been referred with acute GI bleeding secondary to angiodysplasia. In the non-consanguineous F4, HPS was first confirmed in P6, who showed blonde hair, nystagmus and low visual acuity; his older sister was diagnosed with HPS later, at the age of 56 years old (P7), because her OCA was masked using dark brown hair-coloring products. In P8, born from a non-consanguineous family (F5), HPS was suspected early in life, four months of age, upon recognition of OCA, nystagmus, deep visual deficiency and exotropia with compensatory torticollis. Lastly, in the consanguineous Portuguese family (F6), the two affected children (P9 and P10) had also showed a horizontal and torsional nystagmus and reduced visual activity. P10 also suffered from epilepsy and mild development delay. In phenotyping studies, the Spanish patients (P1, P2, P5) showed impaired platelet aggregation to mild agonists and reduced platelet dense granules by FC and EM. No platelet studies could be performed in F2. In Portuguese patients (F4, F5 and F6), the ATP release studies demonstrated a dense granule deficiency (Table 1). Molecular diagnosis was achieved, as a first-line approach, by means of HTS gene panels that revealed: a) F1 (P1 & P2) a homozygous deletion c.2054delC (p.P685L fs17*) in exon 13 of the HPS4, which had been previously reported in one Asian patient who showed BPF; b) F2 (P3 & P4): anovel missense homozygousvariant c.272T>C (p.L91P) in exon 4 of the HPS4. Remarkably, the phenotype of the two Turkish sisters was different, with one having had severe GI bleeding requiring colectomy, and the other had developed BPF. C) F3 (P5): a novel heterozygous variant c.2464C>T (p.R822*) in exon 13 of the HPS3 was detected; d) F4 (P6 & P7) and F5 (P8): here a nonsense variant c.307C>T (p.Q103*) was identified in exon 5 of the DTNBP1, which was previously reported in a Portuguese patient. E) F6 (P9 & P10): these patients carried a novel five base pair duplication in the single exon of HPS6, c.60_64dup (p.L22R fs*33). Conclusions This study reports 10 new HPS patients, which demonstrates the heterogeneous nature of this syndrome and the complex phenotype-genotype correlations. The novel HTStechnology has facilitated the molecular diagnosis of HPS in these patients. Among the underlying molecular pathology, we identified a novel p.L91P variant in HPS4 that is associated with a severe clinical phenotype. Funding Gerencia Regional de Salud (GRS 1647/A/17), Fundación Séneca (19873/GERM/15), Instituto de Salud Carlos III (ISCIII, PI17/01966, PI17/01311,CB15/00055), Grupo de trabajo SETH and Instituto de Investigación Biomédica de Salamanca (IBSAL, IBY17/00006). Table Table. Disclosures No relevant conflicts of interest to declare.
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Kinsella, Jane L., Robert F. Wynn, Brian Bigger, Adrian J. Thrasher, Claire Booth, Karen Buckland, Natalia Izotova, et al. "Ex-Vivo Autologous Stem Cell Gene Therapy Clinical Trial for Mucopolysaccharidosis Type IIIA: Trial in Progress - NCT04201405." Blood 136, Supplement 1 (November 5, 2020): 15–16. http://dx.doi.org/10.1182/blood-2020-141762.
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Autologous ex vivo hematopoietic stem cell gene therapy is particularly relevant in lysosomal storage diseases (LSD) as it offers the prospect of both a safe transplant, as observed in immune deficiency and hematologic illness, and an effective transplant, since it delivers greater enzyme levels to host tissues than is possible in allogeneic transplant. We report early data from such an approach in an allogeneic transplant refractory LSD, Mucopolysaccharidosis type IIIA (MPSIIIA, Sanfilippo syndrome). Background: MPSIIIA is a LSD caused by mutations in the SGSH gene leading to a deficiency of the enzyme N-sulfoglucosamine sulfohydrolase. As a result there is accumulation of heparan sulfate, with clinical manifestations of developmental delay, regression of previously acquired skills, hyperactivity, seizures and progressive cognitive decline leading to an early death at the end of the second decade of life. Unlike some other LSDs, MPSIIIA is unresponsive to allogeneic stem cell transplant (Hoogerbrugge et al., The Lancet 1995; Sivakumur & Wraith, Journal of inherited metabolic disease 1999), with the donor cells unable to deliver enough enzyme for clinically meaningful cross-correction. Significant pre-clinical work undertaken at the University of Manchester led to the design of the lentiviral vector containing the SGSH gene and a CD11b (myeloid) promoter. In murine studies MPSIIIA mice underwent stem cell mobilization and collection and stem cells were transduced with the lentiviral vector ex vivo. The mice received myeloablative busulfan before being infused with the autologous transduced stem cells. Enzyme expression in the brain was high with normalised heparan sulfate and improvement in the behavior of the mice (Sergijenko et al., Molecular Therapy 2013). Transduction and transplant of human CD34+ stem cells to humanized NSG mice demonstrated stable engraftment with no evidence of viral shedding or transformational potential (Ellison et al., Molecular Therapy-Methods & Clinical Development 2019), further adding to the safety profile and the translation of this work to the clinic. Study Design and Methods: This is a phase I/II safety and tolerability study. It is open-label and aims to recruit up to 5 patients. Patients enrolled into the trial are between the age of 3 and 24 months, have confirmed classical MPSIIIA (either by known genotypes, somatic features or family history) and have preserved neurocognitive function (DQ ≥80) before commencing the trial. Patients undergo stem cell mobilization and peripheral collection of CD34+ cells. The SGSH gene under the CD11b promoter is introduced by the lentiviral vector. Patients then receive myeloablative busulfan before infusion of the autologous transduced stem cells. Follow up takes place over 3 years. The primary end point is to assess the safety and tolerability of the transduced stem cell product. The primary efficacy endpoint is SGSH activity in leukocytes at 12 months. Several secondary and exploratory end points are also to be reported including neurocognitive outcomes. Current trial status: We report the preliminary data of the first treated patient recruited to the trial including the mobilization, transplant and sustained engraftment of gene-modified cells by vector copy number. Supra-physiological enzyme expression in multiple lineages - 150 fold increase above median in leukocytes and 200 fold increase above control in myeloid lineage - and substrate reduction in plasma, CSF and urine - reduced in urine to normal range by 3 months - has been observed. Disclosures Bigger: Orchard Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thrasher:Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jones:Orchard Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.
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Andersen, Judith C., Patricia Dhar, Lynnette Essenmacher, Joel Ager, and Robert Sokol. "Determinants of Thrombophilia in an Urban Systemic Lupus Erythematosus Population." Blood 106, no. 11 (November 16, 2005): 4134. http://dx.doi.org/10.1182/blood.v106.11.4134.4134.
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Abstract Patients with systemic lupus erythematosus (SLE) are known to experience thrombosis with higher frequency than the general population, but the demographic and laboratory underpinnings of this phenomenon have been incompletely studied. To characterize clinical and laboratory parameters predisposing to thrombosis in urban systemic lupus patients, medical records of 111 such patients with a history of vascular thrombosis, adverse pregnancy outcome, or considered to be at high risk for thrombosis because of their clinical setting and collagen-vascular disease were reviewed. Extensive investigation of recognized contributors to and markers of inflammation and hypercoagulation, e.g. antiphospholipid antibodies (APLs) had been performed during their clinical evaluation. Population Demographics Subject # (%) # % # % # % Gender 102F (69) 9M (8) 111 (100) Ethnicity 76 AA (69) 29 Cau (26) 6 Other (5) 111 (100) Organ Damage 59 Major(53) 52 Minor(47) 111 (100) Thrombosis 35 Arterial (31) 14 Venous (13) 15 Both (14) 64 (58) Risk Contributor 24 OB (27) 14 APLs (13) 6 Hi-Risk (5) 44 (40) Bleeding 5 (4) 5 (4) African-American women, mean age 43.7 years, were predominantly represented in this patient group (69%). More than half the group had major organ involvement (renal, central nervous system) and vascular thrombosis. Obstetrical issues (high-risk pregnancy management or fetal loss, 22%), APLs (13%), and patients referred for high risk settings (pre-organ transplant, vascular surgery, hormone replacement therapy, 5%), and bleeding history (cerebral hemorrhage, vaginal bleeding, 4%) with hypercoagulability characterized the remainder of the study group. Hemostasis testing further distinguished this population from those previously reported. Neither the Factor V Leiden nor Prothrombin 20210 mutation was identified, while heterozygous (16%) and homozygous (2%) C677T mutations of MTHFR with hyperhomocysteinemia were found. Platelet hyperfunction, either activation threshold lowering (“sticky platelet syndrome”) and/or the homozygous PlA2 genotype, was found in 70% (78/111). Antiphospholipid antibodies were relatively infrequent, and in low concentration when present. Activity of several procoagulant factors (Fibrinogen, Factor VIII, von Willebrand factor, and plasminogen activator inhibitor 1 (PAI-1) was significantly increased, likely reflecting heredity-conditioned response to underlying inflammation. Several patients had mixed results with both pro- and anti-thrombotic tendencies. Platelet dense granule deficiency was associated with bruising/bleeding problems. Thus, in this urban, largely African-American SLE population with thrombosis or clinical settings posing high-risk of thrombosis, platelet hyperfunction and inflammatory procoagulant elevation appear to be of greater importance than antiphospholipid antibodies or the Factor V Leiden or Prothrombin mutations. These differences suggest that strategies for thrombosis prevention in this population should be directed primarily toward suppression of inflammation and modulation of platelet hyperfunction, i.e. toward control of the collagen-vascular disorder and inherited platelet hyperfunction, in the expectation that enlightened prevention may obviate the need for more aggressive life-long anticoagulation measures.
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Hirabayashi, Shinsuke, Brigitte Strahm, Sandra Urbaniak, Axel Karow, Annamaria Cseh, Marry Van Den Heuvel, Selin Aytag, et al. "Unexpected High Frequency of GATA2 Mutations in Children with Non-Familial MDS and Monosomy 7." Blood 120, no. 21 (November 16, 2012): 1699. http://dx.doi.org/10.1182/blood.v120.21.1699.1699.
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Abstract Abstract 1699 Haploinsufficiency of GATA2 results in three overlapping clinical entities unified by the predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): i) familial MDS/AML, ii) Emberger syndrome, and iii) an immunodeficiency termed monocytopenia with mycobacterium avium infections (MonoMAC)/ dendritic cell, monocyte, B- and NK-lymphoid deficiency (DCML). All these conditions manifest with a wide heterogeneity of symptoms predominantly affecting the hematologic and immune systems. To investigate the frequency of GATA2 defects in children and adolescents with MDS registered in the retrospective and prospective studies of the European Working Group of MDS and JMML in Childhood (EWOG-MDS), we first identified children from families with MDS/AML affecting multiple individuals, or children with MDS and preexisting lymphedema or immunodeficiency. We measured telomere length in hematopoietic cells to rule out an underlying defect of the telomerase complex, performed SNP-Array analysis, and excluded cases with germline RUNX1 aberrations. We identified heterozygous GATA2 mutations in 11 offspring of 8 distinct pedigrees: 4 previously reported missense mutations affecting the 2nd zinc finger (ZF2) T357A, S447R and R396Q/W; a novel exon 5 skipping mutation c.1018-10_1037del; and one novel nonsense mutation S201X and two novel frameshift mutations S139CfsX45, and V70LfsX114, all resulting in a premature stop codon prior to ZF2. The median age at diagnosis of MDS was 13.6 (11.0–16.9) years. Karyotype abnormalities were detected in 10/11 (91%) children: in 9 at initial presentation and in one during disease progression. Most patients carried the aneuploidies monosomy 7 (−7; n=5), trisomy 8 (+8; n=4), or both (n=1). Additionally, the recurrent translocation +1,der(1;7)(q10;p10) was detected in three patients. Interestingly, in one patient, the initial karyotype 45,XY,-7 transformed at relapse after hematopoietic stem cell transplantation (HSCT) to 46,XY,-7,+8,+21. Two additional patients with hypocellular MDS since adolescence and GATA2 hotspot mutations referred to us carried the aneuploidies −7 or +8, respectively. We next extended our study to children registered to EWOG-MDS in Germany with non-familial MDS and monosomy 7. Unexpectedly 8/51 (16%) patients with −7 carried GATA2 aberrations: 7 missense mutations within ZF2 and a germline 3.6Mb deletion 3q21.2–21.3 encompassing GATA2. In depth review of patient's history identified preexisting features of immunodeficiency as seen on laboratory tests and clinical exam (i.e. generalized verrucosis) in 5 of these 8 patients. The germline status was confirmed in cases where non-hematopoietic specimens were available. The combined analysis of all 21 patients identified additional comorbidities that, to our knowledge, were previously not reported in patients with GATA2-deficiency. These affected the urogenital system (nonselective glomerular proteinuria in one family, vesicoureteral reflux in a single case), neurodevelopmental delay and aggressive behavior in two cases, and ulcerative colitis in 2 families. At diagnosis of MDS, refractory cytopenia of childhood (RCC) was present in 43% of cases, while 33% presented with RAEB, and remaining 24% of patients with RAEBt and myelodysplasia related AML. Following HSCT as first line therapy, 10 of 12 children are alive, while all 4 children treated with AML-like therapy prior to HSCT succumbed. Five patients with RCC are followed closely with a watch and wait regimen. Finally, to study the genetic factors initiating clonal evolution, we subjected selected cases to targeted next generation sequencing of 103 cancer-associated genes. Based on preliminary data, some GATA2-deficient patients carry acquired mutations of genes previously reported in malignant processes (such as ASXL1, RUNX1, TET2, and 14 more genes). In summary, we identified a high frequency of GATA2 mutations among children and adolescents cases with sporadic MDS with monosomy 7 in children and adolescents. Some of these patients had a mild preexisting immunodeficiency. Outcome following HSCT without prior intensive chemotherapy was similar to what can be expected in children with MDS without GATA2 mutations. The genotype-phenotype correlation and mechanisms of clonal evolution are not understood and warrant further studies. Disclosures: No relevant conflicts of interest to declare.
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Giri, Neelam, Dalia Batista, Constantine Stratakis, Ekaterini T. Tsilou, Hung J. Kim, and Blanche P. Alter. "NCI Fanconi’s Anemia Cohort: Hematology and Beyond." Blood 106, no. 11 (November 16, 2005): 1057. http://dx.doi.org/10.1182/blood.v106.11.1057.1057.
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Abstract Fanconi’s anemia (FA) is an inherited DNA repair disorder with very high risks of aplastic anemia (AA), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and squamous cell carcinomas (SCC). Patients with FA often have physical anomalies, and may develop endocrinopathies; these phenotypic features may be associated with adverse outcomes. While most of these abnormalities have been previously-reported, only prospective follow-up of a meticulously-characterized cohort can accurately quantify the prevalence and natural history of each, and determine whether specific abnormalities are strongly predictive of adverse outcomes; such information will be invaluable for evidence-based management of FA patients. To begin our formal investigation of these associations, we reviewed the medical records of 42 study participants with FA, and began prospective evaluation of a subset of 20 patients who underwent multidisciplinary evaluation at the NIH Clinical Center (FA Clinical Center Cohort - CC). The remaining 22 patients were in the FA Field Cohort (FC). We studied 17 males and 25 females. The CC and FC subjects were similar except that the former were older at the time of study (median 21.5 vs 14.3 yrs in the FC, p=0.01) and had later onset of aplastic anemia (11.8 vs 7.2 yrs, p=0.03). 36/42 (86%) had at least one FA-related congenital anomaly. 11 patients were FANCA, 9 FANCC, and 1 each FANCD1/BRCA2, FANCF, and FANCJ. 34/42 (81%) had aplastic anemia; 10 had mild to moderate and 24 had severe AA. 13/33 (38 %) had clonal cytogenetic bone marrow abnormalities, some for >3 years. 8/42 (19%) developed MDS, one of whom evolved to AML. 12 (29%) underwent BMT, 9 of whom are alive (median 4 yrs, range 9 mo-21 yrs). 3 patients were hematopoietic somatic mosaics, in whom the diagnosis of FA was confirmed by detection of chromosome breakage in skin fibroblasts; all 3 had mutations in FANCA. 23/36 (64%) had hearing loss, 4 of whom had surgery for middle ear bony abnormalities. 28/32 had microcornea, 20 microophthalmia, 21 myopia, and 4 had ptosis. 32/36 (89%) had multiple café-au-lait spots and hyper/hypopigmented areas, and 2 had Sweet’s syndrome with MDS. 9/19 (47%) had leukoplakia; 1 biopsy was positive for SCC. 29/42 (69%) had one or more endocrinopathy, including short stature, hypothyroidism, growth hormone deficiency, glucose intolerance, diabetes, dyslipidemia and metabolic syndrome. 5 patients had mid-line structural anomalies of the brain, and 1 each had a lipoma and a brain tumor. 2 patients had nonalcoholic steatohepatitis, 1 had transfusional hemosiderosis and 1 had a liver adenoma. 7/8 adult females had infertility and premature ovarian failure; 5 males had hypogenitalia. 7/7 females and 2/4 males older than 18 yrs had osteopenia or osteoporosis. 9 patients had 12 prevalent cancers at a median age of 29 yrs (range 5–44), including 5 head and neck, 4 vulvar, and 1 each nasopharyngeal, skin and brain tumor. One of the head and neck SCC occurred 13 years after BMT. Prospective screening at the NIH identified recurrent head and neck SCC in 3 patients. We conclude that FA patients need to be examined frequently in comprehensive subspecialty clinics to identify and treat significant co-morbidities, including hematologic, endocrine, and neoplastic disorders. Analysis of genotype/phenotype/cancer correlations in FA will require thorough evaluations of the type outlined here, involving larger numbers of patients; accrual to, and follow-up of, our FA cohort continues.
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Sadler, Brooke, Charles Minard, Gabe Haller, Christina Gurnett, Sarah H. O'Brien, Allison P. Wheeler, Eric S. Mullins, et al. "Genotype Analysis of Adolescents with Heavy Menstrual Bleeding and Low Von Willebrand Activity - Report of a Multi-Center Study." Blood 136, Supplement 1 (November 5, 2020): 19–20. http://dx.doi.org/10.1182/blood-2020-135886.
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Introduction: Low von Willebrand factor (VWF) activity is prevalent in adolescents with heavy menstrual bleeding (HMB). There is a need to better genetically characterize these patients and improve our understanding of the pathophysiology of their bleeding risk. Methods: One of the main objectives of this multi-center, single arm, observational cohort study was to genotype adolescent females with HMB and low VWF (≥ 30 and ≤ 50 IU/dL) by means of whole exome sequencing (WES), to identify variants throughout the exome that may modulate risk for bleeding. Post-menarchal females < 21 years with HMB (defined as PBAC score >100) and low VWF were eligible for the study. All patients were enrolled by participating centers where blood samples were collected. Exome data for 86 cases and 900 unrelated pediatric (<21 years) controls taken from a genetic study on Chiari 1 Malformation (CM1) were aligned and sorted, and variants called using the Sentieon software package. Annotation including allele frequencies, function, amino acid change and Clinvar rating among others was obtained using ANNOVAR. Variants were retained if there was a genotype call rate of >0.8, GQ>20, AB between 0.3-0.7 and min DP>8. Case/control analyses included common and rare SNP associations, gene burden analysis of both rare nonsynonymous variants and ClinVar 'pathogenic' variants, and gene-set burden analyses. Variants were considered rare if they had a minor allele frequency of <1% in the Genome Aggregation Database (gnomAD). Count differences between cases/controls were determined by Fisher's Exact test. Results: Of the 113 subjects enrolled, 86 had sufficient blood samples collected for WES. The median age was 16.2 years (range: 11.5-19.6). 36% of cases showed variants in VWF vs. 26% of controls (p=0.14). After multiple test correction, WES revealed a significant common variant association in FERMT2 with an LD block with a frequency of 24% in cases and 6% in controls (p=7.5x10-7). Rare variant analysis showed a significant association with an intronic variant in ABCA13 (p=1.6x10-7). Among the gene burden analysis using rare nonsynonymous variants, 2 genes of interest passed multiple test correction: IL12B and DTNBP1. When using ClinVar 'pathogenic' variants as the input for the gene burden analysis, 4 genes of interest passed multiple test correction: HBM, MYLK, RUNX1 and CD36. Gene-set burden analysis revealed 5 significant pathways of interest, including platelet degranulation, platelet alpha granule lumen and erythrocyte differentiation. We then focused a subset of known risk genes and compared the number of missense, nonsense and ClinVar 'pathogenic' variants between cases and controls. GP6, and MTHFR had significantly more missense variants in controls vs. cases (p=0.003 and 0.01, respectively), and F13B approached significance, with more missense variants in controls than cases (p=0.07). Conclusion: We found VWF variants in 36% of subjects, in accordance with previous reports. We found novel SNP associations with variants in FERMT2 and ABCA13.FERMT2 encodes for the integrin, Kindlin 2, which has been shown to be critical for supporting vascular integrity. Several other relevant genes passed multiple test correction in gene burden analyses, including genes known to cause Hermansky-Pudlak syndrome (DTNBP1), familial platelet disorder (RUNX1), platelet glycoprotein IV deficiency (CD36) and aortic aneurysm (MYLK). This association with platelet disorders was strengthened by our gene-set burden results, which implicate several platelet-related pathways. These data suggest that while a subset of HMB patients may have their bleeding explained by variants in VWF, there is a role for other hemostasis, platelet biology and vascular integrity related gene variants which can contribute to the variation in bleeding severity in adolescents with low-VWF related HMB. Study supported by an investigator-initiated research grant from Shire US Inc., now part of Takeda Disclosures O'Brien: Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mullins:Takeda, Bayer: Other: Advisory Board. Sidonio:Takeda: Research Funding. Ragni:Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Srivaths:Shire US Inc., now part of Takeda: Research Funding.
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Haas, Peter S., Michael Schwabe, Chris Fisher, Richard Gibbons, Doug R. Higgs, Emanuel Bissé, and Michael Lübbert. "Two Novel Somatic Mutations of the ATRX Gene in Female Patients with Acquired Alpha Thalassemia of Myelodysplastic Syndrome (ATMDS)." Blood 108, no. 11 (November 16, 2006): 1765. http://dx.doi.org/10.1182/blood.v108.11.1765.1765.
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Abstract Introduction: In contrast to the classical thalassemias, two distinct thalassemias were recently described in which the molecular defect does not reside in the globin genes but in a transcriptional activator of alpha-globin genes. This protein, ATRX, is mutated in the rare inherited disease of alpha-thalassemias (AT) with mental retardation (ATR-X syndrome) whose affected individuals show a mild form of AT. In addition, and independent of the ATR-X syndrome, there have been approximately 100 case reports worldwide of the association of an acquired form of AT with hematological neoplasms, the large majority of those cases being MDS (ATMDS). The clinical characteristics of such patients encompass the typical features of the underlying hematological disorder plus microcytic anemia. The latter is due to massively reduced alpha-globin gene transcription resulting in excess hemoglobin H (HbH), as revealed by supravital staining of peripheral blood erythrocytes and hemoglobin electrophoresis. The molecular defect of ATMDS lies in a mutation of the ATRX protein and, thus, represents a form of acquired alpha-thalassemia. ATMDS shows a striking male preponderance for reasons that are as yet unclear. We systematically studied patients with MDS and low MCV and/or MCH but without iron deficiency for the possible presence of HbH cells (indicative of ATMDS). Supravital staining and sequence analysis of the ATRX gene were performed as described (Steensma et al. Blood.2004;103(6):2019–26). Results: Two female pts with AT-MDS were identified by this strategy. Pat 1 was a 69 year old pt who diagnosed with MDS of the subtype refractory cytopenia with multilineage dysplasia (RCMD), ringed sideroblasts and thrombocytosis (MDS/MPS overlap syndrome, JAK2 negative). She presented with microcytic anemia (Hb 7,5 g/dl, MCV 76,5 fl, MCH 22.4 pg). Supravital staining of a peripheral blood smear revealed massive erythrocytic HbH inclusions. Sequencing of the ATRX coding sequence revealed a novel missense mutation with an A>G transition in codon 2234. This mutation (D2234G) results in an amino acid substitution in ATRX exon 32. It represents the 14th ATRX mutation described thus far and, moreover, the first mutation detected in a female. Pat 2 (61 years old) with initially RCMD and microcytic anemia (Hb 10.4 g/ld, MCV 69 fl, MCH 15.2 pg) had increasing erythrocytosis of 6.93 Mio/μl maximum (also JAK2 negative). Molecular analysis of the ATRX gene also showed a not previously reported ATRX point mutation in exon 8 (G521A) which results in an amino acid change from cysteine to tyrosine and consequently in loss of a zinc finger. Conclusions: Though AT-MDS is mostly diagnosed in males we have identified two female patients, both showing novel ATRX somatic mutations. ATMDS might be more frequent in female than previously thought. Microcytic anemia in association with a hematological neoplasm, most commonly MDS, should alert to ATMDS which is easily diagnosed by supravital staining of peripheral blood smears. The remarkable thrombocytosis and erythrocytosis, respectively, in our 2 pts are at least suggestive of other phenotypic abnormalities possibly associated with the acquired ATRX genotypes on the MDS background.
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Papassotiriou, Ioannis, Pagona Flevari, Christos Poziopoulos, Sofia Zaliou, Vasilis Tsaousis, Katerina Larissi, Maria Dimopoulou, et al. "Non Invasive Evaluation of Bone Marrow Activity in Patients with Sickle Cell Disease: Correlation with Disease Features, Genotype, Markers of Erythropoiesis, Iron Metabolism and Hydroxyurea Treatment." Blood 134, Supplement_1 (November 13, 2019): 4821. http://dx.doi.org/10.1182/blood-2019-121622.
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Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by pathological polymerization of hemoglobin, increased red cell rigidity and poor microvascular blood flow with consequent tissue ischemia and infarction. Thus, hemolytic anemia, vaso-occlusion and vasculopathy are the hallmarks of its clinical presentation. The transferrin receptor (TfR) mediates the transport of iron into cells and the circulating TfR can be measured as soluble transferrin receptor (sTfR). sTfR levels are frequently used to establish the diagnosis of iron deficiency anemia, especially in the context of inflammation, but they also reflect bone marrow erythropoietic activity (BMA) and mass. Erythropoietic activity has been found to be the most important determinant of sTfR levels. In this context, we aimed to study and evaluate bone marrow activity in patients with compound heterozygous HbS and beta-thalassemia (HbS/βthal) based in sTfR measurements and explore possible correlations with of key features of the disease such as: the hemolytic component, vaso-occlusive crises (VOC), acute chest syndrome, venous thrombosis, arterial thrombosis including stroke, avascular necrosis, pulmonary hypertension, hydroxyurea therapy, inflammation and renal injury. along with other biomarkers of erythropoiesis and iron metabolism such as Placental Growth Factor (PlGF), Growth Differentiation Factor-15 (GDF-15), Ferritin and Hepcidin-25. Patients and Methods: Ninety adult Caucasian patients with HbS/βthal [49 patients under hydroxyurea (HU+) treatment and 41 patients without hydroxyurea (HU-) treatment], were included in this study, while 22 apparently healthy individuals of similar age and gender served as controls. None of the patients has received any transfusions at least 6-monthes before enrollment in the study. Along with hematologic and blood chemistry parameters determination, levels of circulating sTfR, PlGF, GDF-15 and Hepcidin-25 were measured in patients with HbS/βthal and controls using RUO and IVD immunoenzymatic techniques. BMA activity was calculated from the established formula: patient-sTFR/meanControl-sTFR. Results: We found that: sTfR levels were markedly elevated in all patients with HbS/βthal compared to controls (4.8±2.2 vs. 1.0±0.2 mg/L, p<0.001), resulting in a 1.6-11.9 fold increase of BMA. No correlation was found between BMA and disease features as well as regarding hydroxyurea treatment BMA (p>0.434). BMA correlated significantly with the markers of the erythropoietic and hemolytic component such as: Hemoglobin (r=-0.434, p<0.001); Reticulocyte Production Index (r=0.645, p<0.001); LDH (r=0.570, p<0.001); Billirubin (r=0.540, p<0.001), PlGF (r=0.597, p<0.001) and Hb A levels (r=-0.493, p<0.001), while no correlation was found between BMA and Hb F levels. Furthermore, BMA values correlated significantly only with GDF-15 (r=0.466, p<0.001), while interestingly no correlation was found between BMA and Ferritin and Hepcidin-25 levels alone (r=0.101, p>0.351 and r=-0.043, p>0.710, respectively), but a negative correlation was found between BMA and Hepcidin-25/Ferritin ratio, (r=-0.330, p=0.005). Conclusions: Our findings demonstrate that all patients with HbS/βthal studied have a significantly increased degree of erythroid BMA as assessed by measurements of sTfR levels. Erythroid BMA correlated significantly with Hepcidin/Ferritin ratio, which is an index of the degree of Hepcidin expression relative to iron overload. The correlation of erythroid BMA with Hb A levels, indicate the important role of βthal genotype in HbS/βthal disease. Furthermore, BMA is not related to hydroxyurea therapy and/or iron metabolism parameters in these patients. This implicates a likely complex action of hydroxyurea, which causes intermittent cytotoxic suppression of erythroid progenitors and cell stress signaling. The latter affects erythropoiesis, leading to recruitment of erythroid progenitors with increased HbF levels, although the number of erythroid progenitors -the main source of sTfR- remains stable. Disclosures Voskaridou: Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees.
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Vichinsky, Elliott, Lynne Neumayr, Sean Trimble, Alexis A. Thompson, Patricia Giardina, Alan R. Cohen, Thomas D. Coates, Ellis J. Neufeld, Althea M. Grant, and Jeanne Boudreaux. "Transfusion Complications in Thalassemia: A Report From the Centers for Disease Control and Prevention (CDC)." Blood 118, no. 21 (November 18, 2011): 340. http://dx.doi.org/10.1182/blood.v118.21.340.340.
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Abstract Abstract 340 Transfusions are the primary therapy for thalassemia (thal) but have significant cumulative risks. The Thalassemia Clinical Research Network recently highlighted the increased rate of alloimmunization in this population1. In 2004, the CDC established a national blood safety monitoring program for thal. The goals of the program were to monitor blood safety and strategies for the management of complications. This report focuses on immune and non-immune transfusion reactions. Methods: The CDC Thalassemia Blood Safety Network is a consortium of thal centers that follow patients longitudinally to determine the transfusion-related complications. Serial demographic, physical, and laboratory data are collected along with blood samples analyzed at the CDC. Data collected includes ethnicity, genotype, phenotype, transfusion data, immunizations, type of red cell product, degree of antigen matching, and chelation therapy. Chronically transfused (CT) patients were defined as requiring at least 8 transfusions annually. Intermittently transfused (IT) patients received less than 8 transfusions annually. Statistical analyses included continuous variables, logistic regression, and multivariant analysis. Results: There were 407 patients including 327 CT patients and 80 IT patients. The genotype of chronically transfused patients included: TM (81%), TI (6%), E-Beta-Thal (6%), and Hemoglobin H/CS (4%). The average age of CT patients was 22.3 years ± 13 and 21.4 years ± 17 in IT patients. The average units CT patients received was 149 ± 103. Hemosiderosis occurred in both patient groups and correlated with transfusion history. The average ferritin (m/L) in each group, respectively, was 2261 and 689. 78% of the total population has received chronic chelation therapy. Multiple organ dysfunction was common in the population, including cardiac disease (13%), gonadal failure (17%), growth hormone deficiency (8%), hypothyroidism (8%), hypoparathyroidism (1.2%), diabetes (10%), and thrombotic events (5.4%). 45% of the population was splenectomized. Transfusion reactions occurred in 48% of patients, including allergic (45%), multiple etiologies (32%), febrile (17%), and hemolytic (5%). Transfusion-associated infection included 58 cases of Hepatitis-C and 4 cases of HIV. Two Hepatitis-C cases occurred after specific blood testing was initiated. Recent cases of bacteremia, malaria, and Babesiosis have been documented. 21% of CT patients and 13% of IT patients developed an alloantibody. The most common antigen specificity included E (25%), Kell (13%), C (9%), Jka (5%), Kpa (4%), HLA (4%), V (3%), c (3%), D (2.5%), WA-1 (2.5%), and S (2.5%). 45% of alloimmunized patients had multiple antibodies. Race, transfusion burden, age and splenectomy predicted alloimmunization. Alloimmunization was found in 31% of splenectomized patients vs. 10% of non-splenectomized patients (p <.0001). The alloimmunization prevalence rose from 10% in young children compared to 54% in older patients. The average units transfused in patients with alloantibodies was 215 ± 104 vs. 126 ± 92 in patients without alloantibodies (p <.0001). Autoantibodies occurred in 6.5% of the population and increased with age and splenectomy. Alloimmunization increased the risk of autoantibodies: 26% of patients with an alloantibody had an autoantibody whereas only 2% of patients without alloantibodies had an autoantibody (p<.0001). Overall, 81% of patients with an autoantibody had an alloantibody. Local institutional policies were the major determinant in the type of units administered. In the last year, 32% of the units were washed and 80% radiated. 40% of patients received standard ABO matching, 47% limited phenotypic matching, and 12% full extended matching. Conclusion: Transfusion-related morbidity is a major problem in thal. Hemosiderosis immunologic and non-immunologic reactions are common. Transfusion-related infections have decreased but new, emerging pathogens have been noted. Disclosures: No relevant conflicts of interest to declare.
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Kawashima, Nozomu, Atsushi Narita, Xinan Wang, Yinyan Xu, Hirotoshi Sakaguchi, Sayoko Doisaki, Hideki Muramatsu, et al. "ALDH2 Polymorphism In Japanese Children With Acquired Aplastic Anemia." Blood 122, no. 21 (November 15, 2013): 3717. http://dx.doi.org/10.1182/blood.v122.21.3717.3717.
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Abstract Introduction Aplastic anemia is a syndrome of bone marrow failure (BMF) characterized by peripheral pancytopenia and marrow hypoplasia. Injury to hematopoietic cells, such as immune-mediated cytotoxicity, can cause aplastic anemia; the successful treatment of aplastic anemia using immunosuppressive therapy supports this hypothesis. Another proposed mechanism is an intrinsic defect of hematopoietic stem cells, which is the presumed major cause of congenital BMF, but this mechanism has not been definitively established in patients with acquired aplastic anemia. Aldehyde dehydrogenase 2 (ALDH2) deficiency resulting from a Glu504Lys substitution (A allele) is prevalent in the Japanese population: the A allele frequency is nearly 50% in the Japanese population. AA homozygotes show scarce catalysis of aldehydes, and GA heterozygotes display strongly reduced catalysis when compared with GG homozygotes. In patients with Fanconi anemia (FA), the most frequent inherited cause of BMF, progression of BMF was strongly accelerated in carriers of the GA and AA allele, possibly due to endogenous DNA damage caused by aldehydes that could not otherwise be repaired through the FA pathway. We studied the role of ALDH2 polymorphism in Japanese children with acquired aplastic anemia. Patients and Methods Seventy-nine Japanese children younger than 15 years who were referred to the Japanese Red Cross Nagoya First Hospital and Nagoya University Hospital were included in this study. Patients were excluded if they had paroxysmal nocturnal hemoglobinuria, toxic exposure to chemicals, or a clinical diagnosis of congenital BMF. Disease severity was classified based on the criteria of the International Aplastic Anemia Study Group as very severe (n = 10), severe (n = 41) and non-severe (n = 28). ALDH2 Glu487Lys polymorphisms (rs671) and alcohol dehydrogenases 1B (ADH1B) Arg47His polymorphisms (rs1229984) were genotyped with site-specific polymerase chain reaction with confronting two-pair primers. Statistical analysis was performed by Fisher’s exact test for categorical data and by Mann-Whitney U test for non-categorical data. P<0.05 was considered to indicate statistical significance. Results Forty children were genotyped with GG, 29 children with GA, and 10 children with AA. The distribution of the ALDH2 variant alleles in children with acquired aplastic anemia was not significantly different from the reported allele frequencies in the healthy Japanese population (GG = 1141, GA = 941, AA = 217; P = 0.4). However, age at diagnosis was significantly lower in children harboring AA (median 2 years, range 0.83-6 years) when compared with children harboring GG (median 10 years, range 1.6-16 years) and GA (median 10 years, range 1-14 years), respectively (P <0.01). In contrast, other clinical characteristics, including duration of disease onset to disease diagnosis, severity of the disease, and peripheral blood cell counts, were not significantly different among the ALDH2 groups. ADH1B may influence the concentration of aldehydes by catalyzing aliphatic alcohol. The ADH1B polymorphism (A allele) confers substantially higher enzymatic activity than the less active form (G allele), which is prevalent in Japanese, and thus may involve aldehyde toxicity. The distribution of the ADH1B variant alleles was not significantly different from the reported allele frequencies in the healthy Japanese population, and age at diagnosis of aplastic anemia was not significantly different among ADH1B variant allele groups in our cohort. Discussion ALDH2 catalyzes acetaldehyde as well as formaldehyde and other aldehydes, which can be genotoxic via DNA-protein crosslinking. Given that our cohort includes only children (alcohol intake is not a factor), intrinsic aldehydes that are mostly produced during lipid oxidation may damage hematopoietic stem cells, resulting in bone marrow failure. In conclusion, endogenous aldehydes may damage hematopoietic cells, resulting in early onset of disease in children with acquired aplastic anemia as well as in patients with FA. Disclosures: No relevant conflicts of interest to declare.
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Chen, Junmei, William Hobbs, Jennie Le, Peter J. Lenting, Philip G. De Groot, and Jose A. Lopez. "Active Von Willebrand Factor (VWF) in Plasma of Sickle Cell Patients Is An Indicator of Disease Severity." Blood 114, no. 22 (November 20, 2009): 2552. http://dx.doi.org/10.1182/blood.v114.22.2552.2552.
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Abstract Abstract 2552 Poster Board II-529 Vasoocclusion, hemolysis and oxidative stress are hallmarks of sickle cell anemia (SCA). Oxidants generated in SCA can stimulate endothelial cell release of ultra-large VWF (ULVWF), which is hyperactive in binding platelets and erythrocytes compared to normal plasma VWF, and binds sickle erythrocytes especially well. VWF levels in plasma as assessed by standard ELISA (VWF:Ag) have consistently been shown to be increased in patients with SCA; however, the extent of increase has not been demonstrated to correlate with disease severity. Given VWF's role as an adhesive ligand for several types of blood cells, including erythrocytes, we hypothesized that its contribution to SCA disease severity and pathophysiology would be better evaluated by measuring both its plasma concentration and its adhesive activity. We assessed several parameters of VWF quantity and function in plasma from SCA patients at disease baseline (n=13 including 9 homozygous sickle cell disease, 2 sickle-β+ thalassemia, 1 sickle-β0 thalassemia, and 1 hemoglobin SC ). Parameters included VWF:Ag, multimer pattern, ADAMTS13 activity, ADAMTS13 antigen, and VWF Activation Factor (VWF-AF). VWF-AF was determined using a llama-derived antibody fragment (nanobody) that detects an active conformation of the VWF A1 domain correlating with enhanced platelet binding. Elevated VWF-AF has been demonstrated in patients with type 2B von Willebrand disease, thrombotic thrombocytopenic purpura, HELLP syndrome, and other thrombotic disorders in which ULVWF is increased. VWF-AF is calculated as the ratio of nanobody binding in patient plasma to that of normal pooled plasma (NPP) at a given VWF:Ag level (the activation factor of NPP is set at 1). We also derived a novel, calculated measure of VWF reactivity present in plasma, termed Total Active VWF (TA-VWF), by multiplying the VWF-AF by VWF:Ag for each patient sample. As expected, all SCA patients had VWF:Ag levels that were higher than in NPP (1.2–3.6 fold) or in ethnically matched control plasma. VWF-AF was elevated in 9/13 individuals (0.6 to 4.4 fold). TA-VWF was increased in 11/13 patients (0.7 to 10.1 fold), which correlated with an increased size of VWF multimers on agarose gels. Individuals with the lowest VWF-AF and TA-VWF were those with genotypes consistent with less severe disease (sickle-β+ thalassemia and Hemoglobin SC). Among individuals with homozygous SS disease and sickle-β0 thalassemia, those with more severe clinical disease had higher TA-VWF than those with mild disease. Furthermore, TA-VWF significantly correlated with plasma lactate dehydrogenase (LDH) (P = 0.007), a measure of hemolysis that is associated with increased risk of pulmonary artery hypertension, leg ulcers, priapism, and sudden death in SCA. Consistent with this finding, TA-VWF also correlated (P < 0.01) with a non-invasive measures of pulmonary artery hypertension, the triscuspid regurgitent jet velocity. Increased VWF-AF was not correlated with increased VWF:Ag. We did not detect deficiency of ADAMTS13 activity using a sensitive assay measuring the ability of plasma ADAMTS13 to cleave a recombinant VWF A2 domain peptide substrate in vitro under static conditions. ADAMTS13 antigen in our patient population was similar to NPP. These findings suggest that elevated levels of active VWF predispose patients with SCA to disease complications. The increased VWF reactivity likely arises from increased endothelial secretion of ULVWF and activation of the VWF A1 domain in plasma of SCA patients. This also suggests that VWF reactivity is a pathophysiologic link between adhesion and hemolysis in SCA, and likely represents a novel therapeutic target. Disclosures: No relevant conflicts of interest to declare.
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Mendonca, Leonardo Oliveira, Alex Isidoro Prado, Izelda Maria Carvalho Costa, Marcia Bandeira, Rafael Dyer, Samar Freschi Barros, Karen Francine Khöler, et al. "Case Report: Expanding Clinical, Immunological and Genetic Findings in Sideroblastic Anemia With Immunodeficiency, Fevers and Development Delay (SIFD) Syndrome." Frontiers in Immunology 12 (April 14, 2021). http://dx.doi.org/10.3389/fimmu.2021.586320.
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Since the first description of the syndrome of sideroblastic anemia with immunodeficiency, fevers and development delay (SIFD), clinical pictures lacking both neurological and hematological manifestations have been reported. Moreover, prominent skin involvement, such as with relapsing erythema nodosum, is not a common finding. Up to this moment, no genotype and phenotype correlation could be done, but mild phenotypes seem to be located in the N or C part. B-cell deficiency is a hallmark of SIFD syndrome, and multiple others immunological defects have been reported, but not high levels of double negative T cells. Here we report a Brazilian patient with a novel phenotype of SFID syndrome, carrying multiple immune defects and harboring a novel mutation on TRNT1 gene.
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López-Nevado, Marta, Luis I. González-Granado, Raquel Ruiz-García, Daniel Pleguezuelo, Oscar Cabrera-Marante, Nerea Salmón, Pilar Blanco-Lobo, et al. "Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management." Frontiers in Immunology 12 (August 10, 2021). http://dx.doi.org/10.3389/fimmu.2021.671755.
Full textAbstract:
Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.
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Martinez, Caridad A., Frederic Ebstein, Sarah K. Nicholas, Marietta De Guzman, Lisa R. Forbes, Ottavia M. Delmonte, Marita Bosticardo, et al. "HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related auto-inflammatory disease." Blood, May 21, 2021. http://dx.doi.org/10.1182/blood.2021011005.
Full textAbstract:
Inborn errors of immunity that present with concomitant immunodeficiency and auto-inflammation are therapeutically challenging; furthermore, complexity is added when they are caused by mutations in genes that encode for proteins expressed beyond immune cells. The ubiquitin-proteasome system is the main intracellular proteolytic machinery and participates in most cellular processes by degrading ubiquitinated proteins. Mutations in proteasome subunits resulting in proteasome deficiency cause a severe auto-inflammatory disease characterized by chronic auto-inflammation neutrophilic dermatosis and fever, collectively referred to as Proteasome Associated Auto-inflammatory Syndromes (PRAAS). POMP is a chaperone for proteasome assembly and AD mutations in POMP cause a form of PRAAS with prominent immunodeficiency referred to as POMP-related auto-inflammation and immune dysregulation (PRAID) manifesting with recurrent, severe and opportunistic infections in addition to inflammatory features that are characteristic for all PRAAS disorders, most importantly early-onset neutrophilic dermatosis. JAK inhibitors partially control the disease in individuals with PRAAS, however life-threatening, recurrent and opportunistic infections in patients with POMP mutations limit immunosuppressive therapies and prompted consideration of hematopoietic stem cell transplant (HSCT). We describe successful HSCT in two patients with POMP deficiency. Despite POMP being ubiquitously expressed, the immunologic and auto-inflammatory phenotype were both ameliorated through HSCT which suggests that the clinical and immunological features of PRAID are predominantly derived from a proteasome defect in hematopoietic cells. To our knowledge, these are the first patients with a form of PRAAS cured by HSCT, opening new therapeutic possibilities for these diseases.