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Gordon W. Stewart - One of the best experts on this subject based on the ideXlab platform.
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south east asian ovalocytosis and the cryohydrocytosis form of Hereditary Stomatocytosis show virtually indistinguishable cation permeability defects
British Journal of Haematology, 2011Co-Authors: Nicole Gabillat, Gordon W. Stewart, Penny J Harrison, Jeroen S Goede, Corrina Mcmahon, L BruceAbstract:The Hereditary stomatocytoses are a group of dominantly inherited conditions in which the osmotic stability of the red cell is compromised by abnormally high cation permeability. This report demonstrates the very marked similarities between the cryohydrocytosis form of Hereditary Stomatocytosis and the common tropical condition south-east Asian ovalocytosis (SAO). We report two patients, one showing a novel cryohydrocytosis variant (Ser762Arg in SLC4A1) and a case of SAO. Both cases showed a mild haemolytic state with some stomatocytes on the blood film, abnormal intracellular sodium and potassium levels which were made markedly abnormal by storage of blood at 0°C, increased cation 'leak' fluxes at 37°C and increased Na(+) K(+) pump activity. In both cases, the anion exchange function of the mutant band 3 was destroyed. Extensive electrophysiological studies comparing the cation leak and conductance in Xenopus laevis oocytes expressing the two mutant genes showed identical patterns of abnormality. These data are consistent with the cryohydrocytosis form of Hereditary Stomatocytosis and we conclude that the cation leak in SAO is indistinguishable from that in cryohydrocytosis, and that SAO should be considered to be an example of Hereditary Stomatocytosis.
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membrane raft actin deficiency and altered ca2 induced vesiculation in stomatin deficient overhydrated Hereditary Stomatocytosis
Biochimica et Biophysica Acta, 2008Co-Authors: Katie D Wilkinson, Gordon W. Stewart, Jane E Turner, Edward T Parkin, Ashley E Garner, P Harrison, Mark Crawford, Nigel M HooperAbstract:In overhydrated Hereditary Stomatocytosis (OHSt), the membrane raft-associated stomatin is deficient from the erythrocyte membrane. We have investigated two aspects of raft structure and function in OHSt erythrocytes. First, we have studied the distribution of other membrane and cytoskeletal proteins in rafts by analysis of detergent-resistant membranes (DRMs). In normal erythrocytes, 29% of the actin was DRM-associated, whereas in two unrelated OHSt patients the DRM-associated actin was reduced to <10%. In addition, there was a reduction in the amount of the actin-associated protein tropomodulin in DRMs from these OHSt cells. When stomatin was expressed in Madin-Darby canine kidney cells, actin association with the membrane was increased. Second, we have studied Ca2+-dependent exovesiculation from the erythrocyte membrane. Using atomic force microscopy and proteomics analysis, exovesicles derived from OHSt cells were found to be increased in number and abnormal in size, and contained greatly increased amounts of the raft proteins flotillin-1 and -2 and the calcium binding proteins annexin VII, sorcin and copine 1, while the concentrations of stomatin and annexin V were diminished. Together these observations imply that the stomatin-actin association is important in maintaining the structure and in modulating the function of stomatin-containing membrane rafts in red cells.
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dehydrated Hereditary Stomatocytosis is associated with neonatal hepatitis
British Journal of Haematology, 2004Co-Authors: David C Rees, Margaret C. Chetty, Bernard Portmann, Colin Ball, Giorgina Mielivergani, Anna Nicolaou, Gordon W. StewartAbstract:Summary Dehydrated Hereditary Stomatocytosis (DHSt) is an inherited haemolytic anaemia associated with increased red cell membrane permeability to Na + and K + . It is increasingly recognized that a syndrome of self-limiting perinatal ascites can accompany the haemolysis. The cause of the perinatal ascites is unknown, and it has been argued that this could be due to cardiovascular, hepatic or lymphatic problems. We describe the case of a 16-year-old girl who presented neonatally with abnormal liver function tests and ascites. She was extensively investigated at that time. A liver biopsy showed hepatitis and fatty changes. Her ascites resolved within 6 months. At the age of 15 years, she developed an episode of acute haemolysis and was re-investigated. A diagnosis of DHSt was made. Pseudohyperkalaemia, due to ex vivo loss of K + from red cells, was present. This study confirms the previously noted association of DHSt, pseudohyperkalaemia and perinatal ascites, and suggests that the latter is of predominantly hepatic origin.
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dehydrated Hereditary Stomatocytosis with transient perinatal ascites
Archives of Disease in Childhood-fetal and Neonatal Edition, 2003Co-Authors: Anna Basu, Margaret C. Chetty, Gordon W. Stewart, Thérèse Cynober, P Carey, J Delaunay, Sam RichmondAbstract:The case is reported of a mother and baby with dehydrated Hereditary Stomatocytosis and perinatal ascites, an autosomal dominant condition not previously reported in Britain. Recognition is important for the management of pregnancy and for avoidance of splenectomy which, if performed, can predispose the patient to fatal thromboembolic events.
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The “stomatin” gene and protein in overhydrated Hereditary Stomatocytosis
Blood, 2003Co-Authors: Britta Fricke, Achille Iolascon, Annette C. Argent, Margaret C. Chetty, Arnold Pizzey, E. Jane H. Turner, Monika Von Düring, Gordon W. StewartAbstract:In overhydrated Hereditary Stomatocytosis (OHSt), Coomassie- and silver-stained polyacrylamide gels show an apparently complete deficit of the 32-kDa membrane protein, stomatin. We have used an anti-stomatin antibody to examine peripheral blood films, bone marrow, splenic tissue, and hepatic tissue from these patients by immunocytochemistry. This technique revealed that, in fact, some red cells did show positive stomatin immunoreactivity; and consistent with this result, Western blot analysis of the red cell membranes confirmed that about one twentieth to one fiftieth of the normal amount of stomatin was in fact present. Flow cytometry, combining immunoreactive quantitation of stomatin expression with thiazole orange staining for reticulocytes, showed that in OHSt, it was the young cells that had more stomatin. Magnetic-activated cell separation studies, using beads to which an anti-transferrin receptor antibody was conjugated, confirmed that in OHSt there was a correspondence between expression of stomatin and the transferrin receptor. Immunocytochemistry and Western blotting revealed that in OHSt patients, the protein was present in spleen, liver, neutrophils, platelets, mono-cytes, and about 50% of the peripheral lymphocytes, with the same distribution as in healthy controls. Neither Southern blots, nor direct sequencing of multiple subclones of the cDNA, nor sequencing of amplicons from genomic DNA revealed any significant abnormality in stomatin gene sequence in these patients. The deficiency of stomatin from red cells appears to be due to a loss of stomatin from these red cells on maturation in the bond marrow and in the circulation. (C) 2003 by The American Society of Hematology.
Achille Iolascon - One of the best experts on this subject based on the ideXlab platform.
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a novel piezo1 mutation in a patient with dehydrated Hereditary Stomatocytosis a case report and a brief review of literature
Italian Journal of Pediatrics, 2020Co-Authors: Daniele Zama, Immacolata Andolfo, Roberta Russo, Achille Iolascon, Giulia Giulietti, Edoardo Muratore, Andrea PessionAbstract:Dehydrated Hereditary Stomatocytosis (DHS) or Hereditary xerocytosis is a rare, autosomal dominant hemolytic anemia characterized by macrocytosis, presence of stomatocytes and dehydration of red blood cells (RBCs). The dehydration is caused by a defect in cellular cation content. The most frequent expression of the pathology is hemolytic well-compensated anemia with high reticulocyte count, a tendency to macrocytosis, increased mean corpuscular hemoglobin concentration (MCHC) and mild jaundice. We here describe a new mutation of PIEZO1 gene, the most frequent mutated gene in DHS, in a family affected by Hereditary hemolytic anemia. We describe the case of a 12-years-old girl with well-compensated chronic hemolysis, increased MCHC and a father who had the same hematological characteristics. After excluding secondary causes of chronic hemolysis and enzymatic defects of the RBCs, microscopic observation of the peripheral blood smear, tests of RBC lysis, ektacytometry, SDS-PAGE and in last instance genetic analysis has been performed. This complex diagnostic workup identified a new variant in the PIEZO1 gene, never described in literature, causative of DHS. This pathogenetic variant was also detected in the father. This case report highlights the importance of a correct and exhaustive diagnostic-workup in patients with clinical suspicious for hemolytic anemia in order to make a differential diagnosis. This is relevant for the management of these patients because splenectomy is contraindicated in DHS due to high thrombotic risk.
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Hereditary Stomatocytosis an underdiagnosed condition
American Journal of Hematology, 2018Co-Authors: Immacolata Andolfo, Roberta Russo, Antonella Gambale, Achille IolasconAbstract:Hereditary stomatocytoses are a wide class of hemolytic anemias characterized by alterations of ionic flux with increased cation permeability that results in inappropriate shrinkage or swelling of the erythrocytes, and water lost or gained osmotically. The last few years have been crucial for new acquisitions in this field in terms of identifying new causative genes and of studying their pathogenetic mechanisms. This review summarizes the main features of erythrocyte membrane transport diseases, dividing them into forms with either isolated erythroid phenotype (nonsyndromic) or extra-hematological manifestations (syndromic), and focusing particularly on the most recent advances regarding dehydrated forms of Hereditary Stomatocytosis and familial pseudohyperkalemia.
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A novel erythroid anion exchange variant (Gly796Arg) of Hereditary Stomatocytosis associated with dyserythropoiesis
Haematologica, 2009Co-Authors: Achille Iolascon, Luigia De Falco, Maria Rosaria Esposito, Rosa Anna Avvisati, P Izzo, Carmelo Piscopo, Andrea Biondani, Antonella PantaleoAbstract:Background Stomatocytoses are a group of inherited autosomal dominant hemolytic anemias and include overhydrated Hereditary Stomatocytosis, dehydrated Hereditary Stomatocytosis, Hereditary cryohydrocytosis and familial pseudohyperkalemia. Design and Methods We report a novel variant of Hereditary Stomatocytosis due to a de novo band 3 mutation (p. G796R-band3 CEINGE) associated with a dyserythropoietic phenotype. Band 3 genomic analysis, measurement at of hematologic parameters and red cell indices and morphological analysis of bone marrow were carried out. We then evaluated the red cell membrane permeability and ion transport systems by functional studies of the patient’s erythrocytes and Xenopus oocytes transfected with mutated band 3. We analyzed the red cell membrane tyrosine phosphorylation profile and the membrane association of the tyrosine kinases Syk and Lyn from the Src-family-kinase group, since the activity of the membrane cation transport pathways is related to cyclic phosphorylation-dephosphorylation events. Results The patient showed mild hemolytic anemia with circulating stomatocytes together with signs of dyserythropoiesis. Her red cells displayed increased Na+ content with decreased K+content and abnormal membrane cation transport activities. Functional characterization of band 3 CEINGE in Xenopus oocytes showed that the mutated band 3 is converted from being an anion exchanger (Cl−, HCO3−) to being a cation pathway for Na+ and K+. Increased tyrosine phosphorylation of some red cell membrane proteins was observed in diseased erythrocytes. Syk and Lyn membrane association was increased in the patient’s red cells compared to in normal controls, indicating perturbation of phospho-signaling pathways involved in cell volume regulation events. Conclusions Band 3 CEINGE alters function from that of anion exchange to cation transport, affects the membrane tyrosine phosphorylation profile, in particular of band 3 and stomatin, and its presence during red cell development likely contributes to dyserythropiesis.
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band 3ceinge gly796arg mutation causes dehydrated Hereditary Stomatocytosis dhs with dyserythropoietic phenotype
Blood, 2008Co-Authors: Luigia De Falco, Maria Rosaria Esposito, Rosa Anna Avvisati, P Izzo, Carmelo Piscopo, Andrea Biondani, Lucia De Franceschi, Achille IolasconAbstract:Stomatocytosis is an inherited autosomal dominant hemolytic anemia and includes overhydrated Hereditary Stomatocytosis (OHS), dehydrated Hereditary Stomatocytosis (DHS), Hereditary cryohydrocytosis (CHC) and familial pseudohyperkalemia (FP). Here, we report a novel variant of Hereditary Stomatocytosis due to a de-novo band 3 mutation due to G>A transition at nucleotide 2500 in exon 17 (p. G796R, band3CEINGE) associated with dyserythropoietic phenotype. This 43-years-old Caucasian female (II-2) with unrelated parents was admitted to our hospital for mild anemia evaluation. The patient was in good health until 7 years when she frequently experienced asthenia. Anemia was first recognized at the age of eighth years with presence of jaundice and hyperchromic urine, but she had never received blood transfusions. We observed a mild hypochromic macrocytic anemia with a hemoglobin level of 11.5 g/dL, a mean cell volume (MCV) of 110 fL, and a mean hemoglobin concentration (MCH) of 36.1 pg, the reticulocyte count was 64 × 103/μL. There was a typical hemolytic features: high levels of indirect bilirubin (3.48 mg/dL) and lactate dehydrogenase ( 567 U/l, v.n. 240– 480 U/l ) with negativity at direct and indirect Coomb’s test. Spleen was enlarged and ultrasonography detected 15 cm of longitudinal size. She was cholecystectomized at the age of 14 years because of numerous symptomatic small stones. Serum iron, soluble transferrin receptor, serum ferritin and transferrin saturation levels were all increased, while the transferrin was in the normal range.Other blood tests including osmotic fragility with incubated and fresh erythrocytes, serum electrolytes, B12 and folate levels, erythrocyte enzyme levels, EMA test and Pink test were normal. Peripheral blood smear showed anisopoikilocytosis with rare stomatocytes and no spherocytes. Bone marrow aspirate showed remarkable dyserythropoiesis with increased number of erythroblasts and binucleate erythroblasts, basophilic erythroblasts with alterations, irregular nuclei maturation, intererythroblastic bridges and erythroblasts with basophilic stippling. She received since the age of 14 yrs a diagnosis for congenital dyserythropoietic anemia type I. Patients red cells showed increase Na+ content and decrease K+ content; reduced Na-K pump activity and increased Na-H exchange, NKCC cotransport and KCC cotransport activities. We then functionally characterized band 3 CEINGE in Xenopus oocytes, showing that the mutated band 3 is converted from anion exchanger (Cl−, HCO3 −) function to unregulated cation pathway for Na+ and K+. The mutated band 3 was also associated with increased tyrosine phosphorylation pattern of some red cell membrane proteins. During erythropoiesis band 3 protein is the last cytoskeletal protein to appear, thus the dyserythropoietic phenotype may be related to a possible role of the mutated band 3 in perturbation of cytoskeleton assembly in the late stage of erythropoiesis, allowing us to conclude for a new variant of Stomatocytosis with dyserythropoietic phenotype.
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The “stomatin” gene and protein in overhydrated Hereditary Stomatocytosis
Blood, 2003Co-Authors: Britta Fricke, Achille Iolascon, Annette C. Argent, Margaret C. Chetty, Arnold Pizzey, E. Jane H. Turner, Monika Von Düring, Gordon W. StewartAbstract:In overhydrated Hereditary Stomatocytosis (OHSt), Coomassie- and silver-stained polyacrylamide gels show an apparently complete deficit of the 32-kDa membrane protein, stomatin. We have used an anti-stomatin antibody to examine peripheral blood films, bone marrow, splenic tissue, and hepatic tissue from these patients by immunocytochemistry. This technique revealed that, in fact, some red cells did show positive stomatin immunoreactivity; and consistent with this result, Western blot analysis of the red cell membranes confirmed that about one twentieth to one fiftieth of the normal amount of stomatin was in fact present. Flow cytometry, combining immunoreactive quantitation of stomatin expression with thiazole orange staining for reticulocytes, showed that in OHSt, it was the young cells that had more stomatin. Magnetic-activated cell separation studies, using beads to which an anti-transferrin receptor antibody was conjugated, confirmed that in OHSt there was a correspondence between expression of stomatin and the transferrin receptor. Immunocytochemistry and Western blotting revealed that in OHSt patients, the protein was present in spleen, liver, neutrophils, platelets, mono-cytes, and about 50% of the peripheral lymphocytes, with the same distribution as in healthy controls. Neither Southern blots, nor direct sequencing of multiple subclones of the cDNA, nor sequencing of amplicons from genomic DNA revealed any significant abnormality in stomatin gene sequence in these patients. The deficiency of stomatin from red cells appears to be due to a loss of stomatin from these red cells on maturation in the bond marrow and in the circulation. (C) 2003 by The American Society of Hematology.
Jean Delaunay - One of the best experts on this subject based on the ideXlab platform.
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alterations of red blood cell metabolome in overhydrated Hereditary Stomatocytosis
Haematologica, 2011Co-Authors: Dhouha Darghouth, Berengere Koehl, Jean Francois Heilier, Geoffrey Madalinski, Petra Bovee, Giel J C G M Bosman, Jean Delaunay, Christophe Junot, Paulhenri RomeoAbstract:Overhydrated Hereditary Stomatocytosis, clinically characterized by hemolytic anemia, is a rare disorder of the erythrocyte membrane permeability to monovalent cations, associated with mutations in the Rh-associated glycoprotein gene. We assessed the red blood cell metabolome of 4 patients with this disorder and showed recurrent metabolic abnormalities associated with this disease but not due to the diminished half-life of their erythrocytes. Glycolysis is exhausted with accumulation of ADP, pyruvate, lactate, and malate. Ascorbate metabolic pathway is altered probably due to a limited entry of dehydroascorbate. Although no major oxydative stress has been reported in patients with overhydrated Hereditary Stomatocytosis, we found decreased amounts of oxydized glutathione, creatine and ergothioneine, suggesting transporter abnormalities and/or uncharacterized oxydative stress. These results pinpoint major metabolic defects of overhydrated Hereditary Stomatocytosis erythrocytes and emphasize the relevance of red blood cell metabolomics for a better understanding of the pathophysiological bases of hemolytic anemia associated with erythrocyte abnormalities.
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evidence for imbalanced furosemide sensitive na k cotransport in Hereditary Stomatocytosis
Scandinavian Journal of Haematology, 2009Co-Authors: Bernadette Chailley, C Feo, R Garay, Georges Dagher, Richard Bruckdorfer, Siegmund Fischer, J P Piau, Jean DelaunayAbstract:The red cells from 5 related patients with Hereditary Stomatocytosis were investigated. Maximal rate constant of Na+ passive permeability was increased while that of K+ passive permeability was nearly normal. Ouabain-sensitive Na+ efflux was elevated. The Na+ component of furosemide-sensitive Na+, K+ cotransport was also increased. However, its K+ component, determined in 2 patients, remained within normal limits, thus departing from the strict 1:1 stoichiometry of the Na+, K+ cotransport system. Yet, intracellular Na+ and K+ concentrations displayed limited and inconstant changes. A variety of abnormally-shaped cells, including stomatocytes, were observed in scanning electron micrographs. Upon differential centrifugation, reticulocytes usually concentrated in the most dense region of the gradient. Red cell deformability, as studied by ektacytometry, was reduced. Membrane phosphatidylcholines and sphingomyelins were increased and decreased, respectively, where-as fatty acid distribution was unchanged. Membrane microviscosity was normal.
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dehydrated Hereditary Stomatocytosis mimicking familial hyperkalaemic hypertension clinical and genetic investigation
European Journal of Haematology, 2007Co-Authors: Thérèse Cynober, Jean Delaunay, S Grootenboer, G Tchernia, Genevieve Beaurain, Flavie Mathieu, Beatrice Fiquet, Xavier JeunemaitreAbstract:: Dehydrated Hereditary Stomatocytosis (DHS) is a rare dominant form of Hereditary haemolytic anaemia. In some families, pseudohyperkalaemia accompanies DHS. Familial hyperkalaemic hypertension (FHHt), a rare autosomal dominant form of arterial hypertension, is associated with genuine hyperkalaemia. We present a large French family in which DHS and FHHt were diagnosed independently in two separate branches. In branch A, mild DHS accompanied by pseudohyperkalaemia was found. In branch B, the proband and her daughter were initially diagnosed with FHHt, based on the coincidence of high blood pressure and hyperkalaemia. After finding out that branches A and B were related, reinvestigation of the affected members of branch B lead to the diagnosis of DHS, yielding the largest DHS kindred known in France. This allowed extensive linkage analysis based on 19 microsatellites markers in 12 affected and 10 unaffected members at 16q24.1qter, where one known DHS locus maps to. A maximal two-point LOD score (4.71 at theta = 0) was obtained for markers D16S3074 and D16S476. Haplotype analysis led to the definition of a new 11.5 cM disease interval with an upper limit at microsatellite D16S3037.
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the Hereditary stomatocytoses genetic disorders of the red cell membrane permeability to monovalent cations
Seminars in Hematology, 2004Co-Authors: Jean DelaunayAbstract:The Hereditary stomatocytoses are mostly accounted for by genetic disorders of red cell membrane permeability to monovalent cations. These conditions, all very rare, are comprised of a hemolytic anemia, frequently macrocytosis, and the presence of abnormally shaped red blood cells. The key test for diagnosis is osmotic gradient ektacytometry, which measures the osmotic resistance and hydration of the red blood cell; the curve depicting the temperature dependence of the cation leak is also important. Syndromes include familial pseudohyperkalemia (FP), which is devoid of hematological features, dehydrated Hereditary Stomatocytosis (DHS), and overhydrated Hereditary Stomatocytosis (OHS). Some forms of DHS may be a pleiotropic, showing pseudohyperkalemia and/or perinatal edema. Perinatal edema, if not properly treated, may be lethal but may also resolve spontaneously prior to or shortly after birth and never reappear. Hereditary cryohydrocytosis, type 1 (CHC 1) is characterized by a dramatic resumption of the leak in vitro as the temperature approaches 0 degrees C; cell hydration seems unaltered. In OHS, stomatin, a membrane protein, is sharply reduced; however, this is a secondary event and the primarily mutated protein remains unknown. Hereditary cryohydrocytosis, type 2 (CHC 2) presents similar to OHS, except that the leak dramatically increases close to 0 degrees C. In addition, hematological manifestations are associated with neurological disorders. Of critical practical importance is that splenectomy in DHS or OHS causes thromboembolic events that may be fatal. The genes involved in Hereditary stomatocytoses have yet to be identified. Apart from the 16q24-qter locus, related to subsets of DHS and FP, and a chromosome 2 locus assigned to a single case of FP, gene mapping has been difficult. The eventual discovery of individual genes will clarify complicated classification of the stomatocytoses, now based solely on phenotype.
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sub lethal hydrops as a manifestation of dehydrated Hereditary Stomatocytosis in two consecutive pregnancies
Prenatal Diagnosis, 2003Co-Authors: Sabine Grootenboermignot, G Tchernia, Aurore Cretien, Ingrid Laurendeau, Mariehelene Poissonnier, Valerie Doireau, Yves Brossard, Jean DelaunayAbstract:Dehydrated Hereditary Stomatocytosis (DHS) is a rare congenital hemolytic anemia mapping to 16q23-q24. We showed recently that it is part of a pleiotropic syndrome likely to display pseudohyperkalemia and/or different forms of fetal and placental fluid collections. Here, we report a woman with DHS. She had two consecutive pregnancies associated with severe fetal hydrops. Hydrops would probably have been lethal in the absence of appropriate removal of ascites and excess amniotic fluid. In utero exchange transfusion, performed once, was useless, because anemia was not pronounced enough to be the cause of the hydrops. In both newborns, ascites resolved within a week following birth and never recurred. The association of hydrops and hemolytic anemia suggests the possibility of DHS. Symptomatic treatment of the hydrops assists survival until spontaneous resorption occurs.
Immacolata Andolfo - One of the best experts on this subject based on the ideXlab platform.
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Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients
'MDPI AG', 2021Co-Authors: Immacolata Andolfo, Antonella Gambale, Barbara Eleni Rosato, Stefania Martone, Roberta Marra, Gian Luca Forni, Valeria Pinto, Magnus Göransson, Vasiliki Papadopoulou, Mathilde GavilletAbstract:Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of Hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All of the cases followed a diagnostic workflow based on a targeted next-generation sequencing panel of 86 genes causative of Hereditary red blood cell defects. We obtained an overall diagnostic yield of 84% of the tested patients. Monogenic inheritance was seen for 69% (107/155), and multi-locus inheritance for 15% (23/155). PIEZO1 and SPTA1 were the most mutated loci. Accordingly, 16/23 patients with multi-locus inheritance showed dual molecular diagnosis of dehydrated Hereditary Stomatocytosis/xerocytosis and Hereditary spherocytosis. These dual inheritance cases were fully characterized and were clinically indistinguishable from patients with Hereditary spherocytosis. Additionally, their ektacytometry curves highlighted alterations of dual inheritance patients compared to both dehydrated Hereditary Stomatocytosis and Hereditary spherocytosis. Our findings expand the genotypic spectrum of red blood cell disorders and indicate that multi-locus inheritance should be considered for analysis and counseling of these patients. Of note, the genetic testing was crucial for diagnosis of patients with a complex mode of inheritance
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a novel piezo1 mutation in a patient with dehydrated Hereditary Stomatocytosis a case report and a brief review of literature
Italian Journal of Pediatrics, 2020Co-Authors: Daniele Zama, Immacolata Andolfo, Roberta Russo, Achille Iolascon, Giulia Giulietti, Edoardo Muratore, Andrea PessionAbstract:Dehydrated Hereditary Stomatocytosis (DHS) or Hereditary xerocytosis is a rare, autosomal dominant hemolytic anemia characterized by macrocytosis, presence of stomatocytes and dehydration of red blood cells (RBCs). The dehydration is caused by a defect in cellular cation content. The most frequent expression of the pathology is hemolytic well-compensated anemia with high reticulocyte count, a tendency to macrocytosis, increased mean corpuscular hemoglobin concentration (MCHC) and mild jaundice. We here describe a new mutation of PIEZO1 gene, the most frequent mutated gene in DHS, in a family affected by Hereditary hemolytic anemia. We describe the case of a 12-years-old girl with well-compensated chronic hemolysis, increased MCHC and a father who had the same hematological characteristics. After excluding secondary causes of chronic hemolysis and enzymatic defects of the RBCs, microscopic observation of the peripheral blood smear, tests of RBC lysis, ektacytometry, SDS-PAGE and in last instance genetic analysis has been performed. This complex diagnostic workup identified a new variant in the PIEZO1 gene, never described in literature, causative of DHS. This pathogenetic variant was also detected in the father. This case report highlights the importance of a correct and exhaustive diagnostic-workup in patients with clinical suspicious for hemolytic anemia in order to make a differential diagnosis. This is relevant for the management of these patients because splenectomy is contraindicated in DHS due to high thrombotic risk.
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Data_Sheet_1_PIEZO1 Hypomorphic Variants in Congenital Lymphatic Dysplasia Cause Shape and Hydration Alterations of Red Blood Cells.pdf
2019Co-Authors: Immacolata Andolfo, Antonella Gambale, Francesco Manna, Gianluca De Rosa, Edoardo Errichiello, Barbara Eleni Rosato, Annalisa Vetro, Valeria Calcaterra, Gloria Pelizzo, Lucia De FranceschiAbstract:PIEZO1 is a cation channel activated by mechanical force. It plays an important physiological role in several biological processes such as cardiovascular, renal, endothelial and hematopoietic systems. Two different diseases are associated with alteration in the DNA sequence of PIEZO1: (i) dehydrated Hereditary Stomatocytosis (DHS1, #194380), an autosomal dominant hemolytic anemia caused by gain-of-function mutations; (ii) lymphatic dysplasia with non-immune fetal hydrops (LMPH3, #616843), an autosomal recessive condition caused by biallelic loss-of-function mutations. We analyzed a 14-year-old boy affected by severe lymphatic dysplasia already present prenatally, with peripheral edema, hydrocele, and chylothoraces. By whole exome sequencing, we identified compound heterozygosity for PIEZO1, with one splicing and one deletion mutation, the latter causing the formation of a premature stop codon that leads to mRNA decay. The functional analysis of the erythrocytes of the patient highlighted altered hydration with the intracellular loss of the potassium content and structural abnormalities with anisopoikolocytosis and presence of both spherocytes and stomatocytes. This novel erythrocyte trait, sharing features with both Hereditary spherocytosis and overhydrated Hereditary Stomatocytosis, complements the clinical features associated with loss-of-function mutations of PIEZO1 in the context of the generalized lymphatic dysplasia of LMPH3 type.
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Table_1_PIEZO1 Hypomorphic Variants in Congenital Lymphatic Dysplasia Cause Shape and Hydration Alterations of Red Blood Cells.docx
2019Co-Authors: Immacolata Andolfo, Antonella Gambale, Francesco Manna, Gianluca De Rosa, Edoardo Errichiello, Barbara Eleni Rosato, Annalisa Vetro, Valeria Calcaterra, Gloria Pelizzo, Lucia De FranceschiAbstract:PIEZO1 is a cation channel activated by mechanical force. It plays an important physiological role in several biological processes such as cardiovascular, renal, endothelial and hematopoietic systems. Two different diseases are associated with alteration in the DNA sequence of PIEZO1: (i) dehydrated Hereditary Stomatocytosis (DHS1, #194380), an autosomal dominant hemolytic anemia caused by gain-of-function mutations; (ii) lymphatic dysplasia with non-immune fetal hydrops (LMPH3, #616843), an autosomal recessive condition caused by biallelic loss-of-function mutations. We analyzed a 14-year-old boy affected by severe lymphatic dysplasia already present prenatally, with peripheral edema, hydrocele, and chylothoraces. By whole exome sequencing, we identified compound heterozygosity for PIEZO1, with one splicing and one deletion mutation, the latter causing the formation of a premature stop codon that leads to mRNA decay. The functional analysis of the erythrocytes of the patient highlighted altered hydration with the intracellular loss of the potassium content and structural abnormalities with anisopoikolocytosis and presence of both spherocytes and stomatocytes. This novel erythrocyte trait, sharing features with both Hereditary spherocytosis and overhydrated Hereditary Stomatocytosis, complements the clinical features associated with loss-of-function mutations of PIEZO1 in the context of the generalized lymphatic dysplasia of LMPH3 type.
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Hereditary Stomatocytosis an underdiagnosed condition
American Journal of Hematology, 2018Co-Authors: Immacolata Andolfo, Roberta Russo, Antonella Gambale, Achille IolasconAbstract:Hereditary stomatocytoses are a wide class of hemolytic anemias characterized by alterations of ionic flux with increased cation permeability that results in inappropriate shrinkage or swelling of the erythrocytes, and water lost or gained osmotically. The last few years have been crucial for new acquisitions in this field in terms of identifying new causative genes and of studying their pathogenetic mechanisms. This review summarizes the main features of erythrocyte membrane transport diseases, dividing them into forms with either isolated erythroid phenotype (nonsyndromic) or extra-hematological manifestations (syndromic), and focusing particularly on the most recent advances regarding dehydrated forms of Hereditary Stomatocytosis and familial pseudohyperkalemia.
Margaret C. Chetty - One of the best experts on this subject based on the ideXlab platform.
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dehydrated Hereditary Stomatocytosis is associated with neonatal hepatitis
British Journal of Haematology, 2004Co-Authors: David C Rees, Margaret C. Chetty, Bernard Portmann, Colin Ball, Giorgina Mielivergani, Anna Nicolaou, Gordon W. StewartAbstract:Summary Dehydrated Hereditary Stomatocytosis (DHSt) is an inherited haemolytic anaemia associated with increased red cell membrane permeability to Na + and K + . It is increasingly recognized that a syndrome of self-limiting perinatal ascites can accompany the haemolysis. The cause of the perinatal ascites is unknown, and it has been argued that this could be due to cardiovascular, hepatic or lymphatic problems. We describe the case of a 16-year-old girl who presented neonatally with abnormal liver function tests and ascites. She was extensively investigated at that time. A liver biopsy showed hepatitis and fatty changes. Her ascites resolved within 6 months. At the age of 15 years, she developed an episode of acute haemolysis and was re-investigated. A diagnosis of DHSt was made. Pseudohyperkalaemia, due to ex vivo loss of K + from red cells, was present. This study confirms the previously noted association of DHSt, pseudohyperkalaemia and perinatal ascites, and suggests that the latter is of predominantly hepatic origin.
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Four new cases of stomatin-deficient Hereditary Stomatocytosis syndrome: association of the stomatin-deficient cryohydrocytosis variant with neurological dysfunction
British journal of haematology, 2004Co-Authors: Britta Fricke, Philippe Quittet, Margaret C. Chetty, Arnold Pizzey, Helen G. Jarvis, C. D. L. Reid, Patricia Aguilar-martinez, A. Robert, Thérèse Cynober, William F. LandeAbstract:This report concerns congenitally Na(+)-K(+) leaky red cells of the 'Hereditary Stomatocytosis' class. Three new isolated cases and one new pedigree are described, and one previously reported case is expanded. In all cases, Western blotting of red cell membranes revealed a deficiency in the 32 kDa membrane protein, stomatin. All showed pronounced cation leaks at 37 degrees C with markedly abnormal intracellular Na(+) and K(+) concentrations, like all other such stomatin-deficient cases. Consistent with recent findings in two previously described British pedigrees, immunocytochemistry demonstrated that the deficiency of stomatin was not complete. On typical blood films, some red cells showed positive stomatin immunoreactivity, while most were negative, although in one case only a minority were negative. All platelets and neutrophils were stomatin positive. The cases differed markedly between themselves with regard to the temperature dependence of the passive leak to K(+). Three showed a simple monotonic temperature dependence, while two showed a minimum at around 20-25 degrees C, such that the cells were extremely leaky at 0 degrees C, giving the phenotype known as 'cryohydrocytosis'. These patients are the only two known cases of stomatin-deficient cryohydrocytosis. Both showed a congenital syndrome of mental retardation, seizures, cataracts and massive hepatosplenomegaly, probably defining a new haemato-neurological syndrome.
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dehydrated Hereditary Stomatocytosis with transient perinatal ascites
Archives of Disease in Childhood-fetal and Neonatal Edition, 2003Co-Authors: Anna Basu, Margaret C. Chetty, Gordon W. Stewart, Thérèse Cynober, P Carey, J Delaunay, Sam RichmondAbstract:The case is reported of a mother and baby with dehydrated Hereditary Stomatocytosis and perinatal ascites, an autosomal dominant condition not previously reported in Britain. Recognition is important for the management of pregnancy and for avoidance of splenectomy which, if performed, can predispose the patient to fatal thromboembolic events.
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The “stomatin” gene and protein in overhydrated Hereditary Stomatocytosis
Blood, 2003Co-Authors: Britta Fricke, Achille Iolascon, Annette C. Argent, Margaret C. Chetty, Arnold Pizzey, E. Jane H. Turner, Monika Von Düring, Gordon W. StewartAbstract:In overhydrated Hereditary Stomatocytosis (OHSt), Coomassie- and silver-stained polyacrylamide gels show an apparently complete deficit of the 32-kDa membrane protein, stomatin. We have used an anti-stomatin antibody to examine peripheral blood films, bone marrow, splenic tissue, and hepatic tissue from these patients by immunocytochemistry. This technique revealed that, in fact, some red cells did show positive stomatin immunoreactivity; and consistent with this result, Western blot analysis of the red cell membranes confirmed that about one twentieth to one fiftieth of the normal amount of stomatin was in fact present. Flow cytometry, combining immunoreactive quantitation of stomatin expression with thiazole orange staining for reticulocytes, showed that in OHSt, it was the young cells that had more stomatin. Magnetic-activated cell separation studies, using beads to which an anti-transferrin receptor antibody was conjugated, confirmed that in OHSt there was a correspondence between expression of stomatin and the transferrin receptor. Immunocytochemistry and Western blotting revealed that in OHSt patients, the protein was present in spleen, liver, neutrophils, platelets, mono-cytes, and about 50% of the peripheral lymphocytes, with the same distribution as in healthy controls. Neither Southern blots, nor direct sequencing of multiple subclones of the cDNA, nor sequencing of amplicons from genomic DNA revealed any significant abnormality in stomatin gene sequence in these patients. The deficiency of stomatin from red cells appears to be due to a loss of stomatin from these red cells on maturation in the bond marrow and in the circulation. (C) 2003 by The American Society of Hematology.
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allogeneic bone marrow transplantation for severe post splenectomy thrombophilic state in leaky red cell membrane haemolytic anaemia of the Stomatocytosis class
British Journal of Haematology, 2003Co-Authors: Jann Bergheim, Margaret C. Chetty, Daniel M Gore, Peter B Ernst, L Brinch, Gordon W. StewartAbstract:The tendency for thrombosis to occur if haemolysis persists after splenectomy is especially marked in "Hereditary Stomatocytosis", in which the red cell membrane "leaks" Na and K. A 21-year-old woman, who was splenectomized in childhood for a congenital haemolytic state, presented with major pulmonary embolism that recurred despite anticoagulation. Tests showed a significant cation leak with a "shallow-slope" abnormality in temperature dependence. Allogeneic bone marrow transplantation caused the thrombophilic state to cease and subsequently anticoagulation was stopped without recurrence of thromboembolism. However, she died 9 months after transplantation: iron overload, intensified by the transfusion demands of the transplant, was a major factor.