Clinical features and molecular analysis of acquired hemoglobin H disease

Higgs, Douglas R.; Wood, W. G.; Barton, Carol; Weatherall, D. J.

doi:10.1016/0002-9343(83)91189-0

Cited by 47 publications

(33 citation statements)

References 24 publications

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“…Table I summarizes main clinical and biological characteristics of the patients with ATRX gene mutation. Their median age was 76 and 5 were men, in accordance with published literature [1]. Of the six patients, 1 had RCUD, 1 CMML, 1 RAEB-2, and 3 RAEB-1.…”

Section: Methodssupporting

confidence: 82%

“…Acquired a-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by somatic missense mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS [1,2]. The ATRX protein is a chromatin-remodeling factor that may act as a transcriptional cofactor and plays an important role in the epigenetic regulation of gene expression [3].…”

Section: Introductionmentioning

confidence: 99%

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Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis

et al. 2015

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Acquired a-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients.

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Section: Methodssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis

et al. 2015

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“…3 In the present case, a hypochromic microcytic blood film ( Figure 1A) prompted further study to elucidate the underlying molecular defect. In contrast to most previously reported cases of ATMDS in which patients who have not undergone transfusion have had more than 10% HbH-containing red blood cells, here supravital staining demonstrated only 0.11% erythrocytes containing HbH inclusions ( Figure 1B).…”

Section: Resultsmentioning

confidence: 72%

“…3 In most patients with ATMDS, a substantial proportion of red blood cells contain HbH inclusions after supravital staining, and severely decreased ␣-globin chain synthesis is paralleled by diminished ␣-globin cytoplasmic and nuclear mRNA levels. 3,4 The common inherited forms of ␣-thalassemia are frequently a consequence of deletions or point mutations affecting the duplicated ␣-globin genes (␣␣/␣␣) on chromosome 16 or, less commonly, deletions of the remote regulatory elements that control ␣-globin expression. 5,6 Germline mutations of ATRX, an X-linked gene encoding a chromatin remodeling protein that regulates the expression of diverse genes, cause mild ␣-thalassemia associated with developmental abnormalities (ATR-X syndrome).…”

Section: Introductionmentioning

confidence: 98%

“…2 Rarely, MDS patients with striking hypochromia, microcytosis, and anisopoikilocytosis are found to have acquired hemoglobin H (HbH) disease (␣-thalassemia); this constellation of findings has been called ␣-thalassemia myelodysplastic syndrome (ATMDS). 3 In most patients with ATMDS, a substantial proportion of red blood cells contain HbH inclusions after supravital staining, and severely decreased ␣-globin chain synthesis is paralleled by diminished ␣-globin cytoplasmic and nuclear mRNA levels. 3,4 The common inherited forms of ␣-thalassemia are frequently a consequence of deletions or point mutations affecting the duplicated ␣-globin genes (␣␣/␣␣) on chromosome 16 or, less commonly, deletions of the remote regulatory elements that control ␣-globin expression.…”

Section: Introductionmentioning

confidence: 98%

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Deletion of the α-globin gene cluster as a cause of acquired α-thalassemia in myelodysplastic syndrome

Steensma

Viprakasit

Hendrick

et al. 2004

Blood

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IntroductionThe myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow disorders characterized by ineffective clonal hematopoiesis, acquired genomic instability, and variable risk for transformation to acute leukemia. 1 Most patients with MDS have macrocytic or normocytic anemia, but occasional patients have microcytic red blood cell indices. 2 Rarely, MDS patients with striking hypochromia, microcytosis, and anisopoikilocytosis are found to have acquired hemoglobin H (HbH) disease (␣-thalassemia); this constellation of findings has been called ␣-thalassemia myelodysplastic syndrome (ATMDS). 3 In most patients with ATMDS, a substantial proportion of red blood cells contain HbH inclusions after supravital staining, and severely decreased ␣-globin chain synthesis is paralleled by diminished ␣-globin cytoplasmic and nuclear mRNA levels. 3,4 The common inherited forms of ␣-thalassemia are frequently a consequence of deletions or point mutations affecting the duplicated ␣-globin genes (␣␣/␣␣) on chromosome 16 or, less commonly, deletions of the remote regulatory elements that control ␣-globin expression. 5,6 Germline mutations of ATRX, an X-linked gene encoding a chromatin remodeling protein that regulates the expression of diverse genes, cause mild ␣-thalassemia associated with developmental abnormalities (ATR-X syndrome). 7 ATRX mutations down-regulate the expression of all 4 ␣-globin genes, but the ␣-globin cluster itself is normal.Recently, we have shown that acquired, somatic mutations in the ATRX gene can also underlie ATMDS syndrome. 8,9 To date, 12 unique pathologic ATRX mutations have been found in patients with typical features of ATMDS, including striking "thalassemic" blood pictures, substantial amounts (more than 10%) of HbH, and severely reduced ␣/␤ globin chain biosynthesis ratios. 8,9 However, we have also studied several patients with MDS who have hypochromic, microcytic, red blood cell morphology, but in whom HbH inclusions are only present in a small proportion of erythrocytes or cannot be detected at all. To date, none of these patients have been shown to have mutations in the ATRX gene; the underlying molecular defect remains unknown.Here we report acquired ␣-thalassemia and rare HbH inclusions in an MDS patient. In contrast to previously reported cases of ATMDS, an abnormal hematopoietic clone in this patient had an acquired deletion involving the telomeric region of one allele of chromosome 16, removing 2 of the 4 ␣-genes (ie, genotype ϪϪ/␣␣). This case illustrates a second, less severe mechanism by which ␣-thalassemia may occur as an acquired abnormality in the context of hematologic malignancy. Study designA 72-year-old white British man had microcytic, hypochromic anemia (hemoglobin count, 10.4 g/dL; mean corpuscular volume, 64 fL; mean corpuscular hemoglobin level, 21.7 pg) and neutropenia (leukocyte count, 4.8 ϫ 10 9 /L with 14.7% neutrophils). Two years earlier, he had undergone partial pneumonectomy for localized lung carcinoma; at that time complete blood count finding...

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Juvenile myelomonocytic leukemia (JMML) with the hematologic phenotype of severe β thalassemia

et al. 1998

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A 3-year-old Filipino-American child with recurrent fever, splenomegaly, anemia, and thrombocytopenia, was found to have a hemoglobin F level of 76.9%. His reticulocyte count was elevated (4.3%), and erythroblasts were present in his peripheral blood. The child's erythrocytes were microcytic (MCV 66.9 fl) but his serum ferritin level was normal. His bone marrow at initial presentation demonstrated normal cellularity without an increase in blast cells. The disease progressed with worsening anemia, leukocytosis, and thrombocytopenia, with increased blasts in his marrow and the appearance of a medi-astinal mass. His liver, spleen, and lymph nodes were found to be infiltrated with myelo-blasts, supporting a diagnosis of juvenile myelomonocytic leukemia (JMML). Analysis of the child's Hb F showed a G / A ratio of 2.2, which was within the characteristic range for JMML. A globin synthesis study using blood reticulocytes showed an /non-globin synthesis ratio of 2.24, typical of severe homozygous thalassemia. Southern blot analysis of blood-leukocyte DNA from the patient and his parents demonstrated no apparent abnormality in the-globin gene promoter or coding regions. The elevated level of Hb F in this child with JMML appeared to be part of an acquired Cooley's anemia-like hema-tologic phenotype. Am. J. Hematol. 58:67-71, 1998.

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Clinical features and molecular analysis of acquired hemoglobin H disease

Cited by 47 publications

References 24 publications

Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis

Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis

Deletion of the α-globin gene cluster as a cause of acquired α-thalassemia in myelodysplastic syndrome

Juvenile myelomonocytic leukemia (JMML) with the hematologic phenotype of severe β thalassemia

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