1/8. Interaction of an alpha( )-thalassemia deletion with either a highly unstable alpha-globin variant (alpha2, codon 59, GGC-->GAC) or a nondeletional alpha-thalassemia mutation (AATAAA-->AATAAG): comparison of phenotypes illustrating "dominant" alpha-thalassemia.Thalassemia syndromes and unstable hemoglobins traditionally represent two phenotypically separate disorders of hemoglobin synthesis. Highly unstable hemoglobin variants, however, often have phenotypic characteristics associated with both ineffective erythropoiesis (thalassemias) and peripheral hemolysis (unstable hemoglobins). Many highly unstable beta chain variants cause a dominant thalassemia-like phenotype, in which simple heterozygotes for such mutations have a clinical expression similar to thalassemia intermedia. The phenotypic expression of highly unstable alpha-globin variants is usually less severe, due mainly to a gene dosage effect, and they are often only characterized on interaction with other alpha-thalassemia mutations, whence they are classified as nondeletional alpha-thalassemia determinants. This study reports the clinical and hematological findings in five cases with rare alpha-thalassemia genotypes: a single patient with the thalassemic alpha2-globin gene codon 59 Gly-->Asp hemoglobin variant in trans to an alpha( )-thalassemia deletion, and four compound heterozygotes for the nondeletional alpha-thalassemia polyadenylation mutation (alpha2 gene AATAAA-->AATAAG or alpha(T-Saudi)alpha/-alpha) and an alpha( )-thalassemia deletion. Evaluation of the clinical and hematological features in these two analogous genotypes clearly demonstrates the more severe clinical expression associated with the alpha-thalassemic unstable hemoglobin variant. In addition, the case in this study with the codon 59 alpha chain variant provides a further example illustrating the spectrum of phenotypes associated with the alpha-thalassemic hemoglobinopathies.- - - - - - - - - - ranking = 1keywords = hemoglobinopathies (Clic here for more details about this article) |
2/8. An infant with severe combined immunodeficiency syndrome, an alpha-thalassemia trait and renal fanconi syndrome.We describe an infant with severe combined immunodeficiency syndrome and an alpha-thalassemia trait who developed a renal fanconi syndrome after his first stem cell transplantation. This syndrome consists of a generalized failure of proximal tubular reabsorption, which leads to a large number of metabolic disturbances. The etiology varies from inherited causes, including an idiopathic form, to acquired causes such as intoxications, immunological disorders and hemoglobinopathies. In this case report we discuss possible explanations of the fanconi syndrome in our patient.- - - - - - - - - - ranking = 1keywords = hemoglobinopathies (Clic here for more details about this article) |
3/8. Triple heterozygosity of a hemoglobin variant: hemoglobin Pyrgos with other hemoglobinopathies.This article is the first report of hemoglobin (Hb) Pyrgos along with other Hbs forming triple-heterozvgous patterns. Of 2 cases, the first occurred in a Thai girl with thalassemic facies, marked anemia, and hepatosplenomegaly, who had Hb Pyrgos in association with Hb H disease with Hb Constant Spring (CS). This case represents a triple heterozygosity comprising Hb Pyrgos, alpha-thalassemia 1, and Hb CS. Hb electrophoresis revealed an abnormal Hb in addition to Hbs CS, A2, A, Bart's, and H. This abnormal Hb moved slightly faster than Hb A but more slowly than Hb Bart's. polymerase chain reaction revealed that the abnormal Hb was caused by a missense mutation within codon 83 of the beta-globin gene (GGC to GAC) resulting in a glycine-to-aspartic acid substitution, which corresponds to Hb Pyrgos. The patient required blood transfusions by the age of 3 years. A splenectomy was performed when she was 5 years old, after which her hematocrit level remained above 32%. The second case was the patient's older sister who was also triple heterozygous (Hb Pyrgos, E, and CS) but was healthy.- - - - - - - - - - ranking = 4keywords = hemoglobinopathies (Clic here for more details about this article) |
4/8. Complex interaction of Hb Hekinan [alpha27(B8) Glu-Asp] and Hb E [beta26(B8) Glu-Lys] with a deletional alpha-thalassemia 1 in a Thai family.Hemoglobin (Hb) Hekinan (alpha27; Glu-Asp) is a rare alpha-chain variant found mainly in Japanese and Chinese whereas Hb E (beta26; Glu-Lys) is common among Southeast Asians. We report a hitherto undescribed condition in which these two variants co-segregate. The proband was a 25-yr-old Thai woman who was encountered with the presence of mild hypochromic microcytosis with Hb 8.2 g/dL, hematocrit (Hct) 26.0%, Mean Corpuscular Value (MCV) 68.6 fL, Mean Corpuscular Hemoglobin (MCH) 21.6 pg and Mean Corpuscular Hemoglobin Concentration (MCHC) 31.5 g/dL. Although Hb electrophoresis at alkaline pH did not show any abnormal band except Hb E in addition to Hb A, high performance liquid chromatography analysis revealed abnormal peaks at the Hb A and Hb E positions. dna analysis of the proband revealed a GAG-GAT mutation at codon 27 of the minor alpha1-globin gene for Hb Hekinan in trans to the South-east Asian (SEA) deletional alpha-thalassemia 1 determinant and a GAG-AAG mutation at codon 26 of the beta-globin gene for Hb E. She was therefore a triple heterozygote for these three anomalies. family study identified that her mother was a double heterozygote for Hb Hekinan and Hb E without alpha-thalassemia whereas her father was a classical Hb H disease patient. The genotype-phenotype relationship observed in this Thai family with complex hemoglobinopathies is presented and a simple dna assay based on the polymerase chain reaction methodology for rapid diagnosis of Hb Hekinan is described.- - - - - - - - - - ranking = 1keywords = hemoglobinopathies (Clic here for more details about this article) |
5/8. Rare thalassemic syndrome caused by interaction of Hb Questembert (alpha1 codon 131, TCT>CCT, Ser>Pro) with an alpha-thalassemia-2 deletion: implications for diagnosis and management.Abnormal globin chain biosynthesis may result in deficient quantity (thalassemia) or structural variation (abnormal hemoglobins) and traditionally, they represent two phenotypically distinct groups of disorders. However, the phenotypic expression of unstable hemoglobin variants often combine features of thalassemia together with variable peripheral hemolysis. To achieve definitive diagnosis in a child presenting with hemolytic anemia along with features associated with thalassemia intermedia, we evaluated clinical, hematological, biochemical, globin biosynthetic and molecular data. Definitive diagnosis was achieved by dna analysis which characterized the proband to be a compound heterozygote for a common alpha-thalassemia-2 deletion (3.7 kb) and Hb Questembert (alpha131[H14] Ser>Pro) caused by a C>T mutation in codon 131 of the alpha1 globin gene in trans. The phenotype of thalassemia intermedia with marked dyserythropoiesis, found in patients inheriting alpha-thalassemia mutations along with unstable alpha-globin variants (i.e., alpha-thalassemic hemoglobinopathies), represents a distinct type of thalassemic syndrome. The proband in this study additionally had variable peripheral hemolysis, presumably related to characteristics of the unstable Hb Questembert. There is minimal experience for the management of such atypical cases and this case illustrates that it is probably insufficient to monitor clinical status in patients with such hemoglobinopathies based only on the levels of hemoglobin.- - - - - - - - - - ranking = 2keywords = hemoglobinopathies (Clic here for more details about this article) |
6/8. Hb Q-thailand [alpha 74(EF3)Asp-->His]: gene organization, molecular structure, and dna diagnosis.Hb Q-thailand [alpha 74(EF3)Asp-->His] is often found in thailand, china, and other Southeast Asian countries. The alpha-Q-thailand gene is strongly linked to an alpha gene deletion and has important implications in the identification and diagnosis of hemoglobinopathies and thalassemias. The alpha-Q-thailand mutation was previously mapped to the alpha 1 gene in a study of Chinese patients. In this paper, a Thai patient with Hb Q-thailand/Hb H disease and his mother were studied at the dna level, and the gene organization of Hb Q-thailand in the Thai patient was found to be the same as that of Chinese patients (i.e. the Hb Q-thailand gene is located on the alpha 1 gene of chromosome #16, while the -4.2 kb or leftward deletion involves the alpha 2 gene). Also, the GAC-->CAC mutation proposed at codon 74, has been confirmed by dna sequencing and a simple and accurate method for diagnosis of the Hb Q-thailand variant has been developed based on restriction enzyme analysis. Since the GAC-->CAC mutation generates new cutting sites for both restriction enzymes Apa LI and Hgi AI, polymerase chain reaction amplification of a specific region around codon 74, followed by digestion with these enzymes and agarose gel electrophoresis of the digested products, permits rapid and accurate identification of Hb Q-thailand.- - - - - - - - - - ranking = 1keywords = hemoglobinopathies (Clic here for more details about this article) |
7/8. Three new alpha-thalassemia point mutations ascertained through newborn screening.We report three new alpha-thalassemia (thal) point mutations detected during newborn screening for hemoglobinopathies. The first mutation is a single nucleotide deletion (-A) that abolishes the translation initiation codon of the alpha2-globin gene, detected in a newborn of Hmong ethnicity who carried the Southeast Asian alpha(0)-thal deletion (alpha(T)alpha/- -(SEA)). The second mutation, a frameshift caused by a single nucleotide deletion in exon 2 of the alpha1-globin gene [codon 78 (-C)], was detected in a Black/Chinese newborn who also carried the Southeast Asian alpha0-thal deletion (alphaalpha(T)/- -(SEA)). The third mutation was a frameshift in exon 3 of the alpha2-globin gene, codons 113/114 (-C). This mutation was detected in a newborn who carried the 3.7 kb alpha( )-thal deletion (alpha(T)alpha/-alpha(3.7)).- - - - - - - - - - ranking = 1keywords = hemoglobinopathies (Clic here for more details about this article) |
8/8. Lack of evidence of permanent engraftment after in utero fetal stem cell transplantation in congenital hemoglobinopathies.The use of fetal hematopoietic stem cells for in utero transplantation to create permanent hematochimerism represents a new concept in fetal therapy. In one fetus with alpha-thalassemia, one with sickle cell anemia, and one with beta-thalassemia, we have transplanted fetal liver cells obtained from legal abortions in gestational weeks 6-11. The fetus with alpha-thalassemia was transplanted twice during pregnancy, in the 15th (20.4 x 10(8) cells/kg) and in the 31st weeks of gestation (1.2 x 10(8) cells/kg), and is now two years of age. One fetus with sickle cell anemia received its transplant in the 13th week of gestation (16.7 x 10(8) cells/kg), and is now one year old. The fetus with beta-thalassemia was transplanted in 18th week (8.6 x 10(8) cells/kg), and is now three months old. Engraftment was evaluated by chromosomal analysis (sex chromosomes), red cell phenotyping, HLA class I and II typing, and PCR (polymerase chain reaction) for y chromosome-specific sequences and dna polymorphisms in cord and peripheral blood. The children with alpha- and beta-thalassemia underwent bone marrow aspirations at 3 and 7 months of age, respectively. In neither of these cases were we able to detect convincing evidence of stem cell engraftment. Thus, the administration of fetal stem cells to fetal recipients after the 12th week of gestation did not result in permanent hematochimerism. It remains to be determined whether the engraftment process can be promoted by earlier transplantations and/or higher cell doses.- - - - - - - - - - ranking = 4keywords = hemoglobinopathies (Clic here for more details about this article) |