Association of mild and severely unstable alpha chain variants: the first observation of a compound heterozygote with Hb Setif [alpha94(G1)Asp-->Tyr (alpha2)] and Hb Agrinio [alpha29(B10)Leu-->Pro (alpha2)] in a Greek family.

Hb Setif is a relatively rare, mildly unstable alpha2-globin hemoglobin (Hb) variant first described in an Algerian family, and subsequently in various populations of the Mediterranean region and the Middle East. Hb Agrinio is a highly unstable variant, classified as a nondeletional alpha-thalassemia (alpha-thal) mutation, which, to date, has only been described in Greece and Cyprus. We report here the clinical and hematological findings in a case of Greek origin, who, following DNA analysis, was characterized with the unusual interaction of the Hb Setif alpha2-globin gene variant at codon 94 variant, in trans to Hb Agrinio, an alpha2-globin gene variant at codon 29. The compound heterozygote proband had only mild anemia with no transfusion requirements and with normal growth and development. We also report the laboratory findings in members of his family, highlighting diagnostic difficulties in the absence of molecular analysis.

A rare thalassemic syndrome caused by interaction of Hb Adana [alpha59(E8)Gly-->Asp] with an alpha+-thalassemia deletion: clinical aspects in two cases.

Hb Adana is a highly unstable and rare alpha-globin hemoglobin (Hb) variant, to date described in only three families, in interaction with other alpha-thalassemia (alpha-thal) deletions. We describe the clinical and hematological findings in two cases from independent families of Albanian origin, who have an interaction of the codon 59 (Gly-->Asp) alpha2-globin gene variant in trans to a 3.7 kb alpha(+)-thal deletion (alpha(codon 59)alpha/-alpha). We report their presenting symptoms and laboratory findings as well as complications and differences in their clinical management. Both cases can be characterized as thalassemia intermedia and illustrate the problems associated with selecting the most appropriate options for patient management, especially in cases with rare underlying genotypes.

Further identification of the hyperunstable alpha-globin chain variant Hb Heraklion [codons 36/37 (-CCC); Pro-->0 (alpha1)] in Greek cases with co-inherited alpha+-thalassemia mutations.

We report four Greek cases (from three unrelated families), who all had a similar atypical thalassemia intermedia phenotype, characterized by chronic moderate anemia, mild hemolysis and splenomegaly in the absence of abnormal hemoglobin (Hb) fractions. In all four cases (two unrelated children and two siblings), DNA analysis identified common alpha(+)-thalassemia (alpha(+)-thal) mutations in trans to the in frame 3 bp deletion (-CCC) on the alpha1-globin gene between codons 36 and 37, which has previously been reported as Hb Heraklion in a single Greek case. Clinical, hematological and biochemical findings in all cases, including a follow-up evaluation of the original case, are described. All the cases originated from the Greek island of Crete.

Clinical response and adverse events in young patients with sickle cell disease treated with hydroxyurea.

The authors studied the long-term clinical and hematological response to hydroxyurea (HU) therapy in young patients, with either S/beta-thalassemia (beta(thal)) (8 patients) or SS (6 patients). All patients with S/beta(thal) responded well to treatment. Longitudinal evaluation of Hb, HbF, and MCV showed a significant increase compared to baseline levels, but the pattern of HbF changes varied among patients. Changes in HbF and Hb correlated well with baseline HbF. Favorable clinical responses, as documented by decline in hospitalization days for vasoocclusive crisis and transfused units of packed red blood cells, were also noted. During treatment, 1 patient was diagnosed with Hodgkin's lymphoma and 2 patients developed bilateral avascular necrosis of the femoral head. HU seems to be effective in a high proportion of young patients with sickle cell disease and in particular with S/beta(thal), but cannot eliminate occurrence of serious adverse events.

A rare example that coinheritance of a severe form of beta-thalassemia and alpha-thalassemia interact in a "synergistic" manner to balance the phenotype of classic thalassemic syndromes.

The coinheritance of beta-thalassemia major with the genotype of Hb H disease is extremely rare, with few reported cases. We investigated the hematological, biochemical, biosynthetic, molecular and pathophysiological parameters to evaluate a rare male patient with this compound syndrome. The patient was studied at first diagnosis during hospitalization at 50 years of age and subsequently followed up for more than a year. Examinations included full hematological, biochemical, biosynthetic, molecular, pathophysiological and clinical parameters. Besides standard parameters, we additionally measured reticulocyte hemoglobin content (CHr), erythropoietin (Epo), soluble transferrin receptors (sTfR), oxygen pressure at 50% hemoglobin saturation (P50), 2,3-bisphosphoglycerate (2,3-BPG), total glutathione (GSHt), oxidized glutathione (GSSG), malonyldialdehyde (MDA), nontransferrin-bound iron (NTBI), vitamins A and E. The male patient was first hospitalized for a 2-day period at 50 years of age, following the finding of marked anemia (hematocrit 20%) during a blood test to investigate the cause of fatigue in the absence of weight-loss or other notable symptomatology. He had never been transfused, maintaining Hb 85-95 g/l. Definitive diagnosis was achieved through DNA studies, which showed coexistence of beta-thalassemia major (IVSI-6 T > C/IVSI-I G > A) with Hb H disease (-alpha(3.7)/-(Med)). Alpha/non-alpha globin chain biosynthesis was completely balanced. Parameters demonstrated a well-compensated anemia with ineffective erythropoiesis and oxidative stress, which was ameliorated following splenectomy. In conclusion, this case is a remarkable example that the coinheritance of severe forms of beta-thalassemia and alpha-thalassemia interact in a "synergistic" manner to almost complete balance the symptoms of classic thalassemia syndromes.

Erythroid bone marrow activity and red cell hemoglobinization in iron sufficient beta-thalassemia heterozygotes as reflected by soluble transferrin receptor and reticulocyte hemoglobin in content. Correlation with genotypes and Hb A(2) levels.

BACKGROUND AND OBJECTIVES: Ferrokinetic studies and erythroid cell ultrastructural studies have indicated some degree of ineffective erythropoiesis in heterozygous beta-thalassemia, although a wide case-to-case variation was observed. In this study we applied rapid biochemical and hematologic measurements to assess erythroid marrow activity (sTfR) and reticulocyte hemoglobin content (CHr) in iron-sufficient individuals with heterozygous beta-thalassemia and investigated the correlation with the degree of globin polypeptide chain imbalance by comparing parameters between beta-thalassemia heterozygotes with genotypes of variable severity. DESIGN AND METHODS: We studied 57 iron-sufficient adults with heterozygous beta-thalassemia, divided into groups according to genotype: group A: beta(silent)-thalassemia heterozygotes, group B: beta(+)-thalassemia heterozygotes and group C: beta(0)-thalassemia heterozygotes. Twenty-one hematologically normal individuals served as controls (group D). We measured hematologic parameters including CHr with a Bayer-Advia 120 hematology analyzer. Hemoglobins were analyzed by high performance liquid chromatography, while biochemical parameters of iron status (iron, ferritin, transferrin and sTfR) were measured with chemical, luminometric and nephelometric methods. RESULTS: We found significant positive correlations between sTfR values for all beta-thalassemia heterozygote groups when plotted against Hb A(2) and Hb F levels (r=0.566, p<0.0001 and r=0.283, p<0.03, respectively) and significantly negative correlation between CHr and Hb A(2) values (r=-0.790, p<0.00001). These data reflect the fine association of globin polypeptide chain imbalance with erythron expansion and the greater degree of ineffective erythropoiesis in beta-thalassemia heterozygotes with more severe genotypes. INTERPRETATION AND CONCLUSIONS: This study is the first demonstration that sTfR and CHr are useful parameters for evaluating the relative severity of different genotypes in heterozygous beta-thalassemia.