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PubMedDate not supplied

Hematologic phenotype of the mutations IVS1-n6 (T-->C), IVS1-n110 (G-->A), and CD39 (C-->T) in carriers of beta-thalassemia in Greece.

The hematologic phenotype was characterized in heterozygotes for three of the most common beta-thalassemia mutations in the Greek population. The study included 17 carriers of beta++ IVS1-n6 (T-->C), 21 carriers of beta+ IVS1-n110 (G-->A), and 17 carriers of beta 0 CD39 (C-->T). The 55 beta-thalassemia heterozygotes were selected from among parents of patients on regular transfusion regimens, and the beta-thalassemia mutation was identified by means of the polymerase chain reaction to amplify the appropriate region of the beta-globin gene and then by allele-specific oligonucleotide hybridization. The assessment of hematologic phenotype included complete blood count and quantitation of hemoglobin HbA2 and HbF and of the globin chain biosynthesis ratio. Comparison and statistical analysis of the hematologic parameters for the three mutations demonstrated no consistent correlation among the three mutations relative to Hb levels, hematocrit, and red cell indices, although heterozygotes for the IVS1-n6 mutation produce red blood cells with slightly higher mean corpuscular volume; significantly lower values of HbA2 (mean, 3.81% +/- 0.62% with four values less than 3.60%) in IVS1-n6 heterozygotes compared with IVS1-n110 heterozygotes (mean, 4.69% +/- 0.48%) and CD39 heterozygotes (mean, 4.75% +/- 0.50%, P < 0.001); and significantly higher HbF levels in CD39 heterozygotes (mean, 2.31% +/- 1.52%) compared with IVS1-n6 heterozygotes (mean, 0.79% +/- 0.45%, P < 0.01) and IVS1-n110 heterozygotes (mean, 1.17% +/- 0.75%, P < 0.01). With respect to the HbA2 levels, the findings are in agreement with previous studies in Mediterranean populations; the slightly higher levels of HbF in CD39 heterozygotes appear to be reported for the first time.

Alleles↗
PubMedDate not supplied

Serum erythropoietin levels in patients with beta thalassemia major and intermedia.

Serum erythropoietin (EPO) levels were determined by radioimmunoassay in 37 beta-thalassemia patients, the phenotype being thalassemia major (TM) in 30 and thalassemia intermedia (TI) in 7. The control group consisted of 37 healthy children. The mean serum EPO levels were significantly higher in patients with both TM (215.1 +/- 144.5) and TI (53.8 +/- 40.2) compared with the control group (9.3 +/- 4.6). Although the mean hemoglobin (Hb) concentrations in the patients with TM and TI were similar (8.6 +/- 0.9 and 8.7 +/- 1.1, respectively), the mean serum EPO level was significantly higher in TM patients than the patients with TI (P < .01). This finding may indicate that some other factors contributing to the metabolic adaptation to low oxygen concentration or improvement of the tissue oxygenation are as effective as the Hb concentration in EPO production. It is also suggestive of the fact that some amount of tissue hypoxia cannot be prevented in spite of polytransfusion regimens in TM patients. Serum EPO levels of TM patients were not found to be age related or correlated with the mean pretransfusional Hb levels. In the TM patients, the serum EPO concentration was not consistently correlated with clinical signs of erythropoietic activity. This may be indicative of personal differences with respect to the sensitivities of erythroid precursors to the increasing EPO levels in TM patients.

Adolescent↗
PubMed2004

Hydrops fetalis caused by homozygous alpha-thalassemia and Rh antigen alloimmunization: report of a survivor and literature review.

Hematologic causes of hydrops fetalis include homozygous alpha-thalassemia and immune hemolytic anemias. We report the case of a boy with hydrops fetalis who had homozygous alpha-thalassemia and alloimmune hemolytic anemia due to anti-E and anti-C blood group antibodies. He received intrauterine red blood cell transfusions and postnatal chronic transfusion with iron chelation therapy. A non-myeloablative sibling stem cell transplant failed. He is now 5 years and 6 months of age, hypothyroid with short stature, but in overall good health. He is one of the oldest reported homozygous alpha-thalassemia survivors and, to our knowledge, the only survivor with immune- and nonimmune-induced hydrops fetalis.

Adult↗
PubMed2006

[Effects of yisui shengxue granules on expressions of alpha-hemoglobin stabilizing protein and erythroid transcription factor GATA-1 mRNAs in bone marrow of patients with beta-thalassemia].

OBJECTIVE: To evaluate the effects of Yisui Shengxue Granules on expressions of alpha-hemoglobin stabilizing protein (AHSP) and erythroid transcription factor GATA-1 mRNAs in bone marrow of patients with beta-thalassemia, and to explore its possible molecular mechanism. METHODS: Twelve patients with beta-thalassemia intermedia were treated with Yisui Shengxue Granules for three months. The blood indexes including hemoglobin (Hb), RBC, fetal hemoglobin (HbF) and reticulated corpuscles (Ret) were examined before and after treatment. Total RNA was extracted from bone marrow karyocyte in 8 patients selected from these 12 patients before and after treatment, and the expression levels of the AHSP and GATA-1 mRNAs were measured by real-time PCR. RESULTS: Yisui Shengxue Granules could not only obviously improve the clinical symptoms of patients with beta-thalassemia intermedia, but also obviously increased the contents of Hb, RBC, HbF and Ret (P<0.05, or P<0.01). The expression levels of AHSP and GATA-1 mRNAs also significantly increased after treatment as compared with those before treatment (P<0.05, or P<0.01). CONCLUSION: The results revealed that one of the possible molecular mechanism of the effects caused by Yisui Shengxue Granules is that it can up-regulate the expression levels of AHSP and erythroid transcription factor GATA-1 mRNAs, enhance the protein synthesis of AHSP which can bind the relative excess free alpha-globin, prevent the formation of alpha -globin-cytotoxic precipitates in red blood cells and decrease the hemolysis.

Adolescent↗
PubMed2005

Effects of variant UDP-glucuronosyltransferase 1A1 gene, glucose-6-phosphate dehydrogenase deficiency and thalassemia on cholelithiasis.

AIM: To test the hypothesis that the variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and thalassemia influence bilirubin metabolism and play a role in the development of cholelithiasis. METHODS: A total of 372 Taiwan Chinese with cholelithiasis who had undergone cholecystectomy and 293 healthy individuals were divided into case and control groups, respectively. PCR and restriction fragment length polymorphism were used to analyze the promoter area and nucleotides 211, 686, 1,091, and 1,456 of the UGT1A1 gene for all subjects and the gene variants for thalassemia and G6PD deficiency. RESULTS: Variation frequencies for the cholelithiasis patients were 16.1%, 25.8%, 5.4%, and 4.3% for A(TA)(6) TAA/A(TA)(7)TAA (6/7), heterozygosity within the coding region, compound heterozygosity, and homozygosity of the UGT1A1 gene, respectively. Comparing the case and control groups, a statistically significant difference in frequency was demonstrated for the homozygous variation of the UGT1A1 gene (P = 0.012, chi(2) test), but not for the other variations. Further, no difference was demonstrated in a between-group comparison of the incidence of G6PD deficiency and thalassemia (2.7% vs 2.4% and 5.1% vs 5.1%, respectively). The bilirubin levels for the cholelithiasis patients with the homozygous variant-UGT1A1 gene were significantly different from the control analog (18.0+/-6.5 and 12.7+/-2.9 micromol/L, respectively; P<0.001, Student's t test). CONCLUSION: Our results show that the homozygous variation in the UGT1A1 gene is a risk factor for the development of cholelithiasis in Taiwan Chinese.

Adult↗
PubMed1999

Laboratory recognition of a rare hemoglobinopathy: hemoglobins SS and SG(Philadelphia) associated with alpha-thalassemia-2.

This article describes the laboratory investigation of an unusual hemoglobinopathy involving hemoglobin (Hb) S, HbSG(Philadelphia), and alpha-thalassemia-2 in a patient whose phenotype was HbSC by alkaline electrophoresis. Findings of a mean corpuscular volume of 62 fL and microcytes on the blood smear were inconsistent with HbSC disease. The patient's clinical course over several years had been mildly symptomatic. Testing in our hospital laboratory using isoelectric focusing and cation-exchange high-performance liquid chromatography to separate hemoglobins showed an unknown variant. Additional studies, including globin chain electrophoresis, reverse-phase high-performance liquid chromatography, and polymerase chain reaction-based DNA analysis were performed at reference laboratories, which reported the following findings: HbG(Philadelphia) associated with alpha-thalassemia-2, HbS and HbG(Philadelphia), and the alpha-globin deletions defining the -alpha3.7/-alpha3.7 genotype. The hemoglobin molecular defects, alpha-thalassemia-2, and the pattern of inheritance are discussed.

Adult↗
PubMed1986

Genetic counseling of asymptomatic carriers in a primary care setting. The effectiveness of screening and counseling for beta-thalassemia trait.

In a prospective, controlled, stratified, experimental effectiveness study of screening and counseling, 25 000 consecutive adults were screened for thalassemia trait. Eight hundred forty-three adults had a mean corpuscular volume less than 77 fL; 192 (22% of those with microcytosis) had hemoglobin A2 greater than 3.5%, proving beta-thalassemia trait. Video-program, neutral-educational, and patient-centered counseling methods produced equal levels of learning, retention, psychologic impact, and effects on life adjustment immediately and at 2 and 10 months after counseling. Ninety-nine percent of the patients told other persons about the counseling, and 43% had 106 others screened. Factors related to having someone else screened included plans to have children (p less than 0.002), being younger (p less than 0.0025), better education (p less than 0.05), and having high knowledge of thalassemia (p = 0.05). For maximum effectiveness, screening and counseling programs should focus on patients for whom a positive result has high significance.

Adolescent↗
PubMed1998

[The heart of the patient with beta thalassemia major. Study with magnetic resonance].

PURPOSE: The main cause of death in beta-thalassemia major patients is congestive heart failure which is traditionally referred to myocardial iron overload. Recently, some investigators have found that cardiac failure is not caused by the iron overload. In their opinion, left-sided heart failure develops years after the onset of acute myocarditis and might be related to a late autoimmune process. Right-sided heart failure is related to the combination of left ventricular diastolic restriction and pulmonary hypertension. The aim of this work is to study myocardial iron overload by MRI and to correlate the signal intensity changes of the myocardium with cardiac function. MATERIAL AND METHODS: Sixteen patients with beta-thalassemia major were examined with a .5 super-conducting unit. SE and cine-GE sequences were used in the 4 chamber and 2 chamber views. Left ventirclar ejection fraction (EF) was calculated by using the biplane area-length method. Right ventricular size was assessed by measuring the end-diastolic anteroposterior diameter (APD). Myocardial signal intensity was evaluated qualitatively and quantitatively (myocardium/subcutaneous fat) in all the beta-thalassemia patients and in 10 normal volunteers. RESULTS: Left ventricular function was decreased (EF < 55%) in 2/16 patients. The right ventricle was dilated in 5/16 patients (APD > 42 mm). The myocardium had a lower signal intensity than that of normal volunteers in 15/16 patients. No statistical correlation was found between myocardial signal intensity and serum ferritine levels or cardiac function. CONCLUSIONS: The small number of patients in our series does not allow any definitive statements. However, our results show that cardiac function is not influenced by myocardial iron overload.

Adolescent↗
PubMed1998

Clinical experience using the Androderm testosterone transdermal system in hypogonadal adolescents and young men with beta-thalassemia major.

beta-Thalassemia major is associated with a high prevalence of hypogonadotropic hypogonadism affecting adolescents and young men with this disease. The pharmacokinetics of Androderm, a non-scrotal permeation-enhanced testosterone transdermal system, was previously studied in this population using three application regimens designed to mimic the nocturnal secretion and circadian patterns of testosterone production characteristics of puberty and young adulthood. In regimen I, designed for prepubertal 14 to 16 year-olds, a single Androderm patch (2.5 mg/day nominal delivery rate) is applied at night and removed 12 hours later in the morning. In regimen II, designed for partially virilized 17 to 19 year-olds, a single Androderm patch is applied nightly for 24 hours. In regimen III, intended for virilized men aged 20 years and older, two Androderm patches (total dose of 5 mg/day) are applied nightly for 24 hours. This report presents the results of a 12-month open label study using these three Androderm regimens to treat nine hypogonadal males with beta-thalassemia (ages 16.8 to 31.8 yr). Our data show that Androderm produced physiologically appropriate testosterone levels, lowered SHBG levels, promoted growth and virilization, increased bone mineral density, and was generally well tolerated in this population of hypogonadal adolescents and young men with beta-thalassemia.

Administration, Cutaneous↗
PubMed1998

Fertility in female patients with thalassemia.

With recent therapeutic advances, thalassemic patients can now reach adulthood and attain reproductive capacity. Endocrine complications due to hemosiderosis and especially hypogonatotropic hypogonadism, which present either with sexual infantilism and primary amenorrhea or with secondary amenorrhea, are common in thalassemic women. The aim of this study was to estimate the frequency of fertility among our female thalassemic patients. Our population included 50 married women with thalassemia major (TM) and 12 with thalassemia intermedia (TI) who are regularly followed in our thalassemic centers. Of the 50 patients with TM, 7 had primary amenorrhea (PA), 9 had secondary amenorrhea (SA), and 34 had normal menstrual function (NM), as did all the patients with TI. Overall we had 62 women who were able to achieve 90 pregnancies and give birth to 87 healthy babies. Most of our patients became pregnant around the age of 25 years. Associated endocrine complications were rare except in the group of patients with PA, as expected. In all patients with PA and SA, the 17 pregnancies were induced (intercourse 10, insemination 3, IVF 4). In the patients with NM and TI, 66 pregnancies were achieved spontaneously and 7 following induction (insemination 3, IVF 4). There were four twin and one triple pregnancies, which all resulted in premature deliveries. Among the seven couples in which both partners had thalassemia major, sperm donation was used in 5 cases, ovum donation in one case, and one pregnancy was achieved spontaneously. These 90 pregnancies resulted in 69 full-term, 12 pre-term, 7 abortions and 2 stillbirths. No severe obstetric complication was observed except for two patients with preeclampsia. One patient with PA who carried the triple pregnancy developed severe cardiac failure, which was successfully treated. Transfusion requirements were increased during pregnancy. Discontinuation of desferrioxamine resulted in elevation of ferritin levels during the second and third trimesters of pregnancy and after delivery. Nine patients who were examined with cardiac echo had a transient increase of ESD and EDD during pregnancy, with return to normal after delivery. Labor was performed by Caesarian section in 26 births (26%) out of the 81 successful pregnancies. These collected data represent the largest number of pregnancies in thalassemic females reported so far and are clearly encouraging for the ultimate improvement of the quality of life in thalassemic patients.

Adult↗
PubMed1998

Fertility in thalassemia: the Greek experience.

Pregnancy in beta-thalassemic patients has become a not unusual event, especially in the last 10 years. The course and outcome of 19 pregnancies in 16 thalassemic women, followed in our unit, 12 with thalassemia major and 4 with thalassemia intermedia, were studied. Genetic counselling was provided and counselling regarding the planning or the continuation of the pregnancy was based mainly on cardiac performance at rest. Cardiac, endocrine and liver function were evaluated at baseline, monitored throughout pregnancy and reevaluated after delivery. Desferrioxamine treatment was discontinued as early as possible. During pregnancy the Hb level was maintained at about 10 g/dl in all women by transfusion. The course of pregnancy was essentially uneventful and elective Cesarean section was performed in all cases. The mean birth weight of the newborns was 3000 g. All babies were normal except for one with exomphalus. Pregnancy was well tolerated by the heart in all women and no endocrinological disorders were observed. In conclusion, pregnancies in beta-thalassemia can be safe for both mothers and their babies with careful selection and appropriate care.

Adult↗
PubMed1999

The influence of hemochromatosis mutations on iron overload of thalassemia major.

BACKGROUND AND OBJECTIVE: Hemochromatosis is a genetic form of iron overload due to a defective HFE gene. Secondary iron overload is the main complication in transfusion-dependent thalassemia patients. In this work we have examined the prevalence of HFE mutations in thalassemia major and evaluated the degree of iron overload of patients with and without HFE mutations. DESIGN AND METHODS: HFE mutations were studied in 71 Italian thalassemic patients and in 189 normal controls, using PCR and restriction enzyme analysis. The degree of iron overload, assessed by serum ferritin and liver iron concentration (LIC), was compared in 17 patients with mutations in the HFE gene, and in 17 subjects with wild type HFE genotype. The two groups of patients had comparable globin gene mutations, were matched for age and were homogeneous for transfusion and chelation history. In all cases the iron balance calculated on the basis of transfusion regimen and iron excreted by chelation was available. RESULTS: The allele frequencies of C282Y and H63D were respectively 1.4% and 12.7% in patients and 1.1% and 11.4% in controls. No case of C282Y homozygosity was recorded among patients. No significant difference was found in terms of serum ferritin, LIC, or the age at chelation start between patients with and without HFE mutations. The single patient with H63D homozygosity was severely iron-loaded. INTERPRETATION AND CONCLUSIONS: Our data suggest that the presence of a single mutation in the HFE gene does not influence the severity of iron loading in thalassemia patients following a regular transfusion and chelation program.

Adolescent↗
PubMed1999

Why are hemoglobin F levels increased in HbE/beta thalassemia?

To try to further define the mechanisms that increase the levels of hemoglobin F (HbF) in the blood of patients with severe forms of beta thalassemia, we have studied two comparable populations of hemoglobin E (HbE)/beta thalassemics, one regularly transfused and one receiving only occasional blood transfusions. Regular transfusion was associated with a significant decrease in soluble transferrin receptor and erythropoietin levels. Globin chain synthesis studies also show a highly significant decrease in HbF synthesis relative to HbE in the transfused patients. This effect was confirmed by sequential data on one patient, studied before and after the commencement of regular blood transfusion; blood transfusion was followed by a marked increase in the alpha/gamma, beta(E)/gamma, and HbE/HbF ratios. These data suggest that the high HbF levels in HbE/beta thalassemia, and other beta thalassemia syndromes, result from increased erythropoietin levels leading to bone marrow expansion, and possibly increased F-cell production, combined with ineffective erythropoiesis giving a survival advantage to F cells. This study also suggests that alteration in blood transfusion regimes must be taken into account when interpreting changes in HbF levels seen in trials of HbF-promoting drugs.

Adolescent↗
PubMedDate not supplied

Legg-Calvé-Perthes disease, protein C deficiency, and beta-thalassemia major: report of two cases.

Legg-Calvé-Perthes disease is an idiopathic osteonecrosis or avascular necrosis of the capital femoral epiphysis and the associated complications thereof occurring in an immature growing child. The association between osteonecrosis of the femoral head and thrombophilia was postulated by Glueck in 1994. We describe Legg-Calvé-Perthes disease associated with protein C deficiency and beta-thalassemia major in two children among a cohort of 79 beta-thalassemia patients treated in our clinic. The association of thrombophilia, aseptic necrosis of the femoral head, and beta-thalassemia has not been previously described in the literature.

Adolescent↗
PubMedDate not supplied

[The molecular basis of dominantly inherited beta-thalassemia].

In this study, we sought to clarity the molecular basis of a dominant inherited beta-thalassemia, found in heterozygosity in a northern Portuguese family with thalassemia intermedia. We characterized: i) the alpha-globin gene cluster structure; ii) the beta-globin gene cluster haplotype; and iii) the beta-thalassemia mutation. The alpha-globin gene cluster was structurally normal. The G-->T transversion at codon 121 of the beta-globin gene was found in the affected individuals in association with Orkin's haplotype V. This is an uncommon, though ubiquitous, mutation. Which has also been found, in association with different haplotypes, in several distant populations. It has only been observed in this three-generation family, in the Portuguese population. We suggest a mechanism to explain the genotype/phenotype correlation.

Adult↗
PubMed2000

[Bone marrow transplantation for beta-thalassemia major].

OBJECTIVE: To examine the feasibility of bone marrow hematopoietic stem cell transplantation for thalassemia major. METHODS: Bone marrow transplantation was performed on a 4-year-old patient with beta-thalassemia major, whose gene mutation was CD41-42/654. The donor was his brother. In the 850ml bone marrow, the nucleated cells were 5.6x10(8)/kg, CD(+)(34) cells 7.8 x 10(6)/kg, and colony-forming-unit-granulocyte-macrophages(CFU-GM) 5.7x10(5)/kg. HLA was one site mismatched, while RBC type matched. Pre-transplant conditions included Busulfan 16mg/kg, cyclophosphamide 200mg/kg and lymphoglobuline 88mg/kg. Cyclosporine and methotrexate were used for prevention of graft-versus-host disease(GVHD). RESULTS: After transplantation, the patient had grade II acute GVHD and cytomegalovirus(CMV) interstitial pneumonia; he was cured. White blood cells(WBC) and neutrophil granulocytes recovered to 1.1 x 10(9)/L and 0.4 x10(9)/L respectively on day 14 post transplantation. WBC was 4.5 x 10(9)/L on day 18, and descended for a time during treating interstitial pneumonia with Ganciclovir. Platelet(Plt) exceeded 50 x 10(9)/L on day 86 and recovered to normal 5 mothers and a half post transplantation. Hb reached 106g/L on day 128. The patient received the last blood transfusion on day 103. Before transplantation, the patient had to receive 200ml blood infusion per month for maintaining Hb 60-90g/L; after transplantation, his Hb kept up >110g/L for 6 months without blood transfusion. The gene type had changed to donor's CD41-42/N heterozygen. CONCLUSION: This is the first report on successful transplantation of bone marrow stem cell for thalassemia major in China, suggesting a new way to treat the disease and to expand the use of BMT. For treatment of CMV interstitial pneumonia post-transplantation, Ganciclovir should be dose enough and be used for at least 2 months.

Child, Preschool↗
PubMed1998

Prenatal diagnosis of thalassemia in Songklanagarind Hospital in southern Thailand.

A thalassemia screening program for pregnant women has been established in Songklanagarind Hospital since 1992. After genetic counseling, a total of 5078 pregnant women accepted entry into a screening program for thalassemia. Couples at risk who should receive prenatal diagnosis were 2.8%. Total cases who accepted prenatal diagnosis were 135. Total clinical cases were 40 (29.6%) with achievement by prenatal diagnosis of 33 cases (82.5%). Genetic amniocentesis is the most acceptable method for prenatal diagnosis. Five cases (12.5%) were misdiagnosed due to contamination of maternal blood cells in amniotic fluid cases. Questionable results were reported in 2 cases (5%). Abortion occurred in one case (0.7%). Improvement of surgical technic in prenatal diagnosis reduced the complications and contamination of maternal cells. This program shows the feasibility of prevention and control of thalassemia disease in southern Thailand.

Adult↗
PubMed2000

Extramedullary haematopoietic tumor producing small intestinal intussusception in a beta-thalassemia/hemoglobin E Thai boy: a case report.

The authors report a case of beta-thalassemia/hemoglobin E disease with extramedullary haematopoietic tumor which developed at the small intestine and caused intussusception. A 7 year-old boy with homozygous beta-thalassemia/hemoglobin E presented with recurrent abdominal pain. The abdominal ultrasonography showed ileo-ileal intussusception with a solid mass as the leading point. Resection of the ileal segment was performed. Pathological examination revealed an extramedullary haematopoietic tumor forming an intraluminal polypoid mass, being the leading point of the intussusception. Extramedullary haematopoiesis in the intestinal tract is rare. To our knowledge, this is the first case of extramedullary haematopoietic tumor that produced intussusception of the small intestine in a beta-thalassemia/hemoglobin E patient.

Child↗