Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced. Existen varios tipos de talasemia, como talasemia alfa y beta. Aprenda las Talasemia beta menor (también llamada rasgo talasémico beta). La causa de este. Carriers are often referred to as having thalassemia minor (or β-thalassemia minor). Carrier testing for individuals at risk (including family.
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University of Washington, Seattle; September 28, ; Last Update: Individuals with thalassemia major have severe anemia and hepatosplenomegaly; they usually come to medical attention within the first two years of life.
Without treatment, affected children have severe failure to thrive and shortened life expectancy. Treatment with a regular transfusion program and chelation therapy, aimed at reducing transfusion iron overload, allows for normal growth and development and may improve the overall prognosis. Individuals with thalassemia intermedia present later and have milder anemia that does not require regular treatment with blood transfusion.
These individuals are at risk for iron overload secondary to increased intestinal absorption of iron as a result of ineffective erythropoiesis. Prevention of secondary complications: Assessment of iron overload through one or more of the following: Evaluation of relatives at risk: If the pathogenic variants have been identified in an affected family member, molecular genetic testing of at-risk sibs should be offered to allow for early diagnosis and appropriate treatment.
Hematologic testing can be used if the pathogenic variants in the family are not known. Women with thalassemia intermedia who have never received a blood transfusion or who received a minimal quantity of blood are at risk for severe alloimmune anemia if blood transfusions are required during pregnancy.
Carrier testing for individuals at risk including family members, gamete donors, and members of at-risk ethnic groups is possible. Once both HBB pathogenic variants have been identified in a couple at risk, prenatal testing and preimplantation genetic diagnosis are possible.
View in own window. Thalassemia intermedia should be suspected in individuals who present at a later age with similar but milder clinical findings. Individuals with thalassemia intermedia do not require regular treatment with blood transfusion. Thalassemia minor is usually clinically asymptomatic, but sometimes a mild anemia is present. Red blood cell indices show microcytic anemia Table 1.
Data from Galanello et al . Qualitative and quantitative hemoglobin analysis by cellulose acetate electrophoresis and DE microchromatography or HPLC identifies the amount and type of hemoglobin present.
Click here pdf for information on the results of in vitro synthesis of radioactive labeled globin chains in affected individuals. The recommended molecular genetic testing approach for beta-thalassemia is single- gene testing:. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.
Sequence analysis detects variants that are benign, likely benign, of uncertain significancelikely pathogenic, or pathogenic. For issues to consider talxsemia interpretation of sequence analysis results, click here. Methods that may be used include: Harteveld et al Shooter et al Reading et al .
These alpha globin chain talasemua damage the erythroid precursors in the bone marrow and in the spleen, causing ineffective erythropoiesis. However, bone marrow examination is usually not necessary for diagnosis of affected individuals. Individuals with thalassemia major usually come to medical attention within the first two years of life; they subsequently require regular red blood cell transfusions to survive. Those who present later and do not menkr require transfusion are said to have thalassemia intermedia.
Clinical presentation of thalassemia major occurs between ages six and 24 months. After age ten to 11 years, affected individuals are at risk of developing severe complications related to iron overload, depending on their compliance with chelation therapy see Management. In individuals who have been regularly transfused, iron overload results mainly from transfusions. The risk for hepatocellular carcinoma is increased secondary to liver viral infection, iron overload, and longer survival [ Borgna-Pignatti et alMoukhadder et al ].
Recent studies show that despite geographic differences, most individuals with transfusion-dependent thalassemia have normal cardiac iron, but a significant proportion have simultaneous liver iron overload [ Aydinok et al b ]. The classic mebor picture of thalassemia major is presently only seen in some developing countries, in which the resources for carrying out long-term transfusion programs are not available.
The most relevant features of untreated or poorly transfused individuals:. Individuals who have not been regularly transfused usually die bsta the first two decades. Individuals who have been poorly transfused are also at risk for complications of iron overload.
Clinical features are pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis, and thrombotic complications resulting from iron accumulation and hypercoagulable state secondary to the lipid membrane composition of the abnormal red blood cells [ Cappellini et al ]. Common mild and silent pathogenic variants are listed in Table 5.
Known molecular mechanisms include the following:. Genetic determinants capable of sustaining continuous production of HbF in adult life outside the HBB gene cluster have been mapped to chromosome 2p16 and chromosome 6q23 [ Uda et al ]. The effect of these loci on the transfusion-free survival probability and on the age at which the patient started regular transfusions was demonstrated [ Danjou et al ]. It is also common in populations of African heritage.
This distribution is quite similar to that of endemic Plasmodium falciparum malaria.
Hemoglobin E HbEwhich is a thalassemic structural variant characterized by the presence of an abnormal structure as well as biosynthetic defect, should be included in this group. The homozygous state for HbE results in a mild hemolytic microcytic anemia. The presence of hyper-unstable hemoglobin should be suspected in any individual with thalassemia intermedia when both parents are hematologically normal or in families with a pattern of autosomal dominant transmission of the thalassemia intermedia phenotype.
HBB sequencing establishes the diagnosis. Comprehensive reviews of the management of thalassemia major and thalassemia intermedia have been published by the Thalassemia International Federation [ Taher et alCappellini et al ] and are available at the TIF website. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron.
Treatment of individuals with thalassemia intermedia is symptomatic and based on splenectomy and folic acid supplementation. For couples who have already had a child with thalassemia and who undertake prenatal diagnosis in a subsequent pregnancy, prenatal identification of HLA compatibility between the affected child and an unaffected fetus allows collection of placental blood at delivery and the option of cord blood transplantation to cure the affected child [ Orofino et al ].
Alternatively, in case of an affected fetus and a previous unaffected child, the couple may decide to continue the pregnancy and pursue BMT later, using the unaffected child as the donor. Unrelated cord blood transplantation has been explored as an alternative option for affected individuals without a suitable HLA-matched unrelated adult donor. However, this strategy may be limited by less-than-adequate cell dose and higher rates of primary graft failure.
One potential strategy may be the use of two cord blood units in order to achieve the desired cell dose, as has been done in individuals with malignancy — although this approach may be associated with a higher rate of acute GVHD, which may add to the burden of morbidity and mortality for this population.
For these reasons, unrelated cord blood transplantation would appear to be a suboptimal strategy for individuals with thalassemia [ Ruggeri et al ].
However, others have found the outcome of unrelated cord blood transplantation to be more favorable. Early detection of anemia, the primary manifestation of the disease, allows early appropriate treatment and monitoring.
The most common secondary complications are those related to transfusional iron overload, which can be prevented by adequate iron chelation. Preliminary studies using in combination the two oral chelators deferasirox and deferiprone appear to be encouraging [ Berdoukas et alFarmaki et al neta, Voskaridou et alElalfy et al ].
Assessment of myocardial siderosis by MRI techniques and monitoring of cardiac function combined with intensification of iron chelation can result in excellent long-term prognoses [ WoodKirk et alChouliaras et al ]. Its origin is multifactorialmaking it difficult to manage.
Treatment involves appropriate hormonal replacement, an effective regimen of transfusion and iron chelation, vitamin D administration, and regular physical activity.
Sufficient evidence exists to support the use of bisphosphonates in talasemiq management of thalassemia-associated osteoporosis to prevent bone loss and improve the bone mineral density. Further research is warranted to establish their anti-fracture efficacy and long-term safety [ Giusti ].
Denosumab and strontium meonr have each been evaluated in only bet single study, while there are no data on the effects of anabolic agents [ Chavassieux et alYassin et al ]. A general beeta for clinical and laboratory evaluation in thalassemia major has been provided by the Thalassemia International Federation [ Cappellini et al ] and is available at the TIF website.
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For individuals with thalassemia major, follow up to monitor the effectiveness of transfusion therapy and chelation therapy and their side effects includes the following:. It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual as early as possible. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. An increasing number of women with thalassemia major and thalassemia intermedia may, therefore, have children.
While hypogonadotropic hypogonadism remains a common condition in thalassemia major, gonadal function is usually intact and fertility is usually retrievable following a closely monitored stimulation therapy. Although larger and more detailed studies are needed, an increased risk for certain complications cannot yet be excluded. For example, women with thalassemia intermedia who had never previously received a blood transfusion or who had received a minimal quantity of blood are reported to be at risk for severe alloimmune anemia if blood transfusions are required during pregnancy [ Origa et al ].
The first clinical trials are expected soon. The efficacy of hydroxyurea treatment in individuals with thalassemia is still unclear. Hydroxyurea prevents hemolysis and hypercoagulability by modifying the defective hemoglobin synthesis and reducing thrombocytosis. A retrospective study found no pulmonary hypertension in 50 individuals with thalassemia intermedia treated with hydroxyurea for seven years [ Karimi et alTaher et al ]. A good response, correlated with particular polymorphisms in the beta-globin cluster i.
However, controlled and randomized studies are warranted to establish the role of hydroxyurea in the management of thalassemia syndromes. The possibility of correction of the molecular defect in hematopoietic stem cells by transfer of a normal gene via a suitable vector or by homologous recombination is being actively investigated. The most promising results in the mouse model have been obtained with lentiviral vectors [ Persons ].
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional.
Carrier testing for at-risk relatives can be done by hematologic or molecular genetic testing. Individuals who should be considered for carrier detection:. Carriers are often identified by analysis of red blood cell indices Table 1which shows microcytosis low MCV and reduced content of Hb per red cell low MCHand by quantitative Hb analysis Table 2which displays HbA 2 greater than 3. Pitfalls in carrier identification by hematologic testing:. Individuals at increased risk. Because of the high carrier rate for HBB pathogenic variants in certain populations and the availability of genetic counseling and prenatal diagnosispopulation screening is ongoing in several at-risk populations in the Mediterranean [ Angastiniotis et al ].
Carrier testing relies on hematologic analysis.