Beta thalassemia (BT) is an inherited disease characterized by the defective synthesis of the beta chains of the hemoglobin molecule due to a genetic mutation. The disease is more common in certain parts of the world and varies in both genotype and phenotypic expression.
Beta thalassemia (BT) is a hereditary disease that affects the formation of the beta chains of the hemoglobin molecule. This leads to the defective hemoglobin and red blood cell production resulting in hemolysis. In the majority of cases, BT is an autosomal recessive disease, however, there are reported cases of an autosomal dominant variant of the disease. BT is more common in certain regions, such as the Mediterranean, Africa, and Asia. This disease may be classified into three categories (BT major, intermedia, and minor) depending on whether affected individuals are homozygous or heterozygous. Moreover, it can occur simultaneously with other abnormalities of hemoglobin formation. Consequently, BT varies widely in its presentation.
BT major (Cooley anemia) is usually diagnosed before the age of 2 years. The major features include hemolytic anemia, microcytic and hypochromic red blood cells, splenomegaly, failure to thrive, diarrhea, growth retardation, fever, and vomiting. Additional features of BT major are leg ulcers, the thickening of the cranium (due to hyperactive bone marrow), increased frequency of long bone fractures, and stunting. Regular blood transfusions are required to manage this condition and consequently, manifestations of iron overload are seen. These may be cardiac in nature, exemplified by heart failure, pericarditis, and dilated myocardiopathy. Liver cirrhosis secondary to iron deposition is also common, along with an increased risk of hepatitis and hepatocellular carcinoma . Furthermore, iron overload can lead to delayed sexual maturation, hypogonadism, diabetes mellitus, and hormonal imbalance caused by the dysfunction of the thyroid, parathyroid, and pituitary glands . Most BT deaths occur due to cardiac complications pericarditis and dilated cardiomyopathy) . Infectious complications, such as human immunodeficiency virus infection and hepatitis viruses B and C infection are also possible in patients receiving multiple transfusions, but are less frequent nowadays due to vaccination and blood screening methods. Other complications may include osteoporosis, hypersplenism, venous thrombosis and pulmonary hypertension.
Affected individuals who do not receive proper therapy have pale or brown pigmented skin or are affected by jaundice. They have a particular appearance with mongoloid eyes, bossing of the skull, depressed nose bridge, maxillary hypertrophy, prominent malar eminence and genu valgus.
BT intermedia is often diagnosed later in life than the major form and exhibits less severe symptoms. These may include splenomegaly, iron overload, and cholelithiasis.
People who have the BT trait, otherwise referred to as BT minor, have a heterozygous genotype and typically do not experience any symptoms.
Entire Body System
Affected individuals also have anemia, which can cause pale skin, weakness, fatigue, and more serious complications. People with beta thalassemia are at an increased risk of developing abnormal blood clots. [ascopost.com]
“Inadequate transfusion increases the risk of certain complications of thalassemia and results in chronic fatigue.” Beyond fatigue, under-treatment of anemia can hinder growth and even lead to heart failure. [celgene.com]
The most common adverse reactions ( 10%) in patients with beta thalassemia were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. FDA granted this application fast track and orphan drug designations. [fda.gov]
This leads to anemia, which can cause fatigue and other complications, including bone deformities, slower growth rates, and organ damage. [rchsd.org]
Required information was gathered through a thorough physical examination of the oral cavity in a private office and a face-to-face interview by an orthodontist and two dentists. Data were analyzed using SPSS version 22.0. [ncbi.nlm.nih.gov]
Failure to Thrive
CASE PRESENTATION: An 8-month-old ethnic Gypsy male infant with failure to thrive from birth, mild jaundice and splenomegaly. Clinical signs were compatible with severe microcytic anemia requiring bi-monthly blood transfusions. [ncbi.nlm.nih.gov]
The major features include hemolytic anemia, microcytic and hypochromic red blood cells, splenomegaly, failure to thrive, diarrhea, growth retardation, fever, and vomiting. [symptoma.com]
The typical clinical presentation consists of an infant developing life-threatening anemia with failure to thrive and jaundice. Patients may have splenomegaly, hepatomegaly, cardiomegaly, and bone malformations. [visualdx.com]
They do not gain weight and grow at the expected rate (failure to thrive) and may develop yellowing of the skin and whites of the eyes (jaundice). Affected individuals may have an enlarged spleen, liver, and heart, and their bones may be misshapen. [ghr.nlm.nih.gov]
Children with beta thalassemia major may have a swollen abdomen or symptoms of anemia or failure to thrive. If the doctor suspects beta thalassemia, he or she will take a blood sample for testing. [rchsd.org]
Untreated or poorly transfused patients show growth retardation, pallor, jaundice, poor musculature, genu valgum, leg ulcers, formation of masses due to extramedullary hematopoiesis, and skeletal changes including deformities in the long bones of the [orpha.net]
Some individuals may develop ‘knock knees’ (genu valgum), a condition in which the legs bend inward so that when a person is standing the knees will touch even if the ankles and feet are not. [rarediseases.org]
valgum 58 31 frequent (33%) Frequent (79-30%) HP:0002857 8 depressivity 58 31 frequent (33%) Frequent (79-30%) HP:0000716 9 muscle weakness 58 31 frequent (33%) Frequent (79-30%),Frequent (79-30%) HP:0001324 10 respiratory insufficiency 58 31 frequent [malacards.org]
In some developing countries, where due to the lack of resources patients are untreated or poorly transfused, the clinical picture of thalassemia major is characterized by growth retardation, pallor, jaundice, poor musculature, genu valgum, hepatosplenomegaly [oadoi.org]
Beta thalassemia is diagnosed via electrophoresis or high-performance liquid chromatography (HPLC), which are techniques that allow the detection of hemoglobin abnormalities. Non-invasive prenatal diagnosis of BT involves analysis of fetal deoxyribonucleic acid material found in the maternal circulation  or by amniocentesis at 14-20 weeks’ gestation or chorionic villi sampling at 8-10 weeks’ gestation. Analysis should be extensive, as over 200 mutations that can cause the disease are known today. They consist of deletions, insertions or gene substitutions.
Electrophoresis and column chromatography show increased hemoglobin A2 levels, up to 4-6%. Severe iron deficiency may mask this manifestation. Hemoglobin F may also be increased. In cases where minor disease is suspected, free erythrocyte porphyrin should be tested. High levels will be found in iron deficiency patients and lead poisoning cases, while normal levels are encountered in beta thalassemia trait individuals.
Hemolysis is demonstrated by low haptoglobin and increased indirect bilirubin and lactate dehydrogenase. The anemia that characterizes chronic disorders is ruled out by determining iron, transferrin and ferritin levels. A bone marrow examination is indicated when other causes of microcytic anemia cannot otherwise be excluded. Prussian blue stain diagnoses sideroblastic anemia.
Complete blood count may reveal low hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin to varying degrees, depending on the severity of the disease . Erythroblasts and abnormal red blood cells may be visualized through a peripheral smear. BT minor may be found incidentally in blood tests, typified by mild, asymptomatic, microcytic anemia, in addition to the presence of target cells and Heinz bodies in the peripheral smear . Extramedullary hematopoiesis is also a common feature which is particularly observed in the liver.
The minor form of thalassemia does not require treatment, but patients should be informed about the nature of their condition. When iron deficiency anemia coexists, it should be promptly corrected. Thalassemia major patients, on the other hand, require scrupulous long-term transfusion therapy, combined with iron chelation and splenectomy. A type of treatment that addresses the etiology of the disease consists of allogeneic hematopoietic transplantation, preferable whenever possible because of its curative nature . However, the physician must keep an open mind about graft failure, graft versus host disease and the required chronic immunosuppressive therapy, all associated with this approach. Supportive measures, consisting of folic acid replacement and complication monitoring and treatment are also important. Gene therapy is currently being investigated. It consists of modified autologous hematopoietic stem cells transplant. The stem cells will previously be modified by a lentiviral vector expressing a normal globin gene and then infused to the patient that had undergone hematopoietic stem cells destruction therapy .
Transfusions are needed in order to maintain the hemoglobin level at 9-10 g/dL. This way, extramedullary hematopoiesis and skeletal changes are prevented and life quality is improved. Alloimmunization can be prevented by only administering similar erythrocytes in terms of ABO and RH antigens. The usual dose is 8-15 mL RBCs per kilogram of body weight . One study  suggests that with this dose, however, males are undertransfused and more often require splenectomy or develop spinal cord compression as a result of paraspinal extramedullary hematopoiesis.
Other new techniques include genome editing techniques that interfere with single-mutation sites and replace them with normal genome [8 ].
Splenectomy is considered to decrease the amount of transfused blood needed and is indicated when the hematocrit value reaches 70% [10 ]. Patients should undergo Haemophilus influenzae, Meningococcus species and Pneumococcus species vaccination first and be at least 6 or 7 years old in order to minimize the risk for postsplenectomy sepsis. They should receive penicillin prophylaxis after the operation and be monitored for postsplenectomy thrombocytosis and ischemic events.
Bilirubin stones, if present, should be removed by laparoscopy or at the same time splenectomy is performed. Several novel therapeutic modalities are currently being investigated: immunomodulation agents, demethylating agents, short-chain fatty acid derivatives, histone deacetylase inhibitors, activin type IIA receptor fusion proteins, erythropoietin  and autologous CD34+ hematopoietic progenitor cells that were transduced with a lentiviral vector encoding the normal human beta-globin gene.
Prognosis is good for thalassemia minor, as they have no significant morbidity or mortality. For those with thalassemia major, prognosis depends on their will to undergo regular transfusions and iron chelation therapy. Disease progression is marked by chronic complications, such as high-output cardiac failure, bone changes, gallstones, liver dysfunction and endocrine dysfunction. Neurologic complications, such as peripheral neuropathy, cognitive impairment or cerebrovascular disease, often subclinical, are also possible .
Beta thalassemia is caused by beta-globin genes mutations, leading to impaired beta-globin synthesis, reduced hemoglobin levels and anemia. The disease is transmitted in an autosomal recessive manner. Depending on the severity of the disease, the beta-globin synthesis may be close to zero (beta-plus thalassemia) or the protein may not be produced at all (beta-zero thalassemia). On a genetic level, the cause is a missense or nonsense mutation in the beta-globin gene. In the minor form, only one of the beta-globin genes is defective, while in the major form both genes are impaired.
The severity of the disease is influenced not only by the genetic traits of the individuals, but by other factors, as well, like the level of expression of fetal hemoglobin, the existence of concomitant alpha thalassemia and sickle cell trait. While the first two factors decrease the severity of the anemia, sickle cell plus beta thalassemia patients may have severe symptoms and may experience complications of sickle cell disease.
The disease is most frequently encountered in Southeast Asia, Africa and the Mediterranean area. Symptoms become apparent after the age of six months, when the complete switch from fetal to adult hemoglobin synthesis has been made.
The severity of the disease is dependent on the imbalance between the alpha globin and no alpha (beta and gamma) globin chains. A diminished amount of beta globin chains causes the alpha chains that remain unassembled to precipitate and trigger oxidative stress to the membrane of the erythrocyte, leading to apoptosis .
As most genetic diseases, this condition cannot be prevented. However, genetic counseling for carriers of the beta thalassemia trait and for symptomatic patients is advisable. Most patient's behavior is improved once they find out the nature of their condition , but this knowledge does not modify their marriage decisions . Screening programs in teenagers have been implemented in some countries, with beneficial results . Prenatal diagnosis is available and seems to stimulate couples where at least one parent has the disease to have children and reduces overall disease incidence, despite the fact that positive results do not always stimulate parents to terminate the pregnancy .
Beta thalassemia is a congenital disease consisting of impaired synthesis of beta globin chains. The severity of this condition varies according to the magnitude of the defect. Thus, thalassemia minor, also known as thalassemia trait, represents a person carrying the mutation, but who is experiencing no symptoms. Beta thalassemia intermedia is characterized by minor anemia symptoms and variable phenotype, while beta thalassemia major patients experience severe disease requiring chronic transfusion therapy. The term beta-0 thalassemia designates the condition where the production of beta globin chain is completely absent, while beta + thalassemia patients still have the ability to produce diminished amounts of this protein.
Patients exhibit signs of anemia, such as pale skin or jaundice, weakness, fatigability, splenomegaly, growth retardation, delayed puberty, leg ulcers and bone deformities due to extramedullary hematopoiesis. Chronic transfusion therapy brings important amounts of iron to the transfused organism, making chelation therapy imperious. Still, iron overload can happen and lead to cardiac and endocrine dysfunction or liver dysfunction. Diagnosis is made using methods like electrophoresis or high-performance liquid chromatography, showing hemoglobin abnormalities. Prenatal diagnosis is also possible. Treatment consists of long-term transfusion therapy, combined with iron chelation and splenectomy. Allogeneic hematopoietic transplantation may be curative and gene therapy is currently being studied.
Beta thalassemia is a congenital disease affecting the production of hemoglobin, the protein that contains iron and carries oxygen to all the cells in the body. If this protein is not properly formed, the number of red blood cells diminishes and anemia sets in, leading to pale skin, weakness, and so on. The disease may be more or less severe, deppending on how serious the genetic defect is. Thalassemia major, the most serious form, causes symptoms within the first 2 years of life and causes such severe anemia, that it can threaten the child's life. The patient experiences failure to thrive (insufficient growth and development), jaundice, enlarged internal organs (heart and spleen), delayed puberty, hormonal abnormalities and abnormally shaped bones. The treatment consists of blood transfusions. These transfusions, unfortunately, bring large amounts of iron to the organism, that may accumulate inside the body. Thalassemia intermedia and minor are milder forms of the disease.
- Borgna-Pignatti C, Vergine G, Lombardo T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol. 2004;124(1):114-117.
- Voskaridou E, Anagnostopoulos A, Konstantopoulos K, et al. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center, randomized, placebo-controlled trial. Haematologica. 2006;91(9):1193-1202.
- Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187-1193.
- Ding C1, Chiu RW, Lau TK, et al. MS analysis of single-nucleotide differences in circulating nucleic acids: application to noninvasive prenatal diagnosis. Proc Natl Acad Sci U S A. 2004;101(29):10762-10767.
- Galanello R, Melis MA, Ruggeri R, et al. Beta0 thalassemia trait in Sardinia. Hemoglobin. 1979;3(1):33-46.
- Jacob HS, Winterhalter KH. The role of hemoglobin heme loss in Heinz body formation: studies with a partially heme-deficient hemoglobin and with genetically unstable hemoglobins. J Clin Invest. 1970;49(11):2008-2016.
- Basu S, Kumar A. Hair-on-end appearance in radiograph of skull and facial bones in a case of beta thalassaemia. Br J Haematol. 2009;144(6):807.
- Srivastava A, Shaji RV. Cure for thalassemia major - from allogeneic hematopoietic stem cell transplantation to gene therapy. Haematologica. 2017;102 (2):214-23.
- Ferrari G, Cavazzana M, Mavilio F. Gene Therapy Approaches to Hemoglobinopathies. Hematol Oncol Clin North Am. 2017;31 (5):835-852.
- Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood. 2011;118(13):3479-88.
- Hapgood G, Walsh T, Cukierman R, et al. Erythropoiesis is not equally suppressed in transfused males and females with β-thalassemia major: are there clinical implications?. Haematologica. 2015; 100 (8):e292-4.
- Fibach E, Rachmilewitz EA. Does erythropoietin have a role in the treatment of ß-hemoglobinopathies?. Hematol Oncol Clin North Am. 2014; 28(2):249-63.
- Nemtsas P, Arnaoutoglou M, Perifanis V, et al. Neurological complications of beta-thalassemia. Ann Hematol. 2015; 94 (8):1261-5.
- Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med 2005;353:1135–46.
- Rowley P, Fisher L, Lipkin M JR: Screening and genetic counseling for r-thalassemia trait in a population unselected for interest: effects on knowledge and mood. Am J Hum Genet. 1979; 3 1:718-30.
- Barrai I, Vullo C: Assessment of prospective genetic counseling in the Ferrara area. Am J Med Genet. 1980; 6:195-204.
- Silvestroni E, Bianco I, Graziani B, et al. Screening of thalassemia carriers in intermediate schools in Latium: results of four year's work. J Med Genet. 1980; 17:161 -4
- Modell B, Ward RHT, Fairweather DVI: Effect of introducing antenatal diagnosis on reproductive behaviour of families at risk for thalassemia major. Br Med J. 1980; 1: 1347 -50.