Thalassemia Case Report

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CASE REPORT THALASSEMIA MAJOR Presenter : Gracelia R. E. Damanik Sam Raj Rayan Day/Date : Tuesday, 22nd of June 2010 Supervisor : dr. Lily Irsa, Sp.A(K)

INTRODUCTION Thalassemias are genetic disorders in globin chain production, inherited autosomal recessive blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains causes the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom of the thalassemias.1,2 Thalassemia was first defined in 1925 when Dr. Thomas B. Cooley described five young children with severe anemia, splenomegaly, and unusual bone abnormalities and called the disorder erythroblastic or Mediterranean anemia because of circulating nucleated red blood cells and because all of his patients were of Italian or Greek ethnicity. In 1932 Whipple and Bradford coined the term thalassemia from the Greek word thalassa, which means the sea (Mediterranean) to describe this entity. Somewhat later, a mild microcytic anemia was described in families of Cooley anemia patients, and it was soon realized that this disorder was caused by heterozygous inheritance of abnormal genes that, when homozygous, produced severe Cooley anemia.2,3 In Europe, Riette described Italian children with unexplained mild hypochromic and microcytic anemia in the same year Cooley reported the severe form of anemia later named after him. In addition, Wintrobe and coworkers in the United States reported a mild anemia in both parents of a child with Cooley anemia. This anemia was similar to the one that Riette described in Italy. Only then was Cooley's severe anemia recognized as the homozygous form of the mild2

hypochromic and microcytic anemia that Riette and Wintrobe described. This severe form was then labeled as thalassemia major and the mild form as thalassemia minor. These initial patients are now recognized to have been afflicted with thalassemia. In the following few years, different types of thalassemia that involved polypeptide chains other than chains were recognized and described in detail. In recent years, the molecular biology and genetics of the thalassemia syndromes have been described in detail, revealing the wide range of mutations encountered in each type of thalassemia.2,4 EPIDEMIOLOGY Certain types of thalassemia are more common in specific parts of the world. thalassemia is much more common in Mediterranean countries such as Greece, Italy, and Spain. Many Mediterranean islands, including Cyprus, Sardinia, and Malta, have a significantly high incidence of severe thalassemia, constituting a major public health problem. For instance, in Cyprus, 1 in 7 individuals carries the gene, which translates into 1 in 49 marriages between carriers and 1 in 158 newborns expected to have b thalassemia major. As a result, preventive measures established and enforced by public health authorities have been very effective in decreasing the incidence among their populations. b thalassemia is also common in North Africa, the Middle East, India, and Eastern Europe. Conversely, thalassemia is more common in Southeast Asia, India, the Middle East, and Africa. Worldwide, 15 million people have clinically apparent thalassemic disorders. Reportedly, disorders worldwide, and people who carry thalassemia in India alone number approximately 30 million. These facts confirm that thalassemias are among the most common genetic disorders in humans; they are encountered among all ethnic groups and in almost every country around the world.2,4,5 Although -thalassemia has >200 mutations, most are rare. Approximately 20 common alleles constitute 80% of the known thalassemias worldwide; 3% of the world's population carries genes for -thalassemia, and in Southeast Asia, 5 10% of the population carries genes for -thalassemia. In a particular area there


are fewer common alleles. In the U.S., an estimated 2,000 individuals have thalassemia.1 ETIOLOGY Thalassemia syndromes are characterized by varying degrees of ineffective hematopoiesis and increased hemolysis. Clinical syndromes are divided into and -thalassemias, each with varying numbers of their respective globin genes mutated. There is a wide array of genetic defects and a corresponding diversity of clinical syndromes. Most -thalassemias are due to point mutations in one or both of the two -globin genes (chromosome 11), which can affect every step in the pathway of -globin expression from initiation of transcription to messenger RNA synthesis to translation and post translation modification. Picture below shows the organization of the genes (i.e., and , which are active in embryonic and fetal life, respectively) and activation of the genes in the locus control region (LCR), which promote transcription of the -globin gene. There are four genes for globin synthesis (two on each chromosome 16). Most -thalassemia syndromes are due to deletion of one or more of the -globin genes rather than to point mutations. Mutations of -globin genes occur predominantly in children of Mediterranean, Southern, and Southeast Asian ancestry. Those of -globin are most common in those of Southeast Asian and African ancestry.6

(source: Manual of Pediatric Hematology and Oncology) Major deletions in thalassemia are unusual (in contrast to thalassemia), and most of the encountered mutations are single base changes, small deletions, or insertions of 1-2 bases at a critical site along the gene, as in the image below.


(source: Thalassemia, Emedicine Multimedia) CLASSIFICATION The thalassemias can be defined as a heterogeneous group of genetic disorders of hemoglobin synthesis, all of which result from a reduced rate of production of one or more of the globin chains of hemoglobin. This basic defect results in imbalanced globin chain synthesis, which is the hallmark of all forms of thalassemia. The thalassemias can be classified at different levels. Clinically, it is useful to divide them into three groups: the severe transfusion-dependent (major) varieties; the symptomless carrier states (minor) varieties; and a group of conditions of intermediate severity that fall under the loose heading thalassemia intermedia. This classification is retained because it has implications for both diagnosis and management.4


-THALASSEMIA2,8 The -thalassemia syndromes are caused by abnormalities of the b-gene complex on chromosome 11. More than 150 different mutations have been described, and most of these are small nucleotide substitutions within the b gene complex. Deletions and mutations that result in abnormal cleavage or splicing of -globin RNA may also result in thalassemia characterized by absent (0) or reduced (+) production of -globin chains.2,7 THALASSEMIA MINOR (THALASSEMIA TRAIT) Heterozygosity for a b-thalassemia gene results in a mild reduction of bchain synthesis and, therefore, a reduction in HbA and mild anemia. Hemoglobin levels are 10 to 20 g/L lower than that of normal persons of the same age and gender, but the anemia may worsen during pregnancy. This mild anemia usually produces no symptoms, and longevity is normal. Thalassemia trait is almost always accompanied by familial microcytosis and hypochromia of the red blood cells. Target cells, elliptocytes, and basophilic stippling are seen on the peripheral blood smear. Almost all individuals with b-thalassemia trait have MCVs less than 75 fL, and mean MCV is 68 fL. In thalassemia trait the MCV is disproportionately low for the degree of anemia because of a red blood cell count that is normal or increased. The RDW is normal in thalassemia trait. The ratio of MCV/RBC (Mentzer index) is 12 in iron deficiency. Iron studies are normal. In an individual with microcytic red blood cells, a diagnosis of bthalassemia trait is confirmed by an elevated HbA2 (22) level. The normal level of HbA2 is 1.5 to 3.4%, and HbA2 >3.5% is diagnostic of the most common form of -thalassemia trait. Levels of HbF (22) are normal ( 10 gr/dl, no paleness, and the PRC transfusion had been finished. DISCUSSION There is family history of Thalassemia of patient with Thalassemia. Symptoms of -thalassemia major develop gradually in the first 6 to 12 months after birth. By the age of 6 to 12 months, most affected infants show pallor, irritability, growth retardation, jaundice, and hepatosplenomegaly as a result of extramedullary hematopoiesis.17,18 Patient did not have family history of Thalassemia. This patient was diagnosed Thalassemia Major in 1 year of life. This patient had pallor before diagnosed with Thalasemia and did not have growth retardation (nutritional status of patient patient was normoweight). There was hepatosplenomegali on physical diagnostic. In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL. Mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) are significantly low, reflecting anemia hypochromic microcyter. Thalassemia major is associated with a markedly elevated RDW, reflecting the extreme anisocytosis. Platelet count is usually normal, unless the spleen is markedly enlarged.1,6 Patient had 5.70 gr%36

of Hb value, so that he had severe anemia, that indicated patient had to get RBC transfusion. In hematology laboratory findings, there was declining of MCV, MCH, and MCHC value, but not significantly, that described the type of anemia hypochromic microcyter. There was inclining of RDW value significantly that reflects the morphology of RBC is anisocytosis. There was thrombocytopenia, unless there was enlarging of spleen. Liver involvement is common in those who undergo long-term transfusions. Early cirrhotic changes can be observed as early as age 7 years in some people with thalassemia. Upregulation of the transport of NTBI is observed in cultured hepatocytes and is likely to occur