β-Thalassemia hijacking ineffective erythropoietin and iron overload: Two case reports and a review of literature.

Thalassemia is a rare, complex disease, representing a group of disorders of hemoglobin synthesis that are characterized by reduced synthesis of either the alpha-globin or β-globin chains of the hemoglobin molecule. Defective synthesis of β-globin resulting from a variety of molecular defects causes β-thalassemia. Thalassemia is an autosomal recessive disorder, which requires prompt diagnosis and an appropriate treatment. Thorough clinical, radiographic and laboratory assessment helps in diagnosing thalassemia and any other hematological disorder. Here, two cases of β-thalassemia showing distinct features are presented and the importance of detailed work-up of the cases has been highlighted.

INTRODUCTION

Thalassemia epitomizes disorders of hemoglobin synthesis, characterized by reduced synthesis of either the alpha-globin or β-globin chains of the hemoglobin molecule. β-Thalassemia encompasses a group of monogenic diseases that have in common defective synthesis of β-globin resulting from a variety of molecular defects that reduce or abolish the normal synthesis of the β-globin chains of hemoglobin.[1] The defects involved are extremely heterogeneous and give rise to a large phenotypic spectrum, with patients that are almost asymptomatic to those requiring regular blood transfusions to sustain life. Being an autosomal recessive disorder characterized by microcytosis and hemolytic anemia, it accounts for thousands of childhood deaths per year, primarily in regions of the world in which malaria used to be endemic.[2] Thorough clinical, radiographic and laboratory assessment is crucial in diagnosing thalassemia along with any other hematological disorder. Two cases of β-thalassemia showing distinct features are presented and the importance of detailed examination of the cases has been highlighted.

CASE REPORTS

Case 1

A 19-year-old male patient presented with the complaint of malaligned teeth in his upper and lower jaws since last 6-7 years he wanted to get it corrected. Past dental history was non-contributory; however, patient gave a history of blood transfusions every 15 days for the past 18 years. History also revealed that the patient was hospitalized for the same about 15 days ago. On examination, the patient seemed to be conscious, cooperative and well-oriented, but with poor built. Lower palpebral conjunctiva showed pallor, but no signs of jaundice, pigmentation, clubbing of nails, skin eruptions or any other deformities, cyanosis or edema were noted. Vital signs were normal. On extra oral examination, patient presented with chipmunk facies type of appearance. Intraoral examination showed malaligned teeth in both upper and lower jaws, chiefly in the anterior region [Figure 1]. Radiographic examination was non-contributory as intraoral periapical radiograph [Figure 2] and lateral cephalogram [Figure 3] did not disclose any abnormality, except for slight variations in the diploic space along with flaring of maxillary anterior teeth, suggestive of malocclusion. Based on the patient's history and clinical presentation, a provisional diagnosis of thalassemia was given. Laboratory investigations made known that the patient had normocytic normochromic anemia. To substantiate with the provisional diagnosis, a hemoglobin electrophoresis was run on paragon gel at a pH of 8.6, which showed an absence of β-globin of hemoglobin. Based on the clinical features, past medical history in association with hematological finding, a final diagnosis of β-thalassemia major was made.

Figure 1

Patient presenting typical chipmunk facies along with malaligned teeth in upper and lower jaws

Figure 2

Intraoral periapical radiograph of Case 1 with no significant findings

Figure 3

Lateral cephalogram of Case 1 showing slight variations in the diploic space

Case 2

An 8-year-old male child was brought by his mother with a complaint of malaligned teeth in upper front region of jaw. Past dental history was non-influential; however a history of blood transfusions since past 7 years was given by patient's mother. On clinical examination, slight malocclusion was noted in upper anterior teeth associated with deep bite [Figure 4]. Radiographic examination was non-related to the medical history as intraoral periapical radiograph [Figure 5] and lateral cephalogram did not show any significant changes [Figure 6]. This patient was also seen to be having normocytic normochromic anemia. Nevertheless, hemoglobin electrophoresis test showed absence of β-globin of hemoglobin, as was observed in the first case. Though the clinical features and radiographic features did not contribute much, with the help of past medical history and laboratory investigation, a diagnosis of β-thalassemia minor was given.

Figure 4

Patient presenting with slight malocclusion in upper anterior teeth

Figure 5

Intraoral periapical radiograph of Case 2 with no significant findings

Figure 6

Lateral cephalogram of Case 2 with no significant findings

DISCUSSION

Thalassemia derives its name from Greek word “thalassa,” meaning sea, as the original cases were reported from the region of the Mediterranean Sea. Cooley and Lee, in 1925, described thalassemia as a severe anemia that is associated with bone changes and splenomegaly.[3] Only later it was established that thalassemia was attributable to a partial autosomal dominant gene, for which the homozygous state was termed thalassemia major and the heterozygous state was termed thalassemia minor. Thalassemia minor occurs only when one defective gene for β-globin molecule is inherited and the patient presents with no significant clinical manifestations, as noted in Case 2. Conversely, when two defective genes for the β-globin molecules are inherited, the patient is affected with thalassemia major, also known as Cooley's anemia or Mediterranean fever and presents with clinical manifestations as observed in Case 1. Furthermore, the disorders less severe than major forms but more severe than minor forms are described as thalassemia intermedia, which has been observed in 10% of patients with the homozygous trait.[4] Thalassemia has been estimated as the most common inherited disorder that affects humans. According to recent reports, approximately out of 14 people only one is carried for different subtypes of thalassemia. Every year about 400,000 infants are born with severe hemoglobinopathies.[5] Thalassemia, found in almost every ethnic group and geographic location,[6] occurs more commonly in the Mediterranean, African, Indian and South-east Asian populations. In developing countries like India, hemoglobinopathies are seen to be increasing in an alarming rate due to lack of proper health-care. Among the thalassemia patients in the world, about 10% belong to Indian sub-continent, with 3-4% of them being carriers.

Thalassemia syndromes are known to constitute a larger group of inherited hematologic disorders termed hemoglobinopathies. Therefore a defect in the structure of the globin chain can cause sickle cell anemia; thalassemia is caused by a defect in the rate of synthesis of one or more globin chain. The genetic defect in thalassemia results in reduced rate of synthesis of one of the globin chains that make up hemoglobin, which in turn can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting sign of thalassemia.[7]

Thalassemia major is generally detected during the 1st year of life because severe microcytic hypochromic anemia develops as fetal hemoglobin synthesis ceases after 3-4 months of age; however in our case, normocytic normochromic anemia was noted. The consequently produced exceptionally fragile red blood cells can survive for only few days in the peripheral circulation, which leads to critically increased rate of hematopoiesis (up to 30 times the normal), in an attempt to maintain adequate oxygenation. This results in massive bone marrow hyperplasia, in association with hepatosplenomegaly and lymphadenopathy due to extramedullary hematopoiesis, which could not be appreciated in the present case.[8] Bone marrow hyperplasia could instigate marked but painless enlargement of the mandible and maxilla, resulting in characteristic “chipmunk” facies, as was eminent in the first case, along with an evidence of frontal bossing. If the patient is untreated, tissue hypoxia worsens and bacterial infections due to pneumococcal organisms often develop. Sooner or later, high-output cardiac failure occurs resulting in death of patients by 1 year of age as a result of infection or cardiac problems.

Blood transfusion is the customary treatment for thalassemia major, administered every 2-3 weeks so as to simulate the normal hematologic state. However, repeated blood transfusions unfortunately lead to iron overload due to constant infusion of exogenous red blood cells, causing hemochromatosis, ultimately leading to death. Heart, liver and endocrine glands are particularly affected by this toxic iron accumulation. To combat this problem, deferoxamine (desferrioxamine), an iron-chelating agent must be given.[9] In current case, fortunately no such complications were noted. Bone marrow transplantation has also been used with considerable success for individuals who are relatively young, have little organ damage and have a human leukocyte antigen - matched donor. For patients with abnormal facial appearance caused by thalassemia, surgical correction can be performed in most of the cases. Prevention of thalassemia is looked-for, either by screening for carriers of the genetic trait or by prenatal diagnosis.

Thalassemia minor can present with β0/β or β+/β genotype. It is an asymptomatic disease with mild anemia or none and very few red cell abnormalities are seen. In the present case, normocytic normochromic anemia was noted. The patients have a normal life expectancy. Diagnosis of β-thalassemia minor requires hemoglobin electrophoresis, which was conducted in our case. Similar to thalassemia major, molecular genetics includes rare gene deletion in β0/β0, defects in transcription, processing or translation of β-globin messenger ribonucleic acid (mRNA). Repeated blood transfusion is the most commonly followed mode of treatment for thalassemia minor.[10] Both patients are being treated by periodic blood transfusions, with an improvement in the general health being noted and the patients are under regular follow-up.

Each of the thalassemia syndromes occurs due to specific gene mutation that is responsible for the decreased production of a specific globin. This mutation could be in the form of deletions, rearrangement of the loci or point mutations leading to impaired transcription, processing, or translation of globin mRNA, causing defective globin production.[4] Variations in the severity of the clinical presentation may be a reflection of the specific alteration in the genetic code, for the reason that over 200 different mutations have been documented for this condition.

Quite a few studies have been carried out to understand the genetic conformation of thalassemia. Thalassemias produce a deficiency of alpha or β-globin, unlike sickle cell disease which produces a specific mutant form of β-globin. β-Globin chains are encoded by a single gene on chromosome 11, while alpha globin chains are enclosed by two closely linked genes on chromosome 16.[11] Thus in a normal person with two copies of each chromosome, there are two loci encoding the β-chain and four loci encoding the alpha chain. Deletion of one of the loci has a high prevalence in people of African or Asian descent, making them more likely to develop alpha thalassemia, while β-thalassemia is common in Africans, Greeks and Italians.

CONCLUSION

To conclude, thalassemia constitutes a group of genetic disorders, which requires prompt diagnosis based on medical history, clinical examination, radiographic assessment, appropriate laboratory investigations in association with genetic studies. Early detection of thalassemia is necessary so that appropriate treatment can be initialized. Irrespective of clinical features and thorough medical history laboratory investigations are must to be carried out in order to detect any blood disorder.