Epidemiological Study among Thalassemia Intermedia Pediatric Patients
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1 Med. J. Cairo Univ., Vol. 78, No. 2, December , Epidemiological Study among Thalassemia Intermedia Pediatric Patients NERMEEN KADDAH, M.D.; KHALED SALAMA, M.D.; AHMED MAHER KADDAH, M.D. and RANIA ATTIA, M.Sc. The Department of Pediatrics, Children Hospital, Faculty of Medicine, Cairo Univesity Abstract Background: Thalassemia intermedia is a term used to define a group of patients with beta thalassemia in whom the clinical severity of the disease is somewhere between the mild symptoms of beta thalassemia trait and the severe manifestations of beta thalassemia major. The diagnosis is a clinical one based on the patient maintaining a satisfactory hemoglobin (Hb) level of at least 6-7g/dl at the time of diagnosis without the need for regular blood transfusions. Objectives: To study the demographic; clinical and laboratory data of patients with thalassemia intermedia. Material and Methods: The present work was a retrospective study on records of patients with thalassemia intermedia attending the hematology clinic, New Children Hospital, Cairo University from It comprised follow-up sheets of 58 thalassemia intermedia patients, from which data were collected including full history and clinical examination, and laboratory investigations including CBC; including Hb, HCT, RBCs, MCV, MCH, also retics and Hb electrophoresis. Results: The age of patients ranged between 1-16 years with a mean age of 4.45 ±2.7. Male to female ratio was 1: There was no history of blood transfusion in 51.7% of patients while 48.3% had history of blood transfusion. Of these patients, 46.4% received blood transfusion only once, 14.3% received twice, 14.3% received 3 times, 25% received blood transfusion 4 times or more. Pallor was the most frequently encountered sign in 86.2% of the patients, while splenomegaly was present in 70.2%, jaundice in 67%, mongoloid features in 65.5%. Hb ranged between gm/dl, while MCV ranged between with a mean of Hb electrophoresis showed Hb A ranging between with a mean 70.25, Hb A2 ranging between with a mean 3.09, and Hb F ranging between with a mean Conclusion: Thalassemia intermedia patients present at older age unlike thalassemia major which usually becomes evident during the 1 st year of life. Pallor is the commonest symptom. Also it may present with jaundice or enlarged abdomen. They usually are able to maintain a satisfactory Hb level of at least 6-7g/dl at the time of diagnosis withoutn the Correspondence to: Dr. Nermeen Kaddah, The Department of Pediatrics, Children Hospital, Faculty of Medicine, Cairo Univesity. need for regular blood transfusion. Some of these patients need no transfusion therapy while others need frequent blood transfusion. Key Words: Thalassemia Intermedia Blood transfusion. Introduction THALASSEMIA intermedia is a term used to describe a group of patients with beta thalassemia in whom the clinical severity of the disease is somewhere between the mild symptoms of beta thalassemia trait and the severe manifestations of beta thalassemia major. The diagnosis is a clinical one based on the patient maintaining a satisfactory hemoglobin level of at least 6-7g/dl at the time of diagnosis without the need for regular blood transfusion [1]. This initial definition of thalassemia intermedia, which was based on clinical observation alone, retained its validity even after some of the specific mutations associated with thalassemia intermedia were recognized because severity of the clinical course remains unpredictable even in known genotypes [1]. For this reason, some patients with a beta thalassemia intermedia genotype are treated as if they have thalassemia major because they present with severe manifestations; similarly others with a thalassemia intermedia genotype are considered to have thalassimia minor because of the mild or even asymptomatic nature of their condition [2]. Because of the significant overlap in clinical severity among the three types of beta thalassemia and despite the fact that several genotypes are associated with the beta thalassemia intermedia picture, the diagnosis continues to be a clinical one regardless of the genotype involved. Moreover, in an individual patient, the diagnosis may change 651
2 652 Epidemiological Study among Thalassemia Intermedia Pediatric Patients from thalassemia intermedia to thalassemia major once the patient begins to have more severe symptoms and to require regular blood transfusions [3]. The aim of this study was to evaluate the demographic, clinical and laboratory data of patients with thalassemia intermedia presenting to the hematology clinic of New Children Hospital of Cairo University. Material and Methods This work was a retrospective study, conducted on records of patients with thalassemia intermedia attending the Haematology Clinic of Children Hospital of Cairo University from 2003 to Data were collected from sheets of patient including full history and clinical examination including the main complaint, age at presentation, residence, blood transfusion requirements, presence of pallor, jaundice, mongoloid facies and hepatosplenomegaly. Also laboratory data were collected including Hb level, hematocrite value, RBCs count, WBCs count, platelet count, MCV, MCH Retics, and also Hb electrophoresis. Statistical analysis: All patients information were tabulated and processed using SPSS 12.0 for Windows XP. Quantitative variables were described by mean and standard deviation. Qualitative variables were described by number and percentage. Correlation between two continuous variables was done using pearson correlation. p-value was significant when less than Results Our study included 58 patients diagnosed as Beta thalassemia intermedia who attended the hematology clinic of Cairo University Children Hospital from The studied cases were 31 females (53.4%) and 27 males (46.6%) with male to female ratio of 1: Regarding the residence of the patients; 30 (51.7%) were from urban areas, while 28 patients (48.3%) were from rural area. The age of the patients ranged from 1-16 years with a mean ± SD of 4.45±2.7. Family history was positive in 35 patients (60.4%), while positive consanguinity was present in 32 patients (55.2%). As Regards history of blood transfusion shown in Fig. (1), there was no history of blood transfusion in 30 patients (51.7%), while 28 patients (48.3%) had history of blood transfusion in the following pattern: 13 patients (46.4%) received blood transfusion only once, 4 patients (14.3%) received blood transfusion twice, 4 patients (14.3%) received blood transfusion three times, and 7 patients (25%) received blood transfusion four times or more. Fig. (2) demonstrates the clinical findings detected in patients on presentation. Pallor was the most frequently encountered sign in 50 patients (86.2%), splenomegaly in 40 patients (70.2%), jaundice in 39 patients (67.2%), and mongoloid features in 38 patients (65.5%). Table (1) shows the blood picture parameters and Hb electrophoresis for studied cases with Hb ranging between gm/dl with a mean ± SD 7.1 ± 1.5, MCV ranging between with a mean ± SD 60.25± 10.7, MCH (pg) ranging between with a mean ± SD 20.23±4, MCHC (%) ranging between with a mean ± SD 33.13±4.48, HCT ranging between with a mean ± SD 21.68±4.93, and retics ranging between with a mean ± SD 2.3± 1.5. Hb electrophoresis results showed Hb A ranging between with a mean ± SD ±25.98, Hb A2 ranging between with a mean ± SD 3.09±2.11, and Hb F ranging between with a mean ± SD 26.47± Table (2) compares Hb electrophoresis parameters in patients with or without mongoloid features, showing Hb A levels were significantly lower in those having mongoloid facial features. No significant difference was found as regards Hb F and Hb A2. Table (1): Blood picture parameters and Hb electrophoresis for studied cases. RBCs Hb HCT MCV MCH MCHC Retics Platelets WBCs Hb A Hb F Hb A 2 Mean SD Median Min. Max Table (2): Hb electrophoresis parameters in patients with or without mongoloid features. Hb A Hb F Hb A 2 Non mongoloid Mongoloid Mean SD Mean SD p-value (S) 0.08 (NS) 0.25 (NS)
3 Nermeen Kaddah, et al. 653 No history of blood transfusion History of blood transfusion 4 times or more 25% Once 46.4% 51.7% 48.3% 3 times 14.3% Fig. (1): History of blood transfusion in the studied thalassemia intermedia patients. Twice 14.3% 50 hematopoiesis, leg ulcers, gall stones and thrombophilia [6]. No. of patients Fig. (2) : Clinical findings of the studied patients. Discussion Thalassemia is one of the most common genetic disorders on a worldwide basis [4]. Thalassemia syndromes are heterogeneous group of inherited disorders characterized by decreased either alpha or beta chain synthesis. Beta thalassemia can be classified clinically into thalassemia trait, intermedia, and major [5]. Thalassemia intermedia encompasses a wide spectrum of beta thalassemic phenotypes. Some thalassemia intermedia patients are asymptomatic until adult life, whereas others are symptomatic as young as 1 year of age [6]. The remarkable variability in clinical severity of thalassemia intermedia depends on the genetic heterogeneity of thalassemias. The progress in molecular biology methods allowed the definition of globin gene defects and partially elucidated the relationship between phenotype and genotype [7]. A number of clinical complications commonly associated with thalassemia intermedia are rarely seen in thalassemia major, including extramedullary The aim of this study was to clarify the demographic, clinical and laboratory data of thalassemia intermedia. This study was conducted on 58 thalassemia intermedia patients, presenting to hematology clinic of Cairo University Children Hospital from 2003 to The mean age at presentation in this study was found to be 4.45 years with a range from 1-16 years. This is with Ballati, et al., [8] with a mean age of 4.5 with age ranging from 2-15 years. This is in contrast with Tyagi, et al., [9] with a mean age of 13.5 years ranging between 6 months-46 years. Regarding history of blood transfusion in the studied patients, 51.7% had no history of blood transfusion, while 48.3% had history of blood transfusion in the following pattern: 46.4% only once, 14.3% twice, 14.3% 3 times and 25% 4 times or more. This in agreement with Tyagi, et al., [9] in which 56.6% of patients required infrequent transfusions, while 43.4% never required blood transfusions. This is in agreement with Taher, et al., [6] in which 52% received no blood transfusions, while 48% received infrequent blood transfusions. This is also in agreement with Taher, et al., [6] who stated that many patients with thalassemia intermedia receive only occasional or no blood transfusion since they are able to maintain hemoglobin levels between 7-9g/dl. Pallor in this study was found to be the main presenting clinical manifestatin (86.2%). This is in agreement with Hassan, [1] who stated that pallor is almost always present to some degree, and also in agreement with De silva, et al., [10]. Considering blood indices: MCV (f.l) mean was 60.25, MCH (pg) was 20.23, MCHC (%) was This in agreement with Karimi, et al., [11] with MCV mean was 64.6, MCH mean was 20.2, MCHC mean was This is also in agreement
4 654 Epidemiological Study among Thalassemia Intermedia Pediatric Patients with Chen, et al., [12] with MCV mean was 62.04, MCH mean was 20.1 and MCHC mean was However in our study, three cases (no 14, 22, 57) MCV almost approaches normal levels (76.6, 76.6, 79.8) respectively. The increase in MCV in beta thalassemia cases could be attributed to high reticulocytic count, blood transfusion, or associated folate deficiency, which normalize blood indices Cao and Moi, [13]. This is also explained by the statement of Galanello, et al., [14] who reported that patients in number of selected beta thalassemia alleles, may have normal or borderline A2 with normal MCV. As regards Hb electrophoresis; Hb A ranged between with a mean 70.25%, A2 ranged between with a mean 3.09%, and Hb F ranged between with a mean 26.47%. This is in agreement with qatanani, et al., [15] in which Hb F mean was 21.04, Hb A2 mean 2.7, Hb A mean was This is also in agreement with Weatherall and Clegg, [7] who stated that in thalassemia intermedia Hb F more likely 10-50% (may be up to 100%) and Hb A2 more likely >4%. This also in agreement with Hassan, [1] who stated that Hb electrophoresis in thalassemia intermedia shows an abnormal pattern. An elevated Hb A2 fraction up to 7% indicates beta thalassemia, typically beta thalassemia trait or certain forms of thalassemia intermedia. In fact Hb A2 of 0% frequently arises from a homozygous deletion of both beta and the delta chain genes because delta chains are needed to produce Hb A2. In the intermedia type, overall Hb F ranges from % and A2 up to 7%. In case no 36 Hb F was 98% Hb A was zero, this may be explained by Galanello and Cao, [16] and Ho, et al., [17] who stated that the mechanism for ameliorating the clinical picture of homozygous beta thalassemia is the coinheritance of an independent genetic determinant that is able to sustain a continuous production of gamma chain in adult life, typical example of this determinant is the non deletion hereditary persistence of HPFH. One of the best known examples is the so called Sardininian delta beta thalassemia, in this condition the delta beta thalassemia chromosome contains two mutations, beta thalassemia mutation (codon 39 no sense) silencing the beta globin chain and a second HPFH mutation in the alpha gamma promoter ( 196 alpha gamma C T) which result in high alpha gamma chain production and at least compensates for the absent beta chain production. Accordingly compound heterozygotes for this mutation and severe beta thalassemia give rise to thalassemia intermedia phenotype, another very common non deletion HPFH determinant, the 158 GyA T mutation is also able to ameliorate the clinical picture of severe thalassia major. Also Cao and Moi, [13] stated that high level of Hb A2 and HbF is related to the nature of the beta thalassemia mutation itself. From this study we can conclude that thalassemia intermedia patients present at an older age unlike thalassemia major which usually becomes evident during the 1 st year of life. Pallor was the commonest manifestation, also it may present with jaundice or hepatosplenomegaly. They are usually able to maintain a satisfactory hemoglobin level of 6-7gm/dl without the need for regular blood transfusion. Many of these patient need no transfusion therapy while some need blood transfusion but usually not frequent. We recommend analysis of the genotype of patients with thalassemia intermedia which is important for early diagnosis of the milder disease thus avoiding regular blood transfusion. Also, regular follow-up of thalassemia intermedia patients for early detection of clinical complicationswhich are commonly associated with thalassemia intermedia and rarely seen in thalassemia major including extramedullary hematopoiesis, leg ulcers, gall stones, and thrombophilia. References 1- HASSAN M. AICH: Thalassemia E-Medicine Journal Sep. 4, Volume 2, No. 9, LILLEYMAN I.S., HANN I.M. and BLAMCHETTE V.: The thalassemia. Pediatr. Haematol.: , NATHAN D.G. and OSKI F.A.: The thalassemia. In: Nathan and Oski's Hematology of Infancy and Childhood. Philadelphia, Pa: W.B. Saunders Co.: 847-9, WINICHAGOON P., FURCHAREONS, CHEN P., et al.: Genetic factors affecting clinical severity in beta thalassemia syndromes. J. Pediatr. Hematol. Oncol., 22: OLIVIERI N.F.: The beta thalassemia. N. Engl. J. Med. 341: , TAHER A., CAPPELLINI M.D. and ISMAEEL H.: Thalassemia: The facts and the controversies. Pediatr. Nurs. Nov-Dec, 29 (6): 447, 9, 451, WEATHERALL D.J. and CLEGG J.B. (eds): The thalassemia syndromes (4th edition) Black-well science Ltd. Oxford, BALLATI G., VANIA A., GENTILONIF, et al.: Thalassemia syndromes in latium: Epidemiological evaluation. Haematologica, 83 (6): , TYAGI S., PATI H.P., TYAGI S., CHOUDHRY V.P. and SAXENA R.: Clinicohematological profile of HBE syndrome in adults and children. Hematology, 9 (1): 57-60, DE SILVA S., FISHER C.A., PREMAWARDHENA A., LAMABADUSURIYA S.P., PETO T.E., PERERA G, OLD J.M., CLEGG J.B., OLIVIERI N.F. and WEATH- ERALL D.J.: Thalassaemia in Sri Lanka: Implications for the future health burden of Asian populations. Sri
5 Nermeen Kaddah, et al. 655 Lanka Thalassaemia Study Group. Lancet, 355 (9206): , KARIMI, DARZI H. and YAVARIAN M.: Haematologic and clinical responses of thalassemia intermedia patient to hydroxyuria during 6 years of therapy in Iran. J. Pediatr. Hematol. Oncol. 37 (7): 380-5, CHEN T.P., LIU T.C., CHANG C.S., CHANG J.G., TSAI H.J. and LIN S.F.: PCR-based analysis of alpha thalassemia in southern Taiwan. Int. J. Hematol. Apr, 75 (3): , CAO A. and MOI P.: Carrier screening and genetic counseling in beta thalassemia. J. Hematol. Aug. 76 suppl. 2: , GALANELLO R. and CAO A.: Relationship between genotype and phenotype: Thalassemia intermedia. Annals of the New York academy of sciences th symposium , QATANANI M., TAHER A., KOUSSA S., NAAMAN R., FISHER C., RUGLESS M., OLD J. and ZAHED L.: β -Thalassaemia intermedia in Lebanon. European Journal of Haematology Volume 64, Issue 4, pages , April, GALANELLO R., BAREELA S., IDEO A., et al.: Genotypes of subjects with borderline Hb A2 levels: Implication for beta thalassemia carrier screening Am. J. Hematol., 46: 79-81, HO P.J., HALL G.W., LUO L.Y., et al.: Beta thalassemia intermedia: Is it possible to predict phenotype from genotype? Br. J. Haematol., 100: 70-8, 2000.
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