History

Fact Explanation
Family history of thalassaemia Normal haemoglobin (Hb) is composed of 2 alpha chains 2 beta chains. Alpha chains are produced by genes on the chromosome 16 and beta globin chains are by chromosome 11. [2] At birth 80% of the Hb are HbF (2 alpha and 2 gamma chains), in which gamma chains are gradually replaced by beta chains starting at the age of 6 months, and result in HbA. HbA is composed of 2 alpha and a beta chains. Beta thalassaemia results from either insufficient or no production of beta chains. It is an inherited disorder with an autosomal recessive inheritance due to the point mutations of the globin chains. [2] Delta beta thalassemia is a type of beta thalassemia, characterized by decreased or absent synthesis of the delta- and beta-globin chains with a compensatory increase in expression of fetal gamma-chain synthesis. Delta-beta-thalassemia is commonly caused by deletions of the entire delta and beta gene sequences. [5] Consanguinity [2] increases the risk of thalassaemia as there is a high risk of meeting two recessive genes. Common presenting age of thalassaemia is 6-24 months of age.
Severity of the disease The heterozygous form of the condition is clinically asymptomatic, but when inherited with heterozygous classical beta-thalassemia, they will have the thalassemia intermedia phenotype. [2]
Shortness of breath Anaemia cause low oxygenation of the blood, Hypoxia can be sensed by the carotid chemoreceptors and it will increase the depth of respiration. If the patient has heart failure anemia can worsen the symptoms. Iron overload due to recurrent blood transfusions can also cause iron deposition in the cardiac tissue which is greatest in the ventricular walls with less in the atria and conduction system result in cardiac failure [2] and exertional shortness of breath.
Lethargy, fatigue Due to the anaemia, the patient feels very tired during exercise. Body lacks sufficient oxygen and energy where the person feels fatigue and lethargy. [6]
Recurrent infections [1] Possible causes could be hypersplenism causing low white blood cell counts, splenectomy associated infections due to encapsulated organisms such as streptococcus, meningococcus and iron overload making the individual vulnerable for infections with Yersinia sp.
Bleeding manifestaions Hypersplenism causing low platelet count. [7]
Right hypochondrial pain Hepatitis [1] can be due to iron deposition in liver in recurrent blood transfusions.
Excessive sleepiness and weight gain Hypothyroidism is an endocrine problem [3] occur due to the iron overload.
Poor school performance May be multifactorial. Chronic disease, recurrent hospital stays, missing the lessons, lethargy due to anaemia and psychological distress are the some o these factors. [4]
Subfertility Hypogonadotropic hypogonadism is common in these patients. [3]
Failure to thrive in children Thalassemia will be clinically evident at the age of major 6 - 24 months. Affected infants are fail to thrive, feeding problems, diarrhea, irritability, recurrent bouts of fever may occur. [8]
Facial-maxillary abnormalities Ineffective erythropoiesis can lead to bone marrow expansion with thinning if the skull bones, skull bossing, prominent malar eminence, depression of the bridge of the nose and mandibular hyperplasia. This can lead to faciomaxillary abnormalities. [9]
References
  1. ASHIOTIS T, ZACHARIADIS Z, SOFRONIADOU K, LOUKOPOULOS D, STAMATOYANNOPOULOS G. Thalassaemia in Cyprus Br Med J [online] 1973 Apr 7, 2(5857):38-42 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1588975
  2. SCRIVER CR, BARDANIS M, CARTIER L, CLOW CL, LANCASTER GA, OSTROWSKY JT. Beta-thalassemia disease prevention: genetic medicine applied. Am J Hum Genet [online] 1984 Sep, 36(5):1024-1038 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1684522
  3. COHEN A. R.. Thalassemia. Hematology [online] 2004 January, 2004(1):14-34 [viewed 31 July 2014] Available from: doi:10.1182/asheducation-2004.1.14
  4. MUSUMECI S, ROMEO MA, PIZZARELLI G, SCHILIRĂ² G, RUSSO G. delta beta-Thalassaemia in Sicily: report of a case of double heterozygosity for A gamma delta beta-thalassaemia and A gamma G gamma delta beta-thalassaemia. J Med Genet [online] 1983 Feb, 20(1):73-75 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1048994
  5. ORKIN SH, GOFF SC, NATHAN DG. Heterogeneity of DNA deletion in gamma delta beta-thalassemia. J Clin Invest [online] 1981 Mar, 67(3):878-884 [viewed 17 August 2014] Available from: doi:10.1172/JCI110105
  6. COATS AJ. Anaemia and heart failure Heart [online] 2004 Sep, 90(9):977-979 [viewed 18 September 2014] Available from: doi:10.1136/hrt.2003.012997
  7. AL-SALEM AH. Splenic Complications of Sickle Cell Anemia and the Role of Splenectomy ISRN Hematol [online] 2011:864257 [viewed 18 September 2014] Available from: doi:10.5402/2011/864257
  8. LAWSON WILLIAM, PATEL ZARA M., LIN FRED Y.. The Development and Pathologic Processes that Influence Maxillary Sinus Pneumatization. Anat Rec [online] 2008 November, 291(11):1554-1563 [viewed 18 September 2014] Available from: doi:10.1002/ar.20774
  9. GALANELLO R, ORIGA R. Beta-thalassemia Orphanet J Rare Dis [online] :11 [viewed 31 July 2014] Available from: doi:10.1186/1750-1172-5-11

Examination

Fact Explanation
Thalassaemic facies When the disease advances, there is ineffective erythropoiesis which can lead to bone marrow expansion with thinning of the skull bones, skull bossing, prominent malar eminence, depression of the bridge of the nose and mandibular hyperplasia. [2]
Pallor [2] Due to the anaemia. [2]
Jaundice [2] Ineffective erythropoiesis causing red cell destruction and hyperbilirubinemia. [2]
Splenomegaly [2] Due to the extravascular haemolysis and extramedullary hematopoiesis. [2]
Hepatomegaly [2] Due extramedullary hematopoiesis.[2]
Features of cardiac failure: elevated jugular venous pressure, tender hepatomegally, peripheral oedema Iron overload due to recurrent blood transfusions can also cause cardiac failure. [1]
Dyspnea Anaemia leading to hypoxia or iron overload due to recurrent blood transfusion causing cardiac failure may be the aetiology for exertional dyspnea. [3]
Murmers Due to the anaemia, they can have flow murmurs. [3]
Injection sites Iron chelation therapy is given as subcutaneous injection.[5]
Growth failure Combination of factors such as chronic disease, loss of appetite, food restriction and recurrent hospital stays may be the cause.[4]
Delayed development of secondary sexual characteristics Iron overload can cause hypogonadism. [1]
References
  1. COHEN A. R.. Thalassemia. Hematology [online] 2004 January, 2004(1):14-34 [viewed 31 July 2014] Available from: doi:10.1182/asheducation-2004.1.14
  2. GALANELLO R, ORIGA R. Beta-thalassemia Orphanet J Rare Dis [online] :11 [viewed 31 July 2014] Available from: doi:10.1186/1750-1172-5-11
  3. COATS AJ. Anaemia and heart failure Heart [online] 2004 Sep, 90(9):977-979 [viewed 18 September 2014] Available from: doi:10.1136/hrt.2003.012997
  4. KYRIAKOU A, SKORDIS N. Thalassaemia and Aberrations of Growth and Puberty Mediterr J Hematol Infect Dis [online] , 1(1):e2009003 [viewed 18 September 2014] Available from: doi:10.4084/MJHID.2009.003
  5. Intensive iron-chelation in thalassaemia. Br Med J [online] 1978 Sep 16, 2(6140):782-783 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1607825

Differential Diagnoses

Fact Explanation
Beta thalassaemia Has the same features of delta-beta thalassaemia, [5] with noramal HbA and abnormally high HbF. In beta thalassaemia, intermedia, HbA2 is elevated. Thalassaemia major has raised HbF with absent or reduced HbA.
Hereditary persistence of fetal Hb Characterized by absent or reduced synthesis of adult hemoglobin (Hb A) and increased synthesis of fetal hemoglobin (Hb F). [6] Alpha-beta-globin chain synthesis ratio and DNA analysis may be necessary to differentiate this from the delta beta thalassaemia.
Iron deficiency anaemia Iron deficiency anaemia is a microcytic hypochromic anaemia. It has specific features such as pica (tendency to eat substances which are not suitable for consumption) , examination will reveal koilonychia (spoon shaped nails) and glossitis apart from the other features of anaemia. [2]
Sideroblastic anemias Sideroblastic anaemia will have hypochromic microcytic anemia as in thalassaemia and, elevated serum iron, decreased unsaturated iron-binding capacity. There is low Fe incorporation into erythrocytes, but normal erythrocyte survival is seen. Bone marrow will show erythroblastic hyperplasia of marrow with increased iron, and marked increase in marrow sideroblasts particularly ringed sideroblasts. [1] Sideroblastic anemia differs from the iron deficiency anaemia as they will have almost complete saturation of the serum transferrin, when compared to thalassaemia.
Juvenile chronic myelomonocytic leukemia with normal kariotype, aplastic anemia These conditions may also have the high HbF giving rise to diagnostic confusion with thalassaemia. [3]
Lead poisoning Lead poisoning is also a type of microcytic hypochromic anaemia. It will have characteristic signs and symptoms of lead poisoning such as abdominal pain, confusion, headache, anemia, irritability, and in severe cases seizures, coma, and death. [4]
References
  1. PRASAD AS, TRANCHIDA L, KONNO ET, BERMAN L, ALBERT S, SING CF, BREWER GJ. Hereditary sideroblastic anemia and glucose-6-phosphate dehydrogenase deficiency in a negro family J Clin Invest [online] 1968 Jun, 47(6):1415-1424 [viewed 27 July 2014] Available from: doi:10.1172/JCI105833
  2. Good Clinical Practice Recommendations for Iron Deficiency Anemia in Pregnancy (IDA) in Pregnancy in India J Obstet Gynaecol India [online] 2011 Oct, 61(5):569-571 [viewed 28 July 2014] Available from: doi:10.1007/s13224-011-0097-5
  3. GALANELLO R, ORIGA R. Beta-thalassemia Orphanet J Rare Dis [online] :11 [viewed 31 July 2014] Available from: doi:10.1186/1750-1172-5-11
  4. GORDON JN, TAYLOR A, BENNETT PN. Lead poisoning: case studies Br J Clin Pharmacol [online] 2002 May, 53(5):451-458 [viewed 18 September 2014] Available from: doi:10.1046/j.1365-2125.2002.01580.x Investigations - for Diag
  5. COHEN A. R.. Thalassemia. Hematology [online] 2004 January, 2004(1):14-34 [viewed 31 July 2014] Available from: doi:10.1182/asheducation-2004.1.14
  6. BETHLENFALVAY NC, MOTULSKY AG, RINGELHANN B, LEHMANN H, HUMBERT JR, KONOTEY-AHULU FI. Hereditary persistence of fetal hemoglobin, beta thalassemia, and the hemoglobin delta-beta locus: further family data and genetic interpretations. Am J Hum Genet [online] 1975 Mar, 27(2):140-154 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1762752

Investigations - for Diagnosis

Fact Explanation
Full blood count Anaemia causes low haemoglobin, low pack cell volume and reduced red cell count. Mean corpuscular volume, mean corpuscular haemoglobin are all reduced as this is a microcytic hypochromic anaemia. Red cell distribution width is normal. Hypersplenism may cause reduction in all 3 cell lines. [2]
Blood picture Will show microcytic hypochromic anaemia with some target cells, anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells)], and nucleated RBC (i.e., erythroblasts). Carriers usually have less RBC morphologic changes and erythroblasts are normally not seen. [2]
Haemoglobin electrophoresis In delta beta thalassaemia in HbA2 is normal , Hb F heterogeneously distributed in the erythrocytes, and low beta/alpha synthetic ratios is seen. They will have unusually high levels of Hb F (range 10 to 20%) [1,3]
High Performance Liquid Chromatography (HPLC) Qualitative and quantitative Hb analysis is done by HPLC. In delta beta thalassemia HbA is normal and HbF is abnormally elevated. [5]
Serum ferritin Can be used to screen for iron deficiency anemia. [4]
References
  1. CAO A, MELIS MA, GALANELLO R, ANGIUS A, FURBETTA M, GIORDANO P, BERNINI LF. Delta beta (F)-thalassaemia in Sardinia. J Med Genet [online] 1982 Jun, 19(3):184-192 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1048864
  2. GALANELLO R, ORIGA R. Beta-thalassemia Orphanet J Rare Dis [online] :11 [viewed 31 July 2014] Available from: doi:10.1186/1750-1172-5-11
  3. MUSUMECI S, ROMEO MA, PIZZARELLI G, SCHILIRĂ² G, RUSSO G. delta beta-Thalassaemia in Sicily: report of a case of double heterozygosity for A gamma delta beta-thalassaemia and A gamma G gamma delta beta-thalassaemia. J Med Genet [online] 1983 Feb, 20(1):73-75 [viewed 17 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1048994
  4. KYRIAKOU A, SKORDIS N. Thalassaemia and Aberrations of Growth and Puberty Mediterr J Hematol Infect Dis [online] , 1(1):e2009003 [viewed 18 September 2014] Available from: doi:10.4084/MJHID.2009.003
  5. PETROU M. Screening for beta thalassaemia Indian J Hum Genet [online] 2010, 16(1):1-5 [viewed 31 July 2014] Available from: doi:10.4103/0971-6866.64934

Investigations - Fitness for Management

Fact Explanation
Haemoglobin Transfusion is done according to blood Hb level. If the Hb is < 7 g/dl for more than two weeks, without any evidence of infection patients will need blood transfusion. [1]
References
  1. GALANELLO R, ORIGA R. Beta-thalassemia Orphanet J Rare Dis [online] :11 [viewed 31 July 2014] Available from: doi:10.1186/1750-1172-5-11

Investigations - Followup

Fact Explanation
Haemoglobin Haemoglobin Transfusion is done according to blood haemoglobin level in order to maintain haemoglobin at around 9-10 g/dl. [1]
Serum ferritin Needs to identify the time start the iron chelation therapy. But this can also be influenced by the other conditions such as inflammatory disorders, liver disease, malignancy. [2]
References
  1. GALANELLO R, ORIGA R. Beta-thalassemia Orphanet J Rare Dis [online] :11 [viewed 31 July 2014] Available from: doi:10.1186/1750-1172-5-11

Investigations - Screening/Staging

Fact Explanation
DNA analysis Can be used to detect the deletions of the DNA sequence and to differentiate it from the hereditory persistance of fetal haemoglobin. [4]
Fasting blood sugar Diabetes mellitus [3] is occurred due to impaired secretion of insulin secondary to chronic pancreatic iron overload and insulin resistance due to iron deposition within liver or skeletal muscle.
Thyroid function tests Hypothyroidism is a known endocrine complication [2] due to iron overload.
Echocardiography Excess iron can be deposited in the myocardium causing impaired ventricular function.[3]
Cardiac Magnetic Resonance Imaging-T2 measurement Used for non-invasive assessment of cardiac iron status. [2]
References
  1. ORKIN S H, GOFF S C, NATHAN D G. Heterogeneity of DNA deletion in gamma delta beta-thalassemia.. J. Clin. Invest. [online] 1981 March, 67(3):878-884 [viewed 17 August 2014] Available from: doi:10.1172/JCI110105
  2. COHEN A. R.. Thalassemia. Hematology [online] 2004 January, 2004(1):14-34 [viewed 31 July 2014] Available from: doi:10.1182/asheducation-2004.1.14
  3. KYRIAKOU A, SKORDIS N. Thalassaemia and Aberrations of Growth and Puberty Mediterr J Hematol Infect Dis [online] , 1(1):e2009003 [viewed 18 September 2014] Available from: doi:10.4084/MJHID.2009.003
  4. BETHLENFALVAY NC, MOTULSKY AG, RINGELHANN B, LEHMANN H, HUMBERT JR, KONOTEY-AHULU FI. Hereditary persistence of fetal hemoglobin, beta thalassemia, and the hemoglobin delta-beta locus: further family data and genetic interpretations. Am J Hum Genet [online] 1975 Mar, 27(2):140-154 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1762752

Management - General Measures

Fact Explanation
Health education Educating the parents, or young child on the nature of the disease, symptoms of anaemia, complications of the disease, method of taking iron chelation therapy at home when needed etc. will improve the compliance for the treatment and improve the quality of life. [5]
Prevention of infections Needs to avoid crowded places especially after splenectomy. They need to be vaccinated for pneumococcal, meningococcal infections prior to the splenectomy. [2]
Psychological support Child might be psychologically distressed due to the nature of the chronic nature of the disease, recurrent hospital stays, recurrent absenteeism from the school and peer bullying etc. So they need proper addressing of these issues. [4]
Diet Drinking tea may reduce iron absorption. Iron rich food like liver, meat and green leaves are best avoided. [1]
Management of complications Hypothyroidism, hypogonadism, growth failure, diabetes mellitus and cardiac failure are the possible complications that need specific management. Cardiac disease is reversible on certain occasions with the help of patients with intensive iron chelation therapy. [3] Thrombosis is a significant complication of thalassemia. Intramuscular depot-testosterone esters at a dose of 50-100 mg twice a month is given till the virilisation in patients with hypogonadism. [1]
Screening [2] Screening is recommended for high risk groups. [2] Providing national premarital screening and genetic counselling is important.
References
  1. GALANELLO RENZO, ORIGA RAFFAELLA. Beta-thalassemia. Array [online] 2010 December [viewed 17 August 2014] Available from: doi:10.1186/1750-1172-5-11
  2. PETROU M. Screening for beta thalassaemia Indian J Hum Genet [online] 2010, 16(1):1-5 [viewed 31 July 2014] Available from: doi:10.4103/0971-6866.64934
  3. COHEN A. R.. Thalassemia. Hematology [online] 2004 January, 2004(1):14-34 [viewed 31 July 2014] Available from: doi:10.1182/asheducation-2004.1.14
  4. KAHENI S, YAGHOBIAN M, SHAREFZADAH GH, VAHIDI A, GHORBANI H, ABDERAHEMI A. Quality of Life in Children with ?-Thalassemia Major at Center for Special Diseases Iran J Ped Hematol Oncol [online] 2013, 3(3):108-113 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921875
  5. KYRIAKOU A, SKORDIS N. Thalassaemia and Aberrations of Growth and Puberty Mediterr J Hematol Infect Dis [online] , 1(1):e2009003 [viewed 18 September 2014] Available from: doi:10.4084/MJHID.2009.003

Management - Specific Treatments

Fact Explanation
Symptomatic management Clinical manifestations of delta-beta thalassaemia are similar to that of thalassemia intermedia which needs symptomatic management. [1] Hypersplenism causing worsening of anemia, retarded growth and mechanical disturbance from the large spleen are the indications for splenectomy in these patients.
Blood transfusion and iron chelation If the disease is advanced they may need blood transfusion and later iron chelation.Iron chelators are used to reduce tissue iron levels, prevent excessive organ iron accumulation and neutralize toxic labile iron pools. [2] Iron chelation is started when the serum ferritin is rise above 1000 ng/ml or once they have had 10-20 transfusions. [1] Deferoxamine and deferasirox are the 2 main types of chelators available. Deferoxamine is available as 24-hour intravenous infusion or subcutaneous 12-hour infusion. [2] Sensorineural hypoacusia, ocular toxicity (night-blindness, blurred vision, decreased visual acuity, impairment of colour vision), retarded growth and skeletal changes, infections by Yersinia Enterocolitica, and other pathogens are the possible complications with desferrioxamine therapy. [1] Deferasirox is given once-daily, orally at a dose of 20 mg/kg/day. Gastrointestinal disturbances, skin rash and increases in serum creatinine are the possible complications. [1] There are studies done on newer chelators such as deferiprone and ICL670, which are orally active. Hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, are parenteral drugs that require less frequent administration than is currently deferoxamine. Deferiprone is the only orally active iron chelator available in practice. [2] Agranulocytosis, nausea, vomiting, gastric discomfort, arthralgia, zinc deficiency, and fluctuating ALT levels are the possible side effects due to iron chelation with deferiprone.
Splenectomy Splenectomy helps to decrease transfusion requirements in people with thalassaemia. It is usually considered when the annual red cell requirement exceeds 180-200 ml/Kg of RBC and if there are other indications for splenectomy such as are symptoms of splenic enlargement, leukopenia and/or thrombocytopenia and increasing iron overload despite good chelation. [1] Due to the risk of postsplenectomy sepsis surgery is usually delayed till 6-7 years of age. Post of penicillin prophylaxis is then started as they are vulnerable to infections with encapsulated organisms such as Pneumococcus species, Meningococcus species, and Haemophilus influenzae.
References
  1. GALANELLO R, ORIGA R. Beta-thalassemia Orphanet J Rare Dis [online] :11 [viewed 31 July 2014] Available from: doi:10.1186/1750-1172-5-11
  2. OHEN A. R.. Thalassemia. Hematology [online] 2004 January, 2004(1):14-34 [viewed 31 July 2014] Available from: doi:10.1182/asheducation-2004.1.14