Clinical presentation of thalassemia varies widely. And while some mutations are known to be particularly severe, the large number of different mutations and combinations thereof doesn't allow for the deduction of which genes are affected from physical examination or evaluation of blood counts. Thus, clinically, minor, intermediate and major forms of the disease are distinguished with regards to the severity:

• Most carriers have minor thalassemia and this condition is largely asymptomatic. Patients don't generally report any complaints, but their hemogram may reveal mild hypochromic microcytic anemia. This is refractory to iron substitution and this observation is often the basis of a thalassemia-oriented workup.
• Thalassemia intermedia is additionally associated with severe hemolytic and aplastic crises. During such episodes, which may be induced by infection, folate deficiency or pregnancy [9], transfusions of blood products may become necessary.
• Major thalassemia is a debilitating, life-threatening disease and affected people require life-long support and regular transfusions.

In symptomatic thalassemia, symptoms provoked by anemia and hemolysis dominate the clinical picture. Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly. Skeletal deformations may be observed and are due to bone marrow overstimulation and consequent expansion of erythroid cells.

• Splenomegaly

  Symptoms and signs result from anemia, hemolysis, splenomegaly, bone marrow hyperplasia, and, if there have been multiple transfusions, iron overload. Diagnosis is based on genetic tests and quantitative Hb analysis. [msdmanuals.com]

  KEYWORDS: Anemia; genotype-phenotype; hemolysis; relationship; splenomegaly; β-thalassemia intermedia (β-TI) [ncbi.nlm.nih.gov]

  Enlarged spleen (splenomegaly). The spleen helps your body fight infection and filter unwanted material, such as old or damaged blood cells. [web.archive.org]

  Patients with Hb H disease often have symptomatic hemolytic anemia and splenomegaly. [merckmanuals.com]

• Massive Splenomegaly

  The large numbers of abnormal RBCs processed by the spleen, together with its hematopoietic response to the anemia if untreated, results in massive splenomegaly, leading to manifestations of hypersplenism. [emedicine.medscape.com]

  "Human immunodeficiency virus-associated hemophagocytosis with iron-deficiency anemia and massive splenomegaly". Clin Infect Dis. 37 (11): e170–3. doi:10.1086/379613. PMID 14614691. ^ Friedman, AD.; Daniel, GK.; Qureshi, WA. (Jun 1997). [en.wikipedia.org]

  Splenectomy is recommended in the setting of massive splenomegaly or hypersplenism. HbH disease will lead to iron overload due to ineffective erythropoiesis and transfusion dependence. [clinicaladvisor.com]

• Anemia

  Thalassemia Thalassemia includes a number of different forms of anemia (red blood cell deficiency). [meddean.luc.edu]

  Transfusion dependent thalassemia The primary signs and symptoms of Cooley’s anemia in infancy, before diagnosis, are those of severe anemia. [danafarberbostonchildrens.org]

  The symptoms of thalassemia major (Cooley’s anemia) generally appear before a child’s second birthday. The severe anemia related to this condition can be life-threatening. [rainbowkids.com]

  Because of this, thalassemia major has been called Mediterranean anemia. [medicinenet.com]

• Fatigue

  In alpha-thalassemia major, people have moderate or severe symptoms of anemia, including fatigue, shortness of breath, paleness, and an enlarged spleen, which leads to a feeling of fullness and abdominal discomfort. [merckmanuals.com]

  You can also take steps on your own to cope with fatigue, such as choosing a healthy diet and exercising regularly. [mayoclinic.org]

  The disorder results in fewer red blood cells, which leads to anemia and fatigue. Thalassemia is an inherited disorder and more common in people of Mediterranean, Middle Eastern, Chinese and Southeast Asian ancestry. [ucsfbenioffchildrens.org]

  Symptoms of iron overload may include: chronic fatigue liver disease abdominal pain heart problems joint pain Non-transfusion dependent thalassemia The most common symptoms of non-transfusion dependent thalassemia are related to anemia: pale skin, lips [danafarberbostonchildrens.org]

• Weakness

  Weak recommendations use "consider" or "suggested" phrasing. Recommendations are explicitly labeled as Strong recommendations or Weak recommendations when a qualified group has explicitly deliberated on making such a recommendation. [dynamed.com]

  In beta-thalassemia major (sometimes called Cooley anemia), people have severe symptoms of anemia, such as fatigue, weakness, and shortness of breath, and they may also have jaundice, causing yellowing of the skin and whites of the eyes, skin ulcers, [merckmanuals.com]

  Abstract We report a case of a thalassemia major male patient with back pain associated to severe weakness in lower extremities resulting in the ability to ambulate only with assistance. [ncbi.nlm.nih.gov]

  These problems include delayed growth, weak bones, and enlarged spleen. Beta thalassemia major causes major problems and can result in early death. [hopkinsmedicine.org]

  Affected individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, fatigue, and more serious complications. What are the types of alpha thalassemia? Two types of alpha thalassemia can cause health problems. [rxlist.com]

• Splenectomy

  Treatment for severe forms may include transfusion, splenectomy, chelation, and stem cell transplantation. [msdmanuals.com]

  […] overwhelming infections after splenectomy can be reduced by immunization with pneumococcal and meningococcal vaccines before splenectomy and antimicrobial prophylaxis with penicillin after splenectomy. [bloodjournal.org]

  In addition, with recent reports of venous thromboembolic events (VTEs) after splenectomy, one should carefully consider the benefits and the risks before splenectomy is advocated. [emedicine.medscape.com]

  However, it can be hard to find a good match with a donor and there are many complications. splenectomy Thalassemia can cause the spleen to enlarge. An enlarged spleen can make anemia worse. A splenectomy is a surgery to remove the spleen. [cancercarewny.com]

  Splenectomy: In thalassemia, the spleen may enlarge (splenomegaly) in an effort to improve RBC production. This is often ineffective and may worsen anemia and/or increase transfusion need. In these circumstances, splenectomy may be considered. [verywell.com]

• Pallor

  Clinical description Onset is during infancy with severe anemia, failure to thrive and progressive pallor. [orpha.net]

  Pallor A girl with circumoral pallor due to scarlet fever Specialty Hematology, and many others Differential diagnosis Hypopigmentation Pallor is a pale color of the skin that can be caused by illness, emotional shock or stress, stimulant use, or anemia [en.wikipedia.org]

  Because the anemia is never severe and, in most instances, the Hb level is not less than 9-10 g/dL, pallor and splenomegaly are rarely observed. [emedicine.medscape.com]

  Other symptoms include: poor growth pallor jaundice enlargement of the liver and spleen due to the breakdown of red cells containing the abnormal hemoglobin leg ulcers bone changes secondary to marrow expansion the appearance of other masses due to the [news-medical.net]

• Dyspnea

  He presented with chest discomfort and progressive dyspnea. Early echocardiogram showed mild pericardial effusion. Four days later, the effusion had increased, impending to cardiac temponade requiring pericardectomy. [ncbi.nlm.nih.gov]

  Non-transfusion dependent thalassemia The most common symptoms of non-transfusion dependent thalassemia are related to anemia: pale skin, lips, hands or under the eyelids increased heart rate (tachycardia) breathlessness, or difficulty catching a breath (dyspnea [danafarberbostonchildrens.org]

  Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly. [symptoma.com]

  Dyspnea or fatigue is reliably reported by the patients. Right heart failure manifests either early or more frequently, during the course of left heart failure. [circheartfailure.ahajournals.org]

• Pulmonary Disorder

  Congenital=congenital disorders. C=cancer. COPD=chronic obstructive pulmonary disease. CKD=chronic kidney disease. CMP=cardiomyopathies. Other cardio=other cardiovascular disease. Drugs=drug use disorders. Alcohol=alcohol use disorders. [ncbi.nlm.nih.gov]

• Exertional Dyspnea

  Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly. [symptoma.com]

• Overeating

  Ethnicity of US and Canadian immigration over the last 100 years: census data from the US and Canada document the changing pattern of immigration for Greek/Italian and Asian populations over the past 100 years. 16 Fig 5. [pediatrics.aappublications.org]

  As a result, patients require frequent red cell transfusions over many years. [clinicaltrials.gov]

  OBJECTIVES: The inherited genetic disorder beta0-thalassemia/Hb E disease is associated with the over-suppression of the master regulator of iron homeostasis, the peptide hormone hepcidin. [ncbi.nlm.nih.gov]

• Failure to Thrive

  Other symptoms include: fussiness paleness frequent infections poor appetite failure to thrive jaundice (yellowing of the skin and whites of the eyes) enlarged organs This form of thalassemia is usually so severe that it requires regular blood transfusions [rainbowkids.com]

  Untreated children have severe failure to thrive and shortened life expectancy. Transfusion programs and chelation therapy allow for normal growth and development. Life expectancy can be into the fifth decade for treated individuals. [meddean.luc.edu]

  He required regular blood transfusions in view of a Hb level of <7.0 g/dL and failure to thrive. He had thalassemic red cell indices and peripheral blood film. [ncbi.nlm.nih.gov]

  Clinical description Onset is during infancy with severe anemia, failure to thrive and progressive pallor. [orpha.net]

  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]

• Abdominal Pain

  Symptoms of iron overload may include: chronic fatigue liver disease abdominal pain heart problems joint pain Non-transfusion dependent thalassemia The most common symptoms of non-transfusion dependent thalassemia are related to anemia: pale skin, lips [danafarberbostonchildrens.org]

  Hepatic Impairment Not studied conclusively. 1 Renal Impairment Not studied specifically. 1 Common Adverse Effects Chromaturia, nausea, vomiting, abdominal pain/discomfort, arthralgia, increased ALT, decreased neutrophil count, neutropenia. 1 Interactions [web.archive.org]

  However, the tip of the spleen may be palpable in a newborn baby up to three months of age.[10] Signs and symptoms[edit] Symptoms may include abdominal pain, chest pain, chest pain similar to pleuritic pain when stomach, bladder or bowels are full, back [en.wikipedia.org]

  Other side effects include nausea, vomiting, abdominal pain, increased liver enzymes, arthralgia, and rarely, zinc deficiency in diabetic patients. LFT’s should be followed monthly and zinc levels every 3-6 months in diabetic patients. [clinicaladvisor.com]

• Early Satiety

  satiety due to splenic encroachment, or the symptoms of anemia due to accompanying cytopenia. [en.wikipedia.org]

• Heart Failure

  Possible Complications Untreated, thalassemia major leads to heart failure and liver problems. It also makes a person more likely to develop infections. [ufhealth.org]

  Severe thalassemia can cause early death (between ages 20 and 30) due to heart failure. Getting regular blood transfusions and therapy to remove iron from the body helps improve the outcome. [medlineplus.gov]

  KEYWORDS: Cardiomyopathy; T2* cardiac magnetic resonance (T2* CMR); diastolic dysfunction; heart failure (HF); iron overload; β-Thalassemia major (β-TM) [ncbi.nlm.nih.gov]

  Because iron absorption may be increased and frequent blood transfusions (providing even more iron) are needed, excessive iron may accumulate and be deposited in the heart muscle, eventually causing iron overload disease and heart failure and early death [merckmanuals.com]

• Hypertension

  Journal of Human Hypertension, 10.1038/jhh.2013.102, 28, 5, (328-332), (2013). [doi.org]

  Pulmonary hypertension: an increasingly recognized complication of hereditary hemolytic anemias and HIV infection. JAMA. 2008 Jan 23. 299(3):324-31. [Medline]. Morris CR, Gladwin MT, Kato GJ. [emedicine.medscape.com]

  On the contrary, pulmonary hypertension seems to be the main cause of cardiovascular morbidity and mortality in thalassemia intermedia. [circheartfailure.ahajournals.org]

• Palpitations

  The main health problems associated with thalassaemia are: anaemia – severe tiredness, weakness, shortness of breath, pounding, fluttering or irregular heartbeats (palpitations) and pale skin caused by the lack of haemoglobin too much iron in the body [nhs.uk]

  Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly. [symptoma.com]

  […] contain iron, aluminum, or zinc. 2 Risk of nausea, which may be decreased by taking deferiprone with food. 1 Possibility of reddish/brown discoloration of the urine, which is not harmful. 1 Importance of seeking immediate medical attention in case of palpitations [web.archive.org]

  Stage III patients have symptoms ranging from palpitations to congestive heart failure. The ejection fraction on echocardiography is decreased. There is normal or decreased ejection fraction on cineangiogram at rest, and it falls on exercise. [patient.info]

• Malocclusion

  CASE DESCRIPTION: A 16-year-old female patient with β-thalasse-mia major was referred with the complaints of severe facial deformity and malocclusion, resulting in psychosocial and functional problems for her. [ncbi.nlm.nih.gov]

  […] thinning of the inner and outer table facial bones rodent or chipmunk facies hypopneumatisation of the frontal, maxillary, and sphenoid sinuses, filled with marrow containing bone 6 the ethmoid sinuses are spared due to lack of red bone marrow 6 dental malocclusion [radiopaedia.org]

  Thalassemia can result in maxillary enlargement, leading to an appearance known as chipmunk face, along with increased spaces between teeth, overbite, and malocclusion. [emedicine.medscape.com]

  Bony deformities (frontal bossing, prominent facial bones, and dental malocclusion). Marked pallor and slight to moderate jaundice. Exercise intolerance, cardiac flow murmur or heart failure secondary to severe anaemia. [patient.info]

• Jaundice

  Some people have jaundice and abdominal fullness or discomfort. Diagnosis usually requires special hemoglobin tests. Mild thalassemia may not require treatment, but severe thalassemia may require bone marrow transplantation. [merckmanuals.com]

  Diagnostic methods Diagnosis is suspected in infants younger than 2 years of age with severe microcytic anemia, mild jaundice and hepatosplenomegaly. [orpha.net]

  Other symptoms include: fussiness paleness frequent infections poor appetite failure to thrive jaundice (yellowing of the skin and whites of the eyes) enlarged organs This form of thalassemia is usually so severe that it requires regular blood transfusions [rainbowkids.com]

  Hemoglobin H (HbH) disease, resulting from three of four alpha globin genes being nonfunctional, is characterized by microcytic hypochromic hemolytic anemia, hepatosplenomegaly, mild jaundice, and sometimes thalassemia-like bone changes. [meddean.luc.edu]

• Hepatosplenomegaly

  They have severe anemia and hepatosplenomegaly. Untreated children have severe failure to thrive and shortened life expectancy. Transfusion programs and chelation therapy allow for normal growth and development. [meddean.luc.edu]

  Hypertrichosis, erythrodontia and reddish-colored urine are often present, as well as hemolytic anemia accompanied by hepatosplenomegaly. [ncbi.nlm.nih.gov]

  Additional signs and symptoms can include severe anemia, an enlarged liver and spleen (hepatosplenomegaly), heart defects, and abnormalities of the urinary system or genitalia. [rxlist.com]

  Hb-Bart's hydrops fetalis syndrome (most severe variant of alpha thalassemia) Intrauterine ascites and hydrops fetalis;, severe hepatosplenomegaly, and often cardiac and skeletal anomalies Incompatible with life (death in utero or shortly after birth) [amboss.com]

  The fetus can also have other problems including severe anemia, enlargement of the liver and spleen (hepatosplenomegaly), and defects in the heart, urinary system, or genitals. [beaumont.org]

• Hepatomegaly

  The 5-year probabilities of OS and DFS in older patients (age ≥ 7 years) without hepatomegaly were 86% (95% CI, 72%-96%) and 83% (95% CI, 67%-94%), respectively. Figure 1 Probability of OS by age and hepatomegaly. [doi.org]

  We report a unique case of compound heterozygosity for these two mutations in a 9-year-old boy who presented with a Hb level of 5.3 g/dL and hepatomegaly at the age of 15 months. [ncbi.nlm.nih.gov]

  Hepatomegaly related to significant extramedullary hematopoiesis is typically found. Patients who have received blood transfusions may have hepatomegaly or chronic hepatitis due to iron overload. [emedicine.medscape.com]

  Feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly and hepatomegaly may occur. [orpha.net]

• Osteoporosis

  KEYWORDS: Calcium transport; Iron transport; Osteoporosis; Thalassemia; Vitamin D [ncbi.nlm.nih.gov]

  Other complications are hypersplenism, venous thrombosis and osteoporosis. [orpha.net]

  Osteoporosis Many people who have thalassemias have bone problems, including osteoporosis (OS-te-o-po-RO-sis). This is a condition in which bones are weak and brittle and break easily. [web.archive.org]

• Arthralgia

  Hepatic Impairment Not studied conclusively. 1 Renal Impairment Not studied specifically. 1 Common Adverse Effects Chromaturia, nausea, vomiting, abdominal pain/discomfort, arthralgia, increased ALT, decreased neutrophil count, neutropenia. 1 Interactions [web.archive.org]

  Other side effects include nausea, vomiting, abdominal pain, increased liver enzymes, arthralgia, and rarely, zinc deficiency in diabetic patients. LFT’s should be followed monthly and zinc levels every 3-6 months in diabetic patients. [clinicaladvisor.com]

  […] life-threatening and thus requires close monitoring of the white blood cell count.[18] Less serious side effects include gastrointestinal symptoms, which were found in 33% of patients in the first year of administration, but fell to 3% in following years; arthralgia [en.wikipedia.org]

  Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient. [aetna.com]

• Back Pain

  Clinical presentations include growth impairment, rickets-like features, back pain, spinal deformities, any sign of nerve compression, severe osteoporosis, and fragility fractures. [ncbi.nlm.nih.gov]

  […] forefoot plantar flexion hindfoot varus[2] lower limb stress fractures[16] knee pain[17] iliotibial band friction syndrome[18] back pain[19] tripping[20] Medical management Medical management is to allow the patient to ambulate without any problems. [physio-pedia.com]

  However, the tip of the spleen may be palpable in a newborn baby up to three months of age.[10] Signs and symptoms[edit] Symptoms may include abdominal pain, chest pain, chest pain similar to pleuritic pain when stomach, bladder or bowels are full, back [en.wikipedia.org]

• Withdrawn

  NCT01724138 Phase 4 Deferasirox 38 A Multicenter, Open-label, Single Arm, Interventional Phase IV Study, to Evaluate the Effect of Deferasirox on Endocrine Complications in Subjects With Transfusion Dependent Thalassemia Withdrawn NCT02069886 Phase 4 [malacards.org]

  In addition, long-term follow-up of these patients will be required to determine the risks of immunosuppression as well as whether or not immunosuppressive therapy can be safely withdrawn, reduced, or otherwise modified”. [aetna.com]

  Children born into study households were recruited at birth, and participants exited if informed consent was withdrawn, if they moved away for more than 2 months, or if they died. [doi.org]

• Frontal Bossing

  bossing (due to bone marrow expansion) Delayed pneumatization of sinuses Marked overgrowth of the maxillae Ribs and long bones becoming boxlike and convex Premature closure of epiphyses resulting in shortened limbs Compression fracture of the spine [emedicine.medscape.com]

  Bony deformities (frontal bossing, prominent facial bones, and dental malocclusion). Marked pallor and slight to moderate jaundice. Exercise intolerance, cardiac flow murmur or heart failure secondary to severe anaemia. [patient.info]

• Headache

  At the age of 18, the described patient presented with progressively worsening lethargy, headaches, dizziness, syncope and Raynaud's phenomenon. [ncbi.nlm.nih.gov]

  White Matter Changes and Headache in Thalassemia Recurrent headache was reported by 61% of patients with thalassemia compared with 22.5% of healthy individuals in a control arm. [hematologyadvisor.com]

  Symptoms of mild or moderate anemia may include: Feeling weak and tired Shortness of breath Lightheadedness or headaches Cold hands and feet Pale skin Symptoms of severe anemia include: Lack of interest in activity Pale appearance Poor appetite/feeding [uvahealth.com]

  Side effects may include headache, nausea, vomiting, diarrhea, tiredness and joint pain. [stjude.org]

• Dizziness

  At the age of 18, the described patient presented with progressively worsening lethargy, headaches, dizziness, syncope and Raynaud's phenomenon. [ncbi.nlm.nih.gov]

  These conditions provoke pallor or jaundice, fatigue, headaches and dizziness. Patients may have breathing difficulties under exercise. [symptoma.com]

  Due to less oxygen in the body, in more acute cases, people experience shortness of breath, dizziness and headaches. Overtime, if there is no adequate supply of oxygen to the cells, bodily organs begin to shut down. [blog.sahave.org]

Initially, laboratory analyses of blood tests are realized. In fact, pathological findings from the patient's hemogram often prompt a tentative diagnosis of thalassemia. Usually, the disease is associated with microcytosis, hypochromia and anemia. The mean corpuscular volume (MCV) is reduced, i.e., values are below 70 fl and 80 fl in children and adults, respectively [5]. Erythrocytes are loaded with few hemoglobin, and mean corpuscular hemoglobin concentrations (MCHC) are lower than physiological values (reference range is 30-35 g/dl). Total hemoglobin concentrations are typically below 10 g/dl in thalassemia intermedia, and below 7 g/dl in thalassemia major (physiological range is 12-17 g/dl). Red blood cell distribution width may be enhanced, and blood films may reveal anisocytosis and poikilocytosis. While thrombocytic counts are generally unaltered, leukocytosis may be detected. Thrombocytopenia and leucopenia may be observed in patients presenting with splenomegaly.

Hemoglobin electrophoresis is needed to assess the composition of hemoglobin with regards to its polypeptide chains. Findings are usually diagnostic for or β-thalassemia. However, in α-thalassemia, molecular biological techniques have to be applied to identify the mutated gene(s) in an individual patient. Polymerase chain reactions may also be carried out to detect specific genetic mutations.

• Enlargement of the Liver

  […] spleen and liver. [columbiadoctors.org]

  Without treatment, the spleen, liver, and heart become enlarged, and bones can become thin, brittle, and deformed. [beaumont.org]

  Complications Complications of thalassemia intermedia include: Iron overload Osteoporosis: Weakening of the bones Extramedullary hematopoiesis: This refers to enlargement of spleen, liver and/or bone marrow to increase red blood cell production. [verywell.com]

  Other symptoms include: poor growth pallor jaundice enlargement of the liver and spleen due to the breakdown of red cells containing the abnormal hemoglobin leg ulcers bone changes secondary to marrow expansion the appearance of other masses due to the [news-medical.net]

  The child develops pale skin, irritability, growth retardation, swelling of the abdomen due to enlargement of the liver and spleen (hepatosplenomegaly) with jaundice. [medicinenet.com]

• Microcytic Anemia

  To save this word, you'll need to log in. thal·as·se·mia | \ ˌtha-lə-ˈsē-mē-ə \ : any of a group of inherited disorders of hemoglobin synthesis (such as Cooley's anemia) that are marked by mild to severe hypochromic and microcytic anemia, result from [merriam-webster.com]

  Many variants of Hb are unstable or have altered affinity for oxygen, and, in heterozygous form can be associated with clinical and hematological manifestations (hemolytic anemia, hypochromic microcytic anemia, erythrocytosis). [ncbi.nlm.nih.gov]

  The diagnosis often is one of exclusion of other causes of microcytic anemia. In beta-thalassemia major, anemia is severe, often with hemoglobin ≤ 6 g/dL (≤ 60 g/L). [merckmanuals.com]

• Erythroblast

  Conclusions: This is the first report on γ -globin induction by downregulation of SOX6 in human erythroblasts derived from β -thalassemia major. [ncbi.nlm.nih.gov]

  Blood analysis shows reduced Hb levels (< 7 g/dl), mean corpuscular volume (MCV) > 50 < 70 fl, and mean corpuscular Hb (MCH) > 12 < 20 pg, anisopoikilocytosis and presence of erythroblasts in the peripheral blood smear. [orpha.net]

  In these cases, one copy of the altered gene in each cell is sufficient to cause the signs and symptoms of beta thalassemia. erythroblastic anemia Mediterranean anemia microcytemia, beta type thalassemia, beta type Akhavan-Niaki H, Derakhshandeh-Peykar [ghr.nlm.nih.gov]

• Heinz Bodies

  Six rare mutations, despite being heterozygote, showed hemolytic anemia which is also called, "dominant-type thalassemia", and some of them demonstrated Heinz bodies in the red blood cells. [ci.nii.ac.jp]

  Six rare mutations, despite being heterozygote, showed hemolytic anemia which is also called, ”dominant-type thalassemia”, and some of them demonstrated Heinz bodies in the red blood cells. [petit.lib.yamaguchi-u.ac.jp]

  bodies from HbH β-thalassemia minor target, hypochromic, microcytic cells β-thalassemia major nucleated RBCs target, hypochromic, microcytic cells Hemoglobin gel-electrophoresis α-thalassemia trait normal 3 gene deletion α-thalassemia HbH (β,β,β,β) 4 [medbullets.com]

  These inclusions are termed Heinz bodies, depicted below. [emedicine.medscape.com]

  Unstable hemoglobin (Heinz body anemia) Certain abnormalities in the globin chain sequence produce a hemoglobin that is intrinsically unstable. When the hemoglobin destabilizes, it forms up into erythrocyte inclusions called Heinz bodies. [web2.iadfw.net]

• Poikilocytosis

  At major thalassemia and intermediate thalassemia, hypochromasia and poikilocytosis are more distinct. Reticulocytes, LDH and bilirubin are increased; haptoglobin is decreased. [lecturio.com]

  This blood smear from an individual with thalassemia shows small (microcytic), pale (hypochromic), variously-shaped (poikilocytosis) red blood cells. These small red blood cells (RBCs) are able to carry less oxygen than normal RBCs. [mountsinai.org]

  Beginning in the first year of life the PBS shows severe anisocytosis and poikilocytosis, targets, elliptocytes, teardrops, and NRBCs. [med-ed.virginia.edu]

  Red blood cell distribution width may be enhanced, and blood films may reveal anisocytosis and poikilocytosis. While thrombocytic counts are generally unaltered, leukocytosis may be detected. [symptoma.com]

  Peripheral blood smear will show hypochromia, microcytosis, anisocytosis, poikilocytosis, and rare nucleated RBCs (erythroblasts). [clinicaladvisor.com]

• Anisopoikilocytosis

  Blood analysis shows reduced Hb levels (< 7 g/dl), mean corpuscular volume (MCV) > 50 < 70 fl, and mean corpuscular Hb (MCH) > 12 < 20 pg, anisopoikilocytosis and presence of erythroblasts in the peripheral blood smear. [orpha.net]

  […] utero or shortly after birth) References:[11][1][2][12] Diagnostics Laboratory tests Blood sample Microcytic hypochromic anemia Signs of hemolysis (↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes) Blood smear: target cells;, teardrop cells;, anisopoikilocytosis [amboss.com]

  Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent. [emedicine.medscape.com]

  Peripheral smear shows target cells, teardrop RBCs, polychromasia, moderate anisopoikilocytosis, and basophilic stippling. Hemoglobin electrophoresis is normal in alpha thalassemia minima and minor. [clinicaladvisor.com]

• Hepatocellular Carcinoma

  KEYWORDS: Hepatitis B virus (HBV); hepatitis C virus (HCV); hepatocellular carcinoma (HCC); iron overload; liver iron concentration (LIC); thalassemia [ncbi.nlm.nih.gov]

  Concomitant viral hepatitis poses further increased risk of hepatocellular carcinoma and cirrhosis. Most thalassemia patients older than 25 years are infected with hepatitis C (HCV). [clinicaladvisor.com]

  With increasing length of survival, hepatocellular carcinoma is becoming an increasing problem. [ 15 ] Desferrioxamine can cause toxicity: Local reaction at the site of injection can be severe. [patient.info]

• Leukocytosis

  While thrombocytic counts are generally unaltered, leukocytosis may be detected. Thrombocytopenia and leucopenia may be observed in patients presenting with splenomegaly. [symptoma.com]

  Reticulocyte count is elevated to 5–8% and leukocytosis is usually present. Platelet count is usually normal, unless the spleen is markedly enlarged. Peripheral blood film examination reveals nucleated RBCs and occasional immature leukocytes. 6.1.2. [intechopen.com]

  Symptoms vary from mild to excruciating pain, with fever and leukocytosis, and may simulate a life-threatening event or progress to one. Chronic transfusion is considered standard treatment of severe complications of sickle cell disease. [aetna.com]

No specific therapy is required thalassemia minor. In contrast, thalassemia major and possible thalassemia intermedia patients may be dependent on regular, treatment throughout life.

• Blood transfusions are realized regularly due to thalassemia major, but may be required by thalassemia intermedia patients during anemic crises or in case of failure to thrive and growth retardation. Ideally, hemoglobin levels should be maintained above 10 g/dl. Patients should understand the necessity of adhering to a determined schedule of blood transfusions in order to raise life quality and life expectancy.
• Chelation therapy is indicated to prevent secondary iron overload, particularly in patients receiving regular transfusions of blood products. Nevertheless, regular monitoring is also recommended to recognize iron overload in patients who don't depend on blood transfusions.
• Dietary supplementation with folic acid compensates for folate deficiency.
• Eventually, splenomegaly may cause splenic sequestration, thrombocytopenia and leucopenia. Affected persons may benefit from splenectomy, but this procedure is not without risks [10].
• Hematopoietic stem cell transplantation may be curative, but the application of this therapeutic approach is limited by the condition of the thalassemia patient and the availability of a matching donor.

For patients presenting with asymptomatic thalassemia, the prognosis is excellent. However, with increasing severity of the disease, morbidity and mortality augment. The life expectancy of an individual patient also depends on their access to health care services. People suffering from thalassemia intermedia or major may require transfusions of blood products, and anemic and aplastic crises are life-threatening if medical attention is not provided in a timely manner. Furthermore, secondary iron overload, anemia and subsequent heart failure may be fatal. Thalassemia patients are at higher risks of developing cholelithiasis, urolithiasis and gout. It is not uncommon to observe growth retardation in affected individuals. Certain types of thalassemia are incompatible with life. α-thalassemia major, for instance, causes hydrops fetalis and death in utero.

Thalassemia results from an insufficient synthesis of functional hemoglobin and this condition is provoked by a wide variety of mutations to be found on chromosomes 11 and 16. Genes encoding for all types of globin chains, i.e., for Hbα, Hbβ, Hbγ and Hbδ, are located on these chromosomes, and this also applies to their respective regulatory sequences. In this context, a total of six genes needs to be considered when discussing thalassemia, and distinct forms of this disease are defined accordingly:

• β-thalassemia is the most common type of thalassemia. In affected individuals, the synthesis of Hbβ is disturbed. Mutations affect gene HBB on chromosome 11.
• There are four genes encoding for Hbα, each one HBA1 and HBA2 inherited from mother and father. Gene defects induce α-thalassemia, but the severity of the disease varies largely: Patients who carry one or two affected genes don't generally show any symptoms, but dysfunction of all four genes is lethal in utero.
• Thalassemia due to mutation of genes HBG1, HBG2 or HBD are less common. Some people carry mutations of several genes encoding for globin chains and are consequently diagnosed with complex thalassemia, e.g., with δβ- or γδβ-thalassemia [3] [4].

All known mutations provoking thalassemia are inherited as an autosomal recessive trait.

Thalassemia is a rather common disease, and occurs in about 1 in 2,500 live births [5]. Incidence rates are even higher among people of African, Asian or Middle Eastern decent, and in determined ethnicities, more than a third of the population carries thalassemia-related mutations [6] [7]. Geographical differences regarding thalassemia incidence very clearly show how natural selection works: Thalassemia provides partial protection against malaria and thus confers an evolutionary advantage to carriers in subtropical and tropical regions, but the opposite is the case in areas without prevalence of this parasitic disease. In general, β-thalassemias predominate, but the ratio between prevalences of α- and β-thalassemia is higher in Africa and Southeast Asia than in other parts of Asia and the Middle East.

Despite thalassemia being a genetic disorder, symptom onset rarely occurs during the first year of life. This is due to an ongoing synthesis of fetal hemoglobin during infancy. In rare cases, production of fetal hemoglobin does not cease until the age of a few years, and this may mask even severe forms of thalassemia.

Females and males are affected equally.

Every hemoglobin molecule consists of four globin chains. In patients aged one year and older, about 97% of total hemoglobin correspond to hemoglobin A1, which is constituted of each two Hbα and Hbβ. The remaining 3% almost exclusively correspond to hemoglobin A2, and this form of hemoglobin is composed by each two Hbα and Hbδ. Other hemoglobin variants play important roles only during fetal and early postnatal development.

Moreover, each globin chain is associated with a heme group that, in turn, contains a ferrous ion. In pulmonary capillaries, iron-containing heme groups bind oxygen and carry it to all kinds of tissues. If this process is disturbed by either qualitative or quantitative alterations of hemoglobin synthesis, oxygen supply to dependent cells would be impaired. Patients suffering from thalassemia dispose of insufficient functional hemoglobin and thus present with hypochromic microcytic anemia.

In an attempt to compensate for a decreased synthesis of Hbα and Hbβ in α- and β-thalassemia, respectively, production of the other globin chain is stimulated in excess [8]. Additionally, Hbγ and Hbδ synthesis may be altered. Such imbalances in globin chain composition provoke the formation of inclusion bodies in circulating erythrocytes, augment oxidative stress and predispose for hemolysis. Premature lysis of erythrocytes further contributes to anemia and shortage of oxygen supply.

If an individual disposes of functional copies of genes HBA1, HBA2 or HBB, the aforedescribed pathophysiological events occur to minor degrees and patients may either be completely asymptomatic or merely show hematological alterations without experiencing any symptoms. Such forms of thalassemia are typically classified as minor thalassemia. Other patients are diagnosed with thalassemia intermedia or major, but there is a smooth transition between all those types of hemoglobinopathy.

Thalassemia is a genetic disorder inherited with an autosomal recessive trait. Thus, patients with a family history of thalassemia may benefit from genetic counseling. Prenatal diagnosis of thalassemia and other hemoglobinopathies can be realized. Nowadays, non-invasive, early applicable methods are available to this end [11].

Thalassemia is a general term referring to different genetic disorders that are all associated with a disturbed hemoglobin synthesis.

A functional hemoglobin molecule consists of four polypeptide chains - generally, each two identical α and β chains (Hbα and Hbβ, respectively) - and four iron-containing heme groups. Only a minor share of human hemoglobin molecules contains γ or δ globin chains (Hbγ and Hbδ, respectively). Genes located on chromosomes 11 and 16 encode for all these globin chains, and mutations of those genes trigger hemoglobinopathies. Both coding sequences and regulatory elements can be affected by mutations and accordingly, two types of hemoglobinopathies are distinguished: Structural hemoglobinopathies, which are associated with dysfunctional hemoglobin due to coding sequence alterations; and thalassemia syndromes, characterized by an insufficient production of functional hemoglobin owing to defective regulation of globin synthesis [1].

As has been implied in the previous paragraph, there is no one gene defect that provokes thalassemia. In fact, several hundred mutations have been related with this disease so far, and while their respective incidence varies largely, it may be surprising to read about high prevalence rates of thalassemia in subtropical and tropical regions of almost all continents. This is due to the fact that carriers of thalassemia-associated mutations are partially protected from the most severe form of malaria, induced by infection with Plasmodium falciparum. More recent studies suggest that protection is not only conferred for malaria tropica, but also for uncomplicated forms of this disease [2].

Thalassemia is a type of hemoglobinopathy, i.e., a condition that affects the ability of hemoglobin and red blood cells to supply all tissues with oxygen. It is a genetic disorder inherited with an autosomal recessive trait. In simple terms, this means that a child will only develop thalassemia if they inherit a mutated gene from both parents.

Under physiological conditions, oxygen is bound to hemoglobin molecules in pulmonary capillaries. In thalassemia patients, however, the capacity for oxygen transport is significantly diminished, since reduced quantities of functional hemoglobin are synthesized. In detail, a hemoglobin molecule consists of distinct protein chains, mainly α and β chains, and thus, thalassemia may result from a disturbed synthesis of either type of chain. As soon as the precise pathomechanism is identified, a patient may be diagnosed with α- or β-thalassemia or less common forms of the disease.

The majority of people carrying gene variants associated with thalassemia do not experience any symptoms. In such cases, thalassemia might be suspected upon laboratory analyses of blood samples realized for any other reasons. More severe forms of thalassemia are characterized by anemia and premature death of red blood cells. These conditions provoke pallor or jaundice, fatigue, headaches and dizziness. Patients may have breathing difficulties under exercise. Anemic crises may be triggered by infection, folate deficiency or pregnancy, and are associated with an acute exacerbation of the aforementioned symptoms.

Mild forms of thalassemia don't require any treatment. Patients diagnosed with thalassemia of intermediate severity may suffer anemic crises and may need occasional transfusions of blood products. Severe thalassemia is a life-threatening disease and affected individuals need to adhere to a strict schedule of regular transfusions. Additionally, drugs may be prescribed to compensate for folate deficiency and possible secondary iron overload.

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