What investigations are recommended for children suspected of having thalassemia major?

Investigations for Thalassemia Major in Children

Children suspected of having thalassemia major require a comprehensive diagnostic workup including complete blood count with peripheral smear, hemoglobin electrophoresis or HPLC, molecular genetic testing, and baseline organ function assessments to establish diagnosis and guide management.

Initial Diagnostic Testing

Essential Hematologic Studies

• Complete Blood Count (CBC) with manual differential and reticulocyte count is the foundational test, revealing severe microcytic hypochromic anemia with hemoglobin typically <7 g/dL 1
• Peripheral blood smear demonstrates marked anisopoikilocytosis, target cells, nucleated red blood cells, and basophilic stippling 1
• Mean Corpuscular Volume (MCV) is characteristically decreased, often below 80 fL, distinguishing thalassemia from other causes of anemia 1, 2
• Red Blood Cell Distribution Width (RDW) may be normal or mildly elevated, helping differentiate from iron deficiency anemia where RDW is typically >14% 1, 2
• Reticulocyte count is elevated, reflecting the compensatory erythropoiesis and chronic hemolysis 3

Definitive Diagnostic Tests

• Hemoglobin electrophoresis or High-Performance Liquid Chromatography (HPLC) is essential to identify the specific hemoglobin pattern 4
  • In β-thalassemia major: predominantly hemoglobin F with absent or markedly reduced hemoglobin A 1
  • In α-thalassemia major: hemoglobin Bart's (γ4) predominates at birth 5
• Molecular genetic testing confirms the specific mutations and is critical for genetic counseling and family screening 2, 5
• Newborn screening in the United States routinely identifies hemoglobinopathies, with abnormal patterns triggering further investigation 4

Baseline Organ Assessment

Iron Status Evaluation

• Serum ferritin establishes baseline iron stores before transfusion therapy begins 6
• Iron studies including serum iron and total iron binding capacity help exclude concurrent iron deficiency 3
• Normal ferritin levels at presentation help differentiate thalassemia trait from iron deficiency anemia 2

Cardiac and Hepatic Evaluation

• Cardiac MRI T2* is the gold standard non-invasive method for assessing myocardial iron deposition, though typically performed after transfusion therapy has begun 6
• Echocardiography provides baseline cardiac function assessment, particularly ejection fraction 6
• Liver MRI T2* assesses hepatic iron overload, with 75% of thalassemia major patients developing liver siderosis over time 6
• These imaging studies are critical because cardiac dysfunction from iron overload is the leading cause of death in thalassemia major 6

Additional Baseline Studies

Bone Marrow Evaluation

• Bone marrow aspirate and biopsy is generally not required for diagnosis of thalassemia major when peripheral blood findings and hemoglobin studies are diagnostic 1
• Bone marrow examination may be indicated if there is diagnostic uncertainty, suspicion of concurrent myelodysplastic syndrome, or megaloblastic changes suggesting folate deficiency 7
• When performed, morphology shows erythroid hyperplasia with ineffective erythropoiesis 1

Nutritional Assessment

• Folate levels should be checked, as folate deficiency can complicate thalassemia major due to increased demands from chronic hemolysis and dyserythropoiesis 7
• Daily folic acid supplementation is necessary in these patients to prevent megaloblastic anemia 7

Family and Genetic Counseling

• Parental testing with CBC, hemoglobin studies, and molecular analysis identifies carrier status 2
• Sibling screening is essential for identifying potential stem cell donors and carriers 2
• Genetic counseling must address reproductive risks, as specific combinations of α-thalassemia mutations can result in hemoglobin Bart's hydrops fetalis, the most common cause of non-immune hydrops in Southeast Asian populations 2

Common Pitfalls to Avoid

• Do not confuse thalassemia trait with thalassemia major: Trait shows mild microcytosis with normal or near-normal hemoglobin, while major presents with severe transfusion-dependent anemia 2
• Do not assume iron deficiency based on microcytosis alone: Thalassemia shows low MCV with normal RDW and normal/elevated RBC count, whereas iron deficiency shows low MCV with elevated RDW and low RBC count 1, 2
• Do not delay molecular diagnosis: Specific mutation identification is critical for prognosis, treatment planning, and family counseling 5
• Do not overlook reticulocyte hemoglobin equivalent (Ret-He): Values ≤27 pg suggest concurrent iron deficiency in thalassemia patients, which requires different management 3