What are the clinical features of thalassemia major in children?

Clinical Features of Thalassemia Major in Children

Thalassemia major presents as a life-threatening profound anemia beginning at 1-2 years of age, requiring lifelong regular blood transfusions (>8 events per year) and iron chelation therapy to prevent cardiac death, which historically accounts for 70% of mortality in these patients. 1, 2

Timing of Clinical Presentation

• Infants are asymptomatic at birth because fetal hemoglobin (HbF, composed of α2γ2 chains) does not require β-globin chains for production 2
• Symptoms emerge at approximately 1-2 years of age as fetal hemoglobin production declines and the physiologic switch to adult hemoglobin (which requires β-chains) occurs 1, 2
• Without treatment, the profound anemia becomes life-threatening by this age, making early diagnosis critical 1, 2

Primary Hematologic Manifestations

• Severe chronic hemolytic anemia results from ineffective erythropoiesis caused by excess α-globin chains that precipitate and damage red blood cell precursors 3, 4
• Microcytic hypochromic anemia is the characteristic laboratory finding 3
• Hemoglobin levels fall to life-threatening levels without transfusion support 4

Skeletal and Growth Abnormalities

• Bone marrow expansion occurs as the body attempts to compensate for chronic severe anemia, leading to characteristic skeletal deformities 3, 4
• Extramedullary hematopoiesis develops in the liver, spleen, and other tissues as the expanded bone marrow proves insufficient 3, 4
• Poor growth and failure to thrive manifest during infancy in untreated or inadequately treated children 4
• Skeletal abnormalities include frontal bossing, maxillary overgrowth, and pathologic fractures from cortical thinning 3, 4

Transfusion Requirements and Iron Overload

• Lifelong regular red blood cell transfusions are mandatory for survival, with the defining criterion being >8 transfusion events per year in adults over 16 years 1, 2, 5
• Each unit of transfused blood contains approximately 200-250 mg of elemental iron, and humans lack physiological mechanisms for iron excretion 1, 2, 5
• Mildly increased gastrointestinal iron absorption related to hepcidin suppression compounds the iron loading from transfusions 1
• Lifelong iron chelation therapy is required to prevent or reverse iron-related organ damage 1, 2, 5

Cardiac Complications (Leading Cause of Death)

• Cardiac iron loading is the leading cause of death, accounting for approximately 70% of mortality in transfusion-dependent patients 1, 2, 5
• Before modern chelation therapy, heart failure was the most common cause of death, with most patients dying by age 10 from cardiac complications 1, 5
• Transfusions reduce the expansion of blood volume seen in chronic anemia, which is a driver of increased cardiac index 1

Endocrine Complications

• Iron deposition in endocrine organs leads to multiple endocrinopathies including growth hormone deficiency, hypogonadism, diabetes mellitus, and hypothyroidism 3
• These complications arise from both the disease itself and from chronic iron overload affecting the pituitary, pancreas, and thyroid glands 3

Hepatic Complications

• Hepatomegaly develops from extramedullary hematopoiesis and iron deposition 3
• Liver iron overload can lead to cirrhosis and hepatic dysfunction if chelation is inadequate 3

Critical Clinical Pitfalls to Avoid

• Do not delay transfusion therapy once the diagnosis is established—profound anemia is life-threatening and transfusions are mandatory for survival 1, 5
• Do not underestimate the importance of iron chelation compliance—cardiac iron loading remains the dominant cause of death even in the modern era 1, 2
• Maintain pre-transfusion hemoglobin levels of 9-10 g/dL with post-transfusion levels of 13-14 g/dL to balance minimization of iron loading with maximization of symptom relief and suppression of ineffective erythropoiesis 1

Prognosis and Curative Options

• Life expectancy has improved dramatically over the past 50 years with increased availability of blood transfusions, iron chelation therapy, and improved iron overload monitoring 3
• Hematopoietic stem cell transplantation remains the only curative option, with current disease-free survival around 80% and overall survival over 90% 5
• Without modern treatment, patients typically died by age 30 from cardiac complications of iron overload 4