Thalassemia syndromes

Group of inherited microcytic, hemolytic anemias caused by decreased production of α- or β-globin chains, leading to imbalanced hemoglobin synthesis and RBC destruction.

• Common in Mediterranean, African, and Asian populations. Severe forms cause life-threatening anemia in infancy (requiring transfusions), while carriers have mild anemia often misdiagnosed as iron deficiency. Recognizing thalassemia prevents unnecessary iron therapy and enables genetic counseling to prevent hydrops fetalis.

• Mild (trait): Asymptomatic or mild fatigue; low MCV, normal iron; often detected on routine CBC. Blood smear: target cells (bullseye RBCs) are common.
• Severe (β-thalassemia major): Infant (6–12 mo) with severe anemia, failure to thrive, pallor, jaundice, and hepatosplenomegaly as fetal hemoglobin wanes. Marrow expansion causes bone deformities (frontal bossing, "chipmunk" facies).
• Severe (α-thalassemia): Hemoglobin H disease (3 α gene deletions) causes moderate hemolytic anemia with splenomegaly but no bone changes. Hydrops fetalis (4 deletions) presents as fetal hydrops (fluid in multiple compartments, high-output cardiac failure) and is usually fatal if untreated.

1. Evaluate microcytic anemia: Check iron studies (low in iron deficiency; normal or high in thalassemia). Thalassemia is suspected if microcytosis is disproportionate to anemia, RBC count is normal/high, and RDW is normal.
2. Confirm with hemoglobin electrophoresis: β-thalassemia shows increased HbA2 (and ↑HbF in major). α-thalassemia trait has normal electrophoresis – DNA analysis may be needed.
3. Family history and ethnicity are clues (e.g., Mediterranean or Asian ancestry). Counsel carriers on prenatal testing (CVS or amnio) to identify severe thalassemia in the fetus.

1. Mild forms (trait): No treatment needed; avoid unnecessary iron. Provide folic acid if any chronic hemolysis; genetic counseling for family planning.
2. Severe forms: Regular packed RBC transfusions (often every 3–4 weeks) to maintain Hb ~9–10 g/dL. Concurrent iron chelation (e.g., deferoxamine/deferasirox) to prevent iron overload (heart failure, liver cirrhosis, endocrine dysfunction).
3. Splenectomy may reduce transfusion needs in some (but increases infection risk; vaccinate and give prophylactic antibiotics).
4. Curative: Hematopoietic stem cell transplant in early life can cure β-thalassemia major. Gene therapy for β-thalassemia (e.g., betibeglogene autotemcel) has been approved. Prenatal options include preimplantation genetic testing to avoid an affected pregnancy.

• Mentzer index (MCV/RBC count): <13 suggests thalassemia, >13 suggests iron deficiency.
• Target cells (codocytes) are classically seen in thalassemia (also in liver disease and post-splenectomy).
• Trait carriers often have normal ferritin and mildly elevated RBC count despite anemia – don't give iron if iron stores are normal!

• Infant with severe anemia (Hb <5) and high-output heart failure (tachycardia, cardiomegaly) → emergency transfusion (suspect β-thalassemia major).
• Transfusion-dependent patient with arrhythmia or endocrinopathy (growth failure, diabetes, hypogonadism) → evaluate for iron overload (deposition in heart, pancreas, etc.) and intensify chelation.
• Pregnancy between two thalassemia carriers (especially α-cis deletion) → 25% risk of hydrops fetalis; ensure prenatal diagnosis early.

1. Microcytic anemia → Check ferritin (iron studies).
2. Normal or high iron, normal ferritin → consider thalassemia (especially if high RBC count, target cells on smear).
3. Do hemoglobin electrophoresis: ↑HbA2 (and ±↑HbF) confirms β-thalassemia trait or major; normal electrophoresis with strong suspicion → genetic test for α-thalassemia.
4. If thalassemia major confirmed → initiate regular transfusions + chelation; family counseling and consider curative transplant.

• 1-year-old of Greek descent with severe hemoglobin 6, massive spleen, bone marrow hyperplasia (crew-cut skull on X-ray) → β-thalassemia major.
• Adult with mild microcytic anemia not improving with iron supplements; electrophoresis shows HbA2 5% (↑) → β-thalassemia minor (trait).
• Stillborn fetus with total body edema (ascites, skin edema) born to Southeast Asian parents who are thalassemia carriers → Hb Bart's hydrops fetalis (α-thalassemia major).