A 4-month-old boy is brought to the clinic by his mother due to concerns of appearing pale. Over the past few days, he has been sleeping more than usual and is less interactive. The boy is exclusively breastfed, and he slept through two of his usual feeding sessions yesterday. He continues to have good urine output. The patient was born at 40 weeks gestation and had a normal nursery course. His mother's prenatal course was unremarkable. However, the patient's newborn screen revealed an extra band representing gamma tetramers on hemoglobin electrophoresis. The patient takes a vitamin D supplement daily. Vital signs are normal. He appears tired and has mild scleral icterus. The remainder of the examination shows no abnormalities. Laboratory evaluation of this patient would most likely show which of the following?
Alpha thalassemia | ||
Genotype | Disorder | Clinical features |
1 gene loss | Alpha thalassemia minima | Asymptomatic, silent carrier |
2 gene loss | Alpha thalassemia minor | Mild microcytic anemia |
3 gene loss | Hemoglobin H disease | Chronic hemolytic anemia |
4 gene loss | Alpha thalassemia major, | Hydrops fetalis: anasarca, |
Normal hemoglobin is a heterotetramer composed of 4 chains:
In patients with alpha-thalassemia, ≥1 alpha genes are deleted. When 3 genes are lost (α-/--), a condition known as hemoglobin H disease, the nonalpha chains accumulate into homotetramers; in children and adults, these homotetramers are composed of beta chains (hemoglobin H) whereas, in fetuses and infants, they are composed of gamma chains (hemoglobin Barts), as seen in this patient.
Hemoglobin H disease usually presents in infancy with chronic hemolysis due to a shorter red blood cell (RBC) lifespan and increased splenic sequestration. Elevated erythrocyte count and reticulocytosis occur as the bone marrow attempts to replenish hemolyzed RBCs. However, RBCs are microcytic (mean corpuscular volume <80 µm3) and hypochromic because hemoglobin accounts for the majority of RBC volume. Characteristic findings on peripheral smear include abundant target cells as a result of the reduced RBC volume.
The presence of gamma tetramers (hemoglobin Barts) on hemoglobin electrophoresis should raise suspicion for alpha-thalassemia; it is classically associated with hydrops fetalis, the most severe form of alpha-thalassemia, which is due to 4 alpha gene loss (--/--) and typically leads to death in utero.
(Choice A) Increased destruction of RBCs seen in microangiopathic hemolytic anemia results in a decreased erythrocyte count and schistocytes on peripheral smear.
(Choice B) Patients with hereditary spherocytosis have a defective RBC membrane protein that results in spherocytes on peripheral smear. Erythrocyte count is decreased due to destruction of spherocytes in the spleen.
(Choice C) Secondary erythrocytosis is characterized by an increase in immature erythrocytes (polychromasia) in response to hypoxia or tumor. Hemoglobin electrophoresis would not show gamma tetramers.
(Choice D) Iron deficiency causes a microcytic, hypochromic anemia similar to thalassemia. However, decreased RBC production due to inadequate iron stores results in a low erythrocyte count and pencil cells on peripheral smear.
Educational objective:
The presence of gamma tetramers (hemoglobin Barts) on hemoglobin analysis is consistent with alpha-thalassemia. Laboratory studies typically reveal a microcytic anemia, an elevated erythrocyte count, and target cells on peripheral smear.