USMLE® Step 1 style questions USMLE
A 2-year-old boy is brought to the clinician by his parents due to easy fatigability and growth delay. They recently immigrated to the United States. The mother did not receive any prenatal care in her home country. The child was born at term by a normal vaginal delivery. He is at the 30th percentile for length and below the 10th percentile for weight. Temperature is 37.2°C (98.9°F), pulse is 115/min, respirations are 25/min, and blood pressure is 85/60 mmHg. Abdominal examination shows hepatosplenomegaly. Hematological tests and hemoglobin electrophoresis are obtained:
Laboratory value Result Hemoglobin (Hb) 10.8 g/dL Hematocrit (Hct) 32% Erythrocyte count 5.7 million/mm3 Hemoglobin A2 (HbA2) 6.5% Fetal hemoglobin (HbF) 60% Hemoglobin A (HbA1) None Hemoglobin S (HbS) None
Which of the following is the most likely diagnosis?
Content Reviewers:Viviana Popa, MD
Contributors:Evan Debevec-McKenney, Jahnavi Narayanan, MBBS, Robyn Hughes, MScBMC, Samantha McBundy, MFA, CMI
Beta thalassemia is a genetic disorder where there’s a deficiency in production of the β-globin chains of hemoglobin, which is the oxygen-carrying protein in red blood cells - or RBCs for short. Beta thalassemia is most commonly seen in Mediterranean, African and South East Asian populations.
Normally, hemoglobin is made up of four globin chains, each bound to a heme group. There are four major globin chain types - alpha (α), beta (β), gamma (γ), and delta (δ). These four globin chains combine in different ways to give rise to different kinds of hemoglobin. First, there’s hemoglobin F (or HbF), where F stands for fetal hemoglobin, and it’s made up of two α-globin and two γ-globin chains. Hemoglobin A (or HbA), the major adult hemoglobin form, is made up of two α-globin and two β-globin chains. Finally, hemoglobin A2 (or HbA2)) accounts for a small fraction of adult hemoglobin in the blood, and it’s made up of two α-globin and two δ-globin chains. With beta thalassemia, there’s either a partial or complete β-globin chain deficiency, due to a point mutation, which is when a single nucleotide in DNA is replaced by another nucleotide, in the beta globin gene present on chromosome 11. And most often, these mutations occur in two regions of the gene called the promoter sequences and splice sites, which affects the way the mRNA is read. The result is either a reduced, or completely absent beta globin chain synthesis.
And since this is an autosomal recessive disease, two mutated copies of this gene, one from each parent, are needed to develop the disease. If the person has just one mutated gene that codes for either a reduced production or absent production of beta globin chains, then they have beta thalassemia minor. If the person has two mutated genes that code for reduced beta globin chain synthesis, then they’re said to have beta thalassemia intermedia. If the person has two β0 mutations then no beta globin chains are produced, and they’re said to have beta thalassemia major.
When there’s a β-globin chain deficiency, free α-chains accumulate within red blood cells, and they clump together to form intracellular inclusions, which damage the red blood cell’s cell membrane. This causes hemolysis, or red blood cells breakdown in the bone marrow; or extravascular hemolysis, when red blood cells are destroyed by macrophages in the spleen. Hemolysis causes hemoglobin to spill out directly into the plasma, where heme is recycled into iron and unconjugated bilirubin. Over time, the excess unconjugated bilirubin leads to jaundice, and excess iron deposits leads to secondary hemochromatosis.
At the same time, hemolysis leads to hypoxia, because there are fewer red blood cells to carry oxygen to organs and tissues. And a consequence of hypoxia is that it signals the bone marrow, and extramedullary tissues like the liver and spleen, to increase red blood cell production, which may cause bone marrow containing bones, like those in the skull and face, as well as the liver and spleen, to enlarge.
Ok, now, beta thalassemia minor is usually asymptomatic. On the other hand, with beta thalassemia major, symptoms do not develop until the first 3 to 6 months of life. That’s because during the first 3 to 6 months of life, fetal hemoglobin is still produced, and that process uses up some of the free α-chains. Common beta thalassemia major signs and symptoms include symptoms of anemia like pallor, shortness of breath, and easy fatigability; jaundice, swollen abdomen due to an enlarged liver and spleen, hepatosplenomegaly; and growth retardation. Complications due to hemochromatosis include arrhythmias, pericarditis, cirrhosis, hypothyroidism and diabetes mellitus.
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