A 3-year-old boy is brought to the physician because of a 1-week history of yellowish discoloration of his eyes and skin. He has had generalized fatigue and mild shortness of breath for the past month. Three weeks ago, he was treated for a urinary tract infection with antibiotics. His father underwent a splenectomy during childhood. Examination shows pale conjunctivae and jaundice. The abdomen is soft and nontender; there is nontender splenomegaly. Laboratory studies show: Hemoglobin 9.1 g/dL Mean corpuscular volume 89 μm3 Mean corpuscular hemoglobin 32 pg/cell Mean corpuscular hemoglobin concentration 37.8% Hb/cell Leukocyte count 7800/mm3 Platelet count 245,000/mm3 Red cell distribution width 22.8% (N=13%–15%) Serum Bilirubin Total 13.8 mg/dL Direct 1.9 mg/dL Lactate dehydrogenase 450 U/L Which of the following is the most likely pathophysiology of these findings?

Decreased spectrin in the RBC membrane

Deficient glucose-6 phosphate dehydrogenase

Decreased synthesis of alpha chains of hemoglobin

A 13-month-old girl is brought to the pediatric clinic by her mother due to progressive abdominal distension, poor feeding, and failure to thrive. The perinatal history was uneventful. The family emigrated from Sudan 8 years ago. The vital signs include: temperature 36.8°C (98.2°F), blood pressure 100/55 mm Hg, and pulse 99/min. The physical examination shows conjunctival pallor, hepatosplenomegaly, and parietal and frontal bossing of the skull. The laboratory test results are as follows: Hemoglobin 8.7 g/dL Mean corpuscular volume 62 μm3 Red cell distribution width 12.2% (normal value is 11.5–14.5%) Reticulocyte count 2.1 % Leucocyte count 10,200/mm3 Platelet count 392,000/mm3 The peripheral blood smear shows microcytic red cells, target cells, and many nucleated red cells. Which of the following is the most likely diagnosis?

Congenital dyserythropoietic anaemia

Glucose-6-phosphate dehydrogenase deficiency

A 4-year-old girl is brought to the doctor by her mother with the complaint of hearing loss, which her mother noticed a few days ago when the girl stopped responding to her name. The mother is anxious and says, “I want my child to get better even if it requires admission to the hospital.” Her family moved to a 70-year-old family home in Flint, Michigan, in 2012. The girl has a known history of beta-thalassemia trait. She has never been treated for hookworm, as her mother states that they maintain “good hygiene standards” at home. On examination, the girl currently uses only 2-syllable words. She is in the 70th percentile for height and 50th for weight. A Rinne test reveals that the girl’s air conduction is greater than her bone conduction in both ears. She does not respond when the doctor calls her name, except when he is within her line of sight. Her lab parameters are: Hemoglobin 9.9 gm% Mean corpuscular volume 80 fl Red blood cell distribution width (RDW) 15.9% Serum ferritin 150 ng/ml Total iron binding capacity 320 µg/dL A peripheral smear shows a microcytic hypochromic anemia with basophilic stippling and a few target cells. Which of the following is the next best step in the management of this patient?

Remove and prevent the child from exposure to the source of lead

Multivitamins with iron supplementation

Chelation therapy if the blood lead level is more than 25 µg/dL

A 3080-g (6-lb 13-oz) male newborn is delivered at term to a 27-year-old woman, gravida 2, para 1. Pregnancy was uncomplicated. He appears pale. His temperature is 36.8°C (98.2°F), pulse is 167/min, and respirations are 56/min. Examination shows jaundice of the skin and conjunctivae. The liver is palpated 2–3 cm below the right costal margin, and the spleen is palpated 1–2 cm below the left costal margin. The lungs are clear to auscultation. No murmurs are heard. His hemoglobin concentration is 10.6 g/dL and mean corpuscular volume is 73 μm3. Hemoglobin DNA testing shows 3 missing alleles. Which of the following laboratory findings is most likely present in this patient?

Increased hemoglobin Barts concentration

A 57-year-old woman comes to the physician because of a 3-month history of easy fatigability and dyspnea on exertion. Menopause occurred 5 years ago. Her pulse is 105/min and blood pressure is 100/70 mm Hg. Physical examination shows pallor of the nail beds and conjunctivae. A peripheral blood smear shows small, pale red blood cells. Further evaluation is most likely to show which of the following findings?

Increased concentration of HbA2

Decreased serum haptoglobin concentration

Increased serum methylmalonic acid concentration

A 21-year-old woman comes to the physician for an annual health maintenance examination. She has no particular health concerns. Laboratory studies show: Hemoglobin 11.2 g/dL Mean corpuscular volume 74 μm3 Mean corpuscular hemoglobin concentration 30% Hb/cell Red cell distribution width 14% (N=13–15) Genetic analysis shows a point mutation in intron 1 of a gene on the short arm of chromosome 11. A process involving which of the following components is most likely affected in this patient?

Small nuclear ribonucleoprotein

A 23-year-old Sicilian male presents to his primary care physician complaining of lethargy, joint pain, and urinary frequency. Vitals signs include T 98.7 F, HR 96 bpm, BP 135/71 mm/Hg, RR 18 breaths/minute, O2 99%. Laboratory findings include: random glucose 326 mg/dL, Hemoglobin 7.1, and elevated reticulocyte count and transferrin saturation. The patient is not surprised that his "blood level is low" and suggests that he might need another transfusion. An echocardiogram demonstrates restrictive cardiomyopathy. The disorder with which this patient presents can be characterized by which of the following?

Absence of the hemoglobin beta-chain

Mutations resulting in copper accumulation

Presence of the fetal hemoglobin

Absence of the hemoglobin alpha-chain

Mutation resulting in increased iron absorption

A 24-year-old Asian woman comes to the office complaining of fatigue. She states that for weeks she has noticed a decrease in her energy. She is a spin instructor, and she has been unable to teach. She said that when she was bringing groceries up the stairs yesterday she experienced some breathlessness and had to rest after ascending 1 flight. She denies chest pain, palpitations, or dyspnea at rest. She has occasional constipation. She recently became vegan 3 months ago following a yoga retreat abroad. The patient has no significant medical history and takes no medications. She was adopted, and her family history is non-contributory. She has never been pregnant. Her last menstrual period was 3 days ago, and her periods are regular. She is sexually active with her boyfriend of 2 years and uses condoms consistently. She drinks a glass of red wine each evening with dinner. She denies tobacco use or other recreational drug use. Her temperature is 99°F (37.2°C), blood pressure is 104/74 mmHg and pulse is 95/min. Oxygen saturation is 98% while breathing ambient air. On physical examination, bilateral conjunctiva are pale. Her capillary refill is 3 seconds. A complete blood count is drawn, as shown below: Hemoglobin: 10 g/dL Hematocrit: 32% Leukocyte count: 10,000/mm^3 with normal differential Platelet count: 200,000/mm^3 A peripheral smear shows hypochromic red blood cells and poikilocytosis. A hemoglobin electrophoresis reveals a minor reduction in hemoglobin A2. Which of the following is most likely to be seen on the patient’s iron studies?

Decreased serum iron and increased TIBC

Normal serum iron and normal TIBC

Increased serum iron and decreased TIBC

Increased serum ferritin and increased iron saturation

Decreased serum iron and decreased TIBC

Thalassemias for USMLE Step 3: High-Yield Internal Medicine Lessons

Thalassemia Basics - Globin Chain Gang

Quantitative defect in globin chain synthesis (α or β), leading to a microcytic, hypochromic anemia.
The imbalance of chains causes ineffective erythropoiesis and hemolysis.
Normal Adult Hemoglobins:
- HbA (Adult): $α_2β_2$ (~95-98%)
- HbA2 (Adult 2): $α_2δ_2$ (~2-3%)
- HbF (Fetal): $α_2γ_2$ (<2%)

Hemoglobin subunit composition changes during development

⭐ Heterozygous thalassemia carriers show increased resistance to severe P. falciparum malaria.

Alpha-Thalassemia - Alpha's Missing Acts

Pathophysiology: Caused by α-globin gene deletions on chromosome 16. Severity depends on the number of deleted genes (out of 4).
- cis deletion (prevalent in Asian populations) vs. trans deletion (prevalent in African populations).
Clinical Spectrum:
- 1 deletion: Silent carrier, asymptomatic.
- 2 deletions: α-thalassemia trait with mild microcytic anemia.
- 3 deletions: HbH disease, where excess β-globin forms $β_4$ tetramers. Leads to severe hemolytic anemia & splenomegaly.
- 4 deletions: Hydrops fetalis (Hb Barts), where excess γ-globin forms $γ_4$ tetramers. It is lethal in utero.

⭐ In HbH disease, the precipitated $β_4$ tetramers (Heinz bodies) are visualized on supravital staining, giving RBCs a characteristic "golf ball" appearance.

Peripheral smear of HbH disease with golf ball cells

Beta-Thalassemia - Beta's Bad Build

Pathophysiology: Point mutations in the β-globin gene on chromosome 11 → ↓ or absent β-globin chain synthesis.
Types:
- Minor (Trait): Heterozygous. Asymptomatic with mild microcytic anemia.
- Major (Cooley's Anemia): Homozygous. Severe, transfusion-dependent anemia.
Clinical Features (Major):
- Ineffective erythropoiesis & extramedullary hematopoiesis → massive hepatosplenomegaly.
- Marrow expansion → "crew-cut" skull X-ray & "chipmunk" facies.
- Presents around 6 months as fetal hemoglobin (HbF) wanes.
Diagnosis (Electrophoresis):
- ↓ HbA ($α₂β₂$)
- ↑ HbA₂ ($α₂δ₂$)
- ↑ HbF ($α₂γ₂$)

Crew-cut skull X-ray in beta-thalassemia

⭐ High-Yield: An elevated HbA₂ level (> 3.5%) is the key diagnostic finding for β-thalassemia minor (trait).

Diagnosis & Management - Spot & Support

Management Strategy:
- Mild (carrier): Genetic counseling.
- Moderate/Severe (Major):
  - Chronic Blood Transfusions: Maintain Hb >9-10 g/dL to support growth and suppress extramedullary hematopoiesis.
  - Iron Chelation: Essential to prevent secondary hemochromatosis. Agents include Deferoxamine, Deferasirox.
  - Splenectomy: Considered if hypersplenism increases transfusion requirements.
Curative Option: Allogeneic hematopoietic stem cell transplantation.

⭐ High-Yield: In β-thalassemia minor, HbA2 levels are characteristically elevated (>3.5%) on electrophoresis, a key diagnostic differentiator.

High‑Yield Points - ⚡ Biggest Takeaways

α-thalassemia is caused by gene deletions on chromosome 16; β-thalassemia results from point mutations on chromosome 11.

Hallmark is microcytic anemia with a normal or ↑ RBC count and a very low MCV.

Unlike iron deficiency, serum iron and ferritin levels are normal or elevated.

Hb electrophoresis is key for diagnosis, showing ↑ HbA2/HbF in β-thalassemia.

Severe forms (β-thal major, HbH disease) require lifelong blood transfusions and iron chelation therapy.

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Thalassemias