Hemoglobinopathies



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Hemoglobinopathies

2002

Ware



  1. A four year old Caucasian male is referred to you for jaundice and possible hemolytic anemia. The referring pediatrician says that the child has always had mild scleral icterus and now has a palpable spleen. Recent laboratory studies include the following: hemoglobin concentration = 9.8 gm/dL; absolute reticulocyte count = 313 x 109/L; total bilirubin = 4.0 mg/dL (direct fraction = 0.4 mg/dL, indirect fraction = 3.6 mg/dL). A hemoglobin electrophoresis on cellulose acetate shows predominantly hemoglobin A but several additional faint bands that could not be identified. Which of the following tests would be the most informative?




  1. Osmotic fragility testing

  2. Hemoglobin electrophoresis on acid citrate

  3. Autohemolysis testing

  4. Heinz body preparation

  5. Quantitative G6PD assay




  1. A ten week old African American male is referred to you for evaluation and management of an abnormal FS newborn hemoglobinopathy screen. Family testing reveals that the father has HbAS, while the mother has only HbA. You repeat the infant’s studies and the lab now reports an FSA pattern on hemoglobin electrophoresis. The most likely diagnosis that explains this infant’s laboratory studies is:




  1. Non-paternity

  2. Sickle + thalassemia

  3. Sickle 0 thalassemia

  4. Sickle cell trait

  5. Sickle cell anemia




  1. A nine year old Caucasian female is referred to you for evaluation of anemia found on a routine physical examination. She is active and the fastest person on her soccer team. Your exam reveals mild icterus, a palpable spleen 2 cm below the left costal margin, and the following laboratory studies: hemoglobin concentration = 8.8 gm/dL; reticulocyte count = 423 x 109/L; MCV = 91 fL. On peripheral blood smear you note polychromasia, with several echinocytes and an occasional spherocyte. There is no family history of blood dyscrasia. The most likely diagnosis is:




  1. Congenital spherocytosis from a spontaneous mutation

  2. 5’ nucleotidase deficiency

  3. G6PD deficiency with extreme lyonization

  4. Hereditary elliptocytosis

  5. Pyruvate kinase deficiency




  1. A previously well three year old Caucasian male presents with pallor, fatigue, and dark urine. One day earlier, he was evaluated by his local pediatrician who prescribed amoxicillin for a possible urinary tract infection, based on dark amber urine and a urine dipstick with 3+ blood. At your evaluation, you learn that the child has not been on any other medications and there is no family history of blood disorders. His exam shows pallor, minimal scleral icterus, and no hepatosplenomegaly. Hemoglobin concentration = 5.5 gm/dL; reticulocyte count = 178 x 109/L; WBC = 12.1 x 109/L with a left shift; platelets = 291 x 109/L. The urine is reddish brown with 2+ protein and 4+ blood on dipstick, and 3 RBC’s and 3 WBC’s per high power field on microscopic analysis. You suspect an autoimmune hemolytic process as the etiology for this sudden-onsent hemoglobinuria, but the direct antiglobulin test (DAT) performed at room temperature is negative. To test this child for a Donath-Landsteiner antibody, you would need to do which of the following:




  1. Repeat the DAT at 4o C

  2. Repeat the DAT at 37o C

  3. Collect the blood at 37o C, then test the serum at 37o C in an indirect antiglobulin test

  4. Collect the blood at 37o C, then incubate serum and cells at 4o C and then 37o C

  5. Collect the blood at 37o C and repeat the DAT at 37o C




  1. A term 3.1 kilogram female infant is noted to have jaundice at 18 hours of life. The mother is A+ and the baby is O+, and the infant’s DAT is negative. Laboratory evaluation on the baby reveals the following: hemoglobin = 14.9 gm/dL; total bilirubin = 15 mg/dL (all indirect). The peripheral blood smear shows numerous spherocytes. The infant does well with phototherapy and supportive care, and is discharged home at 4 days of life. Three weeks later, the infant is thriving with a hemoglobin concentration of 13.4 gm/dL and total bilirubin concentration of 3.1 mg/dL. What is the best diagnostic test to help establish the etiology of this infant’s hemolysis?




  1. Repeat DAT on the infant’s RBC’s

  2. Screening of the maternal serum for RBC antibodies

  3. Tagged RBC study

  4. Osmotic fragility testing at 1 month of life

  5. Osmotic fragility testing at 6-12 months of life




  1. A pediatrician calls you for telephone advice about a 16 month old African-American male with microcytic hypochromic anemia. The anemia was detected on routine screening at one year of life, and several months of oral iron supplementation has not changed the blood counts. Latest laboratory evaluation reveals hemoglobin concentration = 9.7 gm/dL; MCV = 69 fL; reticulocyte count = 80 x 109/L. The hemoglobin electrophoresis shows only normal HbA and the serum ferritin = 51 ng/ml. Review of the newborn hemoglobinopathy screen reveals an FA pattern and 4% Hb Bart’s. The correct diagnosis and follow-up is:




  1. Hemoglobin H disease that warrants a prompt appointment for transfusion therapy

  2. Hemoglobin H disease that needs no further follow-up

  3. Two gene deletion thalassemia that needs quarterly monitoring

  4. Two gene deletion thalassemia that needs education and counseling only

  5. thalassemia silent carrier that needs no further evaluation




  1. A previously healthy 16 year old Caucasian male is referred to you for evaluation of abnormal laboratory studies. He is an active football player who was evaluated for a pre-sports physical. Review of systems reveals only occasional abdominal pain. The abnormal laboratory studies include: hemoglobin concentration = 9.9 gm/dL; MCV = 104 fL; reticulocyte count = 117 x 109/L; WBC = 3.0 with 26% polys, 58% lymphs, 15% monocytes, and 1% eosinophil. The platelet count is 119 x 109/L. Urinalysis specific gravity = 1.009, pH = 6.5, 2+ blood on dipstick, occasional casts but no RBC’s or WBC’s on microscopic analysis. The best diagnostic test to order is which of the following:




  1. CD59 testing on erythrocytes

  2. Hepatitis B serologies

  3. Direct platelet antibody measurement

  4. Erythrocyte adenosine deaminase activity

  5. Direct antiglobulin test




  1. A six week old Pakistani male is referred to you for evaluation of an abnormal “HbF only” result on newborn hemoglobinopathy screening. The infant appears healthy, and the only abnormality you detect on physician examination is a palpable spleen tip 1-2 cm below the left costal margin. The infant’s hemoglobin concentration is 9.5 gm/dL. Repeat hemoglobin electrophoresis confirms HbF only. The mother’s electrophoresis reveals HbA with 6.1% HbA2, but the father is unavailable for testing. The most likely diagnosis is:




  1. thalassemia major

  2. thalassemia minor

  3. Two gene deletion thalassemia

  4. Three gene deletion thalassemia

  5. Four gene deletion thalassemia




  1. Normal adult hemoglobin (22) has a decreased affinity for oxygen in which of the following settings?




  1. Carbon monoxide intoxication

  2. Exposure to sulfa drugs

  3. Increased 2,3 DPG

  4. Methemoglobinemia

  5. Alkalosis




  1. You are called by a local pediatrician regarding a five year old African-American male with recurrent otitis media. The physician is currently treating him for his fourth episode of otitis media over the past 6 months. The doctor would like to prescribe trimethoprim/sulfamethoxazole prophylaxis, but is unsure about its safety since the G6PD status of the child is unknown. Which of the following responses is correct?




  1. All African-American children should be tested for G6PD activity before initiating sulfa therapy

  2. African-American males and females should be tested if there is a family history of hemolysis after sulfa exposure

  3. Only African-American males should be tested before using sulfa

  4. No testing is warranted since the African-American variant of G6PD is relatively mild

  5. No testing is warranted since measurement of G6PD activity does not predict hemolysis




  1. Hemoglobin Constant Spring is best described as which of the following:




  1. -chain variant with a 2 kb DNA deletion

  2. -chain variant with a point mutation in the promoter

  3. -chain variant with a point mutation at the stop codon

  4. -chain variant with a deletion of  and  genes

  5. -chain variant with increased HbF levels




  1. Hemoglobin E is best described as which of the following:




  1. Thalassemia found in Southeast Asia

  2. Thalassemia found in Mediterranean regions

  3. Hemoglobinopathy found in Southeast Asia

  4. Hemoglobinopathy found in Mediterranean regions

  5. Thalassemic hemoglobinopathy




  1. What is the most diagnostic test for 0 thalassemia trait?




  1. Hb F on newborn hemoglobinopathy screening

  2. Hb A2 on newborn hemoglobinopathy screening

  3. Hb Bart’s on newborn hemoglobinopathy screening

  4. Hb A2 after one year of life

  5. Hb Bart’s after one year of life




  1. Compared to normal erythrocytes, spherocytes have:

  1. Increased osmotic fragility at all saline concentrations

  2. Increased osmotic fragility at 0.5% saline

  3. Decreased osmotic fragility at 0.9% saline

  4. Increased levels of 2,3 DPG

  5. More Howell-Jolly bodies

15. Hemoglobin H is most commonly present in which of the following situations?



  1. 3 gene  thalassemia

  2. thalassemia trait

  3.  thalassemia trait

  4. 0/+ thalassemia intermedia

  5.  thalassemia silent carrier

16. In the deoxygenated state, the mutation in sickle hemoglobin primarily affects which of the following interactions?




  1.  globin to  globin

  2.  globin to  globin

C. Hemoglobin tetramer to Hemoglobin tetramer

  1. Heme ring to hemoglobin

  2. Erythrocyte to erythrocyte

Answer Key





  1. D

  2. B

  3. E

  4. D

  5. E

  6. D

  7. A

  8. A

  9. C

  10. D

  11. C

  12. E

  13. D

  14. B

  15. A

  16. C



2004

Ware


2006

Quinn


  1. Hemoglobin E, the most common hemoglobinopathy in the world, is a “thalassemic hemoglobinopathy”. That is, Hgb E is a structural or qualitative variant (26 glu>lys) and its synthesis is also impaired.

What primarily explains the quantitative reduction in the synthesis of this structurally abnormal globin?




    1. The E globin is unstable

    2. The E mutation disrupts a promoter sequence

    3. The E globin only forms tetramers with itself

    4. The E mutation creates an abnormal cryptic splice site *

    5. The E-globin, compared to normal -globin, preferentially binds -globin

Explanation:

The mutation that causes Hgb E creates a cryptic splice site in the -globin gene. Some of the resulting E transcripts are properly spliced, and some are not. The properly spliced transcripts are translated and the globin incorporated into the hemoglobin tetramer, producing Hgb E. The improperly spliced transcripts are not translated, thereby decreasing the overall synthesis of the E globin. Unstable hemoglobins may cause a hemolytic anemia and also some forms of thalassemia, but this is not the primary explanation for the thalassemic features of Hgb E. The remaining choices are incorrect.


  1. You are referred a 2 month-old baby girl whose newborn screening electrophoresis showed an “FS” pattern. You perform parental studies, the results of which are shown here:


Mother: Father:

Hgb A (%) 91 59

Hgb A2 (%) 6 1.5

Hgb F (%) 3 1.5

Hgb S (%) 0 38
You are confused, so you repeat the electrophoresis on the baby and now find an “FSA” pattern.
What is the most likely diagnosis of the baby that explains all the laboratory findings?


  1. Non-paternity

  2. Sickle-0-thalassemia

  3. Homozygous sickle cell anemia

  4. Sickle cell trait

  5. Sickle-+-thalassemia *

Explanation:

The mother has -thalassemia trait and the father has sickle cell trait. Their daughter has sickle-+-thalassemia, having inherited one abnormal hemoglobin gene from each parent. The classical newborn screening pattern in sickle-+-thalassemia is “FSA”; however, the amount of Hgb A produced by a neonate with sickle-+-thalassemia may be so small that it is missed on newborn screening. As the baby ages, Hgb F production (-globin chain production) decreases and Hgb S and A production (-globin chain production), so the amount of Hgb A will increase to a detectable level in the first few months of life.
Sickle cell anemia also produces an FS pattern at birth, but both parents would need to have S trait, and Hgb A would not later appear on the baby’s electrophoresis. Sickle-0-thalassemia also produces an FS pattern at birth, but Hgb A would not later appear on the baby’s electrophoresis. Sickle cell trait would produce and “FAS” pattern at birth. Non-paternity is possible, but there is a more likely plausible explanation.


  1. The two most common forms of sickle cell disease are sickle cell anemia (Hgb SS) and sickle-hemoglobin C disease (Hgb SC).

What complication of sickle cell disease is more likely to occur in young adults with Hgb SC compared to those with Hgb SS?




    1. Ischemic stroke

    2. Acute chest syndrome

    3. Sickle retinopathy *

    4. Pulmonary hypertension

    5. Leg ulcers

Explanation:

All the complications listed except sickle retinopathy occur more frequently in Hgb SS patients. Retinopathy occurs in both Hgb SS and Hgb SC patients, but it is more common in Hgb SC. The higher total hemoglobin concentration, hence higher blood viscosity, is thought to contribute to this tendency.


  1. The steady-state hematologic parameters differ among the common sickle cell diseases.

What is the likely diagnosis of a 10 year-old girl who has the following complete blood count and peripheral smear findings?


WBC 8,500 /mm3

Hgb 11.7 g/dL

Hct 29.4 %

MCV 87 fL

Plt 195,000 /mm3

Retic 4.6%

Peripheral smear: target cells, polychromasia, no irreversibly sickled cells


  1. Sickle-hemoglobin C disease *

  2. Sickle-+-thalassemia

  3. Sickle-0-thalassemia

  4. Sickle cell anemia

  5. Sickle cell anemia with -thalassemia trait

Explanation:

The Hgb concentration is typical for a patient with Hgb SC or S-+-thalassemia, but the most likely explanation is Hgb SC because this individual is normocytic. All of the conditions with thalassemia (b, c, and e) cause microcytic anemia. Although Hgb SS is a normocytic anemia, the mildness of the anemia argues against this choice.


  1. You have followed a boy with sickle cell disease since 2 months of age. His newborn screening showed an “FS” pattern. He took prophylactic penicillin until 5 years of age. At a routine visit at 9 years of age his mother questions you why he has never experienced pain. You review his records and realize that he has never experienced any sickle cell disease-related complications. You obtain a complete blood count and observe the following:

WBC 8,500 /mm3

Hgb 12.1 g/dL

Hct 36.5 %

MCV 85 fL

Plt 205,000 /mm3

Retic 1.4%
Which of the following diagnoses is consistent with his “FS” newborn screening pattern, the clinical history, and the current blood count?


  1. Hgb H disease

  2. Sickle-hemglobin C disease

  3. Sickle-0-thalassemia

  4. Sickle trait

  5. Sickle-HPFH *

Explanation:

The compound heterozygous state for the S (Hgb S) mutation and deletional hereditary persistence of fetal hemoglobin (HPFH) is a benign condition. Classically, the very high and typically pancellular distribution of Hgb F prevents sickling, anemia, and SCD-related complications. Like Hgb SS and sickle-0-thalassemia, Hgb S-HPFH also gives an “FS” pattern at birth.
Sickle trait would produce an “FAS” pattern on newborn screening and normal blood counts. Both Hgb SC and sickle-0-thalassemia would be expected to have anemia and reticulocytosis. Hgb H disease is a form of -thalassemia intermedia, not sickle cell disease, and it would show Hgb Barts on the newborn screening electrophoresis.


  1. Many different types of mutations cause thalassemias, but there are recurring patterns of mutations that are typical of the alpha and beta thalassemias.

What type of mutational event most commonly causes the beta thalassemias?




    1. Point mutations *

    2. Large deletions

    3. Inversions

    4. Translocations

    5. Uniparental disomy

Explanation:

The beta thalassemias are typically caused by point mutations that decrease or abolish the transcription or translation of beta globin genes or transcripts. In contrast, the alpha thalassemias are more commonly caused by deletions of entire alpha globin genes. Deletional forms of beta thalassemia and non-deletional forms of alpha thalassemia do occur, but they are less common. Inversions, translocations, and uniparental disomy do not cause thalassemia.


  1. You are called late at night about 3 year-old boy with sickle cell anemia who presents to the emergency room of your hospital. The brand new intern on duty reports that the child is alert but pale and tachycardic. He is not febrile, and he had been acting well until 12 hours ago. You ask the intern about the abdominal examination, but he is unsure whether he can feel a spleen or not. He reports the following blood counts to you:

WBC 17,500 /mm3

Hgb 4.4 g/dL

Hct 13.2 %

MCV 89 fL

Plt 123,000 /mm3

Retic 29 %
NRBCs 9/100 WBCs
What is the most likely explanation for this child’s acutely severe anemia?


  1. Recovery from recent aplastic crisis

  2. Acute splenic sequestation *

  3. Acute chest syndrome

  4. Hyperhemolysis

  5. Hydroxyurea ingestion

Explanation:

The most likely explanation is acute splenic sequestration, given the acutely severe anemia, brisk reticulocytosis, and NRBCs in the peripheral circulation. Although the intern was unsure about his ability to palpate the spleen, you can infer hypersplenism from the mild thrombocytopenia. Recovery from aplastic crisis would give an anemia with reticulocytosis, but the clinical history and thrombocytopenia argue against this. Hyperhemolysis alone would not cause anemia this severe. There are no respiratory signs or symptoms to suggest acute chest syndrome. Hydroxyurea toxicity would cause myeloid and erythroid suppression and not reticulocytosis.


  1. Thalassemias are caused by a variety of mutations of the alpha, beta, delta, and gamma globin genes. Which of the following types of thalassemia spontaneously resolves during early infancy?




    1. -thalassemia

    2. -thalassemia

    3. -thalassemia

    4. -thalassemia

    5. -thalassemia *

Explanation:

Gamma chain synthesis normally decreases steadily after birth, so Hgb F (22) production consequently falls after birth. This normal developmental decline in  chain synthesis is simultaneously replaced by increasing  and  globin synthesis, producing the adult hemoglobins A (22) and A2 (22) instead of Hgb F. Thus, -thalassemias, which present as a microcytic, hemolytic anemia in neonates, are self-limited disorders. Alpha thalassemias are symptomatic in both fetal and adult life, because the  globin is common to Hgb A, A2, and F. Beta-thalassemias are not apparent at birth, because Hgb F (22) is the predominant Hgb of the fetus and neonate. Beta-thalassemias become apparent in the first several months of life when -globin synthesis should be increasing.


  1. You counsel a couple of Southeast Asian ancestry, both of whom are known to have 2-gene deletion -thalassemia, that they have a 25% chance of having a child with alpha thalassemia major (4-gene deletion -thalassemia).

In the next exam room you must counsel an African-American couple, both of whom are also known to have 2-gene deletion -thalassemia. Neither has Asian heritage. Of the following choices, which is the closest estimate of their risk of having a child with alpha thalassemia major (4-gene deletion -thalassemia)?



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