Hemoglobinopathies



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0% *

  • 25%

  • 50%

  • 75%

  • 100%

    Explanation:

    Two-gene deletion -thalassemia (-thalassemia trait) occurs when two -globin genes are deleted on the same chromosome, in cis (--/), or when they are deleted on opposite chromosomes, in trans (-/-). The Southeast-Asian couple likely both carry the deletions in cis (--/), so their risk of an offspring with 4-gene deletion -thalassemia would be 25%. In contrast, -thalassemia trait nearly always occurs in trans (-/-) among individuals of African ancestry, so the risk to their offspring would be 0% for 4-gene deletion -thalassemia, although 100% would have -thalassemia trait.


    1. A pediatrician calls you on Friday afternoon about a child whose newborn hemoglobinopathy screening showed “Hgb F only” on both screens. The baby is now 4 weeks old, he was born at term to Pakistani parents, and he is asymptomatic and thriving. Because the baby is doing well—and you need to brush up on newborn screening results—you decide to see the child in clinic next week.

    In your weekend readings on newborn screening for hemoglobinopathies you discover that an “F only” pattern in a term baby is indicative of which of the following conditions?




      1. Hgb H disease

      2. Hydrops fetalis (4-gene deletion -thalassemia)

      3. -thalassemia major *

      4. Sickle-+-thalassemia

      5. HPFH trait

    Explanation:

    The absence of any adult hemoglobin (Hgb A) in this term Pakistani neonate likely indicates homozygous -thalassemia major (00). This newborn can make Hgb F (22) but no Hgb A (22), and he will soon be transfusion-dependent. Hgb H disease (three-gene deletion -thalassemia) would give an “FA +Barts” pattern. The clinical scenario is inconsistent with hydrops fetalis (4-gene deletion -thalassemia). Sickle-+-thalassemia would give an “FSA” or, possibly, an “FS” pattern at birth. HPFH trait would produce a “normal” “FA” pattern.

    2009

    Hemoglobinopathies

    Charles T. Quinn, MD MS
    1. You obtain a screening transcranial doppler ultrasound (TCD) study on a 3-year-old boy with sickle-cell anemia (Hgb SS). The time-averaged maximal mean velocities (TAMMVs) in the right and left middle cerebral arteries (MCAs) are 201 and 203 cm/s, respectively. The ultrasonographer tells you that she had trouble performing the study because the child was irritable and cried through most of the procedure. Given the TCD data, what is the best estimate of this child’s yearly risk of overt ischemic stroke?

    A. 0.1%


    B. 1%

    C. 5%


    D. 10%

    E. Indeterminate


    Answer: E

    Explanation: There are many determinants of TAMMV (TCD velocity) besides stenosis in a blood vessel. For example, a child’s state of wakefulness and physical activity can affect the TAMMV. Sleeping can lower TAMMV, while activity and crying can increase it. Therefore, children must lie still and remain quiet and awake during a TCD examination. If this is not achieved, then the study will need to be repeated in the appropriate setting. The best answer in this case is indeterminate, because the apparently “abnormal” TCD velocities (> 199 cm/s) may be due to crying and activity, not vessel disease. The hematocrit also influences TAMMV—the lower the hematocrit the higher the TAMMV.

    2. A 15-year-old African-American female is referred to you for the evaluation of an incidentally discovered anemia. Her father reports that she has been generally well throughout her life, but that her eyes occasionally turn yellow when she gets a cold or the flu. She has never had any unusual or recurring pain. Her growth and development are normal. Her physical examination is remarkable only for a spleen that is 2 cm below the costal margin. The following laboratory studies, obtained by the patient’s pediatrician, are available to you.

    WBC 8,500/mm3

    Hgb 12.1 g/dL

    Hct 35.7%

    MCV 78 fL

    MCHC 36.5 g/dL

    Plt 195,000/mm3

    Retic 1.9%

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

    Sickle solubility test (Sickledex™): negative

    What is this patient’s most likely diagnosis?

    A. Sickle-+-thalassemia

    B. Sickle-Hgb C disease (Hgb SC)

    C. -thalassemia intermedia

    D. Hemoglobin C disease (Hgb CC)

    E. Hemoglobin H disease
    Answer: D

    Explanation: Homozygous Hgb C disease is a condition characterized by a mild, chronic hemolytic anemia. The hemolysis is usually mild, but intermittent mild jaundice can occur. The peripheral smear will show target cells and Hgb crystals, but no sickled cells. The MCHC may also be increased because of RBC dehydration. Affected individuals may also have splenomegaly, especially as adolescents and adults. Splenic function is normal, however, and acute splenic sequestration does not occur. Hgb C disease occurs almost exclusively among individuals with African ancestry. It is not a “sickling” disorder, and it is not one of the sickle-cell diseases.

    The negative sickle solubility test, which excludes the presence of sickle hemoglobin (Hgb S), excludes the diagnoses of sickle-+-thalassemia and sickle-Hgb C disease (Hgb SC). -thalassemia intermedia and Hgb H disease would cause more severe anemia and marked microcytosis, unlike in this patient who has mild anemia and microcytosis.

    3. You are referred a 10-year old girl who had screening laboratory studies that showed an increased Hgb concentration. Her growth and development have been normal. She has always been healthy. She is the star of her soccer team. No one in the family is known to have a blood disease. Her physical examination is normal: it shows no plethora, cyanosis, or organomegaly. You obtain the following laboratory studies.

    WBC 6,500/mm3

    Hgb 15.9 g/dL

    Hct 47.7%

    MCV 85 fL

    Plt 205,000/mm3

    Retic 0.8%

    Hemoglobin electrophoresis: 74% Hgb A; 1.5% Hgb A2; 0.5% Hgb F; and 24% being an unidentified Hgb variant.


    What is the most likely p50 (partial pressure of O2 at which the Hgb is 50% saturated with O2) of this patient’s whole blood?

    A. 19 mmHg

    B. 26 mmHg

    C. 32 mmHg

    D. 45 mmHg

    E. 70 mmHg


    Answer: A

    Explanation: This patient is heterozygous for a variant Hgb with high oxygen affinity. If the oxygen affinity of Hgb is increased, then its oxygen delivery to tissues is decreased. The body compensates physiologically by increasing erythropoietin production, stimulating the bone marrow to increase erythropoiesis, thereby increasing the total Hgb concentration and the oxygen-carrying capacity of the blood. Hence, patients with high oxygen affinity Hgbs have erythrocytosis, but it is functionally appropriate because they maintain appropriate oxygen delivery to their tissues. Individuals with high oxygen affinity mutants usually have mild erythrocytosis, but some may have total Hgb concentrations as high as 18–20 g/dL.

    To determine whether a Hgb has altered oxygen affinity, one must measure its p50 from the oxy-hemoglobin dissociation curve. The p50 is the partial pressure of oxygen at which Hb is 50% saturated with oxygen. Hgb A is 50% saturated at an oxygen tension of about 26 mm Hgb, which is the normal value of p50. The p50 of high affinity Hbs have a low p50 value and a left-shifted curve, whereas low affinity Hgbs have a high p50 value and a right-shifted curve. In this example, answer a. is the only choice with a p50 that is lower than normal (26 mmHg).

    Electrophoresis may identify oxygen affinity variants when the mutation changes the net charge of Hb. However, not all mutations alter net charge, so a normal electrophoretic pattern does not exclude a Hgb with altered oxygen affinity.

    4. Sickle Hgb (Hgb) is a -hemoglobinopathy that polymerizes upon deoxygenation. Which of the following amino acid substitutions is the one that results in abnormal hydrophobic interactions between adjacent deoxy-hemoglobin S molecules?

    A. 6 glutamate to lysine

    B. 6 glutamate to valine

    C. 26 glutamate to lysine

    D. 121 glutamate to glutamine

    E. 121 glutamate to lysine
    Answer: B

    Explanation: The sixth codon of the normal β-globin gene, GAG, codes for glutamic acid. In Hgb S, the adenine nucleotide is replaced by thymidine, producing GTG, which is a codon for valine. This mutation replaces a hydrophilic glutamic acid with a hydrophobic valine in the 6th position of the -globin protein, permitting abnormal hydrophobic interactions between adjacent deoxy-hemoglobin molecules. This change decreases the solubility of Hgb S in the deoxygenated state.

    Answer a. is the Hgb C mutation; c. is the Hgb E mutation; d. is the Hgb D-Punjab mutation; and e. is the Hgb O-Arab mutation.


    5. A 5-year-old Laotian girl who recently moved to this country is referred to you because of chronic anemia. Her height and weight are at the 3rd percentile. She has mild midface prominence and moderate scleral icterus. Her liver and spleen are palpable 2 cm below the costal margins. Both of her parents have been told they have thalassemia trait. You obtain the following laboratory studies.

    WBC 15,500/mm3

    Hgb 7.8 g/dL

    Hct 23.5%

    MCV 51.2 fL

    Plt 356,000/mm3

    Retic 2.1%

    Peripheral smear: Hypochromic, microcytic anemia with marked anisopoikilocytosis and many target cells. Ten nucleated red blood cells are seen for every 100 leukocytes.

    Hemoglobin electrophoresis: 84% Hgb A; 12% Hgb H; 1% Hgb F; 0.5% Hgb A2; and a minor band migrating more slowly than Hgb A2 (at alkaline pH).
    What is the most likely diagnosis?

    A. Hgb H disease (--/-)

    B. Hgb E-+-thalassemia

    C. Hgb H-Constant Spring (--/CS)

    D. Homozygous ()0-thalassemia

    E. Hgb H disease (--/-) with Hgb E trait


    Answer: C

    Explanation: This patient has Hgb H-Constant Spring (--/CS), which results from the coinheritance of alpha thalassemia trait (--) from one parent and a Hgb Constant Spring haplotype (CS) from the other parent. The “slow” band on Hgb electophoresis is Hgb Constant Spring. The Southeast Asian ancestry and the thalassemia intermedia phenotype of this patient are consistent with Hgb H-Constant Spring.

    Hgb E migrates in roughly the same position as Hgb A2, not more slowly than it, so b. and e. are incorrect. Answer d. is incorrect because it is a form of beta-thalassemia that does not result in the production of Hgb H.

    6. Under normal conditions, the human body loses about 1-2 mg of iron per day. When large amounts of iron are received from multiple transfusions of red blood cells, what regulatory mechanism can the body use to increase iron excretion?

    A. Increase renal tubular excretion of iron

    B. Accelerate sloughing of gastrointestinal mucosal cells

    C. Decrease production of hepcidin

    D. Increase lipid peroxidation

    E. None
    Answer: E



    Explanation: The body has no mechanism to increase iron excretion. Iron loss is fixed at 1-2 mg per day despite iron intake. Therefore, iron chelation therapy is needed to prevent transfusional iron overload.

    7. Iron overload produces organ and tissue damage because of the formation of free radicals and reactive oxygen species. What form of iron is responsible for this toxicity?

    A. Ferritin

    B. Hemosiderin

    C. Free heme

    D. Nontransferrin bound iron

    E. Iron-phytate complexes
    Answer: D

    Explanation: Iron is necessary for life, but it is a highly reactive element that must be safeguarded in the body by carrier and storage proteins. A highly reactive component of nontransferrin-bound iron is believed to mediate the formation of radicals and reactive oxygen species that cause lipid peroxidation and other cellular damage. Storage forms of iron, ferritin and hemosiderin, are relatively nontoxic. Iron-phytate complexes (found in the diet) and free heme are not responsible for the toxicity or iron overload.

    8. A 2-month-old girl with African ancestry is scheduled to see you because her newborn screening showed an “F only” pattern. She does not make her clinic appointment, and she is lost to follow-up for 3 years. When she finally returned to medical attention, her pediatrician immediately referred the child to you again. The family had been living in Africa for the past 3 years, but they have now decided to remain in this country. The girl has been entirely well. Her parents say she has had no pallor, jaundice, painful swelling of the hands or feet, recurrent pain, and no known infections. Her height and weight are normal. She has no jaundice, midface prominence, or splenomegaly. You obtain the following laboratory studies.

    WBC 9,500/mm3

    Hgb 13.3 g/dL

    Hct 43.2 %

    MCV 72 fL

    Plt 175,000/mm3

    Retic 0.7%

    Peripheral smear: Mild hypochromia, microcytosis, and poikilocytosis.

    Hemoglobin electrophoresis on the child and her parents show:


    Child: Mother: Father:

    Hgb A (%) 0 74.4 73.2

    Hgb A2 (%) 0 1.1 1.3

    Hgb F (%) 100 24.5 25.5


    What is the child’s diagnosis?

    A. Homozygous ()0-thalassemia

    B. Homozygous deletional HPFH

    C. Homozygous 0-thalassemia

    D. Homozygous Hgb Lepore ( fusion gene)

    E. Homozygous 0-thalassemia


    Answer: B

    Explanation: Deletional hereditary persistence of fetal hemoglobin (HPFH) is a condition caused by defective - and -globin synthesis (the genes are deleted) so that high levels of Hgb F are maintained throughout extrauterine life. HPFH heterozygotes, like the child’s parents, are asymptomatic and have normal blood counts. Their Hgb electrophoresis shows 20%–30% Hgb F. HPFH homozygotes are also asymptomatic and have no thalassemic phenotype, but they do have mild microcytosis and hypochromia. Hgb electrophoresis shows 100% Hgb F and no Hgb A or A2.

    Answers a., c., and d. are clinically severe forms of thalassemia. Homozygous 0-thalassemia has not been reported, but the absence of -globin genes would preclude the formation of Hgb F.

    9. You are referred a 14-year-old boy who has been cyanotic as long as his adoptive parents have known him. He has normal growth, development, and intelligence. He has neither clubbing nor shortness of breath, but he has had some episodes of weakness after severe exertion. Extensive pulmonary and cardiac studies have shown no abnormalities. You obtain the following laboratory studies.

    WBC 6,500/mm3

    Hgb 13.9 g/dL

    Hct 41.7%

    MCV 85 fL

    Plt 250,000/mm3

    Retic 1.4%

    Peripheral smear: normal morphology

    Methemoglobin concentration: 0.7%

    Hemoglobin electrophoresis: 51% Hgb A; 1% Hgb A2; and 48% unidentified band that migrates slightly more slowly than Hgb A (at alkaline pH)


    What is the most likely p50 (partial pressure of O2 at which the Hgb is 50% saturated with O2) of this patient’s whole blood?

    A. 19 mmHg

    B. 26 mmHg

    C. 32 mmHg

    D. 45 mmHg

    E. 70 mmHg


    Answer: E

    Explanation: This patient is heterozygous for a variant Hgb with low oxygen affinity. Individuals with moderately low oxygen affinity Hgb variants (p50 35–55 mmHg) may have “anemia,” because oxygen extraction from Hgb is enhanced. Therefore, despite a low Hb concentration, affected individuals are not functionally anemic because they maintain appropriate oxygen delivery to their tissues.

    However, this patient has a Hgb with greatly decreased oxygen affinity (p50 70–80 mmHg). Such individuals have cyanosis because a substantial fraction of their Hgb is deoxygenated. Moreover, they are not anemic because oxygen extraction actually returns to normal at very high values of p50. As the p50 of different low-affinity Hgbs increases, their oxygen extraction increases until the p50 reaches approximately 55 mmHg, after which oxygen extraction decreases with increasing p50, reaching a normal oxygen extraction at a p50 of about 80 mmHg.

    Answer a. indicates high oxygen affinity, which would produce erythrocytosis. Answer b. is the normal p50. Answers c. and d. indicate moderately low oxygen affinity, which would cause some degree of “anemia”, unlike in this patient. Moreover, the moderate reduction in oxygen affinity indicated by answers c. and d. would not be not sufficient to produce cyanosis.

    10. You have been prescribing hydroxyurea to a teenage boy with sickle-cell anemia (Hgb SS) who has recurrent painful episodes. You started at a dose of 15 mg/kg once daily. You have increased his dose in increments of 5 mg/kg every 2-3 months. He has now been on a dose of 30 mg/kg for 3 months. Despite this, you see no clinical improvement. He still has frequent painful episodes. You obtain a blood count and a Hgb electrophoresis to monitor his therapy.

    WBC 17,500/mm3

    Hgb 6.8 g/dL

    Hct 20.4%

    MCV 78 fL

    Plt 475,000/mm3

    Retic 19.8%

    Peripheral smear: Severe normocytic anemia with polychromasia, many irreversibly sickled cells, and Howell-Jolly bodies.

    Hemoglobin electrophoresis: 94.4% Hgb S; Hgb F 3.5%; and 2.1% Hgb A2


    These values are essentially the same as when he started hydroxyurea 10 months ago. What is the most likely reason for this patient’s poor response to hydroxyurea?

    A. Inadequate dose of hydroxyurea

    B. Inadequate duration of therapy with hydroxyurea

    C. Incorrect diagnosis of sickle cell anemia (Hgb SS)

    D. The patient is a biological non-responder to hydroxyurea

    E. The patient is not adherent to hydroxyurea


    Answer: E

    Explanation: The dose and duration of hydroxyurea therapy are appropriate (answers a. and b.). Although the dose could be increased further, other reasons for nonresponse should be considered first. The blood counts, electrophoresis, and clinical scenario are consistent with a diagnosis of sickle-cell anemia (Hgb SS; answer c.). Although it is possible that this patient is a “nonresponder” to hydroxyurea (answer d.), the most likely answer is that the patient has not been taking his medicine as prescribed. Indeed, he has no macrocytosis and he has both a leukocytosis and thrombocytosis. Expected laboratory effects of hydroxyurea include macrocytosis and a reduction in the leukocyte and platelet counts. Nonadherence to chronic medications is one of the greatest challenges in medicine today, regardless of the underlying disease.
    2011

    Hemoglobinopathies

    Charles T. Quinn, MD MS



    1. A 4 month-old baby, born at term without complications, is now referred to you for an abnormal newborn screening test for hemoglobinopathies. The hemoglobin pattern reported from the first week of life is “F, A” with the addition of a trace amount of hemoglobin (Hgb) Barts.

    What is the significance of Hgb Barts on newborn screening?




    1. The baby has a form of alpha thalassemia

    1. The baby has a form of beta thalassemia

    2. The baby has a form of gamma thalassemia

    3. The baby has a form of delta-beta thalassemia

    4. The baby has a form of HPFH (hereditary persistence of fetal hemoglobin)


    Explanation:

    Newborns make a predominance of fetal Hgb (Hgb F) and a lesser amount of adult Hgb (Hgb A), giving the normal “F, A” pattern on newborn screening. Hgb F is composed of 2  and 2  chains (22). When there is a relative deficiency of alpha chains due to alpha thalassemia, then the relative excess of unpaired gamma chains self-associate to form Hgb Barts, a tetramer of gamma chains (4). The presence of Hgb Barts indicates the presence of alpha thalassemia. All the other choices are abnormalities of the beta globin locus.





    1. You choose to obtain a Hgb electrophoresis on the same baby from question #1 at 4 months of age. The results show the presence of Hgb A (89%) and Hgb F (11%), but no Hgb Barts.

    What does the disappearance of Hgb Barts indicate?




    1. Laboratory error

    1. This baby had a transient, neonatal form of thalassemia

    2. The Hgb F production has increased since birth

    1. An expected developmental phenomenon

    1. Non-paternity


    Explanation:

    Fetal Hgb production progressively decreases after birth and approaches the normal adult values of approximately 1.5 – 2.5% by about 6 months of age in hematologically normal infants. Hgb F production declines with age because gamma chain synthesis declines. Because gamma chain synthesis declines with age, so will the formation of Hgb Barts, a tetramer of gamma chains (4). Therefore, the disappearance of Hgb Barts as the baby ages is an expected developmental phenomenon. Trace amounts of Hgb Barts can be detected by high-sensitivity techniques in older children with one- or two-gene deletion alpha thalassemia, but it is not usually detected by Hgb electrophoresis outside of early infancy. Gamma thalassemia, not alpha thalassemia, is transient, neonatal form of thalassemia.





    1. The same infant from questions #1 and #2 is an African-American boy without Asian ancestry. You determine that he has a 2-gene deletion alpha thalassemia (alpha thalassemia trait).

    From which parent or parents did he almost certainly inherit his alpha gene deletions?




    1. Two deleted genes from the mother

    2. Two deleted genes from the father

    1. One deletion each from the mother and father

    1. Two deletions each from the mother and father

    2. One deletion from either parent and one new mutation


    Explanation:

    Two-gene deletion -thalassemia (-thalassemia trait) can occur when two -globin genes are deleted on the same chromosome, in cis (--/), or when they are deleted on opposite chromosomes, in trans (-/-). Among individuals of African ancestry, -thalassemia trait nearly always occurs in trans (-/-), so this child must have received one alpha gene deletion from the mother and the other from the father. In contrast, individuals of Asian ancestry with alpha thalassemia trait may carry both deletions in cis (--/) or in trans (-/-), so it is possible to inherit 2 deleted genes from one parent in this scenario.





    1. You are seeing a 5 year-old girl with sickle cell anemia (Hb SS) for a regularly scheduled examination. You perform a complete neurologic examination and find no deficits. You obtain a screening transcranial Doppler examination using a non-imaging technique, and this shows the only abnormality to be a time average maximal mean velocity (TAMMV) of 205 cm/s in the left middle cerebral artery.

    What are the chances, approximately, that this girl will remain stroke-free over the next 3 years?




    1. 80%

    1. 60%

    1. 40%

    2. 20%

    3. 1%


    Explanation:

    An abnormal TCD velocity (200 cm/s or higher by STOP Trial criteria) confers a risk of overt stroke over the 3 years following the TCD examination of approximately 40%. Therefore, there is a 60% chance that this patient will remain stroke-free during that same period.





    1. You are seeing a 7 year-old boy with sickle cell anemia (Hb SS) for a regularly scheduled examination. You perform a complete neurologic examination and find no deficits. You obtain a screening transcranial Doppler (TCD) examination, but your hospital bought new ultrasonography equipment and now uses an imaging TCD technique instead of a non-imaging technique. The TCD shows the only abnormality to be a time average maximal mean velocity (TAMMV) of 190 cm/s in the right distal internal carotid artery.

    What are the chances, approximately, that this boy remain will have a stroke in the next 3 years?




    1. 80%

    2. 60%

    1. 40%

    1. 5%

    2. <1%


    Explanation:

    It is important to know that imaging TCD techniques provide lower velocity measurements than non-imaging TCD techniques (in the same vessel in the same person). On average, one needs to add 15 cm/s to an imaging TCD velocity to convert it to a comparable non-imaging velocity. The STOP criteria cut-offs (e.g., abnormal is 200cm/s or greater) are based on non-imaging TCD. So this boy has an “equivalent” TCD velocity of 205 cm/s, and his risk of stroke over the next 3 years is approximately 40%.

    6. The steady-state hematologic parameters differ among the common forms of sickle cell disease. What is the likely diagnosis of a 10 year-old girl who has the following complete blood count and peripheral smear findings?
    WBC 14,500 /mm3

    Hgb 6.5 g/dL

    Hct 19.5 %

    MCV 88 fL

    Plt 415,000 /mm3

    Retic 17% (absolute 370,000)


    Peripheral smear: polychromasia, irreversibly sickled cells


    1. Sickle-hemoglobin C disease (Hgb SC)

    2. Sickle-+-thalassemia (Hgb S+)

    3. Sickle-0-thalassemia (Hgb S0)

    1. Sickle cell anemia (Hgb SS)

    1. Sickle cell anemia (Hgb SS) with -thalassemia trait


    Explanation:

    The Hgb concentration is typical for a patient with Hgb SS or Hgb S0, but the most likely explanation is Hgb SS because this individual is normocytic. Options b, c, and e would be characterized by microcytosis because of the presence of alpha or beta thalassemia. Hgb SC (option a) is not microcytic, but the Hgb concentration of this case is too low to be consistent with Hgb SC. Also note the leukocytosis and thrombocytosis that is characteristic of severe forms of sickle cell disease, such as Hgb SS.





    1. A family presents to you with a newborn baby who was recently identified by newborn screening to have a form of sickle cell disease. The parents are upset because they were told by their obstetrician that they could not have a baby with sickle cell disease because only the mother had sickle cell trait on pre-conception testing. The father was tested for sickle cell trait pre-conception, and he did not have it.

    Assuming that the results of the sickle trait testing were correct and that the father without sickle cell trait is, indeed, the biological father, what type of hematologic abnormality could the father have that could explain the occurrence of sickle cell disease in their child?




    1. G6PD deficiency

    2. alpha thalassemia trait

    1. beta thalassemia trait

    1. Hereditary elliptocytosis

    2. Hgb G Philadelphia trait


    Explanation:

    Even when only one parent has sickle cell trait, a couple can still produce children with sickle cell disease. They cannot have a child with sickle cell anemia, which is homozygosity for Hgb S, but they can have children with compound heterozygous forms of sickle cell disease, such as sickle-hemoglobin C disease (Hgb SC), sickle-+-thalassemia (Hgb S+), or sickle-0-thalassemia (Hgb S0). A negative test for the presence of sickle hemoglobin (Hgb S) does not exclude the presence of other abnormal hemoglobins or thalassemia trait. G6PD deficiency and hereditary elliptocytosis, both common among African-Americans, do not interact with sickle cell trait to produce a form of sickle cell disease. Alpha thalassemia trait and Hgb G Philadelphia trait are both abnormalities of the alpha globin locus; but the coinheritance of Hgb S with certain other beta globin abnormalities is required to produce forms of sickle disease. Among the possible answers, only beta thalassemia trait is an abnormality of the beta globin. So, the child in question has a form of sickle--thalassemia.





    1. By confirmatory testing, you determine that the mother in question #7 indeed has only sickle cell trait and the father in question #7 has only +-thalassemia trait.

    What is the probability for each of their subsequent pregnancies that the child will have a form of sickle cell disease?




    1. <1%

    1. 25%

    1. 50%

    2. 75%

    3. 100%


    Explanation:

    This is straightforward Mendelian inheritance. If one parent has S trait (AS) and the other has beta+-thalassemia trait (A+), then offspring have a 25% chance of having normal hemoglobin (AA), a 50% chance of having trait (either AS or A+), and a 25% chance of having sickle-+-thalassemia (S+).




    1. Beta thalassemia mutations are classified as null mutations if no globin protein is made from the defective gene. These null mutations are symbolized as 0 (beta zero). In contrast, beta thalassemia mutations that decrease the production of beta globin protein, but do not eliminate it entirely, are called + (beta plus) mutations.

    Assume that the father from questions #7 and #8 has a null mutation beta-thalassemia trait (that is, he has 0-thalassemia trait not +-thalassemia trait). The mother’s genotype remains the same: sickle trait (AS). What is the probability for each of their subsequent pregnancies that the child will have a form of sickle cell disease?




    1. <1%

    1. 25%

    1. 50%

    2. 75%

    3. 100%


    Explanation:

    There is no change to the inheritance pattern. 0 and + alleles are inherited in the same way. If one parent has S trait (AS) and the other has beta0-thalassemia trait (A0), then offspring have a 25% chance of having normal hemoglobin (AA), a 50% chance of having trait (either AS or A0), and a 25% chance of having sickle-0-thalassemia (S0).





    1. A 17 year-old boy with sickle cell trait presents with left-sided flank pain and gross hematuria. A CT scan of the abdomen shows an infiltrating mass of the left kidney that enhances with contrast and the presence of retroperitoneal lymphadenopathy.

    The development of which of the following malignancies is associated with sickle cell trait?




    1. Renal cell carcinoma

    1. Renal medullary carcinoma

    1. Rhabdoid tumor of the kidney

    2. Wilms’ tumor

    3. Clear cell sarcoma of the kidney


    Explanation:

    Sickle cell trait is associated with the development of a rare malignant neoplasm of the kidney called renal medullary carcinoma. It is a highly aggressive and almost always fatal cancer. Almost all reported cases had sickle cell trait or a mild form of sickle cell disease like sickle-hemoglobin C disease. The reason why sickle cell trait may predispose to the development of renal medullary carcinoma is unknown.





    1. Isoelectric focusing (IEF) is a laboratory technique used to separate normal and abnormal hemoglobins.

    Lane 3 of the IEF gel below is consistent with which of the following clinical scenarios?





    1. Normal adult

    2. Beta thalassemia trait

    3. Sickle cell trait

    4. Alpha thalassemia trait
  • 1   2   3   4   5


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