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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor={{Rim}}, {{AJL}} {{Alison}}
|QuestionAuthor= {{YD}} (Reviewed by  {{YD}} and  {{AJL}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Pathophysiology, Pharmacology
|MainCategory=Pathophysiology, Pharmacology
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|MainCategory=Pathophysiology, Pharmacology
|MainCategory=Pathophysiology, Pharmacology
|SubCategory=Hematology
|SubCategory=Hematology
|MainCategory=Pathophysiology, Pharmacology
|MainCategory=Pathophysiology, Pharmacology
|MainCategory=Pathophysiology, Pharmacology
|MainCategory=Pathophysiology, Pharmacology
|MainCategory=Pathophysiology, Pharmacology
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|MainCategory=Pathophysiology, Pharmacology
|MainCategory=Pathophysiology, Pharmacology
|SubCategory=Hematology
|SubCategory=Hematology
|Prompt=A 1-year-old male is brought to the pediatrics outpatient clinic for a four week duration of pallor and excessive sleepiness. His mother reports normal development and feeding habits and physical exam is significant for hepatomegaly and marked pallor. Blood tests demonstrate a hemoglobin level of 7.2 g/dL with microcytosis and anisocytosis. Futher testing reveals a mutation in the ALAS2 gene. Which of the following treatments is most appropriate for this patient?  
|Prompt=A 4-year-old boy is brought to the pediatrics outpatient clinic for a 4-week history of pallor and excessive sleepiness. His mother reports normal development and feeding habits. Physical examination is significant for splenomegaly and marked pallor. Work-up is remarkable for a hemoglobin level of 8.8 g/dL with hypochromia and microcytosis. Futher testing reveals a mutation in the ''ALAS2'' gene. What is the most appropriate strategy for the chronic management of this patient?
|Explanation=[[Sideroblastic anemia]] is an inherited disease in which the bone marrow produces ringed sideroblasts, due to defective hemoglobin synthesis and iron accumulation. Most frequently, [[sideroblastic anemia]] is an X-linked disease. The disease manifests due to a deficiency in ALA synthase, the rate limiting step in heme synthesis, secondary to a mutation in the ALAS2 gene. This decrease in heme synthesis leads to an accumulation of non-heme iron around red blood cells, resulting in a characteristic ringed sideroblasts appearance. [[Sideroblastic anemia]] is usually treated with [[pyridoxine]] (vitamin B6), which is a cofactor in the reaction catalyzed by ALA synthase.
|Explanation=Sideroblastic anemia is a heterogeneous group of disorders characterized by the presence of hypochromic microcytic erythrocytes, ineffective erythropoiesis that causes an increase in iron absorption, and mitochondrial iron accumulation in erythroid precursors of the bone marrow. X-linked sideroblastic anemia is the most common form of the disease; it is a relatively less severe form of sideroblastic anemia that is caused by mutations in the delta-aminolevulinate synthase-2 (ALAS2) gene that encodes ALA synthase, an enzyme that requires pyridoxine (vitamin B6) that catalyzes the first step in heme biosynthesis (condensation of succinyl CoA and glycine to form ALA).  
 
|EducationalObjectives= [[Sideroblastic anemia]] is frequently treated with pyridoxine (vitamin B6), a cofactor in the reaction catalyzed by ALA synthase.
|References= Harris JW. X-linked, pyridoxine-responsive sideroblastic anemia. N Engl J Med. Mar 10 1994;330(10):709-11.


X-linked sideroblastic anemia may present anytime between birth and childhood. Clinical severity ranges from an asymptomatic course with incidental diagnosis to a more severe manifestation of severe pallor, fatigue, and dyspnea. Physical examination may be remarkable for pallor and mild splenomegaly. Work-up usually demonstrates microcytic anemia with an increase in reticulocyte count and elevated serum iron levels. Bone marrow aspirate is helpful and shows characteristic ringed sideroblasts. The diagnosis is confirmed by ALAS2 gene testing. Supportive care is the mainstay of management for patients with X-linked sideroblastic anemia. Patients often require frequent monitoring of hematological and iron profiles with lifetime pyridoxine supplementation. Although pyridoxine is usually helpful for patients with X-linked sideroblastic anemia, Hb levels rarely reach normal levels in these patients but is sufficient to keep patients asymptomatic and not transfusion-dependent. A minority of cases may require phlebotomies or iron chelation therapy to prevent iron overload. Prognosis depends on patient response to pyridoxine and is generally good with a normal life expectancy.
|AnswerA=Chronic transfusions
|AnswerA=Chronic transfusions
|AnswerAExp=Chronic transfusions are frequently used to treat patients with [[thalassemia major]] or other bone marrow failure syndromes.  
|AnswerAExp=Chronic transfusions are frequently used for the management of patients with [[thalassemia major]] or other bone marrow failure syndromes.
|AnswerB=Deferioxamine
|AnswerB=Deferoxamine
|AnswerBExp=[[Deferioxamine]] is frequently used in the treatment of iron overload following chronic transfusions. Although [[sideroblastic anemia]] is associated with iron overload, iron chelation is not the first line of therapy.
|AnswerBExp=[[Deferoxamine]] is frequently used for the management of iron overload due to chronic transfusions. Although [[sideroblastic anemia]] is associated with iron overload due to increased transfusions and increased iron absorption, iron chelation is not usually administered chronically for patients with sideroblastic anemia.
|AnswerC=Pyridoxine
|AnswerC=Vitamin B6
|AnswerCExp=See explanation.
|AnswerCExp=[[X-linked sideroblastic anemia]] is frequently pyrodoxine-responsive. Patients with X-linked sideroblastic anemia are generally managed by daily pyridoxine (vitamin B6) supplementation.
|AnswerD=Folic Acid and Vitamin B12
|AnswerD=Vitamin B12
|AnswerDExp=Folic Acid and Vitamin B12 are frequently administered to treat [[megaloblastic anemia]].
|AnswerDExp=Vitamin B12 supplementation is used to manage [[megaloblastic anemia]] due to vitamin B12 deficiency.
|AnswerE=Iron replacement
|AnswerE=Iron replacement
|AnswerEExp=Iron replacement is frequently used to treat patients with [[iron deficiency anemia]].
|AnswerEExp=Iron replacement is required for patients with [[iron deficiency anemia]].
|EducationalObjectives=[[X-linked sideroblastic anemia]] is frequently pyrodoxine-responsive. Patients with X-linked sideroblastic anemia are generally managed by daily pyridoxine (vitamin B6) supplementation.
|References=Harris JW. X-linked, pyridoxine-responsive sideroblastic anemia. N Engl J Med. 1994;330(10):709-11.<br>
Cotter PD, Rucknagel DL, Bishop DF. X-linked sideroblastic anemia: identification of the mutation in the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) in the original family described by Cooley. Blood. 1994;84:3915-24.<br>
First Aid 2014 page 383
|RightAnswer=C
|RightAnswer=C
|WBRKeyword=Sideroblastic anemia, Pyridoxine, Vitamin B6, anemia, genetics, X-linked, pattern of inheritance, inheritance, genome, hemoglobin synthesis, pallor
|WBRKeyword=Sideroblastic anemia, Pyridoxine, Vitamin B6, Anemia, Pallor, X-linked, X-linked sideroblastic anemia
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 00:43, 28 October 2020

 
Author [[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Yazan Daaboul, M.D. and Alison Leibowitz [1])]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Pathophysiology, MainCategory::Pharmacology
Sub Category SubCategory::Hematology
Prompt [[Prompt::A 4-year-old boy is brought to the pediatrics outpatient clinic for a 4-week history of pallor and excessive sleepiness. His mother reports normal development and feeding habits. Physical examination is significant for splenomegaly and marked pallor. Work-up is remarkable for a hemoglobin level of 8.8 g/dL with hypochromia and microcytosis. Futher testing reveals a mutation in the ALAS2 gene. What is the most appropriate strategy for the chronic management of this patient?]]
Answer A AnswerA::Chronic transfusions
Answer A Explanation [[AnswerAExp::Chronic transfusions are frequently used for the management of patients with thalassemia major or other bone marrow failure syndromes.]]
Answer B AnswerB::Deferoxamine
Answer B Explanation [[AnswerBExp::Deferoxamine is frequently used for the management of iron overload due to chronic transfusions. Although sideroblastic anemia is associated with iron overload due to increased transfusions and increased iron absorption, iron chelation is not usually administered chronically for patients with sideroblastic anemia.]]
Answer C AnswerC::Vitamin B6
Answer C Explanation [[AnswerCExp::X-linked sideroblastic anemia is frequently pyrodoxine-responsive. Patients with X-linked sideroblastic anemia are generally managed by daily pyridoxine (vitamin B6) supplementation.]]
Answer D AnswerD::Vitamin B12
Answer D Explanation [[AnswerDExp::Vitamin B12 supplementation is used to manage megaloblastic anemia due to vitamin B12 deficiency.]]
Answer E AnswerE::Iron replacement
Answer E Explanation [[AnswerEExp::Iron replacement is required for patients with iron deficiency anemia.]]
Right Answer RightAnswer::C
Explanation [[Explanation::Sideroblastic anemia is a heterogeneous group of disorders characterized by the presence of hypochromic microcytic erythrocytes, ineffective erythropoiesis that causes an increase in iron absorption, and mitochondrial iron accumulation in erythroid precursors of the bone marrow. X-linked sideroblastic anemia is the most common form of the disease; it is a relatively less severe form of sideroblastic anemia that is caused by mutations in the delta-aminolevulinate synthase-2 (ALAS2) gene that encodes ALA synthase, an enzyme that requires pyridoxine (vitamin B6) that catalyzes the first step in heme biosynthesis (condensation of succinyl CoA and glycine to form ALA).

X-linked sideroblastic anemia may present anytime between birth and childhood. Clinical severity ranges from an asymptomatic course with incidental diagnosis to a more severe manifestation of severe pallor, fatigue, and dyspnea. Physical examination may be remarkable for pallor and mild splenomegaly. Work-up usually demonstrates microcytic anemia with an increase in reticulocyte count and elevated serum iron levels. Bone marrow aspirate is helpful and shows characteristic ringed sideroblasts. The diagnosis is confirmed by ALAS2 gene testing. Supportive care is the mainstay of management for patients with X-linked sideroblastic anemia. Patients often require frequent monitoring of hematological and iron profiles with lifetime pyridoxine supplementation. Although pyridoxine is usually helpful for patients with X-linked sideroblastic anemia, Hb levels rarely reach normal levels in these patients but is sufficient to keep patients asymptomatic and not transfusion-dependent. A minority of cases may require phlebotomies or iron chelation therapy to prevent iron overload. Prognosis depends on patient response to pyridoxine and is generally good with a normal life expectancy.
Educational Objective: X-linked sideroblastic anemia is frequently pyrodoxine-responsive. Patients with X-linked sideroblastic anemia are generally managed by daily pyridoxine (vitamin B6) supplementation.
References: Harris JW. X-linked, pyridoxine-responsive sideroblastic anemia. N Engl J Med. 1994;330(10):709-11.
Cotter PD, Rucknagel DL, Bishop DF. X-linked sideroblastic anemia: identification of the mutation in the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) in the original family described by Cooley. Blood. 1994;84:3915-24.
First Aid 2014 page 383]]

Approved Approved::Yes
Keyword WBRKeyword::Sideroblastic anemia, WBRKeyword::Pyridoxine, WBRKeyword::Vitamin B6, WBRKeyword::Anemia, WBRKeyword::Pallor, WBRKeyword::X-linked, WBRKeyword::X-linked sideroblastic anemia
Linked Question Linked::
Order in Linked Questions LinkedOrder::