WBR0485

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::Pathology, MainCategory::Pathophysiology
Sub Category	SubCategory::Hematology
Prompt	[[Prompt::An 7-month-old boy is brought to an outpatient hematology department with severe pallor. The patient has been admitted to the hospital multiple times for similar symptoms and has received multiple blood transfusions since he was 4 years old. The mother explains that the patient is a product of a normal vaginal delivery with no neonatal complications and normal growth. Physical examination is remarkable for pallor and mild splenomegaly. Blood work-up is significant for Hb= 6.7 g/dL, Hct= 19.8 %, and MCV=72 fL. Findings on bone marrow aspirate are shown below. Which of the following disorders is most likely associated with the patient's condition? ]]
Answer A	AnswerA::Alpha globin gene mutation
Answer A Explanation	[[AnswerAExp::Alpha globin gene mutations are observed in alpha-thalassemia.]]
Answer B	AnswerB::Beta-globin gene mutation
Answer B Explanation	[[AnswerBExp::Beta chain mutations are observed in beta-thalassemia.]]
Answer C	AnswerC::''ALAS2'' mutation
Answer C Explanation	[[AnswerCExp::X-linked sideroblastic anemia is an inherited disease caused by a mutation in the ALAS2 gene that encodes ALA synthase enzyme.]]
Answer D	AnswerD::''Spectrin'' and ''ankyrin'' mutations
Answer D Explanation	[[AnswerDExp::Spectrin and ankyrin mutations are frequently observed in hereditary spherocytosis (HS). Peripheral smear of patients with HS have red blood cells with loss of central pallor.]]
Answer E	AnswerE::''G6PD'' mutation
Answer E Explanation	[[AnswerEExp::G6PD gene mutation results in glucose-6-phosphate dehydrogenase (G6PD) deficiency that causes a decrease in glutathione and an increased susceptibility to oxidant stress. Patients present with back pain, dark-colored urine, and severe pallor following exposure to triggers, such as fava beans intake, infections, or drugs. Labs typically demonstrate anemia and hemoglobinuria. Peripheral smear shows RBCs with Heinz bodies and bite cells.]]
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). ALAS is physiologically present in 2 isozymes: The first isozyme is a housekeeping enzyme (ALAS1), while the second is an erythroid-specific enzyme (ALAS2). X-linked sideroblastic anemia may present anytime between birth and 9 years of age. 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. Rarely do patients with X-linked sideroblastic anemia have glucose intolerance and skin hyperpigmentation. 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 (shown below) with Prussian blue staining (staining involves a non-enzymatic reaction of ferrous iron with ferrocyanide that forms ferric-ferrocyanide). 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. 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. In contrast, congenital sideroblastic anemia is another unique form of sideroblastic anemia that has an autosomal recessive disorder pattern of inheritance, presents early during infancy, and is not pyridoxine-responsive. Acquired sideroblastic anemia is often associated with myelodysplastic syndromes. Educational Objective: X-linked sideroblastic anemia is an inherited disease caused by a mutation in the ALAS2 gene, which encodes ALA synthase enzyme. References: 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. Gupta SK, Rao S, Kar R, Tyagi S, Pati HP. Congenital sideroblastic anemia: A report of two cases. Indian J Pathol Microbiol 2009;52:424-6 Harris JW. X-linked, pyridoxine-responsive sideroblastic anemia. N Engl J Med. 1994;330(10):709-11. First Aid 2014 page 383]]
Approved	Approved::Yes
Keyword	WBRKeyword::Sideroblastic anemia, WBRKeyword::Sideroblasts, WBRKeyword::ALA synthase mutation, WBRKeyword::Blood smear, WBRKeyword::Bone marrow aspirate, WBRKeyword::X-linked, WBRKeyword::Pallor, WBRKeyword::Anemia, WBRKeyword::Pyridoxine, WBRKeyword::X-linked sideroblastic anemia
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::