WBR0151

Author	PageAuthor::William J Gibson
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Gastrointestinal, SubCategory::Hematology
Prompt	[[Prompt::A 1 year old boy is evaluated for a well-child exam. The parents report that their child has appeared listless and disengaged. He has failed to begin sitting on his own and responds poorly to verbal cues. The pediatrician notes that the patient is extremely pale. A complete blood count demonstrates a severe microcytic anemia. Hemoglobin electrophoresis showed 95% fetal hemoglobin and 5% hemoglobin alpha 2. HbS and adult hemoglobin were negative. Treatment for this child’s condition is most likely to cause symptoms most similar to the genetic disease caused by mutations in which of the following?]]
Answer A	AnswerA::JAK2 gene
Answer A Explanation	AnswerAExp::'''Incorrect''' – activating mutations in JAK2 cause polycythemia vera
Answer B	AnswerB::Alpha-aminolevulinic acid synthase gene
Answer B Explanation	AnswerBExp::'''Incorrect''' – mutations in the alpha-aminolevulinic acid synthase gene cause a sideroblastic anemia.
Answer C	AnswerC::HFE gene
Answer C Explanation	AnswerCExp::'''Correct''' – HFE mutations cause hereditary hemochromatosis. Frequent transfusions for beta-thalassemia can cause hemochromatosis.
Answer D	AnswerD::Porphobilinogen deaminase
Answer D Explanation	AnswerDExp::'''Incorrect''' – These mutations cause acute intermittent porphyria.
Answer E	AnswerE::ADAMTS13
Answer E Explanation	AnswerEExp::'''Incorrect''' – Antibodies against ADAMTS13 cause thrombotic thrombocytopenic purpura.
Right Answer	RightAnswer::C
Explanation	[[Explanation::The patient in this vignette is suffering from beta-thalassemia major. Beta thalassemia is most often caused by splice site mutations in the beta-globin gene and is prevalent in mediterannean populations. If both alleles of the beta globin gene have thalassemia mutations, beta thalassemia major is diagnosed. This is a severe microcytic, hypochromic anemia. Untreated, it causes anemia, splenomegaly, and severe bone deformities. It progresses to death before age 20. A hallmark feature of the disease is the “buzz cut” or “hair on end” appearance of the skull on X-ray. This increased spiky opacity is caused by bone marrow expansion in response to chronic anemia. (extramedullary hematopoeisis). Treatment consists of periodic blood transfusion; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Transfusion associated hemochromatosis is a serious complication of beta-thalassemia, but can be managed with iron chelators such as deferoxamine. Mutations of the HFE gene cause a hereditary form of hemochromatosis. Cure is possible by bone marrow transplantation. Educational Objective: Transfusion associated hemochromatosis is a serious complication of beta-thalassemia, but can be managed with iron chelators such as deferoxamine. Mutations of the HFE gene cause a hereditary form of hemochromatosis. References: First Aid 2012 page 381 Educational Objective: References: ]]
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