WBR0150

Author	PageAuthor::William J Gibson
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Hematology, SubCategory::Musculoskeletal/Rheumatology
Prompt	[[Prompt::A 7-year-old male presents to his pediatrician with fatigue and pallor. The patient recently emigrated from Greece and his parents report that he has a long history of “sickliness”. When he became very ill in the past he was taken to the hospital and given a blood transfusion. Complete blood count shows a hemoglobin of 5.7 g/dL, white blood cell count of 12.7x109 /L. platelet count of 250 x 109 /L, and mean corpuscular volume of 70. The child is unusually small and has a pronounced forehead. A radiograph of the skull is shown below. What is the most likely type of mutation that is responsible for this patient’s disease? ]]
Answer A	AnswerA::Splice site mutation
Answer A Explanation	AnswerAExp::Beta thalassemia is most often caused by splice site mutations in the beta globin gene.
Answer B	AnswerB::Nonsense mutation
Answer B Explanation	[[AnswerBExp::Beta thalassemia is most often caused by splice site mutations in the beta globin gene. Nonsense mutations introduce a premature stop codon in the gene. An example of a disorder caused by germline nonsense mutations is Duchenne Muscular Dystrophy.]]
Answer C	AnswerC::Missense mutation
Answer C Explanation	AnswerCExp::Beta thalassemia is most often caused by splice site mutations in the beta globin gene. An example of a disorder caused by germline nonsense mutations is Becker Muscular Dystrophy.
Answer D	AnswerD::Gene deletion
Answer D Explanation	AnswerDExp::Beta thalassemia is most often caused by splice site mutations in the beta globin gene. An example of a disorder caused by deletions is Duchenne Muscular Dystrophy.
Answer E	AnswerE::Gene silencing
Answer E Explanation	AnswerEExp::Beta thalassemia is most often caused by splice site mutations in the beta globin gene. Gene silencing is most often achieved by methylation of the gene promoter. An example of a disorder caused by gene silencing is Prader-Wili syndrome.
Right Answer	RightAnswer::A
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 Mediterranean 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 often progresses to death before age 20. A hallmark feature of beta thalassemia major 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-induced iron overload with chelation therapy. Cure is possible only by bone marrow transplantation. Educational Objective: Beta Thalassemia is caused by splice site mutations in the beta-globin gene. References: First Aid 2014 page 383]]
Approved	Approved::Yes
Keyword	WBRKeyword::Blood, WBRKeyword::Hematology, WBRKeyword::Genetics, WBRKeyword::Thalassemia, WBRKeyword::Beta thalassemia, WBRKeyword::Transfusion, WBRKeyword::Iron, WBRKeyword::Mutation
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::