WBR0097

Author	[[PageAuthor::William J Gibson (reviewed by Rim Halaby, M.D. [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics, MainCategory::Histology
Sub Category	SubCategory::Hematology
Prompt	[[Prompt::A 3-week-old infant is brought to the pediatric emergency department (ED) by his mother for abdominal colics and yellowish skin that first appeared 2 days ago. The mother reports the patient is a product of an uncomplicated normal vaginal delivery and his neonatal course was uneventful. He is currently receiving formula milk. In the ED, physical examination is remarkable for jaundiced skin and icterus; his spleen is soft, non-tender, and easily palpable 4 cm below the left costal margin. Laboratory values reveal decreased RBC count and unconjugated hyperbilirubinemia. A peripheral blood smear from the patient is shown below. Which of the following is most likely responsible for this infant's condition? ]]
Answer A	AnswerA::Mutation of glutamic acid to valine in the beta globin gene
Answer A Explanation	[[AnswerAExp::A missense mutation of the sixth amino acid of the beta-globin gene to valine causes sickle cell anemia. Beta-globin mutations are not associated with hereditary spherocytosis.]]
Answer B	AnswerB::Mutation of three copies of the alpha-globin gene
Answer B Explanation	[[AnswerBExp::Mutation of three copies of the alpha-globin gene would cause the hemoglobin H disease variant of alpha thalassemia.]]
Answer C	AnswerC::Mutation of ankyrin
Answer C Explanation	[[AnswerCExp::Ankyrin mutations are the most common genetic lesion of hereditary spherocytosis. Ankyrin normally serves as the binding partner for spectrin that allows spectrin to be incorporated into cell membranes. Ankyrin deficiency therefore causes a decrease in spectrin localization to the RBC membrane.]]
Answer D	AnswerD::Mutation of spectrin
Answer D Explanation	[[AnswerDExp::Spectrin deficiency is common to all forms of hereditary spherocytosis. However, spectrin deficiency is more often secondary to ankyrin mutations than to spectrin mutations.]]
Answer E	AnswerE::Nonsense mutation in the beta-globin gene
Answer E Explanation	[[AnswerEExp::Nonsense mutations of the beta-globin gene cause beta-thalassemia. A missense mutation of the sixth amino acid of the beta-globin gene to valine causes sickle cell anemia. Beta-globin mutations are not associated with hereditary spherocytosis.]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::The patient in this vignette is most likely suffering from hereditary spherocytosis. Hereditary sphereocytosis is an autosomal dominant condition that causes an hemolytic anemia. It is characterized by the production of red blood cells that are sphere-shaped rather than bi-concave disk shaped (donut-shaped), and therefore more prone to hemolysis. These patients will have a microcytic anemia with an increased mean corpuscular hemoglobin concentration (MCHC). On blood smear, Howell-Jolly bodies may be seen within red blood cells. Signs and symptoms include anemia, jaundice, and an enlarged spleen (splenomegaly). Acute cases can cause hypoxia through anemia and acute kernicterus through hyperbilirubinemia, particularly in newborns. Most cases can be detected soon after birth. The number of immature red blood cells (reticulocyte count) will be elevated. Hereditary spherocytosis is caused by a variety of molecular defects in the genes that code for spectrin (alpha and beta), ankyrin, band 3 protein, protein 4.2, and other erythrocyte membrane proteins. Mutations in ankyrin are the most common and are expected to account for approximately 35 to 65 percent of patients. The most common diagnostic test for hereditary spherocytosis is the osmotic fragility test. Patients with hereditary spherocytosis tend to have acute exacerbation of the disease with viral infection. In particular, these patients may develop aplastic anemia with Parvovirus B19 infection. Educational Objective: Hereditary spherocytosis is caused by mutations in the ankyrin and spectrin genes. Ankyrin mutations are the more common of the two. References: First Aid 2014 page 386 ; First Aid 2012 page 384 Eber SW, Gonzalez JM, Lux ML, et al. Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis. Nat Genet. 1996;13(2):214-8.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Hematology, WBRKeyword::Genetics, WBRKeyword::Hereditary spherocytosis, WBRKeyword::Spherocytosis, WBRKeyword::RBC, WBRKeyword::WJG
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::