WBR0218
| Author | [[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]] |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Genetics |
| Sub Category | SubCategory::Hematology |
| Prompt | [[Prompt::A 2-year-old African-American girl is brought to the emergency department by her father. The girl is continuously crying in pain. On physical examination, the patient's extremities are warm, edematous, and tender to palpation. X ray of the patient's hands and feet reveals tissue swelling but no bony abnormalities. Further questioning reveals that the child is the product of a consanguineous marriage. The patient is then admitted for management with intravenous saline and analgesic agents. Which of the following genetic alterations is most likely responsible for this patient’s condition?]] |
| Answer A | AnswerA::Nonsense mutation |
| Answer A Explanation | [[AnswerAExp::Nonsense mutations refer to the inappropriate insertion of a stop codon resulting in a shortened non-functional protein. An example of a disease caused by a nonsense mutation is Duchenne muscular dystrophy.]] |
| Answer B | AnswerB::Mosaic mutation |
| Answer B Explanation | AnswerBExp::Mosaicism denotes the presence of two or more populations of cells with different genotypes. These genotypes are all present in one individual who has developed from a single fertilized egg. |
| Answer C | AnswerC::Missense mutation |
| Answer C Explanation | AnswerCExp::Sickle cell anemia is caused by a missense mutation in the β-globin gene. |
| Answer D | AnswerD::Splice-site mutation |
| Answer D Explanation | [[AnswerDExp::Splice site mutations interfere with the normal splicing of pre-mRNA to mature mRNA, resulting in a non-functional protein product. An example of a disorder associated with splice-site mutations is β-thalassemia.]] |
| Answer E | AnswerE::Imprinting |
| Answer E Explanation | [[AnswerEExp::Imprinting refers to the allele specific expression of a gene or set of genes. An example of a disorder associated with imprinting is Prader-Willi syndrome.]] |
| Right Answer | RightAnswer::C |
| Explanation | [[Explanation::Sickle cell anemia (SCA) is an autosomal recessive genetic disorder caused by a missense mutation of the β-globin gene (substitution of the normal hydrophilic glutamic acid (GTG) with a hydrophobic valine (GAG) at the 6th position of the β-globin chain). Since valine on different globin chains has the capacity to dock complementary sites, the hydrophobic motif caused by the missense mutation in the deoxygenated HbS tetramer allows the polymerization of HbS by binding 2 hemoglobin molecules at the level of the mutated β-1 and β-2 chains. Binding of these molecules produces polymer nuclei that grow and disrupt the cellular morphology, resulting in cellular dehydration and oxidative stress. The presence of 3 factors determine the rate and severity of Hbs polymerization: Hb deoxygenation, intracellular HbS concentration, and presence of fetal hemoglobin (HbF) in the RBC.
SCA is thus characterized by the abnormal presence of rigid, sickle-shaped RBC. The abnormal RBCs obstruct capillaries and restrict blood flow to an organ, resulting in ischemia, pain, necrosis, and organ damage. Clinical manifestations of SCA are usually not present until the concentration of HbF diminishes beyond infancy. The child in this vignette is suffering from dactylitis, which is often described as the presenting symptom of sickle cell disease. Hand-foot-syndrome due to dactylitis causes painful swelling of the hands and/or feet; it usually affects young children < 3 years of age. Patients eventually develop more complications from vaso-occlusive crises: acute chest syndrome (hypoxia-driven, pneumonia-like illness with fever, respiratory symptoms, and infiltrates on chest x-ray due to vaso-occlusion and/or infections), avascular necrosis of bone, acute abdomen (mesenteric vessel occlusion), splenic disease (splenic sequestration, hyposplenism, and autosplenectomy), renal disease (papillary necrosis), aplastic crises with parvovirus B19 infection, priapism, severe osteomyelitis (commonly due to S. aureus but classically associated with Salmonella spp.), and finally cerebrovascular events (ischemic strokes). SCA is common in Africa and some regions of the Middle East. Diagnosis of SCA is usually by hemoglobin electrophoresis or chromatography. Treatment includes chronic hydroxyurea therapy that increases the concentration of HbF, provides symptomatic relief, and decreases the frequency and intensity of complications. Patients do not regularly require transufsions as patients with β-thalassemia do, but acute transfusions in SCA may only be required for acute exacerbations of anemia, severe acute chest syndrome, stroke, and in cases of multiorgan failure. Bone marrow transplant is the only curative treatment for patients with SCA. It is important to distinguish different terms that are related to sickle cell anemia:
Educational Objective: Sickle cell anemia (SCA) is an autosomal recessive genetic disorder caused by a missense mutation of the β-globin gene (substitution of the normal hydrophilic glutamic acid (GTG) with a hydrophobic valine (GAG) at the 6th position of the β-globin chain). |
| Approved | Approved::Yes |
| Keyword | WBRKeyword::Anemia, WBRKeyword::Sickle cell anemia, WBRKeyword::Sickle cell, WBRKeyword::Sickle cell disease, WBRKeyword::Mutation, WBRKeyword::Hemoglobinopathy, WBRKeyword::Missense mutation, WBRKeyword::Dactylitis, WBRKeyword::HbS, WBRKeyword::HbSS |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |