A 62-year-old man presents to the clinic with a 4-month history of generalized pruritus that is significantly worse after taking a hot shower. He also reports intermittent headaches, dizziness, and a full sensation in his left upper abdomen. Past medical history is negative, and he does not take any medications. Vital signs are within normal limits. On physical examination, his face appears plethoric, and his spleen is palpable 4 cm below the left costal margin.
Laboratory studies show the following:
Hemoglobin: 19.5 g/dL
Hematocrit: 60%
Platelet count: 480,000/μL
White blood cell count: 13,500/μL
Erythropoietin (EPO) level: Low
Which of the following genetic mutations is most likely responsible for this patient’s condition?
The correct answer is:
B) JAK2 V617F point mutation
This patient is presenting with polycythemia vera (PV), a chronic myeloproliferative neoplasm characterized by the autonomous overproduction of all three myeloid lineages (erythrocytic, granulocytic, and megakaryocytic), though erythrocytosis is the most prominent feature. The underlying molecular defect in >95% of PV cases is a somatic point mutation in the Janus kinase 2 (JAK2) gene, most commonly the V617F mutation. This mutation occurs in the pseudokinase domain and leads to constitutive tyrosine kinase activity. As a result, hematopoietic stem cells become hypersensitive to growth factors, allowing for red blood cell production even when erythropoietin (EPO) levels are low. Classic clinical clues for PV include the following:
Aquagenic pruritus: Itching after a hot bath/shower due to mast cell degranulation.
Hyperviscosity symptoms: Headaches, dizziness, and visual disturbances due to sludging of thick blood.
Erythromelalgia: Burning pain and redness in the hands and feet caused by microvascular occlusion.
Thrombotic risk: Increased risk of hepatic vein thrombosis (Budd-Chiari syndrome) and strokes.
Answer choice A: CALR (calreticulin) insertion/deletion, is incorrect. While CALR insertion/deletion is common in other myeloproliferative neoplasms like essential thrombocythemia (ET) and primary myelofibrosis (PMF), it are virtually never seen in polycythemia vera.
Answer choice C: MPL (thrombopoietin receptor) mutation, is incorrect. While. MPL mutation occurs in other myeloproliferative neoplasms like essential thrombocythemia (ET) and primary myelofibrosis (PMF), it are virtually never seen in polycythemia vera.
Answer choice D: t(9;22) translocation involving BCR-ABL1, is incorrect. This is the Philadelphia chromosome characteristic of chronic myelogenous leukemia (CML). While CML is a myeloproliferative disorder, it is defined by a left shift in white cells and does not typically present with isolated erythrocytosis and low EPO.
Answer choice E: t(15;17) translocation involving PML-RARA, is incorrect. This is the hallmark of acute promyelocytic leukemia (APL), which presents with life-threatening disseminated intravascular coagulation (DIC) and pancytopenia rather than a high red cell mass.
Key Learning Point
Polycythemia vera is a stem cell disorder driven by a JAK2 mutation that makes erythroid precursors independent of erythropoietin. Diagnosis is based on high hemoglobin and hematocrit, low serum erythropoietin (EPO), and the presence of the JAK2 mutation. The mainstay of treatment is phlebotomy to keep the hematocrit <45% and low-dose aspirin to reduce thrombotic risk.
