Familial Polycythemia Likely Due to Novel Hemoglobin Variant Hemoglobin Hyden

Adult hemoglobin (HbA) is made up of two pairs of globin chains. Some rare mutations of the globin chains can result in high affinity towards hemoglobin molecule thus changing the equilibrium of normal oxygen loading in lungs and the delivery of same to the tissues. Because of change in the affinity to the oxygen these mutations can result in erythrocytosis (polycythemia). Here we discuss a case of Familial Polycythemia likely due to novel hemoglobin variant.

42-year Caucasian male presents to the clinic with high hemoglobin for several years but otherwise denies any symptoms of headache, vision changes, chest pain. He had history of multiple phlebotomies. His past medical history is significant for Polycythemia, PICC line associated clot, Type2 Diabetes, Hypertension, Epidural abscess. Social history is significant for smokeless tobacco but otherwise non-smoker, non-alcoholic, not an IVDA and doesn't use testosterone. Family history is significant for his sister, her two 14year old daughters and multiple other family members with elevated hemoglobin and undergoes phlebotomies, maternal grandfather died of cancer in his 30s.

Physical examination is only significant for BMI of 32.46 otherwise no skin discoloration or cyanosis. Laboratory data WBC 9.4 with normal differential, hemoglobin 18.2, hematocrit 55.4, platelet count 180,000, peripheral blood smear was within normal limits, negative for JAK-2, normal erythropoietin, negative for hemochromatosis, Oxygen dissociation p50 of 19 which is low indicating left shifted dissociation curve, hemoglobin electrophoresis HbA: 61.2%, HbA2: 3%, HbF: 0%, Beta variant: 35.8%. In order to further characterize beta variant Bidirectional sequence analysis for Molecular alterations was performed and the following alterations were detected Gene: HBB, DNA change: Codon 39, heterozygous CAG>CCG Protein change: P.G1n39Pro. [glutamine (Q) to proline (P)]. HGVS: c.119A>C, p.Q40P, Classification: Likely deleterious variant. (GenBank accession number NM_000518.4).

This is a previously unreported beta chain hemoglobin variant present. This hemoglobin variant is named as Hemoglobin Hyden based on the place where this is found in Hyden, Kentucky. There have been four variants reported at codon 40 of the beta globin gene, which is an external contact site between beta globin and alpha-2 globin. One variant, Hb vassa, is associated with mild hemolytic anemia. The three other variants (Hb Alabama, Hb Tianshui and Hb San Bruno) are not associated with clinical or hematological abnormalities. In our opinion p.Q40P is likely a cause of erythrocytosis as the same mutation is found in atleast three other patients with polycythemia who are unrelated but all of them presenting from same county. In order to further establish the causality it may be beneficial to test first degree relatives in this family in order to determine whether the p.Q40P alteration tracks with disease and is not present in unaffected individuals.

Hemoglobin threshold for phlebotomy to lower the risk of thrombosis and cardiovascular events is yet to be defined.