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ACVK
89393
available to dimerize with a HIF-beta subunit. The heterodimer then induces transcription of many
hypoxia response genes including EPO, VEGF, and GLUT1. HIF-alpha is regulated by von
Hippel-Lindau (vHL) protein-mediated ubiquitination and proteosomal degradation, which requires prolyl
hydroxylation of HIF proline residues. The HIF-alpha subunit is encoded by the HIF2A(EPAS1) gene.
HIF2A is officially known as EPAS1 (endothelial PAS domain protein 1). Enzymes important in the
hydroxylation of HIF-alpha are the prolyl hydroxylase domain proteins, of which the most significant
isoform is PHD2, which is encoded by the EGLN1 gene. Mutations resulting in altered HIF-alpha, PHD2,
and vHL proteins can lead to clinical erythrocytosis. Truncating mutations in the EPOR gene coding for
the erythropoietin receptor can result in erythrocytosis through loss of the negative regulatory cytoplasmic
SHP-1 binding domain leading to Epo hypersensitivity. All currently known mutations have been
localized to exon 8, are mainly missense or small deletions/insertions resulting in stop codons, and are
heterozygous. EPOR mutations are associated with decreased to normal Epo levels and normal p50 values
(see Table).
Useful For: The definitive evaluation of an individual with JAK2-negative erythrocytosis associated
with lifelong sustained increased RBC mass, elevated RBC count, hemoglobin, or hematocrit
Interpretation: An interpretive report will be provided and will include specimen information, assay
information, and whether the specimen was positive for any mutations in the gene. If positive, the
mutation will be correlated with clinical significance, if known.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Patnaik MM, Tefferi A: The complete evaluation of erythrocytosis:
congenital and acquired. Leukemia 2009 May;23(5):834-844 2. McMullin MF: The classification and
diagnosis of erythrocytosis. Int J Lab Hematol 2008;30:447-459 3. Percy MJ, Lee FS: Familial
erythrocytosis: molecular links to red blood cell control. Haematologica 2008 Jul;93(7):963-967 4. Huang
LJ, Shen YM, Bulut GB: Advances in understanding the pathogenesis of primary familial and congenital
polycythaemia. Br J Haematol 2010 Mar;148(6):844-852 5. Maran J, Prchal J: Polycythemia and oxygen
sensing. Pathologie Biologie 2004;52:280-284 6. Lee F: Genetic causes of erythrocytosis and the
oxygen-sensing pathway. Blood Rev 2008;22:321-332 7. Merchant SH, Oliveira JL, Hoyer JD,
Viswanatha DS: Erythrocytosis. In Hematopathology. Second edition. Edited by ED His. Philadelphia,
Elsevier Saunders, 2012, pp 22-723 8. Zhuang Z, Yang C, Lorenzo F, et al: Somatic HIF2A
gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 2012 Sep
6;367(10):922-930
Hereditary Hemorrhagic Telangiectasia, ACVRL1 Gene, Known
Mutation
Clinical Information: Hereditary hemorrhagic telangiectasia (HHT), also known as
Osler-Weber-Rendu syndrome, is an autosomal dominant vascular dysplasia characterized by the
presence of arteriovenous malformations (AVMs) of the skin, mucosa, and viscera. Small AVMs, or
telangiectasias, develop predominantly on the face, oral cavity, and/or hands, and spontaneous, recurrent
epistaxis (nosebleeding) is a common presenting sign. Symptomatic telangiectasias occur in the
gastrointestinal tract of about 30% of HHT patients. Additional serious complications associated with
HHT include transient ischemic attacks, embolic stroke, heart failure, cerebral abscess, massive
hemoptysis, massive hemothorax, seizure, and cerebral hemorrhage. These complications are a result of
larger AVMs, which are most commonly pulmonary, hepatic, or cerebral in origin, and occur in
approximately 30%, 40%, and 10% of individuals with HHT, respectively. HHT is inherited in an
autosomal dominant manner; most individuals have an affected parent. HHT occurs with wide ethnic and
geographic distribution, and it is significantly more frequent than formerly thought. It is most common in
Caucasians, but it occasionally occurs in Asians, Africans, and individuals of Middle Eastern descent. The
overall incidence of HHT in North America is estimated to be between 1:5,000 and 1:10,000. Penetrance
seems to be age related, with increased manifestations occurring over oneâ€s lifetime. For example,
approximately 50% of diagnosed individuals report having nosebleeds by age 10 years, and 80% to 90%
by age 21 years. As many as 90% to 95% of affected individuals eventually develop recurrent epistaxis.
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