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Test ID: HEMP    
Hereditary Erythrocytosis Mutations

Useful For Suggests clinical disorders or settings where the test may be helpful

The definitive evaluation of an individual with JAK2-negative erythrocytosis associated with lifelong sustained increased RBC mass, elevated RBC count, hemoglobin, or hematocrit

Genetics Test Information Provides information that may help with selection of the correct test or proper submission of the test request

This test is a third-order test and should be ordered when the patient meets the following criteria: diagnosis of erythrocytosis, JAK2 V627F is negative, and p50 values are normal.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Erythrocytosis (increased RBC mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (polycythemia vera: PV), or secondary, in response to increased serum erythropoietin (Epo) levels. Secondary erythrocytosis is associated with a number of disorders including chronic lung disease, chronic increase in carbon monoxide (due to smoking), cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other Epo-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory mechanisms may be suspected.

 

Unlike polycythemia vera, hereditary erythrocytosis is not associated with the risk of clonal evolution and should present with isolated erythrocytosis that has been present since birth. A subset of cases are associated with pheochromocytoma and/or paraganglioma formation later in life. It is caused by mutations in several genes and may be inherited in either an autosomal dominant or autosomal recessive manner. A family history of erythrocytosis would be expected in these cases, although it is possible for new mutations to arise in an individual.

 

The genes coding for hemoglobin, beta globin and alpha globin (high-oxygen-affinity hemoglobin variants), hemoglobin-stabilization proteins (2,3 bisphosphoglycerate mutase: BPGM), and the erythropoietin receptor, EPOR, and oxygen-sensing pathway enzymes (hypoxia-inducible factor: HIF/EPAS1, prolyl hydroxylase domain: PHD2/EGLN1, and von Hippel Lindau: VHL) can result in hereditary erythrocytosis (see Table). High-oxygen-affinity hemoglobin variants and BPGM abnormalities result in a decreased p50 result, whereas those affecting EPOR, HIF, PHD, and VHL have normal p50 results. The true prevalence of hereditary erythrocytosis causing mutations is unknown. A subset of hereditary erythrocytosis mutations are associated with subsequent pheochromocytoma/paragangliomas.

 

Table. Erythrocytosis Testing

Gene

Inheritance

Serum Epo

p50

JAK2 V617F

Acquired

Decreased

Normal

JAK2 exon 12

Acquired

Decreased

Normal

EPOR

Dominant

Decreased to normal level

Normal

PHD2/EGLN1

Dominant

Normal level

Normal

BPGM

Recessive

Normal level

Decreased

Beta Globin

Dominant

Normal level to increased

Decreased

Alpha Globin

Dominant

Normal level to increased

Decreased

HIF2A/EPAS1

Dominant

Normal level to increased

Normal

VHL

Recessive

Markedly Increased

Normal

 

The oxygen-sensing pathway functions through an enzyme, hypoxia-inducible factor (HIF) that regulates RBC mass. A heterodimer protein comprised of alpha and beta subunits, HIF functions as a marker of depleted oxygen concentration. When present, oxygen becomes a substrate mediating HIF-alpha subunit degradation. In the absence of oxygen, degradation does not take place and the alpha protein component is 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).

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

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.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This test does not provide a serum erythropoietin (Epo) level. If Epo testing is desired, see EPO / Erythropoietin (EPO), Serum.

 

Polycythemia vera and acquired causes of erythrocytosis should be excluded before ordering this evaluation. The p50 value should be normal.

 

This test is not intended for prenatal diagnosis.

 

Certain mutations have no clinical manifestations and, in essence, are clinically benign. Correlation with all relevant clinical information is necessary to provide appropriate patient care.

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature

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

Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test