Interpretation of the hereditary erythrocytosis profile
A molecular interpretation will be provided when HEMP / Hereditary Erythrocytosis Mutations, Whole Blood is ordered.
Only orderable as part of a profile. For more information see HEMP / Hereditary Erythrocytosis Mutations, Whole Blood.
Medical Interpretation
A molecular interpretation will be provided when HEMP / Hereditary Erythrocytosis Mutations, Whole Blood is ordered.
Whole blood
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Whole blood | Refrigerated (preferred) | 30 days | |
| Ambient | 14 days |
Interpretation of the hereditary erythrocytosis profile
A molecular interpretation will be provided when HEMP / Hereditary Erythrocytosis Mutations, Whole Blood is ordered.
Erythrocytosis (ie, increased red blood cell [RBC] mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (ie, polycythemia vera), 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, kidney 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 small subset of cases is associated with pheochromocytoma or paraganglioma formation. It is caused by variations 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 variants 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 variants is unknown. The hemoglobin genes, HBA1/HBA2 and HBB are not assayed in this profile.
Table. Genes Associated with Hereditary Erythrocytosis
| Gene | Inheritance | Serum EPO | p50 |
| JAK2 V617F | Acquired | Decreased | Normal |
| JAK2 exon 12 | Acquired | Decreased | Normal |
| EPOR | Dominant | Decreased | 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 | Normal to increased | Normal |
The oxygen-sensing pathway functions through an enzyme, hypoxia-inducible factor (HIF), which 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 proteasomal degradation, which requires prolyl hydroxylation of HIF proline residues. The HIF-alpha subunit is encoded by the HIF2A (EPAS1) gene. 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 PHD2 (EGLN1) gene. Variations resulting in altered HIF-alpha, PHD2, and VHL proteins can lead to clinical erythrocytosis. A small subset of variants, in PHD2/EGLN1 and HIF2A/EPAS1, has also been detected in erythrocytic patients presenting with paragangliomas or pheochromocytomas.
Truncating variants 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 variants have been localized to exon 8 and are heterozygous truncating variants. EPOR variants are associated with decreased EPO levels and normal p50 values (see Table).
Only orderable as part of a profile. For more information see HEMP / Hereditary Erythrocytosis Mutations, Whole Blood.
An interpretive report will be provided and will include specimen information, assay information, and whether the specimen was positive for any variations in the gene. If positive, the variant will be correlated with clinical significance if known.
No significant cautionary statements
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8. Zhuang Z, Yang C, Lorenzo F, et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med. 2012;367(10):922-930
9. Ladroue C, Carcenac R, Leporrier M, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359(25):2685-2692
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11. Tarade D, Robinson CM, Lee JE, Ohh M. HIF-2alpha-pVHL complex reveals broad genotype-phenotype correlations in HIF-2aalpha-driven disease. Nat Commun. 2018;9(1):3359
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A hematologist reviews the laboratory data, and an interpretive report is issued.
Monday through Friday
Not Applicable
| Test Id | Test Order Name | Order LOINC Value |
|---|---|---|
| MINT | Molecular Interpretation | 69047-9 |
| Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
|---|---|---|
| 34648 | Molecular Interpretation | 69047-9 |
| 35000 | Reviewed By | 18771-6 |