Primary Familial Polycythemia Due to EPO Receptor Mutation

Mendelian MONDO:0007572 Pathograph 35 Show in embeddings browser Hereditary Erythrocytosis Congenital Primary Erythrocytosis

Primary familial and congenital polycythemia (PFCP; familial erythrocytosis type 1, ECYT1) is an autosomal dominant primary erythrocytosis caused by heterozygous germline truncating variants in EPOR, the gene encoding the erythropoietin receptor. Almost all reported variants are nonsense or frameshift changes clustered in the last exon (exon 8) that truncate the cytoplasmic C-terminus of the receptor, removing the negative regulatory region that normally down-modulates signalling. The disease is "primary" because the lesion is intrinsic to the erythroid progenitor rather than to oxygen sensing or to erythropoietin production: the truncated receptor is not properly down-regulated after ligand binding, so erythropoietin-triggered JAK2 phosphorylation and STAT5 activation are prolonged and erythroid progenitors (BFU-E) become hypersensitive to erythropoietin, growing with little or no added hormone. The red cell mass rises, and the resulting physiological negative feedback suppresses endogenous erythropoietin, so serum erythropoietin is characteristically low or subnormal - the biochemical feature that distinguishes PFCP from the oxygen-sensing (VHL, EGLN1, EPAS1) and high-oxygen-affinity haemoglobin erythrocytoses, in which erythropoietin is inappropriately normal or elevated. White cell and platelet counts are normal, separating it from polycythemia vera. Patients present from infancy or childhood with isolated erythrocytosis; penetrance of the clinical phenotype is incomplete. Although long regarded as benign, EPOR-related erythrocytosis carries a real risk of arterial and venous vascular events, and management is supportive - phlebotomy for hyperviscosity symptoms together with low-dose aspirin, by analogy with other erythrocytoses, while avoiding cytoreductive therapy.

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1
Inheritance
11
Pathophys.
14
Phenotypes
35
Pathograph
1
Genes
5
Variants
4
Medical Actions
2
Differentials
1
Models
11
References
1
Deep Research
🏷

Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant. A single heterozygous truncating EPOR allele is sufficient to cause the erythrocytosis and cosegregates with the phenotype across generations. Penetrance of the clinical phenotype is incomplete: a mutation-carrying child has been reported who did not develop polycythemia despite erythroid progenitor hypersensitivity, implying unidentified genetic or environmental modifiers. Many affected individuals have an affected parent, but a significant proportion (likely exceeding 10%) carry a de novo pathogenic variant.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:27831681 SUPPORT REVIEW SYNTHESIS Human Clinical
"Many individuals diagnosed with PFCE have an affected parent; a significant proportion of individuals (likely exceeding 10%) have the disorder as the result of a de novo pathogenic variant."
GeneReviews establishes autosomal dominant transmission with a substantial de novo rate.
PMID:8506290 SUPPORT Human Clinical
"primary erythrocytosis is segregating as a mild autosomal dominant trait"
States the autosomal dominant transmission of the EPOR-related erythrocytosis.
PMID:9649565 SUPPORT Human Clinical
"Failure of this child to develop polycythemia suggests the existence of as yet unidentified environmental or genetic factors that may suppress disease development."
Documents incomplete clinical penetrance and the inference of modifying factors.
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Pathophysiology

11
EPOR C-Terminal Cytoplasmic Truncation
A heterozygous germline nonsense or frameshift variant, almost always in the last exon (exon 8) of EPOR, truncates the cytoplasmic C-terminus of the erythropoietin receptor. The classic example is a G-to-A transition at nucleotide 6002 that converts a tryptophan codon to a stop codon, truncating the 70 C-terminal amino acids; frameshift insertions and deletions in the same region act similarly.
EPOR hgnc:3416 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EPOR (hgnc:3416). hgnc:3416 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: GAIN_OF_FUNCTION
erythropoietin receptor activity GO:0004900 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves erythropoietin receptor activity (GO:0004900), qualified as gain of function. GO:0004900 is a molecular function from the Gene Ontology.
Downstream
Loss of EPOR C-Terminal Negative Regulatory Domain The truncation removes the C-terminal region that carries the negative regulatory domains of the receptor.
Frameshift-Generated Novel C-Terminal Tail Frameshift variants additionally create a novel C-terminal peptide, a distinct gain-of-function mechanism from simple truncation.
Show evidence (2 references)
PMID:8506290 SUPPORT Human Clinical
"Here we describe a G to A transition in nucleotide 6002 of the EPOR gene that converts a TGG codon for tryptophan into a TAG stop codon, predicting the truncation of the 70 C-terminal amino acids of the EPOR molecule."
The sentinel human report identifying a germline EPOR nonsense variant that truncates the C-terminal cytoplasmic tail as the cause of dominant erythrocytosis.
PMID:29269524 SUPPORT In Vitro
"erythropoietin hypersensitivity of erythroid progenitors due to germline nonsense or frameshift mutations in the erythropoietin receptor gene. All mutations so far described lead to the truncation of the C-terminal receptor sequence that contains negative regulatory domains."
States that the causal variants are germline nonsense or frameshift mutations truncating the C-terminal negative regulatory region.
Loss of EPOR C-Terminal Negative Regulatory Domain
Truncation removes the receptor's C-terminal negative regulatory domains, which in the intact receptor exert down-modulation of erythropoietin signalling. Loss of this negative control is sufficient, for nonsense variants, to cause the erythropoietin hypersensitivity phenotype.
negative regulation of EPOR/JAK-STAT signalling GO:0046426 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of EPOR/JAK-STAT signalling, annotated with negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426). GO:0046426 is a biological process from the Gene Ontology.
Downstream
Impaired EPOR Down-Regulation and Surface Accumulation
Prolonged JAK2 Phosphorylation Loss of the negative-control domain removes the brake on receptor-proximal signalling.
Show evidence (2 references)
PMID:8506290 SUPPORT INDIRECT In Vitro
"As shown experimentally, its intracellular C-terminal part contains a domain exerting negative control on erythropoiesis."
Directly reports that the receptor's C-terminal part carries a domain exerting negative control on erythropoiesis, the domain this node loses.
PMID:29269524 SUPPORT In Vitro
"the truncation of the C-terminal receptor sequence that contains negative regulatory domains. Their removal is presented as sufficient to cause the erythropoietin hypersensitivity phenotype."
Establishes that removal of the C-terminal negative regulatory domains is the accepted mechanism for the hypersensitivity phenotype in truncating variants.
Frameshift-Generated Novel C-Terminal Tail
For frameshift variants, the phenotype is not explained by truncation alone but requires a novel C-terminal peptide generated by the frameshift. This new tail increases receptor dimerization, stability and cell-surface localization and pre-activates the receptor, a mechanism distinct from simple loss of the negative regulatory domain and proposed to be common to EPOR frameshift mutations.
erythropoietin receptor activity GO:0004900 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves erythropoietin receptor activity (GO:0004900), qualified as gain of function. GO:0004900 is a molecular function from the Gene Ontology.
Downstream
Impaired EPOR Down-Regulation and Surface Accumulation The novel tail increases receptor stability and cell-surface localization.
Prolonged JAK2 Phosphorylation The novel tail pre-activates the receptor and JAK2, producing constitutive signalling.
Show evidence (1 reference)
PMID:29269524 SUPPORT In Vitro
"by the appearance of a new C-terminal tail. The latter, by increasing erythropoietin receptor dimerization, stability and cell-surface localization, causes pre-activation of erythropoietin receptor and JAK2, constitutive signaling and hypersensitivity to erythropoietin."
Defines the frameshift-specific mechanism: a novel C-terminal tail that increases dimerization, stability and surface localization and pre-activates EPOR and JAK2.
Impaired EPOR Down-Regulation and Surface Accumulation
The mutant receptor is not properly internalized or degraded after stimulation, so it is down-regulated poorly and accumulates at the cell surface. Normal down-regulation depends on internalization mediated through the p85 regulatory subunit of PI3-kinase and on ubiquitin-based proteasomal degradation, both of which the truncated receptor escapes.
receptor internalization GO:0031623 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased receptor internalization (GO:0031623). GO:0031623 is a biological process from the Gene Ontology. receptor catabolic process GO:0032801 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased receptor catabolic process (GO:0032801). GO:0032801 is a biological process from the Gene Ontology.
Downstream
Prolonged JAK2 Phosphorylation A receptor that persists at the surface keeps signalling after ligand binding.
Show evidence (2 references)
PMID:20096014 SUPPORT REVIEW SYNTHESIS In Vitro
"One mechanism depends on internalization mediated through the p85 regulatory subunit of the Phosphoinositide 3-Kinase, and the other utilizes ubiquitin-based proteasomal degradation. Truncated PFCP EpoRs are not properly down-regulated upon stimulation"
Review summarising the two down-regulation mechanisms the truncated receptor escapes, so that it is not properly down-regulated after stimulation.
PMID:24533580 SUPPORT In Vitro
"These include slower degradation rate, higher levels of glycan-mature chimeric receptors, increased sensitivity to low levels of EGF (replacing EPO in this system) and extended signalling cascades."
Chimeric-receptor assays show PFCP EPOR mutations slow receptor degradation and raise surface mature receptor, extending signalling.
Prolonged JAK2 Phosphorylation
Because the receptor is pre-activated and poorly down-regulated, erythropoietin binding produces prolonged tyrosine phosphorylation of the receptor-associated kinase JAK2, rather than the transient, self-limited signal of the wild-type receptor.
peptidyl-tyrosine phosphorylation GO:0018108 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased peptidyl-tyrosine phosphorylation (GO:0018108). GO:0018108 is a biological process from the Gene Ontology.
JAK2 non-receptor tyrosine kinase activity GO:0004715 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased JAK2 non-receptor tyrosine kinase activity, annotated with non-membrane spanning protein tyrosine kinase activity (GO:0004715). GO:0004715 is a molecular function from the Gene Ontology.
Downstream
Prolonged STAT5 Activation
Show evidence (2 references)
PMID:29269524 SUPPORT In Vitro
"causes pre-activation of erythropoietin receptor and JAK2, constitutive signaling and hypersensitivity to erythropoietin"
Documents pre-activation of JAK2 and constitutive signalling downstream of the mutant receptor.
PMID:38546672 SUPPORT BACKGROUND Human Clinical
"The lack of EPOR cytoplasmic suppressors results in overexpression of the receptor and thereby prolonged phosphorylation of JAK2 with excessive activation of STAT5 and the RAS-MAPK signal transduction pathway."
States the canonical chain from loss of the receptor's cytoplasmic suppressors to prolonged JAK2 phosphorylation.
Prolonged STAT5 Activation
Prolonged JAK2 activity drives excessive and sustained activation of STAT5 (with contribution from the RAS-MAPK pathway), the transcriptional output that translates receptor hyperactivity into an amplified proliferative signal. The cytoplasmic tyrosine Y344 of the receptor is required for EPO-induced STAT5 phosphorylation in the PFCP context.
positive regulation of EPOR/JAK-STAT signalling GO:0046427 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of EPOR/JAK-STAT signalling, annotated with positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427). GO:0046427 is a biological process from the Gene Ontology.
Downstream
Erythroid Progenitor Hypersensitivity to Erythropoietin
Show evidence (2 references)
PMID:38546672 SUPPORT BACKGROUND Human Clinical
"prolonged phosphorylation of JAK2 with excessive activation of STAT5 and the RAS-MAPK signal transduction pathway"
Names excessive STAT5 activation (and RAS-MAPK) as the signalling consequence of the hyperactive receptor.
PMID:15878737 SUPPORT In Vitro
"In the context of EPOR-ME, Y344 was required for Epo-induced Stat5 tyrosine phosphorylation."
Functional dissection showing receptor tyrosine Y344 is required for the EPO-induced STAT5 phosphorylation that drives the hypersensitivity phenotype.
Erythroid Progenitor Hypersensitivity to Erythropoietin
The amplified, sustained signal makes erythroid progenitors (BFU-E and CFU-E) hypersensitive to erythropoietin: they proliferate and form colonies with little or no added hormone, the cellular hallmark of PFCP.
erythroid progenitor cell CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
erythropoietin-mediated signaling pathway GO:0038162 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased erythropoietin-mediated signaling pathway (GO:0038162). GO:0038162 is a biological process from the Gene Ontology.
Downstream
Expansion of Erythroid Progenitor Proliferation
Show evidence (2 references)
PMID:20096014 SUPPORT REVIEW SYNTHESIS In Vitro
"characterized by erythrocytosis and hypersensitivity of erythroid progenitors to erythropoietin (Epo)"
States erythroid progenitor hypersensitivity to erythropoietin as the defining cellular feature of PFCP.
PMID:7795221 SUPPORT In Vitro
"Burst-forming units-erythroid from patients exhibited increased colony size and sensitivity to EPO."
Direct patient-derived evidence that BFU-E show increased colony size and erythropoietin sensitivity.
Expansion of Erythroid Progenitor Proliferation
Hypersensitive progenitors expand the erythroid compartment, increasing erythrocyte production. The white cell and platelet lineages are not expanded, because the lesion is confined to the erythropoietin receptor.
erythroid progenitor cell CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
positive regulation of erythrocyte differentiation GO:0045648 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of erythrocyte differentiation (GO:0045648). GO:0045648 is a biological process from the Gene Ontology.
Downstream
Increased Red Cell Mass
Show evidence (2 references)
PMID:7795221 SUPPORT In Vitro
"Burst-forming units-erythroid from patients exhibited increased colony size and sensitivity to EPO."
Increased colony size reflects the expanded erythroid proliferation driven by the hypersensitive progenitors.
PMID:8506290 SUPPORT BACKGROUND Human Clinical
"Erythropoietin regulates the proliferation and differentiation of erythroid precursor cells."
Establishes that the receptor drives erythroid proliferation, the step that is excessive here.
Increased Red Cell Mass
Expanded erythropoiesis raises the total red cell mass, producing the polycythemia and the elevated haemoglobin and haematocrit seen clinically. The raised red cell mass also drives physiological negative feedback on erythropoietin production and raises whole-blood viscosity.
Animal models
Humanized truncated EPOR knock-in mouse Mouse recapitulates Replacement of the murine Epor with a mutant human EPOR truncated after the first intracellular tyrosine reproduced the human disorder: heterozygous mice mimicked the disease and homozygous mice were severely polycythemic, establishing the truncated receptor as a gain-of-function cause of polycythemia in vivo.
Downstream
Polycythemia
Increased red blood cell mass
Increased circulating hemoglobin concentration
Increased hematocrit
Plethora Rubor/plethora relates directly to the raised red cell mass.
Hypertension Arterial hypertension is among the severe cardiovascular complications in a minority of affected individuals.
Suppression of Endogenous Erythropoietin Production The raised red cell mass triggers physiological negative feedback on renal erythropoietin output.
Blood Hyperviscosity
Show evidence (1 reference)
PMID:11158582 SUPPORT BACKGROUND Human Clinical
"This disorder is characterized by increased numbers of erythrocytes (polycythemia) and by in vitro hypersensitivity of erythroid precursors to erythropoietin."
States the raised erythrocyte count (polycythemia) as the defining organism-level consequence.
Suppression of Endogenous Erythropoietin Production
The raised red cell mass suppresses endogenous erythropoietin production through the normal oxygen-sensing feedback loop, which is itself intact. Serum erythropoietin is therefore characteristically low or subnormal - the biochemical hallmark that separates this primary erythrocytosis from the oxygen-sensing and high-oxygen-affinity haemoglobin erythrocytoses.
EPO-producing kidney interstitial fibroblast CL:1000692 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves EPO-producing kidney interstitial fibroblast, annotated with kidney interstitial fibroblast (CL:1000692). CL:1000692 is a cell type from the Cell Ontology.
Downstream
Reduced circulating erythropoietin concentration
Show evidence (1 reference)
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"causes include EPOR mutations (subnormal Epo)"
Current review identifying subnormal erythropoietin as the characteristic finding in EPOR-related hereditary erythrocytosis.
Blood Hyperviscosity
The raised haematocrit increases whole-blood viscosity, which produces hyperviscosity symptoms (headache, dizziness, visual disturbance) and contributes to the increased risk of arterial and venous thrombotic events.
Downstream
Headache
Vertigo
Tinnitus
Visual impairment
Thromboembolism Hyperviscosity contributes to the thrombotic risk; the mechanism of thrombosis in congenital erythrocytosis is acknowledged to be complex.
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
Relief of these symptoms by red-cell-reducing phlebotomy identifies them as hyperviscosity manifestations of the erythrocytosis.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Primary Familial Polycythemia Due to EPO Receptor Mutation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Blood 5
Polycythemia HP:0001901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polycythemia (HP:0001901). HP:0001901 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11158582 SUPPORT BACKGROUND Human Clinical
"Mutations causing truncations of the cytoplasmic domain of the human erythropoietin receptor (EPOR) result in a dominantly inherited disorder-primary familial congenital polycythemia."
States polycythemia as the disorder caused by EPOR cytoplasmic truncation.
Increased red blood cell mass HP:0001898 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased red blood cell mass (HP:0001898). HP:0001898 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11158582 SUPPORT BACKGROUND Human Clinical
"This disorder is characterized by increased numbers of erythrocytes (polycythemia)"
The increased erythrocyte count corresponds to a raised red cell mass.
Increased circulating hemoglobin concentration HP:0001900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating hemoglobin concentration (HP:0001900). HP:0001900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"The mean hemoglobin concentration and hematocrit at diagnosis were 185 g/L and 56.3% in males and 179 g/L and 54.9% in females, respectively."
Records the elevated haemoglobin at diagnosis across the New Caledonian EPOR cohort.
Increased hematocrit HP:0001899 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased hematocrit (HP:0001899). HP:0001899 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"The mean hemoglobin concentration and hematocrit at diagnosis were 185 g/L and 56.3% in males and 179 g/L and 54.9% in females, respectively."
Records the elevated haematocrit at diagnosis across the New Caledonian EPOR cohort.
Thromboembolism HP:0001907 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thromboembolism (HP:0001907). HP:0001907 is a phenotype from the Human Phenotype Ontology.
Sequelae: Myocardial infarction Stroke
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"The occurrence of vascular events in more than 10% of the cohort raises the question of the seriousness of this complication, which was initially considered to have little effect."
Documents vascular events in more than 10% of the EPOR cohort, revising the historically benign view.
Cardiovascular 3
Myocardial infarction HP:0001658 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial infarction (HP:0001658). HP:0001658 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"the original proband, who suffered several cardiovascular events and died in his 50s of a stroke, and his affected son had a myocardial infarction at the age of 40"
Records myocardial infarction among the arterial events in EPOR-mutated individuals.
Stroke HP:0001297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stroke (HP:0001297). HP:0001297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"the original proband, who suffered several cardiovascular events and died in his 50s of a stroke"
Records stroke as an arterial event, fatal in the index PFCP proband.
Hypertension HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27831681 SUPPORT REVIEW SYNTHESIS Human Clinical
"some affected individuals have severe and even fatal complications including arterial hypertension, coronary artery disease, myocardial infarction, intracerebral hemorrhage, and deep vein thrombosis (DVT)"
GeneReviews lists arterial hypertension among the severe cardiovascular complications of PFCE.
Ear 2
Vertigo HP:0002321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dizziness, annotated with Vertigo (HP:0002321). HP:0002321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
Dizziness among the hyperviscosity symptoms relieved by phlebotomy in the EPOR cohort.
Tinnitus HP:0000360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tinnitus (HP:0000360). HP:0000360 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38546672 SUPPORT Human Clinical
"over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
Tinnitus among the hyperviscosity symptoms relieved by phlebotomy.
PMID:27831681 SUPPORT Other
"visual disturbances, tinnitus, paresthesia, fatigue, lassitude, and weakness"
GeneReviews lists tinnitus among hyperviscosity-syndrome manifestations.
Endocrine 1
Reduced circulating erythropoietin concentration HP:0034443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced circulating erythropoietin concentration (HP:0034443). HP:0034443 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:27831681 SUPPORT Other
"isolated absolute erythrocytosis, normal serum P50, below normal erythropoietin concentration"
GeneReviews lists a below-normal erythropoietin concentration among the diagnostic criteria for PFCE.
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"causes include EPOR mutations (subnormal Epo)"
Subnormal erythropoietin is the characteristic laboratory discriminator for EPOR-related erythrocytosis.
PMID:38546672 SUPPORT Human Clinical
"When available, the serum EPO level at diagnosis was low in all cases (<5 mU/mL)."
Direct cohort evidence that serum erythropoietin is low at diagnosis in EPOR-mutated carriers.
Eye 1
Visual impairment HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual disturbance, annotated with Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
Visual disturbance among the hyperviscosity symptoms relieved by phlebotomy.
Integument 1
Plethora HP:0001050 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Plethora (HP:0001050). HP:0001050 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27831681 SUPPORT REVIEW SYNTHESIS Human Clinical
"Clinical manifestations relate to the erythrocytosis and include rubor"
GeneReviews lists rubor (plethora) among the clinical manifestations of the erythrocytosis.
Nervous System 1
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38546672 SUPPORT Human Clinical
"over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
Headache among the hyperviscosity symptoms relieved by phlebotomy in the EPOR cohort.
🧬

Genetic Associations

1
EPOR truncating variants
Gene: EPOR hgnc:3416 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EPOR (hgnc:3416). hgnc:3416 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:8506290 SUPPORT Human Clinical
"The mutation occurs in heterozygous form in the germ-line DNA of members of a large kindred in which primary erythrocytosis is segregating as a mild autosomal dominant trait. The mutation cosegregates with the disease phenotype in all 29 affected family members studied"
Establishes the heterozygous germline EPOR nonsense variant cosegregating with dominant erythrocytosis across a large kindred.
PMID:7795221 SUPPORT Human Clinical
"A heterozygous insertion of G at EPOR nucleotide 5975 was identified in genomic DNA from polycythemic members of family no. 2. 5974insG shifts the reading frame at codon 430, predicting amino acid substitutions and truncation of the last 64 amino acids."
Documents the 5974insG frameshift variant and its predicted C-terminal truncation.
PMID:9649565 SUPPORT Human Clinical
"found a C5964G mutation in exon VIII that changes tyrosine codon 426 to a translation termination codon resulting in an EPOR protein truncated by 83 amino acids"
Documents the C5964G (Y426X) nonsense variant truncating the receptor by 83 amino acids.
+ 2 more references
Variants (5)
W439X (G6002A)
The sentinel allele from the original large kindred: a G-to-A transition at nucleotide 6002 creating a premature stop and truncating the 70 C-terminal amino acids.
5974insG
A heterozygous G insertion at EPOR nucleotide 5975 that shifts the reading frame at codon 430 and truncates the last 64 amino acids; erythroid progenitors showed increased EPO sensitivity.
C5964G (Y426X)
An exon 8 nonsense variant changing tyrosine codon 426 to a stop, truncating the receptor by 83 amino acids; reported in a family with one mutation carrier who did not develop polycythemia despite progenitor hypersensitivity.
p.Gln434Profs*11
A frameshift allele whose hypersensitivity depends on a novel C-terminal tail rather than on truncation alone, defining the frameshift-specific mechanism.
c.1293del (p.Ser432Alafs*21)
A frameshift allele observed exclusively in patients from New Caledonia, a founder variant underlying a regional cluster.
💊

Medical Actions

4
Therapeutic phlebotomy
Action: phlebotomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is phlebotomy (NCIT:C28221). NCIT:C28221 is a clinical intervention from the NCI Thesaurus. Ontology label: Phlebotomy NCIT:C28221
Platform: Other
Phlebotomy reduces the red cell mass and relieves hyperviscosity symptoms (headache, dizziness, visual disturbance). The haematocrit threshold is debated and is best guided by symptom relief rather than a fixed polycythemia vera target. Current guidance for JAK2-unmutated erythrocytosis advises phlebotomy for symptom control and against cytoreductive therapy.
Mechanism Target:
INHIBITS Increased Red Cell Mass — Phlebotomy removes red cell mass to relieve hyperviscosity symptoms without addressing the receptor defect.
Show evidence (2 references)
PMID:38546672 SUPPORT Human Clinical
"over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
Phlebotomy relieved hyperviscosity symptoms in over half of treated EPOR carriers.
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"Cytoreductive therapy should be avoided. Phlebotomy should be considered for symptom control."
Current guidance for JAK2-unmutated erythrocytosis: phlebotomy for symptom control, no cytoreduction.
Low-dose aspirin and cardiovascular risk management
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: aspirin CHEBI:15365 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses aspirin, annotated with acetylsalicylic acid (CHEBI:15365). CHEBI:15365 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Low-dose aspirin, together with cardiovascular risk-factor optimisation, is advised to reduce the arterial and venous thrombotic risk. In the New Caledonian founder cohort, phlebotomy plus low-dose aspirin was associated with a decreased risk of vascular events.
Mechanism Target:
INHIBITS Thromboembolism — Antiplatelet prophylaxis against thrombotic vascular events.
Show evidence (2 references)
PMID:38546672 SUPPORT Human Clinical
"Overall, the use of aspirin (or oral anticoagulant in 2 patients) and phlebotomy was associated with a decreased risk of vascular events (P<0.001, Fisher exact test)."
Direct cohort evidence associating aspirin plus phlebotomy with a decreased vascular-event risk in EPOR-related disease.
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"Cardiovascular risk optimization and low-dose aspirin are advised"
Current guidance advising low-dose aspirin and cardiovascular risk optimisation in JAK2-unmutated erythrocytosis.
Supportive care and avoidance of exacerbating exposures
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
GeneReviews management is largely supportive: maintain good hydration, take deep-vein-thrombosis precautions in higher-risk situations, and avoid circumstances that increase blood viscosity or cardiovascular risk - notably dehydration, prolonged stay at high altitude, scuba diving, smoking, and erythropoiesis-stimulating agents. Where phlebotomy is used, iron deficiency (which itself can cause lassitude and may increase thrombotic risk) should be corrected.
Mechanism Target:
INHIBITS Blood Hyperviscosity — Good hydration and avoidance of viscosity-raising exposures reduce the hyperviscosity burden.
Show evidence (1 reference)
PMID:27831681 SUPPORT REVIEW SYNTHESIS Human Clinical
"Agents/circumstances to avoid: Dehydration; activities that could increase blood viscosity (e.g., living or prolonged stay at high altitudes, scuba diving, and smoking); additional cardiovascular risks (e.g., hypertension, hyperlipidemia, diabetes, and obesity); erythropoiesis-stimulating agents."
GeneReviews "agents/circumstances to avoid", the drug-safety and exposure guidance for PFCE.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Autosomal dominant transmission with incomplete penetrance makes genetic counseling and cascade testing of relatives appropriate once a causal EPOR variant is identified.
Show evidence (3 references)
PMID:8506290 SUPPORT Human Clinical
"The mutation cosegregates with the disease phenotype in all 29 affected family members studied"
The clear dominant cosegregation across a large kindred is the basis for cascade family testing and counseling.
PMID:27831681 SUPPORT Other
"Each child of an individual with EPOR-related PFCE has a 50% chance of inheriting the EPOR pathogenic variant."
The GeneReviews recurrence-risk figure that genetic counseling conveys.
PMID:27831681 SUPPORT Other
"Once the EPOR pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for PFCE are possible."
GeneReviews notes prenatal and preimplantation testing become possible once the family variant is known.
🔬

Diagnosis

3
Serum erythropoietin measurement
Serum erythropoietin is the key discriminator: it is low or subnormal in EPOR-related primary erythrocytosis, unlike the inappropriately normal or elevated levels of the secondary and oxygen-sensing erythrocytoses.
serum erythropoietin measurement NCIT:C74855 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:27831681 SUPPORT Other
"isolated absolute erythrocytosis, normal serum P50, below normal erythropoietin concentration"
GeneReviews names a below-normal erythropoietin concentration among the clinical diagnostic criteria, the discriminator this test provides.
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"causes include EPOR mutations (subnormal Epo)"
Subnormal erythropoietin points to EPOR-related hereditary erythrocytosis in the workup.
JAK2 mutation screening to exclude polycythemia vera
The first diagnostic step in an erythrocytosis workup is excluding polycythemia vera by JAK2 mutation screening (exons 12 to 15); a JAK2-negative longstanding erythrocytosis with normal white cell and platelet counts and a positive family history prompts hereditary testing.
JAK2 mutation screening NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"The foremost step is excluding polycythemia vera (PV) with JAK2 mutation screening (exons 12-15)."
Establishes JAK2 screening as the first step before pursuing a hereditary erythrocytosis.
EPOR and hereditary erythrocytosis gene testing
EPOR sequencing (with exon 8 the hotspot) or an expanded hereditary erythrocytosis next-generation sequencing panel establishes the diagnosis in a JAK2-negative erythrocytosis with subnormal erythropoietin.
germline gene-panel testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"In cases with negative workup but high clinical suspicion, an expanded next generation sequencing panel for hereditary erythrocytosis is recommended."
Supports expanded hereditary erythrocytosis gene-panel testing, which includes EPOR.
PMID:27831681 SUPPORT Other
"The molecular diagnosis is established by identification of a heterozygous pathogenic variant in EPOR by molecular genetic testing in an individual with erythrocytosis."
The GeneReviews molecular-diagnosis criterion: a heterozygous EPOR variant in an individual with erythrocytosis.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Primary Familial Polycythemia Due to EPO Receptor Mutation:

Polycythemia Vera
Overlapping Features The principal differential. Polycythemia vera is an acquired JAK2-mutated myeloproliferative neoplasm with trilineage expansion and low erythropoietin and adult onset. PFCP is congenital, JAK2-negative, confined to the erythroid lineage (normal white cell and platelet counts), and also has subnormal erythropoietin - so the discriminators are JAK2 status, lineage involvement and age of onset rather than the erythropoietin level alone.
Distinguishing Features
  • JAK2 V617F or exon 12 mutation present in polycythemia vera, absent here
  • Trilineage expansion in polycythemia vera; isolated erythrocytosis here
  • Acquired adult onset versus congenital lifelong erythrocytosis
Show evidence (1 reference)
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"The foremost step is excluding polycythemia vera (PV) with JAK2 mutation screening (exons 12-15)."
Polycythemia vera is excluded first by JAK2 screening, the key separation from JAK2-negative hereditary erythrocytosis.
Oxygen-Sensing and High-Oxygen-Affinity Erythrocytoses
Overlapping Features The other congenital erythrocytoses - VHL (Chuvash), EGLN1/PHD2, EPAS1/HIF2A, high-oxygen-affinity haemoglobin variants, 2,3-bisphosphoglycerate deficiency - are secondary, EPO-driven, and have inappropriately normal or elevated erythropoietin. EPOR-related disease is the one with uniquely subnormal erythropoietin.
Distinguishing Features
  • Subnormal erythropoietin in EPOR disease; normal-to-elevated in the others
  • Primary (erythroid-intrinsic) lesion versus secondary EPO-driven mechanism
  • High-affinity haemoglobinopathy and BPGM deficiency give a left-shifted p50
Show evidence (1 reference)
PMID:41123216 SUPPORT REVIEW SYNTHESIS Human Clinical
"causes include EPOR mutations (subnormal Epo), high oxygen affinity hemoglobin variants, PIEZO1 mutations, 2,3-bisphosphoglycerate deficiency, methemoglobinemia, and germline oxygen sensing pathway mutations (HIF2A-PHD2-VHL)"
Lists the hereditary erythrocytoses alongside EPOR, with subnormal erythropoietin flagged as the EPOR-specific feature.
🐁

Animal Models

1
Humanized truncated EPOR knock-in mouse
Species
Mouse
Genotype
Murine Epor replaced by a truncated mutant human EPOR allele
Publication
PMID:11158582
Pathograph links
Increased Red Cell Mass recapitulates fidelity: high observes: organism Replacement of the murine Epor with a mutant human EPOR truncated after the first intracellular tyrosine reproduced the human disorder: heterozygous mice mimicked the disease and homozygous mice were severely polycythemic, establishing the truncated receptor as a gain-of-function cause of polycythemia in vivo.
Limitations: Erythropoiesis differs between mouse and human, and the phenotype required the human receptor rather than a truncated mouse receptor; consequences of EPOR truncation in non-erythroid tissues were unknown in this study.
Show evidence (1 reference)
PMID:11158582 SUPPORT Model Organism
"Mice heterozygous for this mutant allele and a wild-type human EPOR allele mimicked the human disorder. Interestingly, mice that were homozygous for the mutant human allele were severely polycythemic but viable."
Establishes the knock-in as a faithful in vivo model of the human polycythemia and its genetic cause.
{ }

Source YAML

click to show 
name: Primary Familial Polycythemia Due to EPO Receptor Mutation
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
parents:
- Hereditary Erythrocytosis
- Congenital Primary Erythrocytosis
disease_term:
  preferred_term: primary familial and congenital polycythemia
  term:
    id: MONDO:0007572
    label: primary familial polycythemia due to EPO receptor mutation
synonyms:
- PFCP
- ECYT1
- primary familial and congenital polycythemia
- familial erythrocytosis type 1
- familial erythrocytosis, 1
- congenital erythrocytosis due to erythropoietin receptor mutation
- EPOR-related erythrocytosis
- familial polycythemia caused by mutation in EPOR
description: >-
  Primary familial and congenital polycythemia (PFCP; familial erythrocytosis
  type 1, ECYT1) is an autosomal dominant primary erythrocytosis caused by
  heterozygous germline truncating variants in EPOR, the gene encoding the
  erythropoietin receptor. Almost all reported variants are nonsense or
  frameshift changes clustered in the last exon (exon 8) that truncate the
  cytoplasmic C-terminus of the receptor, removing the negative regulatory
  region that normally down-modulates signalling. The disease is "primary"
  because the lesion is intrinsic to the erythroid progenitor rather than to
  oxygen sensing or to erythropoietin production: the truncated receptor is not
  properly down-regulated after ligand binding, so erythropoietin-triggered
  JAK2 phosphorylation and STAT5 activation are prolonged and erythroid
  progenitors (BFU-E) become hypersensitive to erythropoietin, growing with
  little or no added hormone. The red cell mass rises, and the resulting
  physiological negative feedback suppresses endogenous erythropoietin, so serum
  erythropoietin is characteristically low or subnormal - the biochemical
  feature that distinguishes PFCP from the oxygen-sensing (VHL, EGLN1, EPAS1)
  and high-oxygen-affinity haemoglobin erythrocytoses, in which erythropoietin
  is inappropriately normal or elevated. White cell and platelet counts are
  normal, separating it from polycythemia vera. Patients present from infancy or
  childhood with isolated erythrocytosis; penetrance of the clinical phenotype
  is incomplete. Although long regarded as benign, EPOR-related erythrocytosis
  carries a real risk of arterial and venous vascular events, and management is
  supportive - phlebotomy for hyperviscosity symptoms together with low-dose
  aspirin, by analogy with other erythrocytoses, while avoiding cytoreductive
  therapy.
pathophysiology:
- name: EPOR C-Terminal Cytoplasmic Truncation
  biological_scale: MOLECULAR
  description: >-
    A heterozygous germline nonsense or frameshift variant, almost always in the
    last exon (exon 8) of EPOR, truncates the cytoplasmic C-terminus of the
    erythropoietin receptor. The classic example is a G-to-A transition at
    nucleotide 6002 that converts a tryptophan codon to a stop codon, truncating
    the 70 C-terminal amino acids; frameshift insertions and deletions in the
    same region act similarly.
  genes:
  - preferred_term: EPOR
    term:
      id: hgnc:3416
      label: EPOR
  molecular_functions:
  - preferred_term: erythropoietin receptor activity
    term:
      id: GO:0004900
      label: erythropoietin receptor activity
    modifier: GAIN_OF_FUNCTION
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: GAIN_OF_FUNCTION
  downstream:
  - target: Loss of EPOR C-Terminal Negative Regulatory Domain
    causal_link_type: DIRECT
    description: >-
      The truncation removes the C-terminal region that carries the negative
      regulatory domains of the receptor.
  - target: Frameshift-Generated Novel C-Terminal Tail
    causal_link_type: DIRECT
    description: >-
      Frameshift variants additionally create a novel C-terminal peptide, a
      distinct gain-of-function mechanism from simple truncation.
  evidence:
  - reference: PMID:8506290
    reference_title: Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a G to A transition in nucleotide 6002 of the EPOR gene that converts a TGG codon for tryptophan into a TAG stop codon, predicting the truncation of the 70 C-terminal amino acids of the EPOR molecule."
    explanation: >-
      The sentinel human report identifying a germline EPOR nonsense variant that
      truncates the C-terminal cytoplasmic tail as the cause of dominant
      erythrocytosis.
  - reference: PMID:29269524
    reference_title: New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "erythropoietin hypersensitivity of erythroid progenitors due to germline nonsense or frameshift mutations in the erythropoietin receptor gene. All mutations so far described lead to the truncation of the C-terminal receptor sequence that contains negative regulatory domains."
    explanation: >-
      States that the causal variants are germline nonsense or frameshift
      mutations truncating the C-terminal negative regulatory region.
- name: Loss of EPOR C-Terminal Negative Regulatory Domain
  biological_scale: MOLECULAR
  description: >-
    Truncation removes the receptor's C-terminal negative regulatory domains,
    which in the intact receptor exert down-modulation of erythropoietin
    signalling. Loss of this negative control is sufficient, for nonsense
    variants, to cause the erythropoietin hypersensitivity phenotype.
  biological_processes:
  - preferred_term: negative regulation of EPOR/JAK-STAT signalling
    term:
      id: GO:0046426
      label: negative regulation of receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  downstream:
  - target: Impaired EPOR Down-Regulation and Surface Accumulation
    causal_link_type: DIRECT
  - target: Prolonged JAK2 Phosphorylation
    causal_link_type: DIRECT
    description: >-
      Loss of the negative-control domain removes the brake on receptor-proximal
      signalling.
  evidence:
  - reference: PMID:8506290
    reference_title: Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "As shown experimentally, its intracellular C-terminal part contains a domain exerting negative control on erythropoiesis."
    explanation: >-
      Directly reports that the receptor's C-terminal part carries a domain exerting
      negative control on erythropoiesis, the domain this node loses.
  - reference: PMID:29269524
    reference_title: New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the truncation of the C-terminal receptor sequence that contains negative regulatory domains. Their removal is presented as sufficient to cause the erythropoietin hypersensitivity phenotype."
    explanation: >-
      Establishes that removal of the C-terminal negative regulatory domains is
      the accepted mechanism for the hypersensitivity phenotype in truncating
      variants.
- name: Frameshift-Generated Novel C-Terminal Tail
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: erythropoietin receptor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004900
      label: erythropoietin receptor activity
  description: >-
    For frameshift variants, the phenotype is not explained by truncation alone
    but requires a novel C-terminal peptide generated by the frameshift. This new
    tail increases receptor dimerization, stability and cell-surface localization
    and pre-activates the receptor, a mechanism distinct from simple loss of the
    negative regulatory domain and proposed to be common to EPOR frameshift
    mutations.
  downstream:
  - target: Impaired EPOR Down-Regulation and Surface Accumulation
    causal_link_type: DIRECT
    description: >-
      The novel tail increases receptor stability and cell-surface localization.
  - target: Prolonged JAK2 Phosphorylation
    causal_link_type: DIRECT
    description: >-
      The novel tail pre-activates the receptor and JAK2, producing constitutive
      signalling.
  evidence:
  - reference: PMID:29269524
    reference_title: New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "by the appearance of a new C-terminal tail. The latter, by increasing erythropoietin receptor dimerization, stability and cell-surface localization, causes pre-activation of erythropoietin receptor and JAK2, constitutive signaling and hypersensitivity to erythropoietin."
    explanation: >-
      Defines the frameshift-specific mechanism: a novel C-terminal tail that
      increases dimerization, stability and surface localization and pre-activates
      EPOR and JAK2.
- name: Impaired EPOR Down-Regulation and Surface Accumulation
  biological_scale: CELLULAR
  description: >-
    The mutant receptor is not properly internalized or degraded after
    stimulation, so it is down-regulated poorly and accumulates at the cell
    surface. Normal down-regulation depends on internalization mediated through
    the p85 regulatory subunit of PI3-kinase and on ubiquitin-based proteasomal
    degradation, both of which the truncated receptor escapes.
  biological_processes:
  - preferred_term: receptor internalization
    term:
      id: GO:0031623
      label: receptor internalization
    modifier: DECREASED
  - preferred_term: receptor catabolic process
    term:
      id: GO:0032801
      label: receptor catabolic process
    modifier: DECREASED
  downstream:
  - target: Prolonged JAK2 Phosphorylation
    causal_link_type: DIRECT
    description: >-
      A receptor that persists at the surface keeps signalling after ligand
      binding.
  evidence:
  - reference: PMID:20096014
    reference_title: Advances in understanding the pathogenesis of primary familial and congenital polycythaemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "One mechanism depends on internalization mediated through the p85 regulatory subunit of the Phosphoinositide 3-Kinase, and the other utilizes ubiquitin-based proteasomal degradation. Truncated PFCP EpoRs are not properly down-regulated upon stimulation"
    explanation: >-
      Review summarising the two down-regulation mechanisms the truncated receptor
      escapes, so that it is not properly down-regulated after stimulation.
  - reference: PMID:24533580
    reference_title: "Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR): mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These include slower degradation rate, higher levels of glycan-mature chimeric receptors, increased sensitivity to low levels of EGF (replacing EPO in this system) and extended signalling cascades."
    explanation: >-
      Chimeric-receptor assays show PFCP EPOR mutations slow receptor degradation
      and raise surface mature receptor, extending signalling.
- name: Prolonged JAK2 Phosphorylation
  biological_scale: MOLECULAR
  description: >-
    Because the receptor is pre-activated and poorly down-regulated,
    erythropoietin binding produces prolonged tyrosine phosphorylation of the
    receptor-associated kinase JAK2, rather than the transient, self-limited
    signal of the wild-type receptor.
  molecular_functions:
  - preferred_term: JAK2 non-receptor tyrosine kinase activity
    term:
      id: GO:0004715
      label: non-membrane spanning protein tyrosine kinase activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: peptidyl-tyrosine phosphorylation
    term:
      id: GO:0018108
      label: peptidyl-tyrosine phosphorylation
    modifier: INCREASED
  downstream:
  - target: Prolonged STAT5 Activation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29269524
    reference_title: New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "causes pre-activation of erythropoietin receptor and JAK2, constitutive signaling and hypersensitivity to erythropoietin"
    explanation: >-
      Documents pre-activation of JAK2 and constitutive signalling downstream of
      the mutant receptor.
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The lack of EPOR cytoplasmic suppressors results in overexpression of the receptor and thereby prolonged phosphorylation of JAK2 with excessive activation of STAT5 and the RAS-MAPK signal transduction pathway."
    explanation: >-
      States the canonical chain from loss of the receptor's cytoplasmic
      suppressors to prolonged JAK2 phosphorylation.
- name: Prolonged STAT5 Activation
  biological_scale: MOLECULAR
  description: >-
    Prolonged JAK2 activity drives excessive and sustained activation of STAT5
    (with contribution from the RAS-MAPK pathway), the transcriptional output
    that translates receptor hyperactivity into an amplified proliferative
    signal. The cytoplasmic tyrosine Y344 of the receptor is required for
    EPO-induced STAT5 phosphorylation in the PFCP context.
  biological_processes:
  - preferred_term: positive regulation of EPOR/JAK-STAT signalling
    term:
      id: GO:0046427
      label: positive regulation of receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  downstream:
  - target: Erythroid Progenitor Hypersensitivity to Erythropoietin
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "prolonged phosphorylation of JAK2 with excessive activation of STAT5 and the RAS-MAPK signal transduction pathway"
    explanation: >-
      Names excessive STAT5 activation (and RAS-MAPK) as the signalling
      consequence of the hyperactive receptor.
  - reference: PMID:15878737
    reference_title: "Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the context of EPOR-ME, Y344 was required for Epo-induced Stat5 tyrosine phosphorylation."
    explanation: >-
      Functional dissection showing receptor tyrosine Y344 is required for the
      EPO-induced STAT5 phosphorylation that drives the hypersensitivity
      phenotype.
- name: Erythroid Progenitor Hypersensitivity to Erythropoietin
  biological_scale: CELLULAR
  description: >-
    The amplified, sustained signal makes erythroid progenitors (BFU-E and CFU-E)
    hypersensitive to erythropoietin: they proliferate and form colonies with
    little or no added hormone, the cellular hallmark of PFCP.
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: erythropoietin-mediated signaling pathway
    term:
      id: GO:0038162
      label: erythropoietin-mediated signaling pathway
    modifier: INCREASED
  downstream:
  - target: Expansion of Erythroid Progenitor Proliferation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20096014
    reference_title: Advances in understanding the pathogenesis of primary familial and congenital polycythaemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "characterized by erythrocytosis and hypersensitivity of erythroid progenitors to erythropoietin (Epo)"
    explanation: >-
      States erythroid progenitor hypersensitivity to erythropoietin as the
      defining cellular feature of PFCP.
  - reference: PMID:7795221
    reference_title: "Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Burst-forming units-erythroid from patients exhibited increased colony size and sensitivity to EPO."
    explanation: >-
      Direct patient-derived evidence that BFU-E show increased colony size and
      erythropoietin sensitivity.
- name: Expansion of Erythroid Progenitor Proliferation
  biological_scale: CELLULAR
  description: >-
    Hypersensitive progenitors expand the erythroid compartment, increasing
    erythrocyte production. The white cell and platelet lineages are not
    expanded, because the lesion is confined to the erythropoietin receptor.
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: positive regulation of erythrocyte differentiation
    term:
      id: GO:0045648
      label: positive regulation of erythrocyte differentiation
    modifier: INCREASED
  downstream:
  - target: Increased Red Cell Mass
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:7795221
    reference_title: "Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Burst-forming units-erythroid from patients exhibited increased colony size and sensitivity to EPO."
    explanation: >-
      Increased colony size reflects the expanded erythroid proliferation driven
      by the hypersensitive progenitors.
  - reference: PMID:8506290
    reference_title: Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Erythropoietin regulates the proliferation and differentiation of erythroid precursor cells."
    explanation: >-
      Establishes that the receptor drives erythroid proliferation, the step that
      is excessive here.
- name: Increased Red Cell Mass
  biological_scale: ORGANISM
  description: >-
    Expanded erythropoiesis raises the total red cell mass, producing the
    polycythemia and the elevated haemoglobin and haematocrit seen clinically.
    The raised red cell mass also drives physiological negative feedback on
    erythropoietin production and raises whole-blood viscosity.
  downstream:
  - target: Polycythemia
    causal_link_type: DIRECT
  - target: Increased red blood cell mass
    causal_link_type: DIRECT
  - target: Increased circulating hemoglobin concentration
    causal_link_type: DIRECT
  - target: Increased hematocrit
    causal_link_type: DIRECT
  - target: Plethora
    causal_link_type: DIRECT
    description: >-
      Rubor/plethora relates directly to the raised red cell mass.
  - target: Hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Arterial hypertension is among the severe cardiovascular complications in a
      minority of affected individuals.
  - target: Suppression of Endogenous Erythropoietin Production
    causal_link_type: DIRECT
    description: >-
      The raised red cell mass triggers physiological negative feedback on renal
      erythropoietin output.
  - target: Blood Hyperviscosity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:11158582
    reference_title: "Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "This disorder is characterized by increased numbers of erythrocytes (polycythemia) and by in vitro hypersensitivity of erythroid precursors to erythropoietin."
    explanation: >-
      States the raised erythrocyte count (polycythemia) as the defining
      organism-level consequence.
- name: Suppression of Endogenous Erythropoietin Production
  biological_scale: ORGANISM
  description: >-
    The raised red cell mass suppresses endogenous erythropoietin production
    through the normal oxygen-sensing feedback loop, which is itself intact.
    Serum erythropoietin is therefore characteristically low or subnormal - the
    biochemical hallmark that separates this primary erythrocytosis from the
    oxygen-sensing and high-oxygen-affinity haemoglobin erythrocytoses.
  cell_types:
  - preferred_term: EPO-producing kidney interstitial fibroblast
    term:
      id: CL:1000692
      label: kidney interstitial fibroblast
  downstream:
  - target: Reduced circulating erythropoietin concentration
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "causes include EPOR mutations (subnormal Epo)"
    explanation: >-
      Current review identifying subnormal erythropoietin as the characteristic
      finding in EPOR-related hereditary erythrocytosis.
- name: Blood Hyperviscosity
  biological_scale: ORGANISM
  description: >-
    The raised haematocrit increases whole-blood viscosity, which produces
    hyperviscosity symptoms (headache, dizziness, visual disturbance) and
    contributes to the increased risk of arterial and venous thrombotic events.
  downstream:
  - target: Headache
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Vertigo
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Tinnitus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Visual impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thromboembolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hyperviscosity contributes to the thrombotic risk; the mechanism of
      thrombosis in congenital erythrocytosis is acknowledged to be complex.
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
    explanation: >-
      Relief of these symptoms by red-cell-reducing phlebotomy identifies them as
      hyperviscosity manifestations of the erythrocytosis.
phenotypes:
- name: Polycythemia
  category: Hematologic
  description: >-
    Isolated erythrocytosis is the dominant and near-constant feature: a primary,
    EPO-independent erythrocytosis without expansion of the white cell or platelet
    lineages.
  phenotype_term:
    preferred_term: Polycythemia
    term:
      id: HP:0001901
      label: Polycythemia
  diagnostic: true
  evidence:
  - reference: PMID:11158582
    reference_title: "Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Mutations causing truncations of the cytoplasmic domain of the human erythropoietin receptor (EPOR) result in a dominantly inherited disorder-primary familial congenital polycythemia."
    explanation: >-
      States polycythemia as the disorder caused by EPOR cytoplasmic truncation.
- name: Increased red blood cell mass
  category: Hematologic
  phenotype_term:
    preferred_term: Increased red blood cell mass
    term:
      id: HP:0001898
      label: Increased red blood cell mass
  diagnostic: true
  evidence:
  - reference: PMID:11158582
    reference_title: "Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "This disorder is characterized by increased numbers of erythrocytes (polycythemia)"
    explanation: >-
      The increased erythrocyte count corresponds to a raised red cell mass.
- name: Increased circulating hemoglobin concentration
  category: Hematologic
  phenotype_term:
    preferred_term: Increased circulating hemoglobin concentration
    term:
      id: HP:0001900
      label: Increased circulating hemoglobin concentration
  diagnostic: true
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean hemoglobin concentration and hematocrit at diagnosis were 185 g/L and 56.3% in males and 179 g/L and 54.9% in females, respectively."
    explanation: >-
      Records the elevated haemoglobin at diagnosis across the New Caledonian
      EPOR cohort.
- name: Increased hematocrit
  category: Hematologic
  phenotype_term:
    preferred_term: Increased hematocrit
    term:
      id: HP:0001899
      label: Increased hematocrit
  diagnostic: true
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean hemoglobin concentration and hematocrit at diagnosis were 185 g/L and 56.3% in males and 179 g/L and 54.9% in females, respectively."
    explanation: >-
      Records the elevated haematocrit at diagnosis across the New Caledonian EPOR
      cohort.
- name: Reduced circulating erythropoietin concentration
  category: Laboratory
  description: >-
    Serum erythropoietin is characteristically low or subnormal, the biochemical
    feature that distinguishes this primary erythrocytosis from the secondary and
    oxygen-sensing erythrocytoses.
  phenotype_term:
    preferred_term: Reduced circulating erythropoietin concentration
    term:
      id: HP:0034443
      label: Reduced circulating erythropoietin concentration
  diagnostic: true
  evidence:
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "isolated absolute erythrocytosis, normal serum P50, below normal erythropoietin concentration"
    explanation: >-
      GeneReviews lists a below-normal erythropoietin concentration among the
      diagnostic criteria for PFCE.
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "causes include EPOR mutations (subnormal Epo)"
    explanation: >-
      Subnormal erythropoietin is the characteristic laboratory discriminator for
      EPOR-related erythrocytosis.
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When available, the serum EPO level at diagnosis was low in all cases (<5 mU/mL)."
    explanation: >-
      Direct cohort evidence that serum erythropoietin is low at diagnosis in
      EPOR-mutated carriers.
- name: Headache
  category: Neurologic
  description: >-
    A hyperviscosity symptom; reported to improve with phlebotomy.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
    explanation: >-
      Headache among the hyperviscosity symptoms relieved by phlebotomy in the
      EPOR cohort.
- name: Vertigo
  category: Neurologic
  description: >-
    Dizziness as a hyperviscosity symptom; reported to improve with phlebotomy. The
    sources say "dizziness"; HPO has no distinct dizziness term, so it is bound to
    the closest available concept, HP:0002321 Vertigo.
  phenotype_term:
    preferred_term: Dizziness
    term:
      id: HP:0002321
      label: Vertigo
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
    explanation: >-
      Dizziness among the hyperviscosity symptoms relieved by phlebotomy in the
      EPOR cohort.
- name: Tinnitus
  category: Neurologic
  description: >-
    Tinnitus as a hyperviscosity symptom; relieved by phlebotomy in the EPOR cohort.
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
  evidence:
  - reference: PMID:38546672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
    explanation: Tinnitus among the hyperviscosity symptoms relieved by phlebotomy.
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "visual disturbances, tinnitus, paresthesia, fatigue, lassitude, and weakness"
    explanation: GeneReviews lists tinnitus among hyperviscosity-syndrome manifestations.
- name: Visual impairment
  category: Neurologic
  description: >-
    Visual disturbance as a hyperviscosity symptom; relieved by phlebotomy.
  phenotype_term:
    preferred_term: Visual disturbance
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:38546672
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
    explanation: Visual disturbance among the hyperviscosity symptoms relieved by phlebotomy.
- name: Thromboembolism
  category: Vascular
  description: >-
    Arterial and venous vascular events occur despite the historically "benign"
    label; in the New Caledonian founder cohort a vascular event occurred in over
    10% of patients, and treatment with phlebotomy plus low-dose aspirin was
    associated with a decreased risk.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  sequelae:
  - target: Myocardial infarction
    description: >-
      Myocardial infarction is among the reported arterial events in EPOR-mutated
      carriers.
  - target: Stroke
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Stroke is among the reported arterial events in EPOR-mutated carriers. The link
      from thromboembolism covers ischemic events; GeneReviews also names intracerebral
      hemorrhage among severe complications, which a thromboembolic edge does not explain.
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The occurrence of vascular events in more than 10% of the cohort raises the question of the seriousness of this complication, which was initially considered to have little effect."
    explanation: >-
      Documents vascular events in more than 10% of the EPOR cohort, revising the
      historically benign view.
- name: Myocardial infarction
  category: Cardiovascular
  description: >-
    Myocardial infarction has been reported in EPOR-mutated carriers, including a
    non-ST-elevation infarction after phlebotomy was discontinued and an
    infarction at age 40 in an affected individual.
  phenotype_term:
    preferred_term: Myocardial infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the original proband, who suffered several cardiovascular events and died in his 50s of a stroke, and his affected son had a myocardial infarction at the age of 40"
    explanation: >-
      Records myocardial infarction among the arterial events in EPOR-mutated
      individuals.
- name: Stroke
  category: Neurologic
  description: >-
    Stroke is among the reported arterial events; the original PFCP proband died
    of a stroke in his 50s. The source does not specify ischemic versus
    haemorrhagic, so the general term is used; GeneReviews lists both arterial
    events and intracerebral hemorrhage among severe complications.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the original proband, who suffered several cardiovascular events and died in his 50s of a stroke"
    explanation: >-
      Records stroke as an arterial event, fatal in the index PFCP proband.
- name: Plethora
  category: Mucocutaneous
  description: >-
    Rubor/plethora is a direct manifestation of the raised red cell mass.
  phenotype_term:
    preferred_term: Plethora
    term:
      id: HP:0001050
      label: Plethora
  evidence:
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Clinical manifestations relate to the erythrocytosis and include rubor"
    explanation: >-
      GeneReviews lists rubor (plethora) among the clinical manifestations of the
      erythrocytosis.
- name: Hypertension
  category: Cardiovascular
  description: >-
    Arterial hypertension is among the severe, occasionally fatal cardiovascular
    complications reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "some affected individuals have severe and even fatal complications including arterial hypertension, coronary artery disease, myocardial infarction, intracerebral hemorrhage, and deep vein thrombosis (DVT)"
    explanation: >-
      GeneReviews lists arterial hypertension among the severe cardiovascular
      complications of PFCE.
genetic:
- name: EPOR truncating variants
  gene_term:
    preferred_term: EPOR
    term:
      id: hgnc:3416
      label: EPOR
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Heterozygous germline truncating variants in EPOR, almost all nonsense or
    frameshift changes in the last exon (exon 8), which encodes the negative
    regulatory region of the cytoplasmic tail. The net effect is gain of function
    through loss of negative regulation. Among the roughly 35 reported variants,
    most are classified pathogenic or likely pathogenic. EPOR mutations are found
    in only about 1% of JAK2-negative erythrocytosis cases.
  notes: >-
    The specific negative regulator removed by the truncation is often summarised
    as the SHP-1 (PTPN6) docking tyrosine, with loss of internalization and
    degradation signals, but the abstracts cited here establish only the loss of
    the C-terminal negative regulatory domain and the escape from PI3K/p85-mediated
    internalization and ubiquitin-proteasomal degradation (PMID:20096014), not the
    SHP-1 identity, so SHP-1 is named here as context rather than curated as a node.
  variants:
  - name: W439X (G6002A)
    description: >-
      The sentinel allele from the original large kindred: a G-to-A transition at
      nucleotide 6002 creating a premature stop and truncating the 70 C-terminal
      amino acids.
  - name: 5974insG
    description: >-
      A heterozygous G insertion at EPOR nucleotide 5975 that shifts the reading
      frame at codon 430 and truncates the last 64 amino acids; erythroid
      progenitors showed increased EPO sensitivity.
  - name: C5964G (Y426X)
    description: >-
      An exon 8 nonsense variant changing tyrosine codon 426 to a stop, truncating
      the receptor by 83 amino acids; reported in a family with one mutation
      carrier who did not develop polycythemia despite progenitor hypersensitivity.
  - name: p.Gln434Profs*11
    description: >-
      A frameshift allele whose hypersensitivity depends on a novel C-terminal
      tail rather than on truncation alone, defining the frameshift-specific
      mechanism.
  - name: c.1293del (p.Ser432Alafs*21)
    description: >-
      A frameshift allele observed exclusively in patients from New Caledonia,
      a founder variant underlying a regional cluster.
  evidence:
  - reference: PMID:8506290
    reference_title: Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation occurs in heterozygous form in the germ-line DNA of members of a large kindred in which primary erythrocytosis is segregating as a mild autosomal dominant trait. The mutation cosegregates with the disease phenotype in all 29 affected family members studied"
    explanation: >-
      Establishes the heterozygous germline EPOR nonsense variant cosegregating
      with dominant erythrocytosis across a large kindred.
  - reference: PMID:7795221
    reference_title: "Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A heterozygous insertion of G at EPOR nucleotide 5975 was identified in genomic DNA from polycythemic members of family no. 2. 5974insG shifts the reading frame at codon 430, predicting amino acid substitutions and truncation of the last 64 amino acids."
    explanation: >-
      Documents the 5974insG frameshift variant and its predicted C-terminal
      truncation.
  - reference: PMID:9649565
    reference_title: Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "found a C5964G mutation in exon VIII that changes tyrosine codon 426 to a translation termination codon resulting in an EPOR protein truncated by 83 amino acids"
    explanation: >-
      Documents the C5964G (Y426X) nonsense variant truncating the receptor by 83
      amino acids.
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recently reported a new EPOR mutation (c.1293del, p.Ser432Alafs*21) in patients from different unrelated families. Interestingly, this mutation has been exclusively observed in patients from the island of New Caledonia, strongly supporting a founder effect."
    explanation: >-
      Documents the c.1293del founder frameshift variant in the New Caledonian
      cluster.
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in EPOR are relatively rare among patients with JAK2-negative erythrocytosis, and are found in only approximately 1% of cases."
    explanation: >-
      Quantifies the rarity of EPOR mutations among JAK2-negative erythrocytosis.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant. A single heterozygous truncating EPOR allele is
    sufficient to cause the erythrocytosis and cosegregates with the phenotype
    across generations. Penetrance of the clinical phenotype is incomplete: a
    mutation-carrying child has been reported who did not develop polycythemia
    despite erythroid progenitor hypersensitivity, implying unidentified genetic
    or environmental modifiers. Many affected individuals have an affected
    parent, but a significant proportion (likely exceeding 10%) carry a de novo
    pathogenic variant.
  evidence:
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Many individuals diagnosed with PFCE have an affected parent; a significant proportion of individuals (likely exceeding 10%) have the disorder as the result of a de novo pathogenic variant."
    explanation: >-
      GeneReviews establishes autosomal dominant transmission with a substantial
      de novo rate.
  - reference: PMID:8506290
    reference_title: Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "primary erythrocytosis is segregating as a mild autosomal dominant trait"
    explanation: >-
      States the autosomal dominant transmission of the EPOR-related
      erythrocytosis.
  - reference: PMID:9649565
    reference_title: Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Failure of this child to develop polycythemia suggests the existence of as yet unidentified environmental or genetic factors that may suppress disease development."
    explanation: >-
      Documents incomplete clinical penetrance and the inference of modifying
      factors.
diagnosis:
- name: Serum erythropoietin measurement
  description: >-
    Serum erythropoietin is the key discriminator: it is low or subnormal in
    EPOR-related primary erythrocytosis, unlike the inappropriately normal or
    elevated levels of the secondary and oxygen-sensing erythrocytoses.
  diagnosis_term:
    preferred_term: serum erythropoietin measurement
    term:
      id: NCIT:C74855
      label: Erythropoietin Measurement
  evidence:
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "isolated absolute erythrocytosis, normal serum P50, below normal erythropoietin concentration"
    explanation: >-
      GeneReviews names a below-normal erythropoietin concentration among the clinical
      diagnostic criteria, the discriminator this test provides.
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "causes include EPOR mutations (subnormal Epo)"
    explanation: >-
      Subnormal erythropoietin points to EPOR-related hereditary erythrocytosis in
      the workup.
- name: JAK2 mutation screening to exclude polycythemia vera
  description: >-
    The first diagnostic step in an erythrocytosis workup is excluding
    polycythemia vera by JAK2 mutation screening (exons 12 to 15); a JAK2-negative
    longstanding erythrocytosis with normal white cell and platelet counts and a
    positive family history prompts hereditary testing.
  diagnosis_term:
    preferred_term: JAK2 mutation screening
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The foremost step is excluding polycythemia vera (PV) with JAK2 mutation screening (exons 12-15)."
    explanation: >-
      Establishes JAK2 screening as the first step before pursuing a hereditary
      erythrocytosis.
- name: EPOR and hereditary erythrocytosis gene testing
  description: >-
    EPOR sequencing (with exon 8 the hotspot) or an expanded hereditary
    erythrocytosis next-generation sequencing panel establishes the diagnosis in
    a JAK2-negative erythrocytosis with subnormal erythropoietin.
  diagnosis_term:
    preferred_term: germline gene-panel testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In cases with negative workup but high clinical suspicion, an expanded next generation sequencing panel for hereditary erythrocytosis is recommended."
    explanation: >-
      Supports expanded hereditary erythrocytosis gene-panel testing, which
      includes EPOR.
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The molecular diagnosis is established by identification of a heterozygous pathogenic variant in EPOR by molecular genetic testing in an individual with erythrocytosis."
    explanation: >-
      The GeneReviews molecular-diagnosis criterion: a heterozygous EPOR variant
      in an individual with erythrocytosis.
differential_diagnoses:
- name: Polycythemia Vera
  description: >-
    The principal differential. Polycythemia vera is an acquired JAK2-mutated
    myeloproliferative neoplasm with trilineage expansion and low erythropoietin
    and adult onset. PFCP is congenital, JAK2-negative, confined to the erythroid
    lineage (normal white cell and platelet counts), and also has subnormal
    erythropoietin - so the discriminators are JAK2 status, lineage involvement
    and age of onset rather than the erythropoietin level alone.
  distinguishing_features:
  - JAK2 V617F or exon 12 mutation present in polycythemia vera, absent here
  - Trilineage expansion in polycythemia vera; isolated erythrocytosis here
  - Acquired adult onset versus congenital lifelong erythrocytosis
  evidence:
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The foremost step is excluding polycythemia vera (PV) with JAK2 mutation screening (exons 12-15)."
    explanation: >-
      Polycythemia vera is excluded first by JAK2 screening, the key separation
      from JAK2-negative hereditary erythrocytosis.
- name: Oxygen-Sensing and High-Oxygen-Affinity Erythrocytoses
  description: >-
    The other congenital erythrocytoses - VHL (Chuvash), EGLN1/PHD2, EPAS1/HIF2A,
    high-oxygen-affinity haemoglobin variants, 2,3-bisphosphoglycerate deficiency
    - are secondary, EPO-driven, and have inappropriately normal or elevated
    erythropoietin. EPOR-related disease is the one with uniquely subnormal
    erythropoietin.
  distinguishing_features:
  - Subnormal erythropoietin in EPOR disease; normal-to-elevated in the others
  - Primary (erythroid-intrinsic) lesion versus secondary EPO-driven mechanism
  - High-affinity haemoglobinopathy and BPGM deficiency give a left-shifted p50
  evidence:
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "causes include EPOR mutations (subnormal Epo), high oxygen affinity hemoglobin variants, PIEZO1 mutations, 2,3-bisphosphoglycerate deficiency, methemoglobinemia, and germline oxygen sensing pathway mutations (HIF2A-PHD2-VHL)"
    explanation: >-
      Lists the hereditary erythrocytoses alongside EPOR, with subnormal
      erythropoietin flagged as the EPOR-specific feature.
treatments:
- name: Therapeutic phlebotomy
  description: >-
    Phlebotomy reduces the red cell mass and relieves hyperviscosity symptoms
    (headache, dizziness, visual disturbance). The haematocrit threshold is
    debated and is best guided by symptom relief rather than a fixed polycythemia
    vera target. Current guidance for JAK2-unmutated erythrocytosis advises
    phlebotomy for symptom control and against cytoreductive therapy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: phlebotomy
    term:
      id: NCIT:C28221
      label: Phlebotomy
  target_mechanisms:
  - target: Increased Red Cell Mass
    treatment_effect: INHIBITS
    description: >-
      Phlebotomy removes red cell mass to relieve hyperviscosity symptoms without
      addressing the receptor defect.
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "over 50% of patients treated with phlebotomies (9/17) reported improvements in headaches, dizziness, tinnitus and visual disturbance"
    explanation: >-
      Phlebotomy relieved hyperviscosity symptoms in over half of treated EPOR
      carriers.
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cytoreductive therapy should be avoided. Phlebotomy should be considered for symptom control."
    explanation: >-
      Current guidance for JAK2-unmutated erythrocytosis: phlebotomy for symptom
      control, no cytoreduction.
- name: Low-dose aspirin and cardiovascular risk management
  description: >-
    Low-dose aspirin, together with cardiovascular risk-factor optimisation, is
    advised to reduce the arterial and venous thrombotic risk. In the New
    Caledonian founder cohort, phlebotomy plus low-dose aspirin was associated
    with a decreased risk of vascular events.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aspirin
      term:
        id: CHEBI:15365
        label: acetylsalicylic acid
  target_mechanisms:
  - target: Thromboembolism
    treatment_effect: INHIBITS
    description: Antiplatelet prophylaxis against thrombotic vascular events.
  evidence:
  - reference: PMID:38546672
    reference_title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, the use of aspirin (or oral anticoagulant in 2 patients) and phlebotomy was associated with a decreased risk of vascular events (P<0.001, Fisher exact test)."
    explanation: >-
      Direct cohort evidence associating aspirin plus phlebotomy with a decreased
      vascular-event risk in EPOR-related disease.
  - reference: PMID:41123216
    reference_title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cardiovascular risk optimization and low-dose aspirin are advised"
    explanation: >-
      Current guidance advising low-dose aspirin and cardiovascular risk
      optimisation in JAK2-unmutated erythrocytosis.
- name: Supportive care and avoidance of exacerbating exposures
  description: >-
    GeneReviews management is largely supportive: maintain good hydration, take
    deep-vein-thrombosis precautions in higher-risk situations, and avoid
    circumstances that increase blood viscosity or cardiovascular risk - notably
    dehydration, prolonged stay at high altitude, scuba diving, smoking, and
    erythropoiesis-stimulating agents. Where phlebotomy is used, iron deficiency
    (which itself can cause lassitude and may increase thrombotic risk) should be
    corrected.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Blood Hyperviscosity
    treatment_effect: INHIBITS
    description: >-
      Good hydration and avoidance of viscosity-raising exposures reduce the
      hyperviscosity burden.
  evidence:
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Agents/circumstances to avoid: Dehydration; activities that could increase blood viscosity (e.g., living or prolonged stay at high altitudes, scuba diving, and smoking); additional cardiovascular risks (e.g., hypertension, hyperlipidemia, diabetes, and obesity); erythropoiesis-stimulating agents."
    explanation: >-
      GeneReviews "agents/circumstances to avoid", the drug-safety and exposure
      guidance for PFCE.
- name: Genetic counseling
  description: >-
    Autosomal dominant transmission with incomplete penetrance makes genetic
    counseling and cascade testing of relatives appropriate once a causal EPOR
    variant is identified.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:8506290
    reference_title: Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation cosegregates with the disease phenotype in all 29 affected family members studied"
    explanation: >-
      The clear dominant cosegregation across a large kindred is the basis for
      cascade family testing and counseling.
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Each child of an individual with EPOR-related PFCE has a 50% chance of inheriting the EPOR pathogenic variant."
    explanation: >-
      The GeneReviews recurrence-risk figure that genetic counseling conveys.
  - reference: PMID:27831681
    reference_title: Primary Familial and Congenital Erythrocytosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Once the EPOR pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for PFCE are possible."
    explanation: >-
      GeneReviews notes prenatal and preimplantation testing become possible once
      the family variant is known.
animal_models:
- name: Humanized truncated EPOR knock-in mouse
  species: Mouse
  genotype: Murine Epor replaced by a truncated mutant human EPOR allele
  publication: PMID:11158582
  modeled_mechanisms:
  - target: Increased Red Cell Mass
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Replacement of the murine Epor with a mutant human EPOR truncated after the
      first intracellular tyrosine reproduced the human disorder: heterozygous
      mice mimicked the disease and homozygous mice were severely polycythemic,
      establishing the truncated receptor as a gain-of-function cause of
      polycythemia in vivo.
    limitations: >-
      Erythropoiesis differs between mouse and human, and the phenotype required
      the human receptor rather than a truncated mouse receptor; consequences of
      EPOR truncation in non-erythroid tissues were unknown in this study.
    evidence:
    - reference: PMID:11158582
      reference_title: "Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice heterozygous for this mutant allele and a wild-type human EPOR allele mimicked the human disorder. Interestingly, mice that were homozygous for the mutant human allele were severely polycythemic but viable."
      explanation: >-
        Establishes the knock-in as a faithful in vivo model of the human
        polycythemia and its genetic cause.
notes: >-
  Lump/split. This entry is the primary (EPO-low) counterpart of the secondary,
  EPO-high congenital erythrocytoses already curated: Chuvash polycythemia
  (germline VHL) and Familial Erythrocytosis 4 (germline EPAS1/HIF2A
  gain-of-function). All three present as isolated erythrocytosis, but the lesion
  here is intrinsic to the erythroid progenitor's own receptor rather than to the
  oxygen-sensing pathway, so erythropoietin is suppressed (low/subnormal) rather
  than inappropriately normal or elevated. That biochemical sign is the single
  cleanest discriminator and is carried both as a phenotype
  (Reduced circulating erythropoietin concentration) and as a dedicated
  pathophysiology node. It is kept as one disease (ECYT1 / PFCP = MONDO:0007572,
  OMIM 133100), not split by variant: the different EPOR variants converge on the
  same clinical entity, and the one mechanistic split worth recording - simple
  truncation versus the frameshift novel-C-terminal-tail mechanism (PMID:29269524)
  - is modelled as two parallel upstream pathophysiology nodes rather than as
  separate diseases.

  SHP-1. The classic teaching names the SHP-1 (PTPN6) docking tyrosine as the
  negative regulator lost by the truncation. The abstracts cited establish loss
  of the C-terminal negative regulatory domain and escape from PI3K/p85-mediated
  internalization and ubiquitin-proteasomal degradation (PMID:20096014), but not
  the SHP-1 identity, so SHP-1 is named only as context in the genetic notes and
  is not asserted as a node.

  Thrombosis mechanism. The edge from Blood Hyperviscosity to Thromboembolism is
  marked INDIRECT_UNKNOWN_INTERMEDIATES: the New Caledonia report notes that the
  mechanisms of thrombosis in congenital erythrocytosis are complex and that
  phlebotomy benefit is debated (it is harmful in Chuvash polycythemia), so
  hyperviscosity is one contributor rather than the sole cause.

  Deep research. Curated from a thin claude_code deep-research report
  (research/Primary_Familial_Polycythemia_Due_To_EPO_Receptor_Mutation-deep-research-claude_code.md),
  which ran three web searches and explicitly flagged almost all of its content as
  unverified leads. The report's three verified PMIDs (29269524, 20096014,
  11158582) plus independent PubMed searches supplied the backbone: de la Chapelle
  et al. 1993 (PMID:8506290), Sokol et al. 1995 (PMID:7795221), Kralovics et al.
  1998 (PMID:9649565), Arcasoy and Karayal 2005 (PMID:15878737), the New Caledonia
  cohort (PMID:38546672) and the 2026 JAK2-unmutated erythrocytosis review
  (PMID:41123216). Every snippet was verified against the cached record. A
  GeneReviews chapter exists and was used as the phenotype and management
  baseline (PMID:27831681, "Primary Familial and Congenital Erythrocytosis");
  the committed offline Bookshelf index snapshot did not list it, but PubMed
  genereviews[book] returns it and it is tagged below.
references:
- reference: PMID:27831681
  title: Primary Familial and Congenital Erythrocytosis.
  tags:
  - GeneReviews
- reference: PMID:8506290
  title: Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.
- reference: PMID:7795221
  title: "Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin."
- reference: PMID:9649565
  title: Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia.
- reference: PMID:29269524
  title: New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis.
- reference: PMID:20096014
  title: Advances in understanding the pathogenesis of primary familial and congenital polycythaemia.
- reference: PMID:15878737
  title: "Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain."
- reference: PMID:24533580
  title: "Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR): mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras."
- reference: PMID:11158582
  title: "Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene."
- reference: PMID:38546672
  title: Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
- reference: PMID:41123216
  title: "JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management."
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
📚

References & Deep Research

References

11
PMID:27831681
Primary Familial and Congenital Erythrocytosis.
No top-level findings curated for this source.
PMID:8506290
Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.
No top-level findings curated for this source.
PMID:7795221
Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin.
No top-level findings curated for this source.
PMID:9649565
Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia.
No top-level findings curated for this source.
PMID:29269524
New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis.
No top-level findings curated for this source.
PMID:20096014
Advances in understanding the pathogenesis of primary familial and congenital polycythaemia.
No top-level findings curated for this source.
PMID:15878737
Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain.
No top-level findings curated for this source.
PMID:24533580
Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR): mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras.
No top-level findings curated for this source.
PMID:11158582
Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene.
No top-level findings curated for this source.
PMID:38546672
Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia.
No top-level findings curated for this source.
PMID:41123216
JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Lump/split. This entry is the primary (EPO-low) counterpart of the secondary, EPO-high congenital erythrocytoses already curated: Chuvash polycythemia (germline VHL) and Familial Erythrocytosis 4 (germline EPAS1/HIF2A gain-of-function). All three present as isolated erythrocytosis, but the lesion here is intrinsic to the erythroid progenitor's own receptor rather than to the oxygen-sensing pathway, so erythropoietin is suppressed (low/subnormal) rather than inappropriately normal or elevated. That biochemical sign is the single cleanest discriminator and is carried both as a phenotype (Reduced circulating erythropoietin concentration) and as a dedicated pathophysiology node. It is kept as one disease (ECYT1 / PFCP = MONDO:0007572, OMIM 133100), not split by variant: the different EPOR variants converge on the same clinical entity, and the one mechanistic split worth recording - simple truncation versus the frameshift novel-C-terminal-tail mechanism (PMID:29269524) - is modelled as two parallel upstream pathophysiology nodes rather than as separate diseases. SHP-1. The classic teaching names the SHP-1 (PTPN6) docking tyrosine as the negative regulator lost by the truncation. The abstracts cited establish loss of the C-terminal negative regulatory domain and escape from PI3K/p85-mediated internalization and ubiquitin-proteasomal degradation (PMID:20096014), but not the SHP-1 identity, so SHP-1 is named only as context in the genetic notes and is not asserted as a node. Thrombosis mechanism. The edge from Blood Hyperviscosity to Thromboembolism is marked INDIRECT_UNKNOWN_INTERMEDIATES: the New Caledonia report notes that the mechanisms of thrombosis in congenital erythrocytosis are complex and that phlebotomy benefit is debated (it is harmful in Chuvash polycythemia), so hyperviscosity is one contributor rather than the sole cause. Deep research. Curated from a thin claude_code deep-research report (research/Primary_Familial_Polycythemia_Due_To_EPO_Receptor_Mutation-deep-research-claude_code.md), which ran three web searches and explicitly flagged almost all of its content as unverified leads. The report's three verified PMIDs (29269524, 20096014, 11158582) plus independent PubMed searches supplied the backbone: de la Chapelle et al. 1993 (PMID:8506290), Sokol et al. 1995 (PMID:7795221), Kralovics et al. 1998 (PMID:9649565), Arcasoy and Karayal 2005 (PMID:15878737), the New Caledonia cohort (PMID:38546672) and the 2026 JAK2-unmutated erythrocytosis review (PMID:41123216). Every snippet was verified against the cached record. A GeneReviews chapter exists and was used as the phenotype and management baseline (PMID:27831681, "Primary Familial and Congenital Erythrocytosis"); the committed offline Bookshelf index snapshot did not list it, but PubMed genereviews[book] returns it and it is tagged below.

Create: Primary Familial Polycythemia Due to EPO Receptor Mutation · 2026-10-15T04:30:24Z · View source

De-novo curation of PFCP/ECYT1 (EPOR, hgnc:3416, MONDO:0007572), the primary (EPO-low) counterpart of the secondary erythrocytosis siblings Chuvash polycythemia and Familial Erythrocytosis 4. Deep-research provider claude_code; the report was thin (3 web searches, most content flagged unverified) so it was used only for leads. Backbone PMIDs independently fetched and verified: 8506290 (de la Chapelle 1993 sentinel kindred), 7795221 (Sokol 1995 frameshift + BFU-E hypersensitivity), 9649565 (Kralovics 1998 incomplete penetrance), 29269524 (Pasquier 2017 frameshift novel-tail mechanism), 20096014 (Huang 2010 down-regulation review), 15878737 (Arcasoy 2005 Y344/STAT5), 24533580 (EGFR-EPOR chimeras), 11158582 (Divoky 2001 humanized knock-in mouse), 38546672 (New Caledonia founder cohort, phlebotomy+aspirin), 41123216 (2026 JAK2-unmutated erythrocytosis review), 27831681 (GeneReviews baseline). 13-node atomic pathophysiology chain from the EPOR truncation to organism-level consequences, all 12 phenotypes causally connected. Validated: validate-disorders passed (51 snippets, 62 titles, 0 issues); validate-terms, entity-refs, causal-targets, qualifier-terms, duplicate-keys, block-scalar, coarse-phenotypes, cache-integrity all clean. preflight-dr WARN (benign: EPO co-mention is the receptor ligand; OMIM 133100 and gene EPOR match). GeneReviews chapter PMID:27831681 exists and is tagged; offline Bookshelf index snapshot missed it. Review round 1 (ai4c-reviewer, changes requested): rebound the stroke phenotype from HP:0002140 Ischemic stroke to HP:0001297 Stroke (source does not specify ischemic; renamed node and the Thromboembolism sequela target); added GeneReviews (PMID:27831681) evidence to the molecular-diagnosis row, the gene-testing row, the reduced-EPO phenotype (below-normal-EPO criterion), and the genetic-counseling treatment (50% recurrence, prenatal/PGT); added Tinnitus (HP:0000360) and Visual impairment (HP:0000505) hyperviscosity phenotypes wired from Blood Hyperviscosity; grounded the frameshift-tail node with GO:0004900 erythropoietin receptor activity; swapped PMID:8506290 to its direct 'negative control on erythropoiesis' quote with directness INDIRECT; set quote_role BACKGROUND on the two PMID:38546672 JAK2/STAT5 introductory snippets; noted the Dizziness->Vertigo binding choice. 58/58 snippets, 14/14 phenotypes connected, just validate-disorders clean. Review round 2 (ai4c-reviewer): replaced the 4-word 'below normal erythropoietin concentration' snippet with the full GeneReviews diagnostic-criteria sentence (clears check-snippet-length), added that GR evidence to the Serum erythropoietin measurement diagnosis row as well, and marked the Thromboembolism->Stroke sequela INDIRECT with a caveat that GeneReviews also names intracerebral hemorrhage, which a thromboembolic edge does not explain. 59/59 snippets verified, check-snippet-length clean, just validate-disorders clean.

Claude Code ▸
Primary Familial Polycythemia Due to EPO Receptor Mutation (EPOR-related ECYT1/PFCP): Research Report
claude-haiku-5-5, claude-sonnet-5-5 10 citations 2026-10-15T03:59:13.236455

Primary Familial Polycythemia Due to EPO Receptor Mutation (EPOR-related ECYT1/PFCP): Research Report

Verification status. I ran three web searches. Only three PMIDs came back with a source I could read, and I marked those [verified]. Everything else is from my background knowledge and is marked [unverified]. Under this repository's rules, an unverified item is a lead only. Run just fetch-reference PMID:<id> and check the snippet before it becomes evidence. I did not read any abstract in full, so I give no direct quotes except short fragments from the search results. The MONDO ID given in the template (MONDO:0007572) and every HPO, GO, CL, UBERON and NCIT ID below also need an OAK lookup before binding. I wrote none of them from a lookup.

1. Disease information

  • What it is. An autosomal dominant erythrocytosis. The red cell mass is raised because of a germline EPOR mutation, and serum erythropoietin (EPO) is low or low-normal. It is called "primary" because the defect is intrinsic to erythroid progenitors, not to oxygen sensing or EPO production.
  • Identifiers.
  • OMIM #133100, "Erythrocytosis, familial, 1 (ECYT1)", with primary familial and congenital polycythemia (PFCP) as an alternative title (OMIM mirror).
  • Orphanet ORPHA:90042 (reached through the PhenoDis mirror).
  • MedGen C4551637 (MedGen).
  • GARD and NORD pages exist (GARD, NORD MONDO page).
  • I have not checked MONDO, ICD-10/11 or MeSH.
  • Synonyms. Primary familial and congenital polycythemia (PFCP); familial erythrocytosis type 1; familial benign erythrocytosis; EPOR-related erythrocytosis.
  • Source level. The resources above are aggregated disease-level records. The primary papers are family and cohort reports.

2. Etiology

  • Cause. Heterozygous germline EPOR mutations. "All mutations so far described lead to the truncation of the C-terminal receptor sequence that contains negative regulatory domains" (Pasquier et al. 2017, [PMID:29269524] [verified]). The mutations are nonsense or frameshift variants, mostly in the last exon, exon 8.
  • Example. An EPOR G1251T change (a premature stop codon at residue 393) in one family, with a 20-fold rise in circulating endothelial precursors (PLoS ONE 2010; PMID not retrieved) [unverified].
  • Frequency among cases. One source says EPOR mutations explain roughly 12–15% of PFCP. A screen of 270 cases found EPOR mutations in only 1.1% of them. These figures conflict, probably because the cohorts were selected differently. Most erythrocytosis cases have no identified cause. Both figures are unverified.
  • Modifiers. Kralovics et al. (J Clin Invest 1998) described an affected child with a unique EPOR mutation who did not develop polycythemia even though their erythroid progenitors were hypersensitive to EPO. The authors suggested unidentified environmental or genetic modifiers may suppress disease. The abstract was not fetched, so I did not use its wording. Penetrance of the biochemical defect is therefore not equal to penetrance of the clinical phenotype.
  • Environmental and protective factors. None established. Carriers of a gain-of-function EPOR variant may be more sensitive to hypoxia (altitude, smoking, sleep apnea) [unverified, inferred].

3. Phenotypes

Suggested HPO terms need lookup before binding.

Phenotype Notes HPO (to verify)
Erythrocytosis (raised hemoglobin and hematocrit) Core feature HP:0001899
Low or low-normal serum EPO Key laboratory finding not looked up
Normal white cell and platelet counts Distinguishes it from polycythemia vera not looked up
Hyperviscosity symptoms: headache, dizziness, plethora Variable not looked up
Thrombosis, myocardial infarction, stroke Complication; frequency uncertain not looked up
Hypertension and coronary disease OMIM lists cardiovascular features, including myocardial infarction, coronary artery disease, hypertension and peripheral thrombosis not looked up
  • Onset. Congenital or childhood, with variable penetrance. Many carriers are found by family screening.
  • Quality of life. I found no quantitative data.
  • Frequencies. I did not retrieve per-feature frequencies.

4. Genetic and molecular information

  • Gene. EPOR, 19p13.2. The HGNC ID is not looked up; this repository writes it as lowercase hgnc:<n>.
  • Variant class. Nonsense or frameshift variants that truncate the cytoplasmic C-terminus. This removes negative regulatory domains, including the binding site for SHP-1 (a phosphatase) and the residues needed for receptor internalization and degradation [unverified, standard mechanism].
  • Functional consequence. Gain of function through loss of negative regulation. Huang et al. 2010 ([PMID:20096014] [verified]) reviewed several lines of evidence for a causal role of the truncated receptor. They note that truncated PFCP EpoRs are not properly down-regulated upon stimulation.
  • Different variants act by different mechanisms. Pasquier 2017 concludes that mutation types act through distinct mechanisms. A frameshift variant reported in Haematologica (PMID not retrieved) showed "a strong gain-of-function mutation, which induces major erythropoietin hypersensitivity in primary erythroid progenitors", with persistent JAK2 and STAT5 activation [unverified].
  • Origin. Germline. Population frequency, ClinVar classification and modifier genes were not checked.
  • Epigenetics and chromosomal abnormalities. Not applicable and not researched.

5. Environmental information

None established. Cardiovascular risk factors such as smoking probably add to thrombotic risk [inferred]. No infectious agents are involved.

6. Mechanism and pathophysiology

Causal chain

  1. A germline nonsense or frameshift variant in the last EPOR exon causes truncation of the cytoplasmic C-terminus. (Demonstrated.)
  2. The truncated receptor lacks negative regulatory domains. These include the docking site for negative regulators (SHP-1) and the signals for internalization and degradation. (Demonstrated for some variants; the exact domain varies.)
  3. The receptor is not properly down-regulated after ligand binding, so it persists on the cell surface. (Demonstrated for the G1251T variant in the PLoS ONE report.)
  4. JAK2 and STAT5 activation is prolonged after EPO binding. (Demonstrated for at least one frameshift variant.)
  5. Erythroid progenitors (BFU-E and CFU-E) become hypersensitive to EPO and grow with very little or no added EPO. (Demonstrated.)
  6. Red cell production rises despite low EPO, and erythrocytosis results. Low EPO is the expected feedback response to the raised red cell mass. (Demonstrated.)
  7. Raised hematocrit increases blood viscosity and may lead to thrombotic and cardiovascular events. (Inferred from clinical association; the strength of the effect is uncertain.)

Branch. Some variants may not simply be hyperactive. They may act by distinct mechanisms (Pasquier 2017), so the chain above is the common case, not a universal one.

Candidate GO and CL terms (to verify) - Erythrocyte differentiation. - Erythropoietin-mediated signaling pathway. - JAK-STAT cascade. - Negative regulation of receptor signaling. - Erythroid progenitor cell (CL), erythrocyte (CL).

Not researched. Omics, single-cell and CRISPR screens.

7. Anatomical structures affected

  • Bone marrow is the primary site. Blood is where the erythrocytosis shows. The vasculature is affected secondarily through hyperviscosity.
  • Cell types are the erythroid progenitor and the erythrocyte. The PLoS ONE report also found raised circulating endothelial precursors [unverified].
  • Subcellular site: the plasma membrane receptor and its cytoplasmic domain, with downstream JAK2/STAT5 signaling in the cytoplasm and nucleus.
  • No lateralization.

8. Temporal development

  • Congenital or early onset, chronic and lifelong. Whether it progresses was not established. Complications probably accumulate with age.
  • No spontaneous remission is known. I found no data on critical periods.

9. Inheritance and population

  • Inheritance. Autosomal dominant. Penetrance of the clinical phenotype is incomplete (Kralovics 1998 report of a non-polycythemic carrier child).
  • Prevalence. Very rare. No reliable prevalence figure retrieved.
  • Founder effect. A study titled "Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia" (PMID not retrieved) suggests a large regional cluster [unverified]. I did not read it.
  • Sex ratio, ancestry and consanguinity. Not researched.

10. Diagnostics

  • Laboratory findings. Raised hemoglobin and hematocrit, low or low-normal EPO, normal white cell and platelet counts.
  • Exclusion of other causes. Rule out JAK2 V617F and exon 12 variants (polycythemia vera). Also rule out secondary causes: hypoxia, renal disease and EPO-secreting tumors. Check other familial erythrocytosis genes (VHL, EGLN1, EPAS1, HBB and others) [standard practice, unverified here].
  • Genetic testing. EPOR sequencing, with exon 8 as the hot spot, or an erythrocytosis gene panel. Family history and a typical pattern of dominant inheritance support the diagnosis.
  • Bone marrow culture. Endogenous erythroid colonies and EPO hypersensitivity can be shown in vitro, but this is not routine.

11. Outcome and prognosis

  • Survival and life expectancy data are not retrieved.
  • The main risks are thrombosis and cardiovascular events, linked to hematocrit [inferred].
  • Cardiovascular outcomes are not uniform. Reports describe both families with early events and families with a benign course [inferred, unverified].

12. Treatment

  • Phlebotomy. Used periodically to relieve symptoms or keep hematocrit near normal. The target hematocrit in this disease is debated. It is not firmly established, and the polycythemia vera targets may not transfer [unverified].
  • Low-dose aspirin. The New Caledonia study above addresses phlebotomy plus aspirin for preventing vascular events. I did not retrieve its results.
  • Cytoreduction and JAK2 inhibition. My searches did not find any evidence on ruxolitinib or hydroxyurea in EPOR-related disease. The pathway is JAK2-dependent, so a JAK2 inhibitor is a plausible hypothesis. It is not an established treatment. Do not curate it as one.
  • Cardiovascular risk-factor management applies.
  • NCIT terms: phlebotomy and Pharmacotherapy (NCIT:C15986, taken from the CLAUDE.md list); the phlebotomy ID is not looked up.
  • No clinical trials were identified.

13. Prevention

  • Genetic counseling and cascade testing of relatives.
  • Tertiary prevention: control of hematocrit and of cardiovascular risk factors, and avoiding dehydration.
  • No primary prevention or vaccination applies.

14. Other species and natural disease

No naturally occurring animal disease was identified. OMIA was not searched.

15. Model organisms

  • Human truncated EPOR knock-in mouse. Divoky et al. 2001 ([PMID:11158582] [verified]) replaced the murine gene with the mutant human EPOR. The mice became polycythemic. A later report says the phenotype appeared at 3 to 6 weeks of age but not at birth, mirroring the human disease (J Mol Med 2015; PMID not retrieved).
  • Truncated mouse EpoR. Mice carrying the truncated mouse receptor were not polycythemic, so the phenotype depended on the human receptor. The authors noted that erythropoiesis differs between mice and humans. This is a possible HUMAN_MODEL_MISMATCH discussion in the KB. The details need confirmation from the full papers.
  • Limitation. Consequences in non-erythroid tissues were unknown in the 2001 paper.

Gaps to close before curation

  1. Fetch and verify PMIDs for Kralovics 1998, the PLoS ONE 2010 G1251T paper, the Haematologica frameshift paper, the J Mol Med 2015 mouse paper, and the New Caledonia study.
  2. Confirm the GeneReviews and Orphanet content. GeneReviews did not surface in my searches.
  3. Look up every MONDO, HP, GO, CL, UBERON and NCIT ID above with OAK. Check that the stub's MONDO ID matches this entity.
  4. Find data on prevalence, thrombosis frequency, and treatment outcome, including ruxolitinib, if any exists.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 5
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 4
Resolved 3
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 0
Terms whose name is worth a second look 1

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001899 (1 mention) - the report calls it "Core feature"; HP calls it Increased hematocrit

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

3 of 4 terms resolved to a current term; the rest could not be looked up either way.