EGLN1-related Erythrocytosis and Pheochromocytoma/Paraganglioma Predisposition

Mendelian MONDO:1060184 Pathograph 19 Show in embeddings browser hereditary neoplastic syndrome Congenital Secondary Erythrocytosis

EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition is an autosomal dominant disorder of oxygen sensing caused by heterozygous germline loss-of-function variants in EGLN1, which encodes prolyl hydroxylase domain protein 2 (PHD2), the principal HIF prolyl hydroxylase. In normoxia PHD2 hydroxylates the alpha subunits of hypoxia-inducible factor, marking them for VHL-dependent proteasomal destruction; when PHD2 activity falls, HIF-alpha (predominantly HIF-2-alpha) accumulates despite adequate oxygen — pseudohypoxia. The systemic consequence is inappropriate erythropoietin output with erythrocytosis; the erythropoietin level is generally inappropriately normal for the hemoglobin, occasionally elevated, and rarely low, the arm that dominates the clinical picture and is driven by haploinsufficiency alone. The neoplastic consequence is a predisposition to pseudohypoxic (cluster 1) pheochromocytoma and paraganglioma; this is a two-hit tumor-suppressor mechanism in which somatic loss of the wild-type EGLN1 allele (loss of heterozygosity has been demonstrated in tumor tissue) completes biallelic inactivation in a chromaffin progenitor. ClinGen (SOP11, Childhood/Adolescent/ Young Adult Cancer Predisposition GCEP) classifies the gene-disease relationship as Definitive and lumped familial erythrocytosis 3 (OMIM:609820) and the PPGL predisposition (OMIM:171300) into this single entity. Two points of granularity matter for a reader: tumor development is a very rare event among EGLN1 carriers and shows variable expressivity, so most carriers present with erythrocytosis only; and the PPGL predisposition shares its final common pathway (pseudohypoxic HIF-2-alpha stabilization) with VHL-, EPAS1-, and SDHx-driven PPGL while reaching it from the opposite direction — a direct genetic lesion of the hydroxylase rather than ligase loss or oncometabolite inhibition. This entry is the germline predisposition syndrome and is kept separate from the somatic pheochromocytoma/paraganglioma it predisposes to (design decisions section 3a).

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1
Mappings
1
Inheritance
6
Pathophys.
7
Phenotypes
1
Gaps
19
Pathograph
1
Genes
4
Medical Actions
1
Trials
2
Models
1
Deep Research
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Mappings

MONDO
MONDO:0012353 erythrocytosis, familial, 3 Not Yet Curated
skos:narrowMatch MONDO (OMIM:609820)
ECYT3 (OMIM:609820) is the erythrocytosis-only arm of this gene-disease association. ClinGen's Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP lumped familial erythrocytosis 3 (OMIM:609820) and pheochromocytoma/paraganglioma (OMIM:171300) into the single MONDO:1060184 entity this entry curates (CGGV assertion 647ffb08-3740-43a0-8601-258324e995ab), so ECYT3 is a narrower (erythrocytosis-only) match rather than an equivalent concept.
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Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant. Carriers are heterozygous; a single germline loss-of-function allele produces erythrocytosis through haploinsufficiency, while the tumor predisposition requires a somatic second hit in chromaffin tissue.
Autosomal dominant inheritance
Show evidence (2 references)
CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z SUPPORT Other
"EGLN1 | HGNC:1232 | EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition | MONDO:1060184 | AD | Definitive"
ClinGen records the mode of inheritance as autosomal dominant (AD) for this gene-disease pair.
PMID:24121508 SUPPORT Model Organism
"These studies formally prove that a missense mutation in PHD2 is the cause of the erythrocytosis, show that this occurs through haploinsufficiency"
Establishes the haploinsufficiency basis consistent with dominant inheritance of the erythroid phenotype.
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Discussions and Knowledge Gaps

1
Why is pheochromocytoma/paraganglioma such a rare event among EGLN1 carriers, and what additional factors determine which carriers develop a tumor?
KNOWLEDGE GAP egln1_ppgl_penetrance_gap
Attached to
pathophysiology#Pseudohypoxic Chromaffin Tumorigenesis
Erythrocytosis is near-universal in EGLN1 carriers, but tumor development is a very rare event with marked variable expressivity, and the mouse data suggest the pseudohypoxic chromaffin phenotype depends on dysregulation during adrenal development rather than on PHD2 loss per se. Whether a somatic second hit is necessary and sufficient, or whether additional genetic/developmental events are required, is unresolved.
Show evidence (1 reference)
PMID:37317877 SUPPORT Human Clinical
"showed that tumor development can be considered a very rare event"
Quantifies the rarity of tumor development among EGLN1 carriers, framing the penetrance gap.
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Pathophysiology

6
Germline EGLN1/PHD2 Loss-of-Function
A heterozygous germline loss-of-function variant in EGLN1 reduces the catalytic activity of PHD2, the principal HIF prolyl hydroxylase, in every cell. Reported alleles are missense and truncating (nonsense, frameshift) and the overall mechanism of pathogenicity is loss of function. For the erythroid phenotype this single allele is sufficient: haploinsufficiency and partial deregulation of PHD2 is enough to cause erythrocytosis, so no second hit is required. For the tumor phenotype the constitutional allele is the first hit of a two-hit tumor-suppressor mechanism.
EGLN1 hgnc:1232 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EGLN1 (hgnc:1232). hgnc:1232 is a gene from the HUGO Gene Nomenclature Committee.
HIF prolyl hydroxylase (PHD2) activity GO:0160082 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased HIF prolyl hydroxylase (PHD2) activity, annotated with hypoxia-inducible factor-proline dioxygenase activity (GO:0160082). GO:0160082 is a molecular function from the Gene Ontology.
Downstream
Pseudohypoxic HIF-2-alpha Stabilization Reduced PHD2 activity slows HIF-alpha hydroxylation, so HIF-alpha escapes VHL-dependent degradation and accumulates despite normal oxygen tension.
Somatic Loss of the Wild-Type EGLN1 Allele in Chromaffin Tissue The constitutional loss-of-function allele is present in every chromaffin progenitor, so a single somatic event inactivating the remaining wild-type allele is sufficient to initiate a pseudohypoxic tumor.
Show evidence (2 references)
PMID:16407130 SUPPORT Human Clinical
"We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis"
The first reported human PHD2/EGLN1 variant, establishing that the erythrocytosis arises from decreased PHD2 enzyme activity.
CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z SUPPORT Other
"The mechanism of pathogenicity appears to be loss of function"
ClinGen's conclusion on the direction of effect for the EGLN1 variants in this gene-disease curation.
Pseudohypoxic HIF-2-alpha Stabilization
HIF-alpha subunits accumulate and dimerize with HIF-1-beta at normal oxygen tension. HIF-2-alpha is the dominant effector isoform: in the knock-in mouse the PHD2-associated erythrocytosis is reversed by Hif2a heterozygosity but not Hif1a heterozygosity, and the mouse adrenal-medulla phenotype is likewise HIF-2-alpha- rather than HIF-1-alpha-dependent. The stabilized dimer drives the hypoxia transcriptional program while oxygen is adequate.
HIF-mediated hypoxia response in normoxia GO:0001666 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves HIF-mediated hypoxia response in normoxia, annotated with response to hypoxia (GO:0001666), qualified as gain of function. GO:0001666 is a biological process from the Gene Ontology.
Downstream
Inappropriate Erythropoietin Drive Stabilized HIF-2-alpha transcribes the EPO gene, raising erythropoietin output for the prevailing hemoglobin.
Show evidence (2 references)
PMID:19092153 SUPPORT Human Clinical
"This mutation affects PHD2 function and stabilizes HIF-alpha proteins"
Demonstrates in a patient that the PHD2 variant stabilizes HIF-alpha, the defining molecular step of this node.
PMID:24121508 SUPPORT Model Organism
"The Phd2(P294R/+)-associated erythrocytosis is reversed in a Hif2a(+/-), but not a Hif1a(+/-) background"
Genetic epistasis in the knock-in mouse establishing HIF-2-alpha as the dominant effector isoform for the erythroid arm.
Inappropriate Erythropoietin Drive
HIF-2-alpha drives transcription of the EPO gene so that erythropoietin output is inappropriate for the prevailing hemoglobin. The level is generally inappropriately normal, occasionally frankly elevated, and rarely low; a normal EPO is the usual finding and does not exclude the diagnosis.
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.
cellular response to hypoxia driving EPO transcription GO:0071456 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to hypoxia driving EPO transcription, annotated with cellular response to hypoxia (GO:0071456). GO:0071456 is a biological process from the Gene Ontology.
Downstream
Erythroid Progenitor Expansion Raised erythropoietin signalling expands the erythroid compartment.
Elevated circulating erythropoietin concentration Erythropoietin is inappropriately normal to high for the hemoglobin.
Show evidence (1 reference)
PMID:27774468 SUPPORT REVIEW SYNTHESIS Model Organism
"A knockin mouse model expressing the first reported PHD2-P317R mutation recapitulates the phenotype observed in humans (erythrocytosis with inappropriately normal serum EPO levels)"
States the inappropriately-normal EPO signature of the erythroid phenotype, confirmed in the knock-in mouse.
Erythroid Progenitor Expansion
Erythropoietin-driven expansion of the erythroid compartment raises the red cell mass. Unlike polycythemia vera, white cell and platelet lineages are not expanded.
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.
erythrocyte differentiation GO:0030218 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology.
Animal models
Phd2 P294R knock-in mouse Mouse recapitulates Knock-in of the P294R allele modeling the first human PHD2 variant produces erythrocytosis equivalent to Phd2 heterozygous null, reversed by Hif2a but not Hif1a heterozygosity, proving a haploinsufficiency mechanism acting through HIF-2-alpha.
Downstream
Polycythemia Erythroid expansion raises the red cell mass.
Increased circulating hemoglobin concentration Erythroid expansion raises hemoglobin.
Increased hematocrit Erythroid expansion raises hematocrit, the usual presenting abnormality.
Thromboembolism Erythrocytosis and hyperviscosity contribute to a prothrombotic tendency; thrombotic events are a documented, though uncommon, complication.
Show evidence (1 reference)
PMID:24121508 SUPPORT Model Organism
"These studies formally prove that a missense mutation in PHD2 is the cause of the erythrocytosis, show that this occurs through haploinsufficiency"
The knock-in mouse establishes that PHD2 loss expands the red cell mass through haploinsufficiency.
Somatic Loss of the Wild-Type EGLN1 Allele in Chromaffin Tissue
A somatic event inactivates the remaining wild-type EGLN1 allele in a chromaffin progenitor, completing biallelic PHD2 loss. Loss of heterozygosity of PHD2 has been demonstrated directly in paraganglioma tissue from a carrier, which is the observation that identified EGLN1/PHD2 as a tumor-suppressor gene in this setting.
EGLN1 hgnc:1232 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EGLN1 (hgnc:1232). hgnc:1232 is a gene from the HUGO Gene Nomenclature Committee.
HIF prolyl hydroxylase (PHD2) activity GO:0160082 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased HIF prolyl hydroxylase (PHD2) activity, annotated with hypoxia-inducible factor-proline dioxygenase activity (GO:0160082). GO:0160082 is a molecular function from the Gene Ontology.
Downstream
Pseudohypoxic Chromaffin Tumorigenesis Biallelic PHD2 loss stabilizes HIF-2-alpha in the adrenal medulla and sympathetic/parasympathetic paraganglia, driving a pseudohypoxic tumor.
Show evidence (1 reference)
PMID:19092153 SUPPORT Human Clinical
"we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene"
Direct demonstration of somatic second-hit loss of heterozygosity in the paraganglioma, establishing the two-hit mechanism.
Pseudohypoxic Chromaffin Tumorigenesis
Constitutive HIF-2-alpha activity in chromaffin tissue produces a cluster 1 (pseudohypoxic) pheochromocytoma or paraganglioma. In the mouse, inactivating Phd2 in the adrenal medulla reproduces the gene-expression signature of pseudohypoxic PPGL, and the effect is HIF-2-alpha- rather than HIF-1-alpha-dependent. The tumor arm shows marked variable expressivity and low penetrance, and some tumors arise with little or no erythrocytosis.
chromaffin cell CL:0000166 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chromaffin cell (CL:0000166). CL:0000166 is a cell type from the Cell Ontology.
Animal models
Adrenal-medulla Phd2 conditional knockout mouse Mouse partially recapitulates Adrenal-medulla Phd2 inactivation reproduces the gene-expression signature of pseudohypoxic PPGL in a HIF-2-alpha-dependent manner, but the changes arise only when Phd2 is inactivated during adrenal development, not in adult life, and the model produces developmental abnormalities rather than frank tumors.
Downstream
Pheochromocytoma Adrenal-medullary pseudohypoxic tumor.
Paraganglioma Extra-adrenal pseudohypoxic paraganglial tumor.
Show evidence (2 references)
PMID:34658364 SUPPORT Model Organism
"Investigation of these animals revealed a gene expression pattern closely mimicking that of pseudohypoxic PPGL"
Adrenal-medulla Phd2 inactivation in mice reproduces the pseudohypoxic PPGL expression signature.
PMID:34658364 SUPPORT Model Organism
"These changes were ablated by combined inactivation of Phd2 with Hif-2α, but not Hif-1α"
Establishes HIF-2-alpha as the effector isoform for the chromaffin tumor arm.
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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 EGLN1-related Erythrocytosis and Pheochromocytoma/Paraganglioma Predisposition 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

7
Blood 4
Polycythemia HP:0001901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythrocytosis, annotated with Polycythemia (HP:0001901). HP:0001901 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37317877 SUPPORT Human Clinical
"Patients with PHD2 mutations develop secondary hereditary erythrocytosis with high to normal EPO serum levels, a normal concentration being inappropriate in view of the high hematocrit"
States that PHD2-mutation carriers develop secondary hereditary erythrocytosis, the defining phenotype. Frequency omitted: no source gives a percentage, and this cohort was ascertained through erythrocytosis.
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:27034858 SUPPORT REVIEW SYNTHESIS Human Clinical
"with PHD2 mutations there is moderate erythrocytosis and erythropoietin (Epo) levels are generally low to normal"
Characterizes the magnitude of the erythrocytosis and the accompanying EPO range across reported cases.
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:37317877 SUPPORT Human Clinical
"Patients with PHD2 mutations develop secondary hereditary erythrocytosis with high to normal EPO serum levels, a normal concentration being inappropriate in view of the high hematocrit"
Explicitly ties the PHD2-mutation phenotype to a high hematocrit.
Thromboembolism OCCASIONAL 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.
Show evidence (1 reference)
PMID:27034858 SUPPORT REVIEW SYNTHESIS Human Clinical
"one mutation was associated with sagittal sinus thrombosis"
Reports a thrombotic complication in a PHD2-mutation carrier.
Endocrine 3
Elevated circulating erythropoietin concentration OCCASIONAL HP:0033644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating erythropoietin concentration (HP:0033644). HP:0033644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27034858 SUPPORT REVIEW SYNTHESIS Human Clinical
"twenty-one patients had normal EPO levels, four patients had unexplained elevated levels, two had a low level"
The actual EPO distribution across reported PHD2-mutation carriers: normal in most, elevated in a minority, low in a few — so elevated EPO is the occasional, not the usual, finding.
Pheochromocytoma HP:0002666 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pheochromocytoma (HP:0002666). HP:0002666 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27034858 SUPPORT REVIEW SYNTHESIS Human Clinical
"Two patients with PHD2 substitution mutations were found to have paraganglioma and one of these patients had a concurrent pheochromocytoma"
Documents pheochromocytoma in the spectrum of EGLN1/PHD2 carriers.
Paraganglioma HP:0002668 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paraganglioma (HP:0002668). HP:0002668 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19092153 SUPPORT Human Clinical
"We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation"
The sentinel case establishing paraganglioma in the EGLN1/PHD2 phenotype.
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Genetic Associations

1
EGLN1 germline loss-of-function
Gene: EGLN1 hgnc:1232 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EGLN1 (hgnc:1232). hgnc:1232 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z SUPPORT Other
"23 variants (missense and nonsense) that have been reported in 31 probands in 7 publications"
The genetic evidence base ClinGen scored for this gene-disease curation.
CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z SUPPORT Other
"the following disease entities have been lumped into one disease entity: familial erythrocytosis 3 (OMIM:609820) and pheochromocytoma/paraganglioma (OMIM:171300)"
Records ClinGen's lump decision that the single EGLN1 gene-disease entity spans both the erythrocytosis and the PPGL predisposition curated here.
PMID:36013579 SUPPORT Human Clinical
"we found a novel germline PHD2 (EGLN1) gene variant, c.153G>A, p.W51*, in a patient affected by metastatic Pheo and chronic myeloid leukemia (CML) in the absence of polycythemia"
Documents variable expressivity: a truncating germline EGLN1 variant presenting with metastatic pheochromocytoma and no erythrocytosis.
💊

Medical Actions

4
Tumor surveillance
Action: tumor surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is tumor surveillance, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Because EGLN1 carriers are at risk of pheochromocytoma/paraganglioma, expert reports stress ongoing medical monitoring for tumor development; biochemical (metanephrine) and imaging surveillance are filed under diagnosis.
Show evidence (1 reference)
PMID:37317877 SUPPORT Human Clinical
"it is essential to medically monitor the occurrence of a possible tumor"
Expert recommendation to monitor EGLN1 carriers for tumor development.
Therapeutic phlebotomy and low-dose aspirin
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
There is no targeted therapy proven for the erythrocytosis. By analogy with polycythemia vera, phlebotomy and low-dose aspirin have been suggested for symptomatic hyperviscosity, but the benefit is unproven and the practice is debated; in the related Chuvash erythrocytosis, phlebotomy is associated with increased rather than decreased thrombotic risk.
Mechanism Target:
INHIBITS Erythroid Progenitor Expansion — Phlebotomy removes red cell mass to relieve hyperviscosity symptoms; it does not address the underlying HIF dysregulation.
Show evidence (1 reference)
PMID:37317877 SUPPORT Human Clinical
"by analogy with polycythemia vera, phlebotomies and the use of low-dose aspirin, have been suggested"
The suggested, debated supportive management for the erythrocytosis.
HIF-2-alpha inhibition (belzutifan)
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: belzutifan CHEBI:757730 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses belzutifan (CHEBI:757730). CHEBI:757730 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
HIF-2-alpha is the effector of the pseudohypoxic program, so HIF-2-alpha inhibition is a mechanistically rational therapy for the PPGL arm. Belzutifan, a first-in-class HIF-2-alpha inhibitor, was FDA-approved in May 2025 for patients aged 12 or older with locally advanced, unresectable or metastatic pheochromocytoma/paraganglioma, on the LITESPARK-015 phase 2 trial (26% objective response). There is no EGLN1-specific efficacy data; its relevance here is an extrapolation from the shared HIF-2-alpha pathway.
Mechanism Target:
INHIBITS Pseudohypoxic HIF-2-alpha Stabilization — Belzutifan blocks HIF-2-alpha, the effector of the pseudohypoxic program downstream of PHD2 loss.
Show evidence (3 references)
PMID:41301064 SUPPORT REVIEW SYNTHESIS Human Clinical
"In May 2025, the FDA approved belzutifan for adult and pediatric patients ≥12 y with locally advanced, unresectable, or metastatic PPGLs"
Establishes the current regulatory status: belzutifan is approved for advanced PPGL in patients aged 12 and older, not merely investigational.
PMID:41124218 SUPPORT Human Clinical
"the percentage of participants with a confirmed objective response was 26%"
The LITESPARK-015 phase 2 efficacy result behind the approval.
PMID:39426935 SUPPORT REVIEW SYNTHESIS Human Clinical
"one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs"
Review describing belzutifan as a HIF-2-alpha-directed therapy for metastatic PPGL; graded HUMAN_CLINICAL because the quote describes a clinical trial of the drug.
Surgical resection of pheochromocytoma/paraganglioma
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
Surgical resection, with standard perioperative alpha-blockade for catecholamine-secreting tumors, is the curative treatment of a localized pheochromocytoma or paraganglioma, as for hereditary PPGL generally.
Mechanism Target:
INHIBITS Pseudohypoxic Chromaffin Tumorigenesis — Resection removes the chromaffin tumor.
Show evidence (2 references)
PMID:36013579 SUPPORT Human Clinical
"Surgery is the curative option in non-metastatic and metastatic PPGL, and in patients with metastatic disease, tumor resection has been reported to increase overall survival"
States that surgical resection is the curative treatment of PPGL.
PMID:36013579 SUPPORT Human Clinical
"Medical therapy with alpha-blockers is necessary before surgery"
Supports the perioperative alpha-blockade named in the description.
🔬

Diagnosis

3
Germline next-generation sequencing panel
EGLN1 is one of the hereditary pheochromocytoma/paraganglioma susceptibility genes on targeted next-generation-sequencing panels, where it accounts for a small minority of positive cases; it is also on congenital-erythrocytosis gene panels reached from the erythroid presentation.
germline gene-panel testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:34309460 SUPPORT Human Clinical
"Five genes were involved (RET, n = 3; SDHB, n = 3; SDHD, n = 2; EGLN1, n = 1; and NF1, n = 1)"
Shows EGLN1 among the germline genes identified by PPGL panel testing, at low frequency.
Serum erythropoietin measurement
Serum erythropoietin in the workup of the erythrocytosis. It is generally inappropriately normal for the hemoglobin and only occasionally elevated, so a normal result is the common finding and does not exclude the diagnosis.
serum erythropoietin measurement NCIT:C74855 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27034858 SUPPORT REVIEW SYNTHESIS Human Clinical
"twenty-one patients had normal EPO levels, four patients had unexplained elevated levels, two had a low level"
The EPO distribution across reported carriers, showing that a normal result is usual and does not exclude the diagnosis.
Plasma and urinary metanephrine measurement
Biochemical screening for a catecholamine-secreting pheochromocytoma or paraganglioma, as for hereditary PPGL generally.
plasma and urinary metanephrine measurement NCIT:C116198 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:36013579 SUPPORT Human Clinical
"The recommended diagnostic workup for suspected Pheo/PGL (PPGL) includes plasma free metanephrines and fractionated urinary metanephrines"
The recommended biochemical workup for a suspected PPGL.
🔬

Clinical Trials

1
NCT04924075 PHASE_II RECRUITING
LITESPARK-015, a phase 2 trial of belzutifan (a HIF-2-alpha inhibitor) monotherapy in advanced pheochromocytoma/paraganglioma and other tumors with HIF-2-alpha alterations; the PPGL cohort read out a 26% objective response and supported the 2025 FDA approval. No EGLN1-specific arm.
Target Phenotypes: Pheochromocytoma HP:0002666 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Pheochromocytoma (HP:0002666). HP:0002666 is a phenotype from the Human Phenotype Ontology. Paraganglioma HP:0002668 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Paraganglioma (HP:0002668). HP:0002668 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04924075 SUPPORT Other
"This is a study to evaluate the efficacy and safety of belzutifan monotherapy in participants with advanced pheochromocytoma/paraganglioma (PPGL)"
The registry record establishing the trial's identity and scope.
🐁

Animal Models

2
Phd2 P294R knock-in mouse
Species
Mouse
Genotype
Phd2(P294R/+) knock-in (models human PHD2 P317R)
Publication
PMID:24121508
Pathograph links
Erythroid Progenitor Expansion recapitulates fidelity: high observes: organism Knock-in of the P294R allele modeling the first human PHD2 variant produces erythrocytosis equivalent to Phd2 heterozygous null, reversed by Hif2a but not Hif1a heterozygosity, proving a haploinsufficiency mechanism acting through HIF-2-alpha.
Show evidence (1 reference)
PMID:24121508 SUPPORT Model Organism
"These studies formally prove that a missense mutation in PHD2 is the cause of the erythrocytosis, show that this occurs through haploinsufficiency"
Establishes this model as a faithful recapitulation of the human erythroid phenotype and its mechanism.
Adrenal-medulla Phd2 conditional knockout mouse
Species
Mouse
Genotype
TH-Cre conditional Phd2 inactivation in adrenal medulla
Publication
PMID:34658364
Pathograph links
Pseudohypoxic Chromaffin Tumorigenesis partially recapitulates fidelity: moderate observes: tissue Adrenal-medulla Phd2 inactivation reproduces the gene-expression signature of pseudohypoxic PPGL in a HIF-2-alpha-dependent manner, but the changes arise only when Phd2 is inactivated during adrenal development, not in adult life, and the model produces developmental abnormalities rather than frank tumors.
Limitations: The phenotype is a developmental gene-expression signature rather than a formed tumor, and it could not be reproduced by inactivating Phd2 in adult life, so the model captures the pseudohypoxic program but not the full tumorigenic process in a mature animal.
Show evidence (1 reference)
PMID:34658364 SUPPORT Model Organism
"they could not be reproduced by inactivation of Phd2 in adult life, suggesting that they arise from dysregulation of this pathway during adrenal development"
Documents the developmental-window limitation that bounds the fidelity of this model.
{ }

Source YAML

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name: EGLN1-related Erythrocytosis and Pheochromocytoma/Paraganglioma Predisposition
creation_date: "2026-10-13T19:42:52Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Disorder of Oxygen Sensing
parents:
- hereditary neoplastic syndrome
- Congenital Secondary Erythrocytosis
disease_term:
  preferred_term: EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition
  term:
    id: MONDO:1060184
    label: EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition
synonyms:
- PHD2-related erythrocytosis
- EGLN1/PHD2-associated congenital erythrocytosis with paraganglioma
- familial erythrocytosis 3
- ECYT3
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012353
      label: erythrocytosis, familial, 3
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO (OMIM:609820)
    mapping_justification: >-
      ECYT3 (OMIM:609820) is the erythrocytosis-only arm of this gene-disease
      association. ClinGen's Childhood, Adolescent, and Young Adult Cancer
      Predisposition GCEP lumped familial erythrocytosis 3 (OMIM:609820) and
      pheochromocytoma/paraganglioma (OMIM:171300) into the single MONDO:1060184
      entity this entry curates (CGGV assertion
      647ffb08-3740-43a0-8601-258324e995ab), so ECYT3 is a narrower
      (erythrocytosis-only) match rather than an equivalent concept.
description: >-
  EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition
  is an autosomal dominant disorder of oxygen sensing caused by heterozygous
  germline loss-of-function variants in EGLN1, which encodes prolyl hydroxylase
  domain protein 2 (PHD2), the principal HIF prolyl hydroxylase. In normoxia PHD2
  hydroxylates the alpha subunits of hypoxia-inducible factor, marking them for
  VHL-dependent proteasomal destruction; when PHD2 activity falls, HIF-alpha
  (predominantly HIF-2-alpha) accumulates despite adequate oxygen — pseudohypoxia.
  The systemic consequence is inappropriate erythropoietin output with
  erythrocytosis; the erythropoietin level is generally inappropriately normal
  for the hemoglobin, occasionally elevated, and rarely low, the arm that
  dominates the clinical picture and is driven by haploinsufficiency alone. The
  neoplastic consequence is a predisposition to pseudohypoxic (cluster 1)
  pheochromocytoma and paraganglioma; this is a two-hit tumor-suppressor
  mechanism in which somatic loss of the wild-type EGLN1 allele (loss of
  heterozygosity has been demonstrated in tumor tissue) completes biallelic
  inactivation in a chromaffin progenitor. ClinGen (SOP11, Childhood/Adolescent/
  Young Adult Cancer Predisposition GCEP) classifies the gene-disease
  relationship as Definitive and lumped familial erythrocytosis 3 (OMIM:609820)
  and the PPGL predisposition (OMIM:171300) into this single entity. Two points of
  granularity matter for a reader: tumor development is a very rare event among
  EGLN1 carriers and shows variable expressivity, so most carriers present with
  erythrocytosis only; and the PPGL predisposition shares its final common
  pathway (pseudohypoxic HIF-2-alpha stabilization) with VHL-, EPAS1-, and
  SDHx-driven PPGL while reaching it from the opposite direction — a direct
  genetic lesion of the hydroxylase rather than ligase loss or oncometabolite
  inhibition. This entry is the germline predisposition syndrome and is kept
  separate from the somatic pheochromocytoma/paraganglioma it predisposes to
  (design decisions section 3a).
pathophysiology:
- name: Germline EGLN1/PHD2 Loss-of-Function
  biological_scale: MOLECULAR
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  description: >-
    A heterozygous germline loss-of-function variant in EGLN1 reduces the
    catalytic activity of PHD2, the principal HIF prolyl hydroxylase, in every
    cell. Reported alleles are missense and truncating (nonsense, frameshift) and
    the overall mechanism of pathogenicity is loss of function. For the erythroid
    phenotype this single allele is sufficient: haploinsufficiency and partial
    deregulation of PHD2 is enough to cause erythrocytosis, so no second hit is
    required. For the tumor phenotype the constitutional allele is the first hit
    of a two-hit tumor-suppressor mechanism.
  genes:
  - preferred_term: EGLN1
    term:
      id: hgnc:1232
      label: EGLN1
  molecular_functions:
  - preferred_term: HIF prolyl hydroxylase (PHD2) activity
    term:
      id: GO:0160082
      label: hypoxia-inducible factor-proline dioxygenase activity
    modifier: DECREASED
  downstream:
  - target: Pseudohypoxic HIF-2-alpha Stabilization
    description: >-
      Reduced PHD2 activity slows HIF-alpha hydroxylation, so HIF-alpha escapes
      VHL-dependent degradation and accumulates despite normal oxygen tension.
    causal_link_type: DIRECT
  - target: Somatic Loss of the Wild-Type EGLN1 Allele in Chromaffin Tissue
    description: >-
      The constitutional loss-of-function allele is present in every chromaffin
      progenitor, so a single somatic event inactivating the remaining
      wild-type allele is sufficient to initiate a pseudohypoxic tumor.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:16407130
    reference_title: A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis"
    explanation: >-
      The first reported human PHD2/EGLN1 variant, establishing that the
      erythrocytosis arises from decreased PHD2 enzyme activity.
  - reference: CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z
    reference_title: "EGLN1 / EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity appears to be loss of function"
    explanation: >-
      ClinGen's conclusion on the direction of effect for the EGLN1 variants in
      this gene-disease curation.
- name: Pseudohypoxic HIF-2-alpha Stabilization
  biological_scale: MOLECULAR
  description: >-
    HIF-alpha subunits accumulate and dimerize with HIF-1-beta at normal oxygen
    tension. HIF-2-alpha is the dominant effector isoform: in the knock-in mouse
    the PHD2-associated erythrocytosis is reversed by Hif2a heterozygosity but not
    Hif1a heterozygosity, and the mouse adrenal-medulla phenotype is likewise
    HIF-2-alpha- rather than HIF-1-alpha-dependent. The stabilized dimer drives
    the hypoxia transcriptional program while oxygen is adequate.
  biological_processes:
  - preferred_term: HIF-mediated hypoxia response in normoxia
    term:
      id: GO:0001666
      label: response to hypoxia
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: Inappropriate Erythropoietin Drive
    description: >-
      Stabilized HIF-2-alpha transcribes the EPO gene, raising erythropoietin
      output for the prevailing hemoglobin.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:19092153
    reference_title: PHD2 mutation and congenital erythrocytosis with paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation affects PHD2 function and stabilizes HIF-alpha proteins"
    explanation: >-
      Demonstrates in a patient that the PHD2 variant stabilizes HIF-alpha, the
      defining molecular step of this node.
  - reference: PMID:24121508
    reference_title: A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The Phd2(P294R/+)-associated erythrocytosis is reversed in a Hif2a(+/-), but not a Hif1a(+/-) background"
    explanation: >-
      Genetic epistasis in the knock-in mouse establishing HIF-2-alpha as the
      dominant effector isoform for the erythroid arm.
- name: Inappropriate Erythropoietin Drive
  biological_scale: TISSUE
  description: >-
    HIF-2-alpha drives transcription of the EPO gene so that erythropoietin
    output is inappropriate for the prevailing hemoglobin. The level is generally
    inappropriately normal, occasionally frankly elevated, and rarely low; a
    normal EPO is the usual finding and does not exclude the diagnosis.
  cell_types:
  - preferred_term: EPO-producing kidney interstitial fibroblast
    term:
      id: CL:1000692
      label: kidney interstitial fibroblast
  biological_processes:
  - preferred_term: cellular response to hypoxia driving EPO transcription
    term:
      id: GO:0071456
      label: cellular response to hypoxia
    modifier: INCREASED
  downstream:
  - target: Erythroid Progenitor Expansion
    description: >-
      Raised erythropoietin signalling expands the erythroid compartment.
    causal_link_type: DIRECT
  - target: Elevated circulating erythropoietin concentration
    description: Erythropoietin is inappropriately normal to high for the hemoglobin.
  evidence:
  - reference: PMID:27774468
    reference_title: The role of PHD2 mutations in the pathogenesis of erythrocytosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "A knockin mouse model expressing the first reported PHD2-P317R mutation recapitulates the phenotype observed in humans (erythrocytosis with inappropriately normal serum EPO levels)"
    explanation: >-
      States the inappropriately-normal EPO signature of the erythroid phenotype,
      confirmed in the knock-in mouse.
- name: Erythroid Progenitor Expansion
  biological_scale: TISSUE
  description: >-
    Erythropoietin-driven expansion of the erythroid compartment raises the red
    cell mass. Unlike polycythemia vera, white cell and platelet lineages are not
    expanded.
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: erythrocyte differentiation
    term:
      id: GO:0030218
      label: erythrocyte differentiation
    modifier: INCREASED
  downstream:
  - target: Polycythemia
    description: Erythroid expansion raises the red cell mass.
  - target: Increased circulating hemoglobin concentration
    description: Erythroid expansion raises hemoglobin.
  - target: Increased hematocrit
    description: Erythroid expansion raises hematocrit, the usual presenting abnormality.
  - target: Thromboembolism
    description: >-
      Erythrocytosis and hyperviscosity contribute to a prothrombotic tendency;
      thrombotic events are a documented, though uncommon, complication.
  evidence:
  - reference: PMID:24121508
    reference_title: A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These studies formally prove that a missense mutation in PHD2 is the cause of the erythrocytosis, show that this occurs through haploinsufficiency"
    explanation: >-
      The knock-in mouse establishes that PHD2 loss expands the red cell mass
      through haploinsufficiency.
- name: Somatic Loss of the Wild-Type EGLN1 Allele in Chromaffin Tissue
  biological_scale: MOLECULAR
  conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
  description: >-
    A somatic event inactivates the remaining wild-type EGLN1 allele in a
    chromaffin progenitor, completing biallelic PHD2 loss. Loss of heterozygosity
    of PHD2 has been demonstrated directly in paraganglioma tissue from a carrier,
    which is the observation that identified EGLN1/PHD2 as a tumor-suppressor
    gene in this setting.
  genes:
  - preferred_term: EGLN1
    term:
      id: hgnc:1232
      label: EGLN1
  molecular_functions:
  - preferred_term: HIF prolyl hydroxylase (PHD2) activity
    term:
      id: GO:0160082
      label: hypoxia-inducible factor-proline dioxygenase activity
    modifier: DECREASED
  downstream:
  - target: Pseudohypoxic Chromaffin Tumorigenesis
    description: >-
      Biallelic PHD2 loss stabilizes HIF-2-alpha in the adrenal medulla and
      sympathetic/parasympathetic paraganglia, driving a pseudohypoxic tumor.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:19092153
    reference_title: PHD2 mutation and congenital erythrocytosis with paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene"
    explanation: >-
      Direct demonstration of somatic second-hit loss of heterozygosity in the
      paraganglioma, establishing the two-hit mechanism.
- name: Pseudohypoxic Chromaffin Tumorigenesis
  biological_scale: TISSUE
  description: >-
    Constitutive HIF-2-alpha activity in chromaffin tissue produces a cluster 1
    (pseudohypoxic) pheochromocytoma or paraganglioma. In the mouse, inactivating
    Phd2 in the adrenal medulla reproduces the gene-expression signature of
    pseudohypoxic PPGL, and the effect is HIF-2-alpha- rather than
    HIF-1-alpha-dependent. The tumor arm shows marked variable expressivity and
    low penetrance, and some tumors arise with little or no erythrocytosis.
  cell_types:
  - preferred_term: chromaffin cell
    term:
      id: CL:0000166
      label: chromaffin cell
  downstream:
  - target: Pheochromocytoma
    description: Adrenal-medullary pseudohypoxic tumor.
  - target: Paraganglioma
    description: Extra-adrenal pseudohypoxic paraganglial tumor.
  evidence:
  - reference: PMID:34658364
    reference_title: Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Investigation of these animals revealed a gene expression pattern closely mimicking that of pseudohypoxic PPGL"
    explanation: >-
      Adrenal-medulla Phd2 inactivation in mice reproduces the pseudohypoxic PPGL
      expression signature.
  - reference: PMID:34658364
    reference_title: Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These changes were ablated by combined inactivation of Phd2 with Hif-2α, but not Hif-1α"
    explanation: >-
      Establishes HIF-2-alpha as the effector isoform for the chromaffin tumor
      arm.
phenotypes:
- name: Polycythemia
  category: Hematologic
  description: >-
    Erythrocytosis is the dominant and near-constant feature. It is a secondary,
    EPO-driven erythrocytosis (congenital secondary erythrocytosis), not a
    pan-myeloproliferative state.
  phenotype_term:
    preferred_term: Erythrocytosis
    term:
      id: HP:0001901
      label: Polycythemia
  diagnostic: true
  evidence:
  - reference: PMID:37317877
    reference_title: Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with PHD2 mutations develop secondary hereditary erythrocytosis with high to normal EPO serum levels, a normal concentration being inappropriate in view of the high hematocrit"
    explanation: >-
      States that PHD2-mutation carriers develop secondary hereditary
      erythrocytosis, the defining phenotype. Frequency omitted: no source gives
      a percentage, and this cohort was ascertained through erythrocytosis.
- 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:27034858
    reference_title: "Erythrocytosis due to PHD2 Mutations: A Review of Clinical Presentation, Diagnosis, and Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "with PHD2 mutations there is moderate erythrocytosis and erythropoietin (Epo) levels are generally low to normal"
    explanation: >-
      Characterizes the magnitude of the erythrocytosis and the accompanying EPO
      range across reported cases.
- name: Increased hematocrit
  category: Hematologic
  phenotype_term:
    preferred_term: Increased hematocrit
    term:
      id: HP:0001899
      label: Increased hematocrit
  diagnostic: true
  evidence:
  - reference: PMID:37317877
    reference_title: Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with PHD2 mutations develop secondary hereditary erythrocytosis with high to normal EPO serum levels, a normal concentration being inappropriate in view of the high hematocrit"
    explanation: >-
      Explicitly ties the PHD2-mutation phenotype to a high hematocrit.
- name: Elevated circulating erythropoietin concentration
  category: Hematologic
  description: >-
    Erythropoietin is usually inappropriately normal for the hemoglobin and only
    occasionally frankly elevated; across one review series of reported carriers
    most had normal EPO, a minority elevated, and a few low. A normal EPO is the
    common finding and does not exclude the diagnosis. Frank elevation, bound by
    HP:0033644 here, is the minority presentation.
  phenotype_term:
    preferred_term: Elevated circulating erythropoietin concentration
    term:
      id: HP:0033644
      label: Elevated circulating erythropoietin concentration
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:27034858
    reference_title: "Erythrocytosis due to PHD2 Mutations: A Review of Clinical Presentation, Diagnosis, and Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "twenty-one patients had normal EPO levels, four patients had unexplained elevated levels, two had a low level"
    explanation: >-
      The actual EPO distribution across reported PHD2-mutation carriers: normal
      in most, elevated in a minority, low in a few — so elevated EPO is the
      occasional, not the usual, finding.
- name: Thromboembolism
  category: Vascular
  description: >-
    Thrombotic complications are documented but uncommon among EGLN1 carriers;
    reported events include cerebral venous (sagittal sinus) and portal vein
    thrombosis.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:27034858
    reference_title: "Erythrocytosis due to PHD2 Mutations: A Review of Clinical Presentation, Diagnosis, and Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "one mutation was associated with sagittal sinus thrombosis"
    explanation: >-
      Reports a thrombotic complication in a PHD2-mutation carrier.
- name: Pheochromocytoma
  category: Neoplastic
  description: >-
    Adrenal-medullary pseudohypoxic (cluster 1) tumor. A rare manifestation of
    the syndrome; among carriers ascertained through erythrocytosis, concurrent
    pheochromocytoma has been reported.
  phenotype_term:
    preferred_term: Pheochromocytoma
    term:
      id: HP:0002666
      label: Pheochromocytoma
  evidence:
  - reference: PMID:27034858
    reference_title: "Erythrocytosis due to PHD2 Mutations: A Review of Clinical Presentation, Diagnosis, and Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Two patients with PHD2 substitution mutations were found to have paraganglioma and one of these patients had a concurrent pheochromocytoma"
    explanation: >-
      Documents pheochromocytoma in the spectrum of EGLN1/PHD2 carriers.
- name: Paraganglioma
  category: Neoplastic
  description: >-
    Extra-adrenal pseudohypoxic paraganglial tumor. The paraganglioma in the
    index tumor case was recurrent and showed somatic loss of the wild-type
    PHD2 allele.
  phenotype_term:
    preferred_term: Paraganglioma
    term:
      id: HP:0002668
      label: Paraganglioma
  evidence:
  - reference: PMID:19092153
    reference_title: PHD2 mutation and congenital erythrocytosis with paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation"
    explanation: >-
      The sentinel case establishing paraganglioma in the EGLN1/PHD2 phenotype.
genetic:
- name: EGLN1 germline loss-of-function
  gene_term:
    preferred_term: EGLN1
    term:
      id: hgnc:1232
      label: EGLN1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Heterozygous germline EGLN1 (PHD2) variants, both missense and truncating
    (nonsense, frameshift); the mechanism of pathogenicity is loss of function.
    ClinGen included 23 missense and nonsense variants reported in 31 probands
    across 7 publications in its curation. Erythrocytosis follows from
    haploinsufficiency (a single allele is sufficient); the rare
    pheochromocytoma/paraganglioma follows a two-hit tumor-suppressor mechanism,
    with somatic loss of heterozygosity of the wild-type allele demonstrated in
    tumor tissue. Tumor development is a very rare event among carriers and the
    PPGL spectrum shows variable expressivity, so additional genetic events are
    likely contributory.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z
    evidence:
    - reference: CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z
      reference_title: "EGLN1 / EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "EGLN1 | HGNC:1232 | EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition | MONDO:1060184 | AD | Definitive"
      explanation: >-
        ClinGen gene-disease validity row for this exact MONDO disease, classified
        Definitive under SOP11.
  evidence:
  - reference: CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z
    reference_title: "EGLN1 / EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "23 variants (missense and nonsense) that have been reported in 31 probands in 7 publications"
    explanation: >-
      The genetic evidence base ClinGen scored for this gene-disease curation.
  - reference: CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z
    reference_title: "EGLN1 / EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the following disease entities have been lumped into one disease entity: familial erythrocytosis 3 (OMIM:609820) and pheochromocytoma/paraganglioma (OMIM:171300)"
    explanation: >-
      Records ClinGen's lump decision that the single EGLN1 gene-disease entity
      spans both the erythrocytosis and the PPGL predisposition curated here.
  - reference: PMID:36013579
    reference_title: "Novel Germline PHD2 Variant in a Metastatic Pheochromocytoma and Chronic Myeloid Leukemia, but in the Absence of Polycythemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found a novel germline PHD2 (EGLN1) gene variant, c.153G>A, p.W51*, in a patient affected by metastatic Pheo and chronic myeloid leukemia (CML) in the absence of polycythemia"
    explanation: >-
      Documents variable expressivity: a truncating germline EGLN1 variant
      presenting with metastatic pheochromocytoma and no erythrocytosis.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant. Carriers are heterozygous; a single germline
    loss-of-function allele produces erythrocytosis through haploinsufficiency,
    while the tumor predisposition requires a somatic second hit in chromaffin
    tissue.
  evidence:
  - reference: CGGV:assertion_647ffb08-3740-43a0-8601-258324e995ab-2025-09-09T160000.000Z
    reference_title: "EGLN1 / EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EGLN1 | HGNC:1232 | EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition | MONDO:1060184 | AD | Definitive"
    explanation: >-
      ClinGen records the mode of inheritance as autosomal dominant (AD) for this
      gene-disease pair.
  - reference: PMID:24121508
    reference_title: A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These studies formally prove that a missense mutation in PHD2 is the cause of the erythrocytosis, show that this occurs through haploinsufficiency"
    explanation: >-
      Establishes the haploinsufficiency basis consistent with dominant
      inheritance of the erythroid phenotype.
diagnosis:
- name: Germline next-generation sequencing panel
  description: >-
    EGLN1 is one of the hereditary pheochromocytoma/paraganglioma susceptibility
    genes on targeted next-generation-sequencing panels, where it accounts for a
    small minority of positive cases; it is also on congenital-erythrocytosis
    gene panels reached from the erythroid presentation.
  diagnosis_term:
    preferred_term: germline gene-panel testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:34309460
    reference_title: Cost-minimization analysis of sequential genetic testing versus targeted next-generation sequencing gene panels in patients with pheochromocytoma and paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five genes were involved (RET, n = 3; SDHB, n = 3; SDHD, n = 2; EGLN1, n = 1; and NF1, n = 1)"
    explanation: >-
      Shows EGLN1 among the germline genes identified by PPGL panel testing, at
      low frequency.
- name: Serum erythropoietin measurement
  description: >-
    Serum erythropoietin in the workup of the erythrocytosis. It is generally
    inappropriately normal for the hemoglobin and only occasionally elevated, so
    a normal result is the common finding and does not exclude the diagnosis.
  diagnosis_term:
    preferred_term: serum erythropoietin measurement
    term:
      id: NCIT:C74855
      label: Erythropoietin Measurement
  evidence:
  - reference: PMID:27034858
    reference_title: "Erythrocytosis due to PHD2 Mutations: A Review of Clinical Presentation, Diagnosis, and Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "twenty-one patients had normal EPO levels, four patients had unexplained elevated levels, two had a low level"
    explanation: >-
      The EPO distribution across reported carriers, showing that a normal result
      is usual and does not exclude the diagnosis.
- name: Plasma and urinary metanephrine measurement
  description: >-
    Biochemical screening for a catecholamine-secreting pheochromocytoma or
    paraganglioma, as for hereditary PPGL generally.
  diagnosis_term:
    preferred_term: plasma and urinary metanephrine measurement
    term:
      id: NCIT:C116198
      label: Metanephrine Measurement
  evidence:
  - reference: PMID:36013579
    reference_title: "Novel Germline PHD2 Variant in a Metastatic Pheochromocytoma and Chronic Myeloid Leukemia, but in the Absence of Polycythemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The recommended diagnostic workup for suspected Pheo/PGL (PPGL) includes plasma free metanephrines and fractionated urinary metanephrines"
    explanation: >-
      The recommended biochemical workup for a suspected PPGL.
treatments:
- name: Tumor surveillance
  description: >-
    Because EGLN1 carriers are at risk of pheochromocytoma/paraganglioma, expert
    reports stress ongoing medical monitoring for tumor development; biochemical
    (metanephrine) and imaging surveillance are filed under diagnosis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: tumor surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:37317877
    reference_title: Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is essential to medically monitor the occurrence of a possible tumor"
    explanation: >-
      Expert recommendation to monitor EGLN1 carriers for tumor development.
- name: Therapeutic phlebotomy and low-dose aspirin
  description: >-
    There is no targeted therapy proven for the erythrocytosis. By analogy with
    polycythemia vera, phlebotomy and low-dose aspirin have been suggested for
    symptomatic hyperviscosity, but the benefit is unproven and the practice is
    debated; in the related Chuvash erythrocytosis, phlebotomy is associated with
    increased rather than decreased thrombotic risk.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: phlebotomy
    term:
      id: NCIT:C28221
      label: Phlebotomy
  target_mechanisms:
  - target: Erythroid Progenitor Expansion
    treatment_effect: INHIBITS
    description: >-
      Phlebotomy removes red cell mass to relieve hyperviscosity symptoms; it does
      not address the underlying HIF dysregulation.
  evidence:
  - reference: PMID:37317877
    reference_title: Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "by analogy with polycythemia vera, phlebotomies and the use of low-dose aspirin, have been suggested"
    explanation: >-
      The suggested, debated supportive management for the erythrocytosis.
- name: HIF-2-alpha inhibition (belzutifan)
  description: >-
    HIF-2-alpha is the effector of the pseudohypoxic program, so HIF-2-alpha
    inhibition is a mechanistically rational therapy for the PPGL arm. Belzutifan,
    a first-in-class HIF-2-alpha inhibitor, was FDA-approved in May 2025 for
    patients aged 12 or older with locally advanced, unresectable or metastatic
    pheochromocytoma/paraganglioma, on the LITESPARK-015 phase 2 trial (26%
    objective response). There is no EGLN1-specific efficacy data; its relevance
    here is an extrapolation from the shared HIF-2-alpha pathway.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: belzutifan
      term:
        id: CHEBI:757730
        label: belzutifan
  target_mechanisms:
  - target: Pseudohypoxic HIF-2-alpha Stabilization
    treatment_effect: INHIBITS
    description: >-
      Belzutifan blocks HIF-2-alpha, the effector of the pseudohypoxic program
      downstream of PHD2 loss.
  evidence:
  - reference: PMID:41301064
    reference_title: Update on Systemic Therapies for Metastatic/Unresectable Pheochromocytomas and Paragangliomas and Future Directions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In May 2025, the FDA approved belzutifan for adult and pediatric patients ≥12 y with locally advanced, unresectable, or metastatic PPGLs"
    explanation: >-
      Establishes the current regulatory status: belzutifan is approved for
      advanced PPGL in patients aged 12 and older, not merely investigational.
  - reference: PMID:41124218
    reference_title: Belzutifan for Advanced Pheochromocytoma or Paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the percentage of participants with a confirmed objective response was 26%"
    explanation: >-
      The LITESPARK-015 phase 2 efficacy result behind the approval.
  - reference: PMID:39426935
    reference_title: Current views on the role of HIF-2α in the pathogenesis and syndromic presentation of pheochromocytoma and paraganglioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs"
    explanation: >-
      Review describing belzutifan as a HIF-2-alpha-directed therapy for
      metastatic PPGL; graded HUMAN_CLINICAL because the quote describes a
      clinical trial of the drug.
- name: Surgical resection of pheochromocytoma/paraganglioma
  description: >-
    Surgical resection, with standard perioperative alpha-blockade for
    catecholamine-secreting tumors, is the curative treatment of a localized
    pheochromocytoma or paraganglioma, as for hereditary PPGL generally.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Pseudohypoxic Chromaffin Tumorigenesis
    treatment_effect: INHIBITS
    description: Resection removes the chromaffin tumor.
  evidence:
  - reference: PMID:36013579
    reference_title: "Novel Germline PHD2 Variant in a Metastatic Pheochromocytoma and Chronic Myeloid Leukemia, but in the Absence of Polycythemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgery is the curative option in non-metastatic and metastatic PPGL, and in patients with metastatic disease, tumor resection has been reported to increase overall survival"
    explanation: >-
      States that surgical resection is the curative treatment of PPGL.
  - reference: PMID:36013579
    reference_title: "Novel Germline PHD2 Variant in a Metastatic Pheochromocytoma and Chronic Myeloid Leukemia, but in the Absence of Polycythemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Medical therapy with alpha-blockers is necessary before surgery"
    explanation: >-
      Supports the perioperative alpha-blockade named in the description.
clinical_trials:
- name: NCT04924075
  phase: PHASE_II
  status: RECRUITING
  description: >-
    LITESPARK-015, a phase 2 trial of belzutifan (a HIF-2-alpha inhibitor)
    monotherapy in advanced pheochromocytoma/paraganglioma and other tumors with
    HIF-2-alpha alterations; the PPGL cohort read out a 26% objective response and
    supported the 2025 FDA approval. No EGLN1-specific arm.
  target_phenotypes:
  - preferred_term: Pheochromocytoma
    term:
      id: HP:0002666
      label: Pheochromocytoma
  - preferred_term: Paraganglioma
    term:
      id: HP:0002668
      label: Paraganglioma
  evidence:
  - reference: clinicaltrials:NCT04924075
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This is a study to evaluate the efficacy and safety of belzutifan monotherapy in participants with advanced pheochromocytoma/paraganglioma (PPGL)"
    explanation: >-
      The registry record establishing the trial's identity and scope.
animal_models:
- name: Phd2 P294R knock-in mouse
  species: Mouse
  genotype: Phd2(P294R/+) knock-in (models human PHD2 P317R)
  publication: PMID:24121508
  modeled_mechanisms:
  - target: Erythroid Progenitor Expansion
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Knock-in of the P294R allele modeling the first human PHD2 variant produces
      erythrocytosis equivalent to Phd2 heterozygous null, reversed by Hif2a but
      not Hif1a heterozygosity, proving a haploinsufficiency mechanism acting
      through HIF-2-alpha.
    evidence:
    - reference: PMID:24121508
      reference_title: A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These studies formally prove that a missense mutation in PHD2 is the cause of the erythrocytosis, show that this occurs through haploinsufficiency"
      explanation: >-
        Establishes this model as a faithful recapitulation of the human erythroid
        phenotype and its mechanism.
- name: Adrenal-medulla Phd2 conditional knockout mouse
  species: Mouse
  genotype: TH-Cre conditional Phd2 inactivation in adrenal medulla
  publication: PMID:34658364
  modeled_mechanisms:
  - target: Pseudohypoxic Chromaffin Tumorigenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Adrenal-medulla Phd2 inactivation reproduces the gene-expression signature
      of pseudohypoxic PPGL in a HIF-2-alpha-dependent manner, but the changes
      arise only when Phd2 is inactivated during adrenal development, not in adult
      life, and the model produces developmental abnormalities rather than frank
      tumors.
    limitations: >-
      The phenotype is a developmental gene-expression signature rather than a
      formed tumor, and it could not be reproduced by inactivating Phd2 in adult
      life, so the model captures the pseudohypoxic program but not the full
      tumorigenic process in a mature animal.
    evidence:
    - reference: PMID:34658364
      reference_title: Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "they could not be reproduced by inactivation of Phd2 in adult life, suggesting that they arise from dysregulation of this pathway during adrenal development"
      explanation: >-
        Documents the developmental-window limitation that bounds the fidelity of
        this model.
discussions:
- discussion_id: egln1_ppgl_penetrance_gap
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Pseudohypoxic Chromaffin Tumorigenesis
  prompt: >-
    Why is pheochromocytoma/paraganglioma such a rare event among EGLN1 carriers,
    and what additional factors determine which carriers develop a tumor?
  rationale: >-
    Erythrocytosis is near-universal in EGLN1 carriers, but tumor development is a
    very rare event with marked variable expressivity, and the mouse data suggest
    the pseudohypoxic chromaffin phenotype depends on dysregulation during adrenal
    development rather than on PHD2 loss per se. Whether a somatic second hit is
    necessary and sufficient, or whether additional genetic/developmental events
    are required, is unresolved.
  evidence:
  - reference: PMID:37317877
    reference_title: Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed that tumor development can be considered a very rare event"
    explanation: >-
      Quantifies the rarity of tumor development among EGLN1 carriers, framing the
      penetrance gap.
notes: >-
  Lump/split: curated as a single DISEASE at the MONDO:1060184 level, following
  ClinGen's explicit lumping of familial erythrocytosis 3 (OMIM:609820) and the
  PPGL predisposition (OMIM:171300). The erythrocytosis-only concept ECYT3
  (MONDO:0012353) is covered here as a skos:narrowMatch mapping; its curation
  stub was deleted in the same change since this lumped entry subsumes it.
  Germline vs somatic: the germline allele drives
  erythrocytosis by haploinsufficiency; PPGL requires a somatic second hit (LOH
  demonstrated in tumor, PMID:19092153). No post-zygotic mosaic arm is sourced for
  EGLN1, so HP:0001442 is not bound. Onset/pediatric framing: erythrocytosis is
  congenital and can be detected from childhood, but the reviewed series do not
  report per-age onset distributions for EGLN1 specifically, so no onset ages are
  asserted. No GeneReviews chapter covers EGLN1-related erythrocytosis: a PubMed
  genereviews[book] search for EGLN1 returned nothing. The Primary Familial and
  Congenital Erythrocytosis GeneReviews chapter is the EPOR disease (primary
  erythrocytosis with below-normal erythropoietin), the mechanistic opposite of
  this HIF-pathway secondary erythrocytosis, and the Hereditary
  Paraganglioma-Pheochromocytoma Syndromes chapter is the SDHx syndrome and does
  not cover EGLN1 (both confirmed by reading their cached abstracts); neither is
  this disease's baseline. The falcon deep-research report was used only as a
  lead; all claims were verified against the primary sources and the ClinGen
  (CGGV) record.
📚

References & Deep Research

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: curated as a single DISEASE at the MONDO:1060184 level, following ClinGen's explicit lumping of familial erythrocytosis 3 (OMIM:609820) and the PPGL predisposition (OMIM:171300). The erythrocytosis-only concept ECYT3 (MONDO:0012353) is covered here as a skos:narrowMatch mapping; its curation stub was deleted in the same change since this lumped entry subsumes it. Germline vs somatic: the germline allele drives erythrocytosis by haploinsufficiency; PPGL requires a somatic second hit (LOH demonstrated in tumor, PMID:19092153). No post-zygotic mosaic arm is sourced for EGLN1, so HP:0001442 is not bound. Onset/pediatric framing: erythrocytosis is congenital and can be detected from childhood, but the reviewed series do not report per-age onset distributions for EGLN1 specifically, so no onset ages are asserted. No GeneReviews chapter covers EGLN1-related erythrocytosis: a PubMed genereviews[book] search for EGLN1 returned nothing. The Primary Familial and Congenital Erythrocytosis GeneReviews chapter is the EPOR disease (primary erythrocytosis with below-normal erythropoietin), the mechanistic opposite of this HIF-pathway secondary erythrocytosis, and the Hereditary Paraganglioma-Pheochromocytoma Syndromes chapter is the SDHx syndrome and does not cover EGLN1 (both confirmed by reading their cached abstracts); neither is this disease's baseline. The falcon deep-research report was used only as a lead; all claims were verified against the primary sources and the ClinGen (CGGV) record.

Create: EGLN1-related Erythrocytosis and Pheochromocytoma/Paraganglioma Predisposition · 2026-10-13T20:18:39Z · View source

Created the germline EGLN1/PHD2 oxygen-sensing predisposition entry (MONDO:1060184). Mechanism: heterozygous germline EGLN1 loss-of-function -> reduced HIF prolyl hydroxylase activity -> pseudohypoxic HIF-2-alpha stabilization -> EPO-driven secondary erythrocytosis (haploinsufficiency, no second hit) and, via a somatic second hit (LOH demonstrated in tumor, PMID:19092153), cluster-1 pseudohypoxic pheochromocytoma/paraganglioma. entry_type DISEASE. Lump/split surfaced: curated at MONDO:1060184 following ClinGen's (CGGV Definitive, SOP11) explicit lumping of ECYT3 (OMIM:609820) and PPGL (OMIM:171300); ECYT3 (MONDO:0012353) recorded as skos:narrowMatch. Germline vs somatic kept distinct; no mosaic arm sourced so HP:0001442 not bound. Two pathophysiology nodes conform to germline_two_hit_tumor_predisposition (first-hit / second-hit). Two mouse models wired (Phd2 P294R knock-in erythrocytosis RECAPITULATES; adrenal-medulla Phd2-cKO pseudohypoxic PPGL PARTIALLY_RECAPITULATES). KNOWLEDGE_GAP discussion on PPGL penetrance. One falcon/Edison deep-research report was run and used only as a lead (14/14 refs resolved, no confabulation); all claims verified against primary sources and the CGGV record. Validated with just validate, validate-terms, count-verified-snippets (29/29), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-genereviews (NO_CHAPTER), list-gene-term-mismatches (0), check-block-scalar-comments, gene-activity-grounding, and validate-disorders. Gaps: no per-age onset distribution for EGLN1 specifically; no GeneReviews chapter covers EGLN1-related erythrocytosis (PFCE chapter is EPOR primary erythrocytosis; Hereditary PGL-Pheo chapter is SDHx).

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 43 citations 2026-10-13T20:13:28.399561

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: EGLN1-related Erythrocytosis and Pheochromocytoma/Paraganglioma Predisposition
  • MONDO ID: MONDO:1060184 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on EGLN1-related Erythrocytosis and Pheochromocytoma/Paraganglioma Predisposition covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Evidence scope. This is a very rare, germline EGLN1 (PHD2)–associated condition in which erythrocytosis can precede a pheochromocytoma or paraganglioma (PPGL). The clearest directly examined human example is the recurrent abdominal paraganglioma reported by Ladroue and colleagues in 2008. Most EGLN1-related erythrocytosis cases have not been reported to develop tumors. Consequently, findings for all familial erythrocytosis type 3 (ECYT3) cases, or for PPGLs of other genotypes, must not be entered as measured frequencies or outcomes for this narrower dual-phenotype condition. The evidence below distinguishes a human case, other human cohorts, experimental models, and general PPGL guidance. (ladroue2008phd2mutationand pages 1-2, ladroue2008phd2mutationand pages 2-4, wilson2016erythrocytosisdueto pages 6-7)

1. Disease information and identifiers

EGLN1 encodes prolyl hydroxylase domain protein 2, an oxygen-dependent regulator of hypoxia-inducible factors (HIFs). Impaired regulation can cause increased red-cell production; exceptionally, a carrier also develops a neural-crest-derived PPGL. Useful names include PHD2-related erythrocytosis with paraganglioma, EGLN1-related PPGL–polycythemia, and, for the broader erythrocytosis phenotype, familial erythrocytosis type 3/ECYT3. “Polycythemia” in the older case literature means erythrocytosis here, not necessarily JAK2-positive polycythemia vera. (ladroue2008phd2mutationand pages 1-2, ladroue2008phd2mutationand pages 2-4, OpenTargets Search: familial erythrocytosis,paraganglioma-EGLN1)

The requested MONDO:1060184 is provisionally recorded as the supplied identifier; it could not be independently verified against a current MONDO release in the available evidence. The distinguishable broader ECYT3 entry is MONDO:0012353. The available evidence does not establish a separate OMIM, Orphanet, MeSH, ICD-10, or ICD-11 identifier specific to the combined phenotype. These should remain unverified, rather than substituting the codes for polycythemia vera or for an unrelated PPGL syndrome. This report synthesizes published, aggregated disease-level literature and one identifiable published patient; it is not an individual’s EHR extract. (ladroue2008phd2mutationand pages 2-4, OpenTargets Search: familial erythrocytosis,paraganglioma-EGLN1)

2. Etiology, risk, protection, and environment

The established initiating factor is a heterozygous germline EGLN1 variant that impairs PHD2 activity. For the original tumor-associated patient, the variant is c.1121A>G, p.(His374Arg); analysis of his paraganglioma showed loss of heterozygosity involving the wild-type allele, providing case-level evidence for an additional, acquired tumor event. Heterozygous EGLN1 variants cause erythrocytosis in other families, but a molecular finding in an erythrocytosis patient does not by itself establish PPGL risk for that particular allele. A review identified two PHD2-substitution carriers with paragangliomas, one also reported to have pheochromocytoma; this is a count of reported cases, not a penetrance estimate. (ladroue2008phd2mutationand pages 2-4, ladroue2008phd2mutationand pages 6-7, wilson2016erythrocytosisdueto pages 6-7)

A first-degree relative of a carrier of a confirmed pathogenic germline variant may inherit that variant; autosomal-dominant transmission is supported for familial PHD2-associated erythrocytosis, while the original tumor-associated proband was the only family member reported to have erythrocytosis or tumor. Tumor penetrance, variant-specific risk, genetic anticipation, founder effects, carrier frequency, and a role for consanguinity or germline mosaicism cannot be quantified for this syndrome. Other oxygen-sensing genes, notably VHL and EPAS1, belong in the differential diagnosis, not in a list of proven modifier genes for EGLN1 disease. (wilson2016erythrocytosisdueto pages 7-8, ladroue2008phd2mutationand pages 2-4)

Low oxygen exposure, smoking, sleep-disordered breathing, and other acquired causes can independently increase hematocrit and complicate interpretation; a 2024 cohort noted different severity between two brothers carrying the same EGLN1 VUS, one of whom smoked, but did not establish a causal gene–smoking interaction. No environmental toxin, infection, diet, protective allele, vaccine, or lifestyle intervention has been demonstrated to prevent EGLN1-associated PPGL. Claims about high-altitude adaptation should not be transferred to the rare tumor-predisposition variant without allele-specific evidence. (doma2024utilityofnextgeneration pages 4-6, wilson2016erythrocytosisdueto pages 7-8)

3. Phenotypes and suggested HPO annotations

Direct case evidence is more informative than percentages. At first evaluation in 1988, age 30, the index man had an erythrocyte count of 6.2 million/mm³, hematocrit 61.6%, and hemoglobin 20.2 g/dL; oxygen saturation was 96.5% and measured erythropoietin (EPO) 18 mU/mL. Bone marrow showed erythroid hyperplasia without fibrosis, and erythroid colonies were EPO-dependent. His abdominal para-aortic paraganglioma was recognized at approximately age 43; recurrence was subsequently investigated and resected. EPO measured 48 mU/mL before the second operation and 32 mU/mL eight days afterward, but EPO mRNA was not detected in the tumor. Thus, elevated circulating EPO must not automatically be interpreted as proof that the tumor secretes EPO. (ladroue2008phd2mutationand pages 1-2, ladroue2008phd2mutationand pages 2-4)

Phenotype/type Onset, course, and severity supported by evidence HPO term suggestion; frequency and quality-of-life qualification
Erythrocytosis; hematologic sign/laboratory abnormality Persistent from young adulthood in the index case; hematocrit 61.6% initially. Broader PHD2 erythrocytosis is often described as moderate, with EPO generally low or normal. Erythrocytosis and increased hemoglobin concentration/increased hematocrit: select the current HPO labels and verify their identifiers before import. Fatigue or hyperviscosity effects are plausible but not quantitatively measured for this syndrome. (ladroue2008phd2mutationand pages 2-4, wilson2016erythrocytosisdueto pages 7-8)
Abdominal paraganglioma; tumor manifestation In the index case, approximately age 43, para-aortic, surgically removed, subsequently recurrent; the initial main tumor measured 3.5 × 3.5 cm, with additional 13- and 8-mm nodules. Paraganglioma; abdominal paraganglioma if an exact HPO term exists. Case-level recurrence is established; carrier-level occurrence is unknown. (ladroue2008phd2mutationand pages 2-4)
Pheochromocytoma; tumor manifestation Reported concurrently in one of the two PHD2 tumor-associated patients summarized by a review; detailed onset and denominator of all carriers are unavailable. Pheochromocytoma. Do not enter “50%” as penetrance: 1/2 refers only to the selected tumor reports. (wilson2016erythrocytosisdueto pages 6-7)
Hypertension; clinical sign Mild hypertension was treated in the original patient. Catecholamine-driven episodic symptoms are possible in PPGL generally, but not established as frequent in this genotype. Hypertension. Individual-level severity and quality-of-life impact have not been measured systematically. (ladroue2008phd2mutationand pages 1-2, garciacarbonero2021multidisciplinarypracticeguidelines pages 15-17)
Thrombosis; possible complication A review notes a sagittal-sinus thrombosis with a PHD2 substitution elsewhere; it must not be assigned to the Ladroue patient or treated as a frequency for the combined syndrome. Annotate thrombosis only against the applicable, separately verified case and HPO term. (wilson2016erythrocytosisdueto pages 7-8)

The original tumor had Zellballen histology, chromogranin-A-positive chief cells, and S100-positive sustentacular cells. These are pathology findings for that tumor, not a unique immunohistochemical diagnostic signature of EGLN1. No disease-specific behavioral phenotype, EQ-5D/SF-36 score, symptom-frequency distribution, or validated severity scale was identified. (ladroue2008phd2mutationand pages 2-4)

4. Genetic and molecular information

EGLN1/PHD2 is the causal gene. The best documented dual-phenotype allele, c.1121A>G; p.(His374Arg), is a germline missense change involving a conserved catalytic-region residue; experimental assays show reduced function and HIF stabilization. The original tumor additionally had somatic loss of the wild-type allele. This is stronger functional evidence than an untested rare missense call, but a current ACMG/AMP classification and a current gnomAD allele frequency for this precise allele were not independently verified here and should not be invented. The available papers do not establish a disease-specific recurrent large structural rearrangement, aneuploidy, or chromosomal-microarray signature. (ladroue2008phd2mutationand pages 2-4, ladroue2008phd2mutationand pages 6-7, welander2011geneticsandclinical pages 7-8)

Variant interpretation must be phenotype-specific. A 2024 study of 40 patients with otherwise idiopathic erythrocytosis detected two candidate heterozygous EGLN1 changes, c.1072C>T/p.(Pro358Ser) in two brothers and c.1124A>G/p.(Glu375Gly) in one other individual. Both remained variants of uncertain significance; the report did not establish PPGL in these carriers. A separate 2024 cohort of 118 sporadic erythrocytosis patients reported EGLN1 findings, frequently alongside variants in other genes. These are ascertainment-selected erythrocytosis cohorts, not estimates of syndrome prevalence or cancer penetrance. No validated EGLN1-specific modifier locus, epigenetic marker, tumor metabolomic signature, single-cell atlas, spatial-transcriptomic profile, or CRISPR therapeutic screen was established by the retrieved patient evidence. (doma2024utilityofnextgeneration pages 4-6, benetti2024coexistenceofmultiple pages 6-7)

For a knowledge base, annotate HGNC-approved symbol EGLN1 and PHD2 protein; verify the current numeric HGNC, NCBI Gene, transcript, ClinVar accession/classification, and population-frequency fields against their live records before assigning identifiers. Record germline variant and tumor-acquired LOH as distinct evidence items. The additional EGLN2/PHD1 case reported in the broader PPGL–polycythemia literature must not be re-labeled an EGLN1 case. (ladroue2008phd2mutationand pages 2-4, welander2015geneticalterationsin pages 58-61, garciacarbonero2021multidisciplinarypracticeguidelines pages 10-11)

5. Environmental and lifestyle information

There is no identified infectious agent, transmissible exposure, occupation, or established toxin that causes this Mendelian condition. Smoking or hypoxia may create additional acquired erythrocytosis and affect diagnostic measurements, but are not proven initiating lesions for EGLN1-related tumors. Routine cardiovascular risk reduction and evaluation of acquired hypoxia are reasonable clinical measures, not demonstrated genotype-specific protection. (doma2024utilityofnextgeneration pages 4-6, wilson2016erythrocytosisdueto pages 7-8)

6. Mechanism and pathophysiology

Ordered causal chain; evidentiary status is explicit:

  1. Germline EGLN1 p.(His374Arg) leads to impaired PHD2 oxygen-sensing/prolyl-hydroxylase activity (demonstrated for the original variant in cell assays). (ladroue2008phd2mutationand pages 6-7, ladroue2008phd2mutationand pages 2-4)
  2. Reduced PHD2-dependent HIF-α hydroxylation leads to less efficient pVHL recognition, ubiquitination, and proteasomal degradation, resulting in HIF-α stabilization (established pathway; mutant-cell effects demonstrated). Oxygen, iron and 2-oxoglutarate are relevant PHD cosubstrates. (ladroue2008phd2mutationand pages 1-2, ladroue2008phd2mutationand pages 6-7, jucht2024phd13oxygensensors pages 12-13)
  3. In EPO-regulating tissues, enhanced HIF signaling leads to increased erythropoietic drive and ultimately results in erythrocytosis (HIF-2α/EPO tissue connection strongly supported by conditional mice; the exact source of EPO in the original patient was not proved). EPO-dependent marrow erythropoiesis was observed; the original tumor was negative for EPO mRNA. (ladroue2008phd2mutationand pages 2-4, jucht2024phd13oxygensensors pages 7-8)
  4. Tumor branch: a subsequently acquired loss of the remaining wild-type EGLN1 allele leads to more profound local loss of PHD2 regulation (tumor LOH demonstrated); consequent persistent pseudohypoxic signaling may contribute to paraganglionic-cell survival, altered differentiation, and tumor formation (tumor-forming link is an inference, not a proven complete causal pathway in that individual). (ladroue2008phd2mutationand pages 6-7, ladroue2008phd2mutationand pages 2-4, jucht2024phd13oxygensensors pages 12-13)
  5. Tumor growth leads to an abdominal paraganglioma and potential recurrence (observed). A catecholamine-secreting tumor could lead to hypertension or crises, but secretion and causal attribution of the index patient’s mild hypertension must not be assumed. (ladroue2008phd2mutationand pages 1-2, ladroue2008phd2mutationand pages 2-4, garciacarbonero2021multidisciplinarypracticeguidelines pages 15-17)

The original mutant protein accumulated less efficiently than wild type in transfected cells, and its defective reporter activity persisted after expression was adjusted; at matched protein amounts, wild-type PHD2 reporter activity was approximately 2.5-fold that of His374Arg for HIF-2α, with a comparable HIF-1α finding. A 2024 synthesis of rodent deletions reports HIF-2α-dependent EPO production and erythrocytosis after conditional PHD2 loss. Developmental, tyrosine-hydroxylase-lineage PHD2 deletion yields an abnormal, pseudohypoxic adrenal-medullary phenotype, whereas adult deletion did not reproduce that pattern; this does not establish a faithful mouse model of a human EGLN1 PPGL. (ladroue2008phd2mutationand pages 6-7, jucht2024phd13oxygensensors pages 7-8, jucht2024phd13oxygensensors pages 12-13)

Suggested annotations, subject to identifier verification: GO biological processes cellular response to hypoxia, protein hydroxylation, regulation of HIF-mediated transcription, and erythrocyte differentiation; GO cellular components cytosol, nucleus, and proteasome for the relevant steps. Suggested cell types are renal EPO-producing interstitial fibroblast-like cells, erythroid progenitor cells, and paraganglionic/chromaffin cells; map these to exact CL IDs after checking the current ontology rather than assuming one CL term covers all paraganglionic populations. Candidate ChEBI annotations are molecular oxygen, iron(II), 2-oxoglutarate, and erythropoietin-related entities as appropriate; EPO itself is a protein, not a small-molecule metabolite. SDHx-associated succinate accumulation and hypermethylation are other-genotype mechanisms, not demonstrated EGLN1-tumor findings. (ladroue2008phd2mutationand pages 1-2, jucht2024phd13oxygensensors pages 7-8, zhikrivetskaya2017molecularmarkersof pages 6-7)

7. Anatomical structures affected

The blood and hematopoietic system are directly affected by erythrocytosis. The index tumor involved extra-adrenal para-aortic paraganglionic tissue; the kidneys’ EPO-regulating interstitium and bone-marrow erythroid precursors are mechanistically relevant, with kidney-cell attribution informed substantially by model organisms rather than patient biopsy. A separate reported carrier also had an adrenal-medullary pheochromocytoma. Suggested UBERON mappings are blood, bone marrow, kidney, adrenal medulla, and an appropriately verified abdominal paraganglion term; do not code every carrier as having all these tumor sites. The para-aortic location establishes an abdominal site, but a general bilateral or unilateral tendency cannot be estimated. Subcellular annotation should distinguish PHD2-dependent hydroxylation from downstream nuclear HIF transcription and proteasomal degradation. (ladroue2008phd2mutationand pages 2-4, wilson2016erythrocytosisdueto pages 6-7, ladroue2008phd2mutationand pages 1-2, jucht2024phd13oxygensensors pages 7-8)

8. Temporal development

The original patient’s persistent erythrocytosis was recognized at 30 years and the abdominal tumor at approximately 43 years, demonstrating that a hematologic presentation may precede detectable PPGL by years. Tumor recurrence was suspected in 2003, corroborated by ¹³¹I-MIBG imaging in 2004, and treated with a second resection. No standardized age-of-onset distribution, presymptomatic stages, progression rate, spontaneous remission probability, or critical developmental window has been established for human carriers. In experimental mice, timing of PHD2 deletion changes the adrenal phenotype, but it does not supply a human surveillance-onset age. Erythrocytosis may persist after tumor removal; tumor excision is not presumed to correct the underlying germline defect. (ladroue2008phd2mutationand pages 1-2, ladroue2008phd2mutationand pages 2-4, jucht2024phd13oxygensensors pages 12-13)

9. Inheritance and population

Familial PHD2-related erythrocytosis generally fits autosomal-dominant inheritance, with apparently isolated germline cases also reported. Importantly, inheritance of an EGLN1 variant and development of a PPGL are different endpoints: the precise penetrance of the latter is unknown. No reliable incidence, prevalence per 100,000, sex ratio, ancestry distribution, founder effect, or population carrier frequency was identified for the combined syndrome. General-PPGL estimates such as approximately 2 cases per million per year describe all genotypes together and cannot be entered as EGLN1-syndrome incidence. Likewise, the 2024 40-person idiopathic-erythrocytosis cohort and 118-person erythrocytosis cohort cannot estimate population prevalence. (wilson2016erythrocytosisdueto pages 7-8, ladroue2008phd2mutationand pages 2-4, doma2024utilityofnextgeneration pages 4-6, benetti2024coexistenceofmultiple pages 6-7)

10. Diagnosis and screening

Clinical work-up. Confirm persistent absolute erythrocytosis with repeated CBC, hematocrit, and—where needed—red-cell-mass assessment. Measure serum EPO and assess oxygenation and acquired causes; exclude JAK2-associated polycythemia vera, and consider hemoglobin electrophoresis/oxygen-affinity testing and a congenital erythrocytosis panel. A normal EPO result does not exclude PHD2-related erythrocytosis: the published review counted 21 normal, four elevated, and two low EPO results among its reviewed PHD2 cases, with others unknown. The original case had EPO-dependent erythroid colonies, without evidence that its tumor produced EPO. (wilson2016erythrocytosisdueto pages 7-8, ladroue2008phd2mutationand pages 2-4)

If a PPGL is suspected, use plasma-free or urine-fractionated metanephrines, interpreted with attention to sampling conditions and interfering factors; consider additional biochemistry according to tumor phenotype. Localize a biochemically or clinically suspected lesion with CT or MRI, and choose functional imaging, such as MIBG or somatostatin-receptor PET, according to clinical purpose and tumor characteristics. Histology confirms tumor identity after appropriately planned surgery; unprepared biopsy of a possible functional PPGL is not an appropriate substitute for biochemical and imaging assessment. Routine ECG/cardiac evaluation is directed by blood pressure, symptoms, and perioperative risk rather than being a diagnostic test for the genotype. (garciacarbonero2021multidisciplinarypracticeguidelines pages 13-15, mercadoasis2018pheochromocytomaagenetic pages 6-10, garciacarbonero2021multidisciplinarypracticeguidelines pages 15-17)

Genetic testing. A germline next-generation-sequencing panel is generally more informative than testing EGLN1 alone when erythrocytosis plus PPGL is unexplained. Include EGLN1, EPAS1, VHL, and other erythrocytosis and PPGL genes according to the differential; confirm clinically relevant variants and classify them under current ACMG/AMP criteria with segregation and functional evidence as available. Clinical-exome sequencing or WES/WGS can help when a well-designed panel is unrevealing or a structural/atypical lesion is suspected, but a negative assay does not exclude variants it does not detect. CMA, karyotyping, FISH, mitochondrial-genome assays, and repeat-expansion testing are not routine tests for this single-gene presentation. RNA, proteomic, metabolomic, or methylation testing is not established as a clinical diagnostic test specific to this syndrome. Genotype-directed testing of relatives is appropriate after identifying a pathogenic or likely pathogenic familial variant; a VUS alone should not be used as a definitive predictive result. (garciacarbonero2021multidisciplinarypracticeguidelines pages 10-11, doma2024utilityofnextgeneration pages 4-6, ladroue2008phd2mutationand pages 2-4, cascon2023geneticbasesof pages 6-8)

Differential diagnosis. Consider acquired hypoxia or EPO-producing lesions; JAK2-positive polycythemia vera; EPOR-related primary familial erythrocytosis; high-affinity hemoglobin and BPGM-related conditions; and VHL-, EPAS1-, or other hypoxia-pathway disorders. In particular, EPAS1/HIF-2α-associated PPGL–polycythemia, which may involve somatic mosaic variants and somatostatinomas, should not be merged with germline EGLN1 disease. Other hereditary PPGL genes, particularly SDHx, remain relevant even when erythrocytosis has an independent cause. (wilson2016erythrocytosisdueto pages 7-8, welander2015geneticalterationsin pages 58-61, doma2024utilityofnextgeneration pages 4-6, garciacarbonero2021multidisciplinarypracticeguidelines pages 10-11)

11. Prognosis and outcomes

There are no defensible genotype-specific five- or ten-year survival, mortality, life-expectancy, metastasis-risk, thrombosis-risk, disability, or quality-of-life estimates for the combined disorder. The index patient’s tumor recurred and was resected again; that is evidence of possible recurrence, not a cohort-level recurrence rate. Likewise, the prognosis of SDHB- or SDHA-related PPGL must not be assigned to EGLN1. High hematocrit, hypertension, functional-tumor complications, recurrence, and possible thrombotic complications warrant clinical assessment, but no validated EGLN1-specific prognostic biomarker or risk model is available. (ladroue2008phd2mutationand pages 2-4, wilson2016erythrocytosisdueto pages 6-7, garciacarbonero2021multidisciplinarypracticeguidelines pages 18-19)

12. Treatment and current implementation

Manage each manifestation, rather than claiming a proven genotype-curative therapy.

  • Erythrocytosis: hematology-directed venesection/phlebotomy was used in the index case, initially targeting hematocrit below 45%. That is one patient’s regimen, not an evidence-based universal target for hereditary PHD2 erythrocytosis or a justification for automatically applying polycythemia-vera treatment rules. Evaluate symptoms, thrombosis history, iron status, and individual risk when considering repeat phlebotomy or aspirin. No EGLN1-specific aspirin efficacy, response percentage, or pharmacogenomic rule was found. Suggested NCIT intervention concepts, pending exact code verification: phlebotomy, aspirin therapy when independently indicated. (ladroue2008phd2mutationand pages 1-2, wilson2016erythrocytosisdueto pages 7-8)
  • Localized PPGL: complete resection is generally the potentially curative tumor treatment. For a pheochromocytoma or functional paraganglioma, multidisciplinary guidance recommends 7–14 days of preoperative adrenergic blockade; a beta blocker, if required, is added only after alpha blockade. Examples are doxazosin or phenoxybenzamine for alpha blockade. The original patient underwent two abdominal tumor operations. Suggested NCIT concepts: paraganglioma resection, adrenalectomy when anatomically indicated, alpha-adrenergic blockade, and beta-adrenergic blockade; verify term identifiers. (garciacarbonero2021multidisciplinarypracticeguidelines pages 15-17, ladroue2008phd2mutationand pages 2-4)
  • Advanced PPGL: systemic treatment is selected by disease course, tumor imaging, and specialist assessment. A later development, belzutifan, inhibits HIF-2α and was approved in May 2025 for eligible patients aged 12 years or older with locally advanced unresectable or metastatic PPGL; a cited overall PPGL trial summary reports 26% objective response in 72 patients, not an EGLN1-specific response rate. ClinicalTrials.gov NCT04924075, first posted 11 June 2021, studies belzutifan across several advanced-tumor cohorts including PPGL; its registry does not establish efficacy in confirmed EGLN1 carriers. Belzutifan can cause anemia and hypoxia, relevant considerations in any patient with an erythrocytosis background. Radionuclide or other systemic therapies are likewise general advanced-PPGL options, not validated EGLN1-directed treatments. Suggested NCIT concepts: HIF-2α inhibitor therapy and radiopharmaceutical therapy, with exact codes to verify. (ghosh2025updateonsystemic pages 9-11, NCT04924075 chunk 1, garciacarbonero2021multidisciplinarypracticeguidelines pages 17-18)

No disease-specific gene replacement, editing, antisense, cell therapy, checkpoint inhibitor, rehabilitation protocol, or combination regimen with proven benefit was identified. HIF–PHD inhibitors used for anemia would act in the opposite mechanistic direction from correcting PHD2-deficient erythrocytosis and are not a treatment for this disease. (jucht2024phd13oxygensensors pages 12-13, ladroue2008phd2mutationand pages 6-7)

13. Prevention and surveillance

Primary prevention: no intervention can prevent inheritance or is proved to prevent PPGL in a carrier. Genetic counseling supports cascade testing and informed reproductive planning when a familial pathogenic variant has been established; prenatal or preimplantation testing is a case-specific counseling matter, not a population-screening program. There is no pertinent vaccine, antimicrobial prophylaxis, or neonatal screening program. Secondary prevention: investigate newly identified erythrocytosis and possible tumor symptoms, and consider individualized tumor surveillance for a confirmed pathogenic-variant carrier. The original investigators specifically recommended stringent follow-up, but they did not establish an EGLN1-specific starting age, scan interval, or measured screening benefit. Tertiary prevention: control hematologic or hemodynamic problems and surveil for recurrent tumor after treatment. (ladroue2008phd2mutationand pages 6-7, ladroue2008phd2mutationand pages 2-4, cascon2023geneticbasesof pages 6-8)

As extrapolation from general hereditary-PPGL guidance, long-term review can include symptoms, blood pressure, and metanephrines; imaging is tailored to suspected or biochemically silent disease. Published multidisciplinary guidelines recommend at least ten years after resection for PPGL in general and lifelong individualized follow-up for hereditary PPGL. Their imaging interval of every 2–3 years in some silent-tumor circumstances is not an EGLN1-validated protocol; SDHx-specific pediatric starting ages must not be imported as such. (garciacarbonero2021multidisciplinarypracticeguidelines pages 18-19, jhawar2022newinsightson pages 6-7)

14. Other species and naturally occurring disease

The reported dual-phenotype patients are human (Homo sapiens; NCBI Taxon 9606). Egln1/PHD2 is evolutionarily conserved and is studied in mouse (Mus musculus; NCBI Taxon 10090). No independently confirmed naturally occurring, ortholog-variant-defined erythrocytosis plus PPGL syndrome in another species, affected breed or VBO identifier, veterinary prevalence, or cross-species transmission was found. It is not infectious and has no zoonotic route. A paraganglioma with erythrocytosis in another animal would not by itself establish an EGLN1 ortholog disorder; the genotype would need confirmation. Exact ortholog NCBI Gene IDs should be verified before import. (ladroue2008phd2mutationand pages 6-7, jucht2024phd13oxygensensors pages 12-13)

15. Experimental models and limitations

Human cells/in vitro: transfected human 293T/HEK-293 cells expressing His374Arg PHD2 demonstrate reduced mutant protein accumulation and impaired suppression of HIF-responsive reporters. This directly assays the allele but cannot reproduce the inherited hematologic course or spontaneous tumor formation. Mouse genetic models: induced or tissue-restricted Egln1 deletion increases EPO and erythrocytosis; conditional adrenal-medullary deletion produces HIF-2α-dependent developmental/pseudohypoxic changes. Global null, conditional, and heterozygous models have different biological consequences, and a complete experimental knockout should not be equated with the original human heterozygous missense allele. The reviewed adrenal model establishes a tumor-relevant molecular state, not necessarily a bona fide recurrent PPGL. MGI/IMSR allele and stock identifiers, zebrafish or other models, and patient-derived organoids/iPSCs require independent validation before database annotation. (ladroue2008phd2mutationand pages 6-7, jucht2024phd13oxygensensors pages 7-8, jucht2024phd13oxygensensors pages 12-13)

Selected exact abstract evidence and publication links

  • Human case — Ladroue et al., New England Journal of Medicine, 18 December 2008, “PHD2 mutation and congenital erythrocytosis with paraganglioma.” The paper’s summary states: “We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation.” It adds: “we demonstrate loss of heterozygosity of PHD2 in the tumor.” DOI: 10.1056/NEJMoa0806277. A PMID for this paper was not confirmed from the accessed record and is intentionally not guessed. (ladroue2008phd2mutationand pages 1-2)
  • Human case/review — Wilson et al., Case Reports in Hematology, February 2016: its abstract states, “Two patients with PHD2 substitution mutations were found to have paraganglioma and one of these patients had a concurrent pheochromocytoma.” DOI: 10.1155/2016/6373706. This is a review-derived case count, not population statistics. (wilson2016erythrocytosisdueto pages 1-2)
  • Human cohort — Doma et al., Frontiers in Medicine, September 2024: the abstract reports “40 patients with idiopathic erythrocytosis” and describes p.(Pro358Ser) and p.(Glu375Gly) as EGLN1 variants of uncertain significance. DOI: 10.3389/fmed.2024.1440712. This is not a PPGL-incidence study. (doma2024utilityofnextgeneration pages 4-6)
  • Experimental-model review — Jucht and Scholz, Pflügers Archiv, March 2024: the abstract identifies PHD1–3 as “Fe2+- and 2-oxoglutarate-dependent dioxygenase[s]” that hydroxylate HIF-α. DOI: 10.1007/s00424-024-02944-x. (jucht2024phd13oxygensensors pages 12-13, jucht2024phd13oxygensensors pages 7-8)
  • Clinical guidance — Garcia-Carbonero et al., Clinical & Translational Oncology, May 2021: provides multidisciplinary PPGL diagnostic, perioperative, treatment, and follow-up guidance; its recommendations are not a validated EGLN1-specific protocol. DOI: 10.1007/s12094-021-02622-9. (garciacarbonero2021multidisciplinarypracticeguidelines pages 13-15, garciacarbonero2021multidisciplinarypracticeguidelines pages 15-17, garciacarbonero2021multidisciplinarypracticeguidelines pages 18-19)

Knowledge-base caution: No independently checked numeric HPO/GO/CL/UBERON/ChEBI/NCIT codes, OMIM/Orphanet mappings, current ClinVar classification, gnomAD frequency, or primary-paper PMID are supplied above. The concept labels are annotation suggestions; assign numeric ontology identifiers only after live ontology/database verification. Where the literature consists of a small number of reports, enter observations as case-level evidence with their citation and ascertainment, not as disease-wide frequency, penetrance, or prognosis. (ladroue2008phd2mutationand pages 2-4, wilson2016erythrocytosisdueto pages 6-7, doma2024utilityofnextgeneration pages 4-6)

References

  1. (ladroue2008phd2mutationand pages 1-2): Charline Ladroue, Romain Carcenac, Michel Leporrier, Sophie Gad, Claire Le Hello, Françoise Galateau-Salle, Jean Feunteun, Jacques Pouysségur, Stéphane Richard, and Betty Gardie. Phd2 mutation and congenital erythrocytosis with paraganglioma. The New England journal of medicine, 359 25:2685-92, Dec 2008. URL: https://doi.org/10.1056/nejmoa0806277, doi:10.1056/nejmoa0806277. This article has 251 citations and is from a highest quality peer-reviewed journal.

  2. (ladroue2008phd2mutationand pages 2-4): Charline Ladroue, Romain Carcenac, Michel Leporrier, Sophie Gad, Claire Le Hello, Françoise Galateau-Salle, Jean Feunteun, Jacques Pouysségur, Stéphane Richard, and Betty Gardie. Phd2 mutation and congenital erythrocytosis with paraganglioma. The New England journal of medicine, 359 25:2685-92, Dec 2008. URL: https://doi.org/10.1056/nejmoa0806277, doi:10.1056/nejmoa0806277. This article has 251 citations and is from a highest quality peer-reviewed journal.

  3. (wilson2016erythrocytosisdueto pages 6-7): Rachel Wilson, Nausheen Syed, and Prabodh Shah. Erythrocytosis due to phd2 mutations: a review of clinical presentation, diagnosis, and genetics. Case Reports in Hematology, 2016:1-8, Feb 2016. URL: https://doi.org/10.1155/2016/6373706, doi:10.1155/2016/6373706. This article has 31 citations.

  4. (OpenTargets Search: familial erythrocytosis,paraganglioma-EGLN1): Open Targets Query (familial erythrocytosis,paraganglioma-EGLN1, 16 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  5. (ladroue2008phd2mutationand pages 6-7): Charline Ladroue, Romain Carcenac, Michel Leporrier, Sophie Gad, Claire Le Hello, Françoise Galateau-Salle, Jean Feunteun, Jacques Pouysségur, Stéphane Richard, and Betty Gardie. Phd2 mutation and congenital erythrocytosis with paraganglioma. The New England journal of medicine, 359 25:2685-92, Dec 2008. URL: https://doi.org/10.1056/nejmoa0806277, doi:10.1056/nejmoa0806277. This article has 251 citations and is from a highest quality peer-reviewed journal.

  6. (wilson2016erythrocytosisdueto pages 7-8): Rachel Wilson, Nausheen Syed, and Prabodh Shah. Erythrocytosis due to phd2 mutations: a review of clinical presentation, diagnosis, and genetics. Case Reports in Hematology, 2016:1-8, Feb 2016. URL: https://doi.org/10.1155/2016/6373706, doi:10.1155/2016/6373706. This article has 31 citations.

  7. (doma2024utilityofnextgeneration pages 4-6): Saša Anžej Doma, Nika Kraljić, Aleša Kristan, Nataša Debeljak, Aleš Maver, Tadej Pajič, and Irena Preložnik Zupan. Utility of next-generation sequencing in identifying congenital erythrocytosis in patients with idiopathic erythrocytosis. Frontiers in Medicine, Sep 2024. URL: https://doi.org/10.3389/fmed.2024.1440712, doi:10.3389/fmed.2024.1440712. This article has 3 citations.

  8. (garciacarbonero2021multidisciplinarypracticeguidelines pages 15-17): R. Garcia-Carbonero, F. Matute Teresa, E. Mercader-Cidoncha, M. Mitjavila-Casanovas, M. Robledo, I. Tena, C. Alvarez-Escola, M. Arístegui, M. R. Bella-Cueto, C. Ferrer-Albiach, and F. A. Hanzu. Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas. Clinical & Translational Oncology, 23:1995-2019, May 2021. URL: https://doi.org/10.1007/s12094-021-02622-9, doi:10.1007/s12094-021-02622-9. This article has 226 citations and is from a peer-reviewed journal.

  9. (welander2011geneticsandclinical pages 7-8): Jenny Welander, Peter Söderkvist, and Oliver Gimm. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-related cancer, 18 6:R253-76, Dec 2011. URL: https://doi.org/10.1530/erc-11-0170, doi:10.1530/erc-11-0170. This article has 475 citations and is from a domain leading peer-reviewed journal.

  10. (benetti2024coexistenceofmultiple pages 6-7): Andrea Benetti, MD Irene Bertozzi, PhD, Giulio Ceolotto, Irene Cortella, Daniela Regazzo, Giacomo Biagetti, Elisabetta Cosi, and Prof Maria Luigia Randi, MD. Coexistence of multiple gene variants in some patients with erythrocytoses. Mediterranean Journal of Hematology and Infectious Diseases, 16:e2024021, Feb 2024. URL: https://doi.org/10.4084/mjhid.2024.021, doi:10.4084/mjhid.2024.021. This article has 6 citations.

  11. (welander2015geneticalterationsin pages 58-61): Jenny Welander. Genetic alterations in pheochromocytoma and paraganglioma. Linköping University Medical Dissertations, Apr 2015. URL: https://doi.org/10.3384/diss.diva-114806, doi:10.3384/diss.diva-114806. This article has 1 citations.

  12. (garciacarbonero2021multidisciplinarypracticeguidelines pages 10-11): R. Garcia-Carbonero, F. Matute Teresa, E. Mercader-Cidoncha, M. Mitjavila-Casanovas, M. Robledo, I. Tena, C. Alvarez-Escola, M. Arístegui, M. R. Bella-Cueto, C. Ferrer-Albiach, and F. A. Hanzu. Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas. Clinical & Translational Oncology, 23:1995-2019, May 2021. URL: https://doi.org/10.1007/s12094-021-02622-9, doi:10.1007/s12094-021-02622-9. This article has 226 citations and is from a peer-reviewed journal.

  13. (jucht2024phd13oxygensensors pages 12-13): Agnieszka E. Jucht and Carsten C. Scholz. Phd1-3 oxygen sensors in vivo—lessons learned from gene deletions. Pflugers Archiv, 476:1307-1337, Mar 2024. URL: https://doi.org/10.1007/s00424-024-02944-x, doi:10.1007/s00424-024-02944-x. This article has 13 citations.

  14. (jucht2024phd13oxygensensors pages 7-8): Agnieszka E. Jucht and Carsten C. Scholz. Phd1-3 oxygen sensors in vivo—lessons learned from gene deletions. Pflugers Archiv, 476:1307-1337, Mar 2024. URL: https://doi.org/10.1007/s00424-024-02944-x, doi:10.1007/s00424-024-02944-x. This article has 13 citations.

  15. (zhikrivetskaya2017molecularmarkersof pages 6-7): Svetlana O. Zhikrivetskaya, Anastasiya V. Snezhkina, Andrew R. Zaretsky, Boris Y. Alekseev, Anatoly V. Pokrovsky, Alexander L. Golovyuk, Nataliya V. Melnikova, Oleg A. Stepanov, Dmitry V. Kalinin, Alexey A. Moskalev, George S. Krasnov, Alexey A. Dmitriev, and Anna V. Kudryavtseva. Molecular markers of paragangliomas/pheochromocytomas. Oncotarget, 8:25756-25782, Feb 2017. URL: https://doi.org/10.18632/oncotarget.15201, doi:10.18632/oncotarget.15201. This article has 53 citations.

  16. (garciacarbonero2021multidisciplinarypracticeguidelines pages 13-15): R. Garcia-Carbonero, F. Matute Teresa, E. Mercader-Cidoncha, M. Mitjavila-Casanovas, M. Robledo, I. Tena, C. Alvarez-Escola, M. Arístegui, M. R. Bella-Cueto, C. Ferrer-Albiach, and F. A. Hanzu. Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas. Clinical & Translational Oncology, 23:1995-2019, May 2021. URL: https://doi.org/10.1007/s12094-021-02622-9, doi:10.1007/s12094-021-02622-9. This article has 226 citations and is from a peer-reviewed journal.

  17. (mercadoasis2018pheochromocytomaagenetic pages 6-10): Leilani B. Mercado-Asis, Katherine I. Wolf, Ivana Jochmanova, and David Taïeb. Pheochromocytoma: a genetic and diagnostic update. Endocrine Practice, 24:78-90, Jan 2018. URL: https://doi.org/10.4158/ep-2017-0057, doi:10.4158/ep-2017-0057. This article has 85 citations and is from a peer-reviewed journal.

  18. (cascon2023geneticbasesof pages 6-8): Alberto Cascón, Bruna Calsina, María Monteagudo, Sara Mellid, Alberto Díaz-Talavera, Maria Currás-Freixes, and Mercedes Robledo. Genetic bases of pheochromocytoma and paraganglioma. Journal of Molecular Endocrinology, Apr 2023. URL: https://doi.org/10.1530/jme-22-0167, doi:10.1530/jme-22-0167. This article has 91 citations and is from a peer-reviewed journal.

  19. (garciacarbonero2021multidisciplinarypracticeguidelines pages 18-19): R. Garcia-Carbonero, F. Matute Teresa, E. Mercader-Cidoncha, M. Mitjavila-Casanovas, M. Robledo, I. Tena, C. Alvarez-Escola, M. Arístegui, M. R. Bella-Cueto, C. Ferrer-Albiach, and F. A. Hanzu. Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas. Clinical & Translational Oncology, 23:1995-2019, May 2021. URL: https://doi.org/10.1007/s12094-021-02622-9, doi:10.1007/s12094-021-02622-9. This article has 226 citations and is from a peer-reviewed journal.

  20. (ghosh2025updateonsystemic pages 9-11): Imani Ghosh, Olivia Benson, Jorge H. Hernandez-Felix, Frank I. Lin, Karel Pacak, and Jaydira del Rivero. Update on systemic therapies for metastatic/unresectable pheochromocytomas and paragangliomas and future directions. Cancers, 17:3702, Nov 2025. URL: https://doi.org/10.3390/cancers17223702, doi:10.3390/cancers17223702. This article has 6 citations.

  21. (NCT04924075 chunk 1): Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015). Merck Sharp & Dohme LLC. 2021. ClinicalTrials.gov Identifier: NCT04924075

  22. (garciacarbonero2021multidisciplinarypracticeguidelines pages 17-18): R. Garcia-Carbonero, F. Matute Teresa, E. Mercader-Cidoncha, M. Mitjavila-Casanovas, M. Robledo, I. Tena, C. Alvarez-Escola, M. Arístegui, M. R. Bella-Cueto, C. Ferrer-Albiach, and F. A. Hanzu. Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas. Clinical & Translational Oncology, 23:1995-2019, May 2021. URL: https://doi.org/10.1007/s12094-021-02622-9, doi:10.1007/s12094-021-02622-9. This article has 226 citations and is from a peer-reviewed journal.

  23. (jhawar2022newinsightson pages 6-7): Sakshi Jhawar, Yasuhiro Arakawa, Suresh Kumar, Diana Varghese, Yoo Sun Kim, Nitin Roper, Fathi Elloumi, Yves Pommier, Karel Pacak, and Jaydira Del Rivero. New insights on the genetics of pheochromocytoma and paraganglioma and its clinical implications. Cancers, 14:594, Jan 2022. URL: https://doi.org/10.3390/cancers14030594, doi:10.3390/cancers14030594. This article has 101 citations.

  24. (wilson2016erythrocytosisdueto pages 1-2): Rachel Wilson, Nausheen Syed, and Prabodh Shah. Erythrocytosis due to phd2 mutations: a review of clinical presentation, diagnosis, and genetics. Case Reports in Hematology, 2016:1-8, Feb 2016. URL: https://doi.org/10.1155/2016/6373706, doi:10.1155/2016/6373706. This article has 31 citations.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

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References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 14
On topic 6
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 2
Resolved 2
Unresolved (possible confabulation) 0
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Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:1060184 (2 mentions) - the report calls it "if available"; MONDO calls it EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition