Vein of Galen malformation

Congenital MONDO:0015196 Pathograph 26 Show in embeddings browser

Vein of Galen malformation is a congenital high-flow arteriovenous shunt in which primitive choroidal or subependymal cerebral arteries connect directly to the median prosencephalic vein of Markowski without an intervening capillary network. The traditional name "aneurysm" is misleading: the dilated venous collector is the embryonic precursor of the vein of Galen rather than an aneurysmal mature vein. The lesion is thought to arise during the sixth to eleventh weeks of fetal development. The low-resistance shunt can divert a large share of cardiac output, producing high-output cardiac failure and pulmonary hypertension, while arterial steal and cerebral venous hypertension contribute to brain injury, hydrocephalus, seizures, and later neurodevelopmental impairment. Cardiac and neurological consequences are therefore parallel expressions of the same high-flow lesion. Human genetic and functional studies implicate dysregulated signaling in developing endothelium. Loss of RASA1-mediated Ras suppression and impaired EPHB4 kinase-dependent signaling are compatible with excessive downstream Ras/ERK/MAPK activity rather than a simple failure of Ras signaling; other vascular-development genes have different levels of evidence. These changes disturb angiogenesis and arterial-venous specification before the anatomical shunt and its hemodynamic consequences emerge. A caution that the outcome literature makes explicit: long-term results are worse than medium-term follow-up suggests, even in children who had no encephalomalacia at birth.

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1
Inheritance
6
Pathophys.
12
Phenotypes
2
Gaps
26
Pathograph
6
Genes
2
Medical Actions
2
Differentials
2
Trials
4
Models
1
Deep Research
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Inheritance

1
Autosomal dominant susceptibility in a gene-associated subset HP:0000006
This inheritance pattern applies to the subset associated with genes such as EPHB4, RASA1, and ACVRL1, not to every person with VOGM. A heterozygous allele can be transmitted in an autosomal dominant manner, but unaffected carriers demonstrate incomplete penetrance and variable expressivity; Mendelian allele transmission must not be presented as the child's probability of developing VOGM. That disease recurrence risk is not quantified. The EPHB4 mouse work supports a possible second-hit mechanism, but it does not prove that every human lesion requires a somatic second event.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (2 references)
PMID:37978175 SUPPORT Human Clinical
"These findings together show incomplete penetrance and variable expressivity of transmitted variants in the related CM-AVM genes RASA1 and EPHB4 in VOGM."
Direct human family evidence that transmitted EPHB4 and RASA1 variants do not determine the focal lesion with complete penetrance.
PMID:37978175 SUPPORT Model Organism
"Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele."
PARTIAL and deliberately so. This is a mouse result offered as a candidate explanation for incomplete penetrance in humans, not a demonstration that human non-penetrance is caused by a second hit.
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Discussions and Knowledge Gaps

2
Does vein of Galen malformation require a somatic second hit on top of an inherited variant, and if so what and where is it?
KNOWLEDGE GAP OPEN vogm_second_hit_requirement
Attached to
pathophysiology#Dysregulated Endothelial Developmental Signaling
Mice carrying a patient-derived EPHB4 kinase-domain variant developed the angiogenic defect only when a second-hit allele was present. That single conditional clause reconciles inherited susceptibility alleles with a disease that often appears only once in a family. If a second event is required, the identity of that event is unknown in humans. It could be a somatic mutation confined to the developing cerebral endothelium, in which case it would be invisible to blood-derived sequencing and would explain both the non-penetrant carrier parents and the focal, single-lesion anatomy of a disease whose germline variant is present in every cell. It could equally be a second germline variant elsewhere, or a non-genetic developmental contingency. Endoluminal coil sampling has now recovered lesional endothelial cells safely enough for single-cell RNA sequencing, but the published study presents somatic and second-hit DNA analysis as future work rather than a completed result. The biological question therefore remains open while the sampling barrier has become experimentally tractable.
Proposed experiments
Matched deep DNA sequencing of coil-sampled lesional endothelium and blood
vogm_lesion_somatic_sequencing
During clinically indicated embolization, use endoluminal coils to obtain lesional endothelial cells and sequence their DNA against matched blood from patients carrying a germline EPHB4 or RASA1 variant, with methods validated for picogram input and low variant fractions. Recurrent second hits present in lesion and absent from blood would support the two-hit model in humans; adequate negative results across a series would weaken it. Single-cell RNA clusters alone cannot adjudicate this DNA-level question.
Show evidence (1 reference)
PMID:38747605 SUPPORT Human Clinical
"All 6 families that were solicited to participate in the study agreed and provided informed consent. ETS was performed a total of 10 times (owing to staged procedures involving the same subject), in 3 arteries and 7 veins."
Demonstrates repeated in situ sampling in the exact patient population and therefore supports feasibility of the proposed matched-DNA experiment.
Show evidence (2 references)
PMID:38747605 SUPPORT Human Clinical
"No periprocedural complications related to ETS were encountered, and no subjects were lost to follow-up."
Supports feasibility and observed procedural safety of lesion-cell sampling in the six-patient cohort, not the unperformed second-hit analysis.
PMID:38747605 SUPPORT Human Clinical
"Pedigrees were assembled to eventually compare germline DNA against EC's retrieved by ETS to identify somatic and second-hit mutations."
The word "eventually" makes the evidence boundary explicit: matched DNA analysis was planned, not reported as a positive finding.
Why do children with vein of Galen malformation do worse at school age than medium-term follow-up predicts, even when no encephalomalacia was present at birth?
KNOWLEDGE GAP OPEN vogm_long_term_deterioration
Attached to
pathophysiology#Cerebral Arterial Steal pathophysiology#Cerebral Venous Hypertension
The outcome literature states plainly that long-term results are less favourable than short- and medium-term assessment suggests, and that this holds even in the absence of encephalomalacia at birth. That combination is the interesting part: a normal-looking neonatal brain does not guarantee a normal-functioning school-age child. Several explanations are compatible with it and none is established. Chronic hypoperfusion and venous hypertension may injure developing tissue in ways that structural imaging does not show; the cognitive demands that reveal impairment may simply not exist in infancy; or residual shunting after treatment may continue to affect a brain that is still developing. Distinguishing them matters directly for what families are told at discharge and for how long children are followed.
Proposed experiments
School-age neurocognitive outcome against neonatal and follow-up imaging
vogm_school_age_imaging_correlation
Follow a treated cohort to school age with formal neurocognitive assessment and serial imaging, testing whether later impairment is predicted by residual shunt, by interval imaging change, or by neither. If neither predicts it, the injury is occurring below the resolution of structural imaging, which is itself the finding.
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Pathophysiology

6
Dysregulated Endothelial Developmental Signaling
VOGM-associated variants converge on signaling programs active in developing cerebral endothelium, but their effects are not accurately described as a uniform loss of Ras signaling. RASA1 is a Ras suppressor, EPHB4 kinase-domain variants lack detectable phosphotyrosine and impair kinase-dependent control, and the PTPN11 variant reported in one proband constitutively activates Ras signaling. ACVRL1, NOTCH1, and ITGB1 implicate additional endothelial developmental pathways. Integrated exome and single-cell transcriptomic analysis places this susceptibility in developing endothelial cells.
endothelial cell of the developing cerebral vasculature CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of the developing cerebral vasculature, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
EPHB4 hgnc:3395 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EPHB4 (hgnc:3395). hgnc:3395 is a gene from the HUGO Gene Nomenclature Committee. RASA1 hgnc:9871 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RASA1 (hgnc:9871). hgnc:9871 is a gene from the HUGO Gene Nomenclature Committee. ACVRL1 hgnc:175 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ACVRL1 (hgnc:175). hgnc:175 is a gene from the HUGO Gene Nomenclature Committee. NOTCH1 hgnc:7881 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOTCH1 (hgnc:7881). hgnc:7881 is a gene from the HUGO Gene Nomenclature Committee. ITGB1 hgnc:6153 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ITGB1 (hgnc:6153). hgnc:6153 is a gene from the HUGO Gene Nomenclature Committee. PTPN11 hgnc:9644 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PTPN11 (hgnc:9644). hgnc:9644 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
COS-7 cells expressing VOGM-associated EPHB4 kinase-domain variants CELL LINE Measures stability and phosphorylation of patient-associated EPHB4 variants to define the proximal molecular defect.
Downstream
Impaired Developmental Angiogenesis and Arteriovenous Specification Dysregulated signaling in fetal endothelium impairs remodeling of primitive vascular plexuses and development of the arterial-capillary-venous hierarchy.
Cutaneous vascular lesions In the gene-associated subset, pleiotropic endothelial susceptibility can also manifest as capillary malformations or other cutaneous vascular lesions; the variant-specific intermediates and relationship to the focal cerebral lesion remain unresolved.
Show evidence (3 references)
PMID:37978175 SUPPORT Human Clinical
"we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes"
Establishes the scale and design of the analysis that identified the signalling regulators and localised them to a cell type.
PMID:37978175 SUPPORT Human Clinical
"Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology."
States the conclusion this node is built on: the pathophysiology is located in developing endothelial cells, a cell type at a time, rather than in an anatomical structure.
PMID:37978175 SUPPORT Human Clinical
"These data suggest that genetic dysregulation of Ras signaling is an important driver of VOGM pathogenesis"
Supports dysregulation rather than the incorrect claim of uniformly reduced Ras signaling.
Impaired Developmental Angiogenesis and Arteriovenous Specification
Failure to remodel primitive vascular plexuses through sprouting angiogenesis disrupts the normal arterial-capillary-venous hierarchy. This separates the molecular signaling abnormality from the later anatomical lesion: the developmental process is impaired before a focal artery-to-vein connection persists.
Animal models
EPHB4 p.Phe867Leu knock-in mouse Mouse partially recapitulates Reproduces the developmental process this node asserts is disturbed, disordered angiogenesis and loss of arterial-capillary-venous hierarchy, using a variant taken from a patient rather than a null allele.
acvrl1a/b-depleted zebrafish with human allele rescue Zebrafish rescues Wild-type human ACVRL1 rescues the venous dilation while the patient allele does not, establishing the variant as loss of function.
EPHB4-knockdown zebrafish with human allele rescue Zebrafish rescues Establishes that the patient alleles are functionally deficient, by showing that wild-type protein rescues the vascular defect while the truncated variant fails to.
Downstream
Persistent Embryonic Arteriovenous Shunt Failure of angiogenesis and arteriovenous specification provides the developmental context for a direct shunt to persist, although the steps that make the human lesion focal remain unresolved.
Show evidence (2 references)
PMID:37978175 SUPPORT Computational
"Pathway analysis showed VOGM genes are enriched in growth-factor-regulated, tyrosine receptor kinase-associated signaling, which regulates vasculogenesis, angiogenesis, and arterio-venous specification"
Links the human genetic signal to the specific developmental vascular processes represented by this node.
PMID:37978175 SUPPORT Model Organism
"impaired remodeling of primitive vascular plexuses by VEGF-regulated sprouting angiogenesis, a process required for development of hierarchical arterial-capillary-venous networks"
Directly identifies the developmental process disrupted by the patient-derived EPHB4 kinase-domain variant in fetal endothelial cells.
Persistent Embryonic Arteriovenous Shunt
The anatomical lesion. Primitive choroidal or subependymal arteries connect directly to the median prosencephalic vein of Markowski without an intervening capillary network. The embryonic venous collector persists and dilates under high flow. The resulting low-resistance circuit produces the cardiac, arterial-steal, and venous-hypertension branches modeled downstream.
Downstream
High-Output Circulatory Overload A low-resistance arteriovenous channel returns a large volume to the right heart without perfusing tissue.
Cerebral Venous Hypertension Arterial pressure transmitted to the venous side raises cerebral venous pressure.
Cerebral Arterial Steal Flow preferentially entering the low-resistance shunt is flow not delivered to brain parenchyma.
Show evidence (3 references)
PMID:37978175 SUPPORT Human Clinical
"Vein of Galen malformations (VOGMs), the most common and severe arteriovenous malformations (AVMs) of the human neonatal brain11,12, directly connect primitive choroidal or subependymal cerebral arteries to the MPV without an intervening capillary network."
Defines the arterial feeders, embryonic venous collector, and absent capillary network that distinguish the lesion.
PMID:36588762 SUPPORT Human Clinical
"The congenital malformation develops during weeks 6-11 of fetal development."
Gives the developmental window in which the shunt forms, which is what makes this an embryonic persistence rather than an acquired lesion.
PMID:36588762 SUPPORT Human Clinical
"Vein of Galen malformation (VGM) results from an aneurysmal aberration with an arteriovenous shunting of blood and is the most frequent arteriovenous malformation in infants and fetuses."
States the arteriovenous shunting that defines the lesion and its standing as the commonest such malformation in this age group.
High-Output Circulatory Overload
The dominant threat to the newborn. A large fraction of cardiac output passes through the low-resistance shunt and returns rapidly to the right heart, which raises venous return, cardiac workload, and pulmonary blood flow. The heart may be structurally normal yet unable to sustain this volume demand.
Downstream
Congestive heart failure The clinical syndrome, presenting in the neonatal period.
Pulmonary arterial hypertension Reached through sustained pulmonary overcirculation.
Hydrops fetalis Severe fetal high-output cardiac failure can progress through venous congestion to generalized edema and effusions. The phenotype evidence is case-level and establishes occurrence, not frequency.
Cardiomegaly Sustained fetal volume overload can produce dilation of the cardiac chambers and outflow tracts. The phenotype evidence is case-level and does not establish how often this occurs.
Tricuspid regurgitation Modelled through the chamber dilation and haemodynamic strain of fetal high-output failure. The cited case documents the finding but does not by itself establish its frequency or an invariant causal sequence.
Show evidence (1 reference)
PMID:36588762 SUPPORT Human Clinical
"Infants often die from high-output congestive heart failure."
States both the mechanism and that it is the usual cause of death, which is why this node rather than the neurological arm dominates neonatal management.
Cerebral Venous Hypertension
Raised pressure throughout the cerebral venous system, transmitted from the arterial side across the shunt. It impairs cerebrospinal fluid absorption and produces hydrocephalus, and contributes to the parenchymal injury that determines long-term neurological outcome.
Downstream
Hydrocephalus Modelled provisionally as predominantly impaired cerebrospinal fluid absorption under raised venous pressure. Obstruction by the dilated venous pouch, haemorrhage-related obstruction, or ex-vacuo ventricular enlargement after parenchymal injury may instead or additionally contribute in an individual patient.
Macrocephaly Reached through hydrocephalus and the mass of the dilated venous pouch in a skull whose sutures have not yet fused. The compliance of the infant skull is what makes this a visible sign rather than a pressure crisis.
Prominent scalp veins Raised pressure in the cerebral venous system is decompressed through emissary veins into the scalp, so the collateral route becomes visible on the surface. The sign is the venous hypertension made external.
Intracranial hemorrhage A recognised event in this disease rather than a demonstrated consequence of this node. Both raised venous pressure and the fragility of an abnormally constructed vasculature are plausible routes, and the cited evidence describes haemorrhage in individual patients without establishing which. The intermediates are marked unknown for that reason.
Show evidence (2 references)
PMID:35547535 SUPPORT Human Clinical
"Locoregional venous hypertension associated with cerebral arteriovenous malformations is likely to lead to an epileptic seizure or neurological deficit due to vascular steal or chronic venous ischemia in all types of malformations."
States the mechanism directly rather than listing it: venous hypertension around the malformation injures brain through steal and chronic venous ischaemia. The authors hedge with "is likely to", and that hedge is left standing rather than sharpened.
PMID:37978175 SUPPORT Human Clinical
"Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
Puts hydrocephalus at roughly half of probands at diagnosis, which is what makes this arm worth modelling separately from the cardiac one.
Cerebral Arterial Steal
Blood entering the low-resistance shunt is blood not delivered to brain parenchyma, producing chronic hypoperfusion of developing tissue. Together with venous hypertension this is the route to the parenchymal injury, seizures, and developmental impairment that dominate outcome in survivors of the cardiac phase.
Downstream
Global developmental delay Reached through chronic hypoperfusion and parenchymal injury of the developing brain.
Seizure Consequent on cortical injury.
Show evidence (2 references)
PMID:35547535 SUPPORT Human Clinical
"Locoregional venous hypertension associated with cerebral arteriovenous malformations is likely to lead to an epileptic seizure or neurological deficit due to vascular steal or chronic venous ischemia in all types of malformations."
Names vascular steal explicitly as a route from the malformation to seizure and neurological deficit, which is exactly the claim this node makes. The authors' own hedge is preserved.
PMID:35547535 SUPPORT Human Clinical
"our case series confirms the higher risk of bleeding in AVFs related to HHT-associated variants (p = 0.034) and the risk of neurological deficit or seizure at onset (p < 0.0001)"
Quantifies neurological deficit and seizure as presenting events in these shunts, giving the node a measured clinical consequence rather than an inferred one.
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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 Vein of Galen malformation 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

12
Cardiovascular 3
Congestive heart failure FREQUENT HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-output congestive heart failure, annotated with Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37978175 SUPPORT Human Clinical
"Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
Gives 40 per cent of 114 probands at diagnosis, which supports the FREQUENT band. Note this counts the feature at diagnosis in a cohort that reached endovascular treatment, so it will understate the burden among neonates who present in extremis.
PMID:36588762 SUPPORT Human Clinical
"Infants often die from high-output congestive heart failure."
Establishes both the phenotype and its lethality in infancy.
Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31713850 SUPPORT Human Clinical
"Risk of postnatal death was associated with severe neonatal cardiac failure (p=0.007) or isosystemic or suprasystemic pulmonary hypertension (p=0.014)."
Directly reports pulmonary hypertension and its association with postnatal mortality in a long-term cohort.
Cardiomegaly HP:0001640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomegaly (HP:0001640). HP:0001640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18299642 SUPPORT Human Clinical
"The sonographic examination also revealed cardiomegaly with dilatation of all the four chambers and outflow tracts, tricuspid regurgitation and mild pericardial effusion."
Directly documents fetal cardiomegaly and chamber dilation in one VOGM case; it does not support a frequency estimate.
Head and Neck 1
Macrocephaly FREQUENT HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37978175 SUPPORT Human Clinical
"Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
Macrocephaly in 48 per cent of probands at diagnosis, equal with hydrocephalus and consistent with the two sharing a cause.
Metabolism 1
Hydrops fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18299642 SUPPORT Human Clinical
"An ultrasonographic scan repeated in our institution confirmed the presence of hydrops fetalis with generalized skin edema, mild pericardial effusion and ascites."
Direct case-level evidence of hydrops in a fetus with the malformation. It establishes occurrence without supporting a population frequency.
Nervous System 3
Hydrocephalus FREQUENT HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37978175 SUPPORT Human Clinical
"Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
Reports hydrocephalus in 48 per cent of 114 probands at diagnosis, which is the basis for the FREQUENT band.
Global developmental delay FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:37978175 SUPPORT Human Clinical
"Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
Developmental delay in 54 per cent at diagnosis, the commonest single feature in the cohort, which supports the FREQUENT band.
PMID:31713850 SUPPORT Human Clinical
"Among survivors, 19 had a good outcome with normal schooling and 14 had a poor outcome."
Quantifies outcomes at school age, with a substantial minority of survivors doing poorly.
PMID:31713850 SUPPORT Human Clinical
"Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth."
The clinically decisive caveat: outcomes deteriorate relative to earlier assessment, and a normal-appearing neonatal brain does not exclude it.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35547535 SUPPORT Human Clinical
"our case series confirms the higher risk of bleeding in AVFs related to HHT-associated variants (p = 0.034) and the risk of neurological deficit or seizure at onset (p < 0.0001)"
Reports seizure at onset as a measured presenting event with a p value, rather than as an item on a list of variables the study recorded.
PMID:35547535 SUPPORT Human Clinical
"Locoregional venous hypertension associated with cerebral arteriovenous malformations is likely to lead to an epileptic seizure or neurological deficit due to vascular steal or chronic venous ischemia in all types of malformations."
Connects the seizure to the mechanism this entry models, venous hypertension and steal, rather than leaving it as an unexplained association.
Other 4
Tricuspid regurgitation HP:0005180 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tricuspid regurgitation (HP:0005180). HP:0005180 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18299642 SUPPORT Human Clinical
"The sonographic examination also revealed cardiomegaly with dilatation of all the four chambers and outflow tracts, tricuspid regurgitation and mild pericardial effusion."
Directly documents fetal tricuspid regurgitation in one VOGM case; no frequency or prognostic fraction is inferred.
Prominent scalp veins HP:0001043 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent scalp veins (HP:0001043). HP:0001043 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37978175 SUPPORT Human Clinical
"Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
PARTIAL because the source counts prominent face AND/OR scalp vasculature together at 45 per cent, while the HPO term available covers scalp veins alone. The composite proportion is therefore only upper-bound context for this term and does not justify assigning it a frequency category.
Cutaneous vascular lesions OCCASIONAL
The 22% frequency applies to the cohort's combined category of cutaneous vascular lesions, not specifically to capillary malformation or cutaneous telangiectasia.
Show evidence (1 reference)
PMID:37978175 SUPPORT Human Clinical
"Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
The combined category occurred in 22% of 114 VOGM probands, supporting the OCCASIONAL band while not resolving lesion subtype.
Intracranial hemorrhage HP:0002170 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial hemorrhage (HP:0002170). HP:0002170 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37978175 SUPPORT Human Clinical
"Interestingly, both patients had intracranial hemorrhage, progressive macrocephaly, and shunt-dependent hydrocephalus."
PARTIAL: two ITGB1-variant patients, which establishes that the phenotype occurs but says nothing about how often. No frequency is asserted.
🧬

Genetic Associations

6
EPHB4
Gene: EPHB4 hgnc:3395 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EPHB4 (hgnc:3395). hgnc:3395 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (3 references)
PMID:29444212 SUPPORT Human Clinical
"In a cohort of 51 patients, we found five affected individuals with heterozygous mutations in EPHB4 including de novo frameshift"
Reports the variant findings in a defined cohort, including a de novo frameshift, which is the strongest form of genetic evidence available in a sporadic malformation.
PMID:37978175 SUPPORT Human Clinical
"Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development."
Quantifies the enrichment rather than asserting it, and names the functional relationship with RASA1 that makes the two genes one mechanism rather than two coincidences.
PMID:35547535 SUPPORT Human Clinical
"on the contrary, EPHB4 variants were only seen in genuine vein of Galen aneurysmal malformation."
A genotype-phenotype distinction with direct management consequences: an EPHB4 variant argues for a true malformation rather than a pial fistula draining into the vein of Galen, and the two are treated differently.
RASA1
Gene: RASA1 hgnc:9871 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RASA1 (hgnc:9871). hgnc:9871 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:35547535 SUPPORT Human Clinical
"RASA1 variants were identified in all types of shunts."
Establishes that RASA1 variation spans shunt types, which is the basis for treating endothelial Ras dysregulation as the shared upstream node rather than assigning genotypes to lesion subtypes.
PMID:37978175 SUPPORT Human Clinical
"We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7)."
The single strongest genetic statement in this disease. A two-thousand-fold de novo burden reaching genome-wide significance is not a candidate-gene association; it is close to the ceiling of what exome burden testing can show.
ACVRL1
Gene: ACVRL1 hgnc:175 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ACVRL1 (hgnc:175). hgnc:175 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:37978175 SUPPORT Human Clinical
"Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree."
Names the gene directly in probands and, more tellingly, in a multi-generational pedigree, which is the segregation evidence a single proband cannot give.
PMID:37978175 SUPPORT Model Organism
"These phenotypes were rescued by mRNA co-injection of wild-type human ACVRL1 but not of VOGM-mutant human ACVRL1 Cys344Tyr"
Allele-specific rescue supports functional impairment of the VOGM-associated ACVRL1 variant, while the zebrafish phenotype remains an analog rather than the human lesion.
NOTCH1
Gene: NOTCH1 hgnc:7881 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NOTCH1 (hgnc:7881). hgnc:7881 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN
Show evidence (1 reference)
PMID:37978175 SUPPORT Human Clinical
"Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree."
Names the gene among those carrying damaging variants in probands.
ITGB1
Gene: ITGB1 hgnc:6153 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ITGB1 (hgnc:6153). hgnc:6153 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN
Show evidence (2 references)
PMID:37978175 SUPPORT Human Clinical
"Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree."
Names the gene among those carrying damaging variants in probands.
PMID:37978175 SUPPORT Human Clinical
"Interestingly, both patients had intracranial hemorrhage, progressive macrocephaly, and shunt-dependent hydrocephalus."
PARTIAL: describes the phenotype of the two carriers, which is a genotype-phenotype observation in two people rather than an established correlation.
PTPN11
Gene: PTPN11 hgnc:9644 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PTPN11 (hgnc:9644). hgnc:9644 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN
Show evidence (3 references)
PMID:37978175 SUPPORT Human Clinical
"Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree."
Names the gene among those carrying damaging variants in probands.
PMID:37978175 SUPPORT Human Clinical
"p.Tyr63Cys disrupts SHP2 autoinhibition and causes constitutive Ras signaling activation"
Supports the activating direction of the reported allele while the candidate-level disease relationship remains UNKNOWN.
PMID:37978175 SUPPORT Human Clinical
"To our knowledge, this is the first report of a de novo PTPN11 variant in a VOGM patient."
PARTIAL because a first single-patient report identifies a candidate but cannot establish a gene-disease relationship.
💊

Medical Actions

2
Endovascular Embolization
Action: Endovascular embolizationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Endovascular embolization, annotated with Embolization Therapy (NCIT:C15230). NCIT:C15230 is a clinical intervention from the NCI Thesaurus. Ontology label: Embolization Therapy NCIT:C15230
Platform: Surgery
The primary treatment closes arterial feeders or the venous side of the shunt with liquid embolic material and/or coils, often across staged procedures. Timing balances neonatal cardiopulmonary instability against procedural risk. Outcomes have improved, but long-term results remain worse than medium-term follow-up implies.
Mechanism Target:
INHIBITS Persistent Embryonic Arteriovenous Shunt — Occludes the arteriovenous connection directly, which is why it addresses the cardiac, venous and steal consequences together rather than one at a time.
Show evidence (2 references)
PMID:38747605 SUPPORT Human Clinical
"Current methods for closing the AV shunt rely on percutaneous transarterial or transvenous access with microcatheters, followed by vascular occlusion with liquid embolics and/or coils."
Directly supports the procedure's route and mechanism at the shunt.
PMID:35547535 SUPPORT Human Clinical
"While endovascular embolization has clearly improved the outcome, several recent case series (7, 8) have shown that the long-term prognosis in this malformation is more severe than the usually described medium-term prognosis (9-11)."
States both halves honestly: embolization has clearly improved outcome, and long-term prognosis is nonetheless more severe than medium-term reports suggest.
Show evidence (3 references)
PMID:38747605 SUPPORT Human Clinical
"Endovascular embolization represents the primary treatment but typically requires several procedures, staged over months to years."
Establishes embolization as primary treatment and documents the commonly staged treatment course.
PMID:31713850 SUPPORT Human Clinical
"Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth."
PARTIAL and recorded as a limit on the treatment rather than support for it. Survivors of successful treatment still do worse than earlier follow-up predicted, which is what a family needs told.
PMID:35547535 SUPPORT Human Clinical
"It is lethal in almost 100% of cases if left untreated."
The comparator that gives the previous caveat its proportion. Long-term outcomes after treatment are worse than medium-term follow-up implies, and the alternative is near-certain death.
Long-term neurodevelopmental rehabilitation
Platform: Behavioral / lifestyle
School-age survivors can have neuropsychological disorders that affect learning even when earlier outcome was classified as good, and may require appropriate rehabilitation or medical management. The cited cohort does not specify a rehabilitation protocol or drug regimen and does not establish treatment efficacy, so none is asserted here.
Show evidence (1 reference)
PMID:31713850 SUPPORT Human Clinical
"Even patients with good outcome often have neuropsychological disorders that may have repercussions on learning and requiring appropriate rehabilitation or medical management."
PARTIAL because the cohort supports the need for individualized supportive rehabilitation or medical management but does not test a specific intervention or quantify its benefit.
🔬

Diagnosis

6
Prenatal ultrasonography
Prenatal ultrasound can reveal deep cerebral arteriovenous shunts when the venous drainage is markedly dilated. Cortical cerebral fistulas can be more difficult to identify with this modality.
Fetal Ultrasound Imaging NCIT:C222238 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35547535 SUPPORT Human Clinical
"A likely reason is that most AV-shunts caused by HHT-associated or RASA1 variants are related to cortical cerebral fistulas, difficult to identify in prenatal imaging, especially by ultrasound, compared to deep cerebral AV-shunts with large dilatations of the venous drainage."
Supports prenatal ultrasound as an imaging modality for the deep, dilated-venous-drainage pattern while preserving the source's contrast with less conspicuous cortical fistulas.
Fetal magnetic resonance imaging
Establishes the prenatal diagnosis, evaluates the brain and venous anatomy, and measures the falcine sinus. Falcine-sinus width is a prognostic marker, not a standalone definition of the lesion.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40171650 SUPPORT Human Clinical
"Overall, 59 patients (55% male and 45% female) diagnosed with vein of Galen malformation via fetal magnetic resonance imaging from 2002 to 2024 were included."
Directly documents fetal MRI as the modality by which this clinical cohort was diagnosed.
Fetal echocardiography
Assesses the fetal haemodynamic burden of the shunt by measuring cardiac output and its change around intervention. It complements neurovascular imaging rather than defining the cerebral anatomy.
Echocardiography Test NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40788723 SUPPORT Human Clinical
"Fetal echocardiography showed a mean 33.4% reduction (range, 16%-46%) in cardiac output."
Directly documents fetal echocardiography measuring cardiac output in the VOGM intervention cohort.
Magnetic resonance angiography
Defines the shunt and deep venous drainage anatomy needed to distinguish a true VOGM from a fistula that drains into an enlarged mature vein of Galen. The defining finding is disconnection from normal deep cerebral venous drainage, which instead uses alternative routes.
Magnetic Resonance Angiography NCIT:C190557 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35547535 SUPPORT Human Clinical
"A true VGAM corresponded to a choroidal arteriovenous shunt draining directly into the embryonic precursor of the vein of Galen with normal deep cerebral venous drainage via alternative venous delivery routes, and without identifiable connection between the vascular malformation and the deep..."
Directly states the vascular and deep-venous anatomy that MRI or MRA can demonstrate to classify a genuine VOGM.
Catheter angiography
Confirms the direct shunt and delineates arterial feeders and venous drainage before endovascular treatment. Angiographic anatomy also distinguishes a true malformation, whose deep cerebral veins use alternative drainage routes, from a pial or choroidal fistula that drains into an enlarged mature vein of Galen.
Angiography NCIT:C190556 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:38747605 SUPPORT Human Clinical
"Diagnosis was confirmed by catheter angiography."
Direct statement that catheter angiography confirmed VOGM in the prospective endoluminal-sampling cohort.
PMID:35547535 SUPPORT Human Clinical
"A true VGAM corresponded to a choroidal arteriovenous shunt draining directly into the embryonic precursor of the vein of Galen with normal deep cerebral venous drainage via alternative venous delivery routes, and without identifiable connection between the vascular malformation and the deep..."
Defines the anatomy that angiography or MR angiography must establish to separate a genuine VOGM from a fistula draining into the mature vein.
Bicêtre score assessment
A clinical assessment used to judge suitability for intervention in neonates and infants with VOGM. The cited six-patient cohort reports that the score supported intervention, but does not supply score components, thresholds, or independent performance validation; none are inferred here.
Bicêtre neonatal evaluation score
Show evidence (1 reference)
PMID:38747605 SUPPORT Human Clinical
"All patients were seemed suitable for clinical intervention based on Bicetre score."
PARTIAL because it directly documents use of the score for intervention suitability but does not define or validate the scoring system.
🩻

Imaging Findings

2
Wide falcine sinus on fetal MRI
Increased mediolateral falcine-sinus diameter on fetal MRI is a prognostic marker associated with mortality, cardiac dysfunction, brain parenchymal abnormalities, ventriculomegaly, and developmental delay. It helps stratify risk but does not by itself define VOGM.
Mri
Wide falcine sinus brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON)
No sufficiently specific HP or NCIT imaging-finding term for falcine-sinus width was verified; the precise preferred term is retained without a forced broader code.
Show evidence (2 references)
PMID:40171650 SUPPORT Human Clinical
"A wide FS is robustly predictive of a high risk for mortality, cardiac dysfunction, brain parenchymal abnormalities at birth, and short- and intermediate-term neurodevelopmental delay."
Directly supports the fetal MRI finding and its prognostic rather than pathognomonic role.
PMID:40171650 SUPPORT Human Clinical
"FS predicted mortality (P=8.04×10-9), right ventricular systolic dysfunction at discharge (P=0.02), brain parenchymal abnormalities at birth (P=0.02) and discharge (P=0.02), ventriculomegaly at birth (P=0.03), and developmental delay at 1 month (P=0.001), 6 months (P=0.001), and 12 months (P=0.002)."
Supplies the measured associations, including ventriculomegaly, without converting predictive associations into causal effects.
Direct cerebral arteriovenous shunt to the median prosencephalic vein
Angiography demonstrates primitive choroidal or subependymal arterial supply entering the median prosencephalic vein without an intervening capillary network. The collector and deep-venous drainage pattern define a genuine VOGM and separate it from a fistula draining into the mature vein of Galen.
Angiography Diagnostic
Direct cerebral arteriovenous shunt to the median prosencephalic vein brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON)
Generic cerebral arteriovenous-malformation terms are broader than this defining anatomy, so the imaging finding is kept as a precise preferred term without an ontology code.
Show evidence (1 reference)
PMID:37978175 SUPPORT Human Clinical
"Vein of Galen malformations (VOGMs), the most common and severe arteriovenous malformations (AVMs) of the human neonatal brain11,12, directly connect primitive choroidal or subependymal cerebral arteries to the MPV without an intervening capillary network."
States the defining vascular anatomy represented by the angiographic finding.
📈

Progression

1
Long-term outcome after treatment
School-age follow-up shows that survival and an initially reassuring scan do not guarantee normal function. In a VOGM-specific cohort, 33 of 52 patients were alive at long-term assessment; 14 of the 33 survivors had a poor outcome, and neurodevelopmental alterations were common even among those classified as having a good outcome. Results were less favorable than short- and medium-term reports, including among children without encephalomalacia at birth.
Show evidence (3 references)
PMID:31713850 SUPPORT Human Clinical
"At the long-term evaluation time-point, 33 patients were alive and 19 patients had died."
Gives the VOGM-specific long-term survival count.
PMID:31713850 SUPPORT Human Clinical
"Among survivors, 19 had a good outcome with normal schooling and 14 had a poor outcome."
Supports the outcome split stated for the 33 survivors.
PMID:31713850 SUPPORT Human Clinical
"Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth."
The counterweight: later assessment is worse than earlier assessment, and a normal neonatal brain does not exclude it.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Vein of Galen malformation:

Pial arteriovenous fistula draining into an enlarged vein of Galen
Overlapping Features The critical differential, and the reason the distinction is curated rather than assumed. A pial arteriovenous fistula or malformation may drain into a secondarily dilated vein of Galen and look similar on imaging, but it is a different lesion with different anatomy, different genetics, and a different risk profile for intervention. Calling it a vein of Galen malformation would import the wrong treatment expectations.
Show evidence (1 reference)
PMID:35547535 SUPPORT Human Clinical
"Misclassifications of AVFs or arteriovenous malformations that drain into a dilated vein of Galen as true VGAMs are also frequent"
Directly identifies the recurrent diagnostic misclassification represented by this differential.
Dural arteriovenous fistula of infancy
Overlapping Features Another high-flow shunt presenting with cardiac failure and venous hypertension in infancy, arising in dural rather than pial or choroidal vessels. Distinguished angiographically by the feeding vessels and the site of the shunt.
Show evidence (1 reference)
PMID:35547535 SUPPORT Human Clinical
"the shunt is located in the torcular, and the arterial feeders belong to the dural branches, suggesting a dural sinus malformation."
A case-level example shows the angiographic features that redirect a presumed VOGM diagnosis to a dural lesion; graded PARTIAL because it is not a cohort-wide diagnostic study.
🔬

Clinical Trials

2
NCT04434729 NOT_APPLICABLE ACTIVE_NOT_RECRUITING
First-in-human single-group fetal embolization study. Seven pregnancies were enrolled and five procedures succeeded. Three embolized children were alive without neurodevelopmental delay at reported follow-up, but overall mortality was 43%; five pregnancies had unscheduled delivery and three of those were preterm. These early data establish feasibility, not comparative efficacy.
Target Phenotypes: High-output congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets High-output congestive heart failure, annotated with Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
clinicaltrials:NCT04434729 SUPPORT Human Clinical
"This is a prospective, single-arm non-randomized interventional study of fetuses to assess the safety and efficacy of fetal embolization of Vein of Galen Malformation (VOGM)."
States the design and the intervention.
PMID:40788723 SUPPORT Human Clinical
"Seven patients were enrolled; 5 underwent successful embolization."
Reports enrollment and technical success in the first published study cohort.
PMID:40788723 SUPPORT Human Clinical
"Overall mortality was 43%, and 43% were meeting milestones at 6 months. Three embolized patients (aged 8, 18, and 24 months) survived, all without neurodevelopmental delay."
Gives the reported early survival and neurodevelopmental outcomes without implying a controlled treatment effect.
+ 1 more reference
NCT07483255 NOT_APPLICABLE RECRUITING
Follow-on interventional study planning enrollment of twenty pregnancies and fetal embolization at or after thirty-four weeks of gestation.
Target Phenotypes: High-output congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets High-output congestive heart failure, annotated with Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT07483255 SUPPORT Human Clinical
"Subjects will receive a one-time study intervention of fetal embolization, at or after 34 weeks of gestation."
States the intervention and the gestational threshold that defines the trial's risk trade-off.
🧫

Experimental Models

1
COS-7 cells expressing VOGM-associated EPHB4 kinase-domain variants CELL_LINE
A reductionist cell-line assay used to separate mutant-protein abundance from kinase function. The three VOGM-associated kinase-domain variants had abundance and decay comparable to wild type but lacked detectable phosphotyrosine, supporting impaired EPHB4 kinase-dependent signaling rather than protein instability.
Wild-type EPHB4 EPHB4 p.Lys650Asn EPHB4 p.Arg838Trp EPHB4 p.Phe867Leu
Organism
African green monkey NCBITaxon:9534 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in African green monkey, annotated with Chlorocebus aethiops (NCBITaxon:9534). NCBITaxon:9534 is an organism from the NCBI Taxonomy.
Cell source
COS-7 immortalized cell line
Culture
Transient expression of wild-type or mutant EPHB4 followed by immunoblotting and immunoprecipitation
Publication
PMID:37978175
Pathograph links
Dysregulated Endothelial Developmental Signaling measures fidelity: low Measures stability and phosphorylation of patient-associated EPHB4 variants to define the proximal molecular defect.
Limitations: COS-7 is a nonhuman, non-endothelial immortalized cell line and does not reproduce fetal cerebrovascular development or the anatomical shunt. The assay distinguishes protein stability from phosphorylation but cannot alone resolve whether absent phosphotyrosine reflects blocked kinase activity or faster dephosphorylation.
Readouts
EPHB4 steady-state abundance and protein decay
Direction: UNCHANGED
Interpretation: Comparable abundance and decay indicate that the kinase-domain variants do not primarily act by destabilizing EPHB4 protein.
Show evidence (1 reference)
PMID:37978175 SUPPORT In Vitro
"Cycloheximide block of protein translation revealed polypeptide decay rates of EPHB4 VOGM mutants similar to that of WT EPHB4"
Direct comparison of mutant and wild-type decay rates in transfected COS-7 cells.
EPHB4 phosphotyrosine signal
Direction: ABOLISHED
Interpretation: Absence of detectable phosphotyrosine supports compromised kinase-dependent signaling while leaving increased dephosphorylation as an alternative interpretation.
Show evidence (1 reference)
PMID:37978175 SUPPORT In Vitro
"none of the VOGM-associated EPHB4 kinase domain mutants contained detectable phosphotyrosine as detected by anti-pTyr immunoblotting of whole-cell lysates and anti-EPHB4 immunoprecipitates"
Direct assay result for the mutant proteins.
Show evidence (1 reference)
PMID:37978175 SUPPORT In Vitro
"These findings strongly suggest that VOGM-associated EPHB4 D-mis variants block the protein tyrosine kinase activity of EPHB4 or render EPHB4 phospho-sites more susceptible to dephosphorylation."
States the mechanistic interpretation and retains the source's alternative explanation rather than resolving it beyond the assay.
Show evidence (1 reference)
PMID:37978175 SUPPORT In Vitro
"The steady-state abundance of Lys650Asn, Arg838Trp, and Phe867Leu EPHB4 variants expressed in Cos-7 cells approximated that of WT EPHB4"
Establishes the cell-line expression experiment and the preserved-abundance result.
🐁

Animal Models

3
EPHB4 p.Phe867Leu knock-in mouse
The mechanistic centrepiece of the current genetics, and the model that explains why a dominantly inherited variant produces a sporadic-looking disease. Mice carrying a patient-derived EPHB4 kinase-domain missense change develop disordered angiogenesis and fail to build a proper artery-capillary-vein hierarchy, which is the developmental process this entry places at the top of its pathograph. The finding that matters most is conditional: the phenotype appeared only when a second-hit allele was also present. That converts incomplete penetrance from a shrug into a testable two-hit requirement, and it is the reason an inherited variant can sit silently in a parent.
Species
Mouse
Genotype
Ephb4 kinase-domain missense p.Phe867Leu, with a second-hit allele
Publication
PMID:37978175
Pathograph links
Impaired Developmental Angiogenesis and Arteriovenous Specification partially recapitulates fidelity: moderate Reproduces the developmental process this node asserts is disturbed, disordered angiogenesis and loss of arterial-capillary-venous hierarchy, using a variant taken from a patient rather than a null allele.
Limitations: The mice show disrupted developmental angiogenesis, not a vein of Galen aneurysmal malformation, so the model supports the upstream node and not the lesion itself. The phenotype also requires a second-hit allele, which means the model demonstrates a sensitised genetic context rather than the sufficiency of the patient variant alone.
Readouts
Hierarchical development of arterial-capillary-venous networks
Direction: ALTERED
Interpretation: Structural correlate of disordered endothelial development, observed only in the presence of a second-hit allele.
Show evidence (1 reference)
PMID:37978175 SUPPORT Model Organism
"Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele."
Reports the measurement and, critically, its condition.
Show evidence (1 reference)
PMID:37978175 SUPPORT Model Organism
"Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele."
Supports treating this model as informative for the endothelial developmental node, with the second-hit condition carried alongside rather than dropped.
acvrl1a/b-depleted zebrafish with human allele rescue
The functional test behind the ACVRL1 assignment, built on the same rescue logic as the EPHB4 fish model. Depleting the two zebrafish acvrl1 paralogues produced massive dilation of a cranial vein, and the defect was corrected by wild-type human ACVRL1 messenger RNA but not by the patient Cys344Tyr form. That asymmetry is the whole argument: it shows the human variant is not merely rare but functionally deficient.
Species
Zebrafish
Genotype
acvrl1a/b depletion in the Tg(kdr:gfp)zn1 reporter line, rescued with wild-type or Cys344Tyr human ACVRL1 mRNA
Publication
PMID:37978175
Pathograph links
Impaired Developmental Angiogenesis and Arteriovenous Specification rescues fidelity: moderate Wild-type human ACVRL1 rescues the venous dilation while the patient allele does not, establishing the variant as loss of function.
Limitations: The dilated vessel is the primordial hindbrain channel, not a median prosencephalic vein of Markowski, which zebrafish do not have. The model therefore tests allele function against a broadly analogous venous phenotype rather than reproducing the human lesion, and depletion is not the heterozygous state patients carry.
Readouts
Calibre of the venous primordial hindbrain channel and posterior connecting segment
Direction: RESTORED
Interpretation: Restored by wild-type human ACVRL1 and not by the patient allele, which is what converts the variant into a demonstrated loss of function.
Show evidence (1 reference)
PMID:37978175 SUPPORT Model Organism
"These phenotypes were rescued by mRNA co-injection of wild-type human ACVRL1 but not of VOGM-mutant human ACVRL1 Cys344Tyr"
States the rescue result and its allele specificity.
Show evidence (1 reference)
PMID:37978175 SUPPORT Model Organism
"we found that Acvrl1a/b depletion in the Tg(kdr:gfp)zn1 reporter fish line (see Methods) resulted in VOGM-like massive dilation of the venous primordial hindbrain channel and posterior connecting segment"
Establishes the model and the vascular phenotype it produces.
EPHB4-knockdown zebrafish with human allele rescue
A knockdown model used as a functional assay rather than as a phenocopy of the human malformation. Its value is the rescue design: wild-type human EPHB4 corrects the brain vascular defect and the truncated disease-associated form does not, which converts a candidate variant into a demonstrated loss-of-function.
Species
Zebrafish
Genotype
ephb4 morpholino knockdown, rescued with wild-type or truncated human EPHB4
Publication
PMID:29444212
Pathograph links
Impaired Developmental Angiogenesis and Arteriovenous Specification rescues fidelity: moderate Establishes that the patient alleles are functionally deficient, by showing that wild-type protein rescues the vascular defect while the truncated variant fails to.
Limitations: The zebrafish defect is a general brain vascular abnormality rather than a vein of Galen malformation; no median prosencephalic vein of Markowski exists to persist, so the model tests allele function rather than reproducing the human lesion. It is also a morpholino knockdown rather than a germline mutant.
Show evidence (1 reference)
PMID:29444212 SUPPORT Model Organism
"This model allowed us to investigate EPHB4 loss-of-function mutations in this disease by the ability to rescue the brain vascular defect in knockdown zebrafish co-injected with wild-type, but not truncated EPHB4"
States the rescue design and its result, which is what makes the model a functional test of the human alleles.
Show evidence (1 reference)
PMID:29444212 SUPPORT Model Organism
"This model allowed us to investigate EPHB4 loss-of-function mutations in this disease by the ability to rescue the brain vascular defect in knockdown zebrafish co-injected with wild-type, but not truncated EPHB4"
Supports treating this model as informative for the functional consequence of the patient variants.
{ }

Source YAML

click to show 
name: Vein of Galen malformation
creation_date: "2026-08-16T00:00:00Z"
description: >-
  Vein of Galen malformation is a congenital high-flow arteriovenous shunt in
  which primitive choroidal or subependymal cerebral arteries connect directly
  to the median prosencephalic vein of Markowski without an intervening capillary
  network. The traditional name "aneurysm" is misleading: the dilated venous
  collector is the embryonic precursor of the vein of Galen rather than an
  aneurysmal mature vein. The lesion is thought to arise during the sixth to
  eleventh weeks of fetal development.

  The low-resistance shunt can divert a large share of cardiac output, producing
  high-output cardiac failure and pulmonary hypertension, while arterial steal
  and cerebral venous hypertension contribute to brain injury, hydrocephalus,
  seizures, and later neurodevelopmental impairment. Cardiac and neurological
  consequences are therefore parallel expressions of the same high-flow lesion.

  Human genetic and functional studies implicate dysregulated signaling in
  developing endothelium. Loss of RASA1-mediated Ras suppression and impaired
  EPHB4 kinase-dependent signaling are compatible with excessive downstream
  Ras/ERK/MAPK activity rather than a simple failure of Ras signaling; other
  vascular-development genes have different levels of evidence. These changes
  disturb angiogenesis and arterial-venous specification before the anatomical
  shunt and its hemodynamic consequences emerge.

  A caution that the outcome literature makes explicit: long-term results are
  worse than medium-term follow-up suggests, even in children who had no
  encephalomalacia at birth.
category: Congenital
disease_term:
  preferred_term: Vein of Galen malformation
  term:
    id: MONDO:0015196
    label: vein of Galen aneurysm
synonyms:
- Vein of Galen aneurysmal malformation
- VGAM
- VOGM
- Vein of Galen aneurysm
notes: >-
  Nomenclature, which matters here more than usual. The disease name contains two
  inaccuracies that shape how it is misunderstood: it is not an aneurysm, and the
  dilated vessel in the true malformation is the embryonic median prosencephalic
  vein of Markowski rather than the mature vein of Galen. The MONDO label is
  retained as the disease term because that is the ontology's identifier for the
  concept, but the description and nodes use the anatomically accurate account.

  A scope distinction that changes management. True vein of Galen aneurysmal
  malformation must be separated from a pial arteriovenous fistula or
  arteriovenous malformation that merely drains into a secondarily enlarged vein
  of Galen. The two look similar on imaging and are not the same lesion: their
  anatomy, their genetics, and the risk profile of treating them differ. That
  distinction is curated as a differential rather than left implicit.

  Provider note. Built from an Edison Falcon deep-research report. Falcon cites
  by DOI and internal corpus keys rather than PMIDs, so its cited DOIs were
  resolved to PubMed records and all evidence verified against those. Every
  ontology identifier was verified independently against the ontologies rather
  than taken from the report, following identifier errors found in other entries
  built from this provider in the same batch.

  Dataset audit. The exome, developmental-cerebrovasculature transcriptomic, and
  endoluminal-biopsy studies support mechanisms in this entry, but no stable
  public accession for a VOGM-specific reusable dataset was verified. Publications
  are therefore cited as evidence without fabricating a `datasets` record.

  Population epidemiology audit. No population-based incidence estimate is
  asserted because none could be verified in the cached sources reviewed for
  this entry. A previously curated 30% figure described VOGM as a proportion of
  pediatric vascular malformations, not population prevalence or incidence, and
  was removed rather than relabelled as a population measure.
pathophysiology:
- name: Dysregulated Endothelial Developmental Signaling
  biological_scale: CELLULAR
  description: >-
    VOGM-associated variants converge on signaling programs active in developing
    cerebral endothelium, but their effects are not accurately described as a
    uniform loss of Ras signaling. RASA1 is a Ras suppressor, EPHB4 kinase-domain
    variants lack detectable phosphotyrosine and impair kinase-dependent control,
    and the PTPN11 variant reported in one proband constitutively activates Ras
    signaling. ACVRL1, NOTCH1, and ITGB1 implicate additional endothelial
    developmental pathways. Integrated exome and single-cell transcriptomic
    analysis places this susceptibility in developing endothelial cells.
  genes:
  - preferred_term: EPHB4
    term:
      id: hgnc:3395
      label: EPHB4
  - preferred_term: RASA1
    term:
      id: hgnc:9871
      label: RASA1
  - preferred_term: ACVRL1
    term:
      id: hgnc:175
      label: ACVRL1
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  - preferred_term: ITGB1
    term:
      id: hgnc:6153
      label: ITGB1
  - preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  cell_types:
  - preferred_term: endothelial cell of the developing cerebral vasculature
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes"
    explanation: >-
      Establishes the scale and design of the analysis that identified the
      signalling regulators and localised them to a cell type.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology."
    explanation: >-
      States the conclusion this node is built on: the pathophysiology is located
      in developing endothelial cells, a cell type at a time, rather than in an
      anatomical structure.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data suggest that genetic dysregulation of Ras signaling is an important driver of VOGM pathogenesis"
    explanation: >-
      Supports dysregulation rather than the incorrect claim of uniformly reduced
      Ras signaling.
  downstream:
  - target: Impaired Developmental Angiogenesis and Arteriovenous Specification
    causal_link_type: DIRECT
    description: >-
      Dysregulated signaling in fetal endothelium impairs remodeling of primitive
      vascular plexuses and development of the arterial-capillary-venous hierarchy.
  - target: Cutaneous vascular lesions
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In the gene-associated subset, pleiotropic endothelial susceptibility can
      also manifest as capillary malformations or other cutaneous vascular
      lesions; the variant-specific intermediates and relationship to the focal
      cerebral lesion remain unresolved.
- name: Impaired Developmental Angiogenesis and Arteriovenous Specification
  biological_scale: TISSUE
  description: >-
    Failure to remodel primitive vascular plexuses through sprouting angiogenesis
    disrupts the normal arterial-capillary-venous hierarchy. This separates the
    molecular signaling abnormality from the later anatomical lesion: the
    developmental process is impaired before a focal artery-to-vein connection
    persists.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Pathway analysis showed VOGM genes are enriched in growth-factor-regulated, tyrosine receptor kinase-associated signaling, which regulates vasculogenesis, angiogenesis, and arterio-venous specification"
    explanation: >-
      Links the human genetic signal to the specific developmental vascular
      processes represented by this node.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "impaired remodeling of primitive vascular plexuses by VEGF-regulated sprouting angiogenesis, a process required for development of hierarchical arterial-capillary-venous networks"
    explanation: >-
      Directly identifies the developmental process disrupted by the
      patient-derived EPHB4 kinase-domain variant in fetal endothelial cells.
  downstream:
  - target: Persistent Embryonic Arteriovenous Shunt
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failure of angiogenesis and arteriovenous specification provides the
      developmental context for a direct shunt to persist, although the steps
      that make the human lesion focal remain unresolved.
- name: Persistent Embryonic Arteriovenous Shunt
  biological_scale: TISSUE
  description: >-
    The anatomical lesion. Primitive choroidal or subependymal arteries connect
    directly to the median prosencephalic vein of Markowski without an
    intervening capillary network. The embryonic venous collector persists and
    dilates under high flow. The resulting low-resistance circuit produces the
    cardiac, arterial-steal, and venous-hypertension branches modeled downstream.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vein of Galen malformations (VOGMs), the most common and severe arteriovenous malformations (AVMs) of the human neonatal brain11,12, directly connect primitive choroidal or subependymal cerebral arteries to the MPV without an intervening capillary network."
    explanation: >-
      Defines the arterial feeders, embryonic venous collector, and absent
      capillary network that distinguish the lesion.
  - reference: PMID:36588762
    reference_title: "Recurrent Vein of Galen Aneurysmal Malformation as a Presentation of Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The congenital malformation develops during weeks 6-11 of fetal development."
    explanation: >-
      Gives the developmental window in which the shunt forms, which is what makes
      this an embryonic persistence rather than an acquired lesion.
  - reference: PMID:36588762
    reference_title: "Recurrent Vein of Galen Aneurysmal Malformation as a Presentation of Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vein of Galen malformation (VGM) results from an aneurysmal aberration with an arteriovenous shunting of blood and is the most frequent arteriovenous malformation in infants and fetuses."
    explanation: >-
      States the arteriovenous shunting that defines the lesion and its standing
      as the commonest such malformation in this age group.
  downstream:
  - target: High-Output Circulatory Overload
    causal_link_type: DIRECT
    description: >-
      A low-resistance arteriovenous channel returns a large volume to the right
      heart without perfusing tissue.
  - target: Cerebral Venous Hypertension
    causal_link_type: DIRECT
    description: >-
      Arterial pressure transmitted to the venous side raises cerebral venous
      pressure.
  - target: Cerebral Arterial Steal
    causal_link_type: DIRECT
    description: >-
      Flow preferentially entering the low-resistance shunt is flow not delivered
      to brain parenchyma.
- name: High-Output Circulatory Overload
  biological_scale: ORGANISM
  description: >-
    The dominant threat to the newborn. A large fraction of cardiac output passes
    through the low-resistance shunt and returns rapidly to the right heart, which
    raises venous return, cardiac workload, and pulmonary blood flow. The heart
    may be structurally normal yet unable to sustain this volume demand.
  evidence:
  - reference: PMID:36588762
    reference_title: "Recurrent Vein of Galen Aneurysmal Malformation as a Presentation of Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants often die from high-output congestive heart failure."
    explanation: >-
      States both the mechanism and that it is the usual cause of death, which is
      why this node rather than the neurological arm dominates neonatal
      management.
  downstream:
  - target: Congestive heart failure
    causal_link_type: DIRECT
    description: >-
      The clinical syndrome, presenting in the neonatal period.
  - target: Pulmonary arterial hypertension
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reached through sustained pulmonary overcirculation.
  - target: Hydrops fetalis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Severe fetal high-output cardiac failure can progress through venous
      congestion to generalized edema and effusions. The phenotype evidence is
      case-level and establishes occurrence, not frequency.
  - target: Cardiomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained fetal volume overload can produce dilation of the cardiac
      chambers and outflow tracts. The phenotype evidence is case-level and does
      not establish how often this occurs.
  - target: Tricuspid regurgitation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Modelled through the chamber dilation and haemodynamic strain of fetal
      high-output failure. The cited case documents the finding but does not by
      itself establish its frequency or an invariant causal sequence.
- name: Cerebral Venous Hypertension
  biological_scale: TISSUE
  description: >-
    Raised pressure throughout the cerebral venous system, transmitted from the
    arterial side across the shunt. It impairs cerebrospinal fluid absorption and
    produces hydrocephalus, and contributes to the parenchymal injury that
    determines long-term neurological outcome.
  notes: >-
    A limit on what the cited sources actually demonstrate, kept explicit. That
    venous hypertension exists locoregionally and injures tissue is directly
    stated in the literature quoted below. The specific route to hydrocephalus,
    impaired cerebrospinal fluid absorption against a raised venous pressure, is
    the conventional physiological account and is not itself demonstrated by any
    source cited in this entry; the downstream edge is graded accordingly.
  evidence:
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Locoregional venous hypertension associated with cerebral arteriovenous malformations is likely to lead to an epileptic seizure or neurological deficit due to vascular steal or chronic venous ischemia in all types of malformations."
    explanation: >-
      States the mechanism directly rather than listing it: venous hypertension
      around the malformation injures brain through steal and chronic venous
      ischaemia. The authors hedge with "is likely to", and that hedge is left
      standing rather than sharpened.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
    explanation: >-
      Puts hydrocephalus at roughly half of probands at diagnosis, which is what
      makes this arm worth modelling separately from the cardiac one.
  downstream:
  - target: Hydrocephalus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Modelled provisionally as predominantly impaired cerebrospinal fluid
      absorption under raised venous pressure. Obstruction by the dilated venous
      pouch, haemorrhage-related obstruction, or ex-vacuo ventricular enlargement
      after parenchymal injury may instead or additionally contribute in an
      individual patient.
  - target: Macrocephaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reached through hydrocephalus and the mass of the dilated venous pouch in a
      skull whose sutures have not yet fused. The compliance of the infant skull
      is what makes this a visible sign rather than a pressure crisis.
  - target: Prominent scalp veins
    causal_link_type: DIRECT
    description: >-
      Raised pressure in the cerebral venous system is decompressed through
      emissary veins into the scalp, so the collateral route becomes visible on
      the surface. The sign is the venous hypertension made external.
  - target: Intracranial hemorrhage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A recognised event in this disease rather than a demonstrated consequence
      of this node. Both raised venous pressure and the fragility of an
      abnormally constructed vasculature are plausible routes, and the cited
      evidence describes haemorrhage in individual patients without establishing
      which. The intermediates are marked unknown for that reason.
- name: Cerebral Arterial Steal
  biological_scale: TISSUE
  description: >-
    Blood entering the low-resistance shunt is blood not delivered to brain
    parenchyma, producing chronic hypoperfusion of developing tissue. Together
    with venous hypertension this is the route to the parenchymal injury,
    seizures, and developmental impairment that dominate outcome in survivors of
    the cardiac phase.
  evidence:
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Locoregional venous hypertension associated with cerebral arteriovenous malformations is likely to lead to an epileptic seizure or neurological deficit due to vascular steal or chronic venous ischemia in all types of malformations."
    explanation: >-
      Names vascular steal explicitly as a route from the malformation to
      seizure and neurological deficit, which is exactly the claim this node
      makes. The authors' own hedge is preserved.
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our case series confirms the higher risk of bleeding in AVFs related to HHT-associated variants (p = 0.034) and the risk of neurological deficit or seizure at onset (p < 0.0001)"
    explanation: >-
      Quantifies neurological deficit and seizure as presenting events in these
      shunts, giving the node a measured clinical consequence rather than an
      inferred one.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reached through chronic hypoperfusion and parenchymal injury of the
      developing brain.
  - target: Seizure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Consequent on cortical injury.
phenotypes:
- name: Congestive heart failure
  category: Cardiovascular
  description: >-
    High-output cardiac failure presenting in the neonatal period, and the
    commonest cause of death. The heart is structurally normal; it is failing
    against a volume load imposed by a lesion in the head.
  phenotype_term:
    preferred_term: High-output congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  frequency: FREQUENT
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
    explanation: >-
      Gives 40 per cent of 114 probands at diagnosis, which supports the
      FREQUENT band. Note this counts the feature at diagnosis in a cohort that
      reached endovascular treatment, so it will understate the burden among
      neonates who present in extremis.
  - reference: PMID:36588762
    reference_title: "Recurrent Vein of Galen Aneurysmal Malformation as a Presentation of Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants often die from high-output congestive heart failure."
    explanation: >-
      Establishes both the phenotype and its lethality in infancy.
- name: Pulmonary arterial hypertension
  category: Cardiovascular
  description: >-
    Raised pulmonary arterial pressure from sustained overcirculation, compounding
    the cardiac failure.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:31713850
    reference_title: "Long-term outcome of vein of Galen malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk of postnatal death was associated with severe neonatal cardiac failure (p=0.007) or isosystemic or suprasystemic pulmonary hypertension (p=0.014)."
    explanation: >-
      Directly reports pulmonary hypertension and its association with postnatal
      mortality in a long-term cohort.
- name: Hydrops fetalis
  category: Prenatal
  description: >-
    Generalized fetal edema with effusions and ascites can accompany severe
    high-output cardiac failure from the cerebral shunt. Evidence here is a
    directly observed VOGM case; no frequency is inferred from it.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:18299642
    reference_title: "Nonimmune hydrops fetalis secondary to aneurysm of the vein of Galen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An ultrasonographic scan repeated in our institution confirmed the presence of hydrops fetalis with generalized skin edema, mild pericardial effusion and ascites."
    explanation: >-
      Direct case-level evidence of hydrops in a fetus with the malformation. It
      establishes occurrence without supporting a population frequency.
- name: Cardiomegaly
  category: Cardiovascular
  description: >-
    Fetal cardiac enlargement with dilation of all four chambers and the outflow
    tracts, observed during high-output failure despite a structurally normal
    heart. The evidence is case-level, so no frequency is assigned.
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: PMID:18299642
    reference_title: "Nonimmune hydrops fetalis secondary to aneurysm of the vein of Galen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sonographic examination also revealed cardiomegaly with dilatation of all the four chambers and outflow tracts, tricuspid regurgitation and mild pericardial effusion."
    explanation: >-
      Directly documents fetal cardiomegaly and chamber dilation in one VOGM
      case; it does not support a frequency estimate.
- name: Tricuspid regurgitation
  category: Cardiovascular
  description: >-
    Fetal tricuspid regurgitation can accompany chamber dilation and high-output
    cardiac failure. A single directly observed case supports occurrence, not a
    frequency category.
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: PMID:18299642
    reference_title: "Nonimmune hydrops fetalis secondary to aneurysm of the vein of Galen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sonographic examination also revealed cardiomegaly with dilatation of all the four chambers and outflow tracts, tricuspid regurgitation and mild pericardial effusion."
    explanation: >-
      Directly documents fetal tricuspid regurgitation in one VOGM case; no
      frequency or prognostic fraction is inferred.
- name: Hydrocephalus
  category: Neurological
  description: >-
    Ventricular enlargement modelled provisionally as arising predominantly from
    impaired cerebrospinal fluid absorption under raised cerebral venous pressure.
    Obstruction by the dilated venous pouch, haemorrhage-related obstruction, and
    ex-vacuo enlargement after parenchymal injury remain alternative or additional
    explanations in an individual patient.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  frequency: FREQUENT
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
    explanation: >-
      Reports hydrocephalus in 48 per cent of 114 probands at diagnosis, which is
      the basis for the FREQUENT band.
- name: Global developmental delay
  category: Neurological
  description: >-
    Developmental impairment in survivors, and the outcome that matters most once
    the cardiac crisis is past. Long-term results are explicitly worse than
    medium-term follow-up suggests, and that applies even to children who had no
    encephalomalacia at birth, which means an initially reassuring neonatal
    assessment does not settle the prognosis.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
    explanation: >-
      Developmental delay in 54 per cent at diagnosis, the commonest single
      feature in the cohort, which supports the FREQUENT band.
  - reference: PMID:31713850
    reference_title: "Long-term outcome of vein of Galen malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among survivors, 19 had a good outcome with normal schooling and 14 had a poor outcome."
    explanation: >-
      Quantifies outcomes at school age, with a substantial minority of survivors
      doing poorly.
  - reference: PMID:31713850
    reference_title: "Long-term outcome of vein of Galen malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth."
    explanation: >-
      The clinically decisive caveat: outcomes deteriorate relative to earlier
      assessment, and a normal-appearing neonatal brain does not exclude it.
- name: Seizure
  category: Neurological
  description: >-
    Seizures from cortical injury, part of the neurological morbidity in
    survivors.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our case series confirms the higher risk of bleeding in AVFs related to HHT-associated variants (p = 0.034) and the risk of neurological deficit or seizure at onset (p < 0.0001)"
    explanation: >-
      Reports seizure at onset as a measured presenting event with a p value,
      rather than as an item on a list of variables the study recorded.
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Locoregional venous hypertension associated with cerebral arteriovenous malformations is likely to lead to an epileptic seizure or neurological deficit due to vascular steal or chronic venous ischemia in all types of malformations."
    explanation: >-
      Connects the seizure to the mechanism this entry models, venous
      hypertension and steal, rather than leaving it as an unexplained
      association.
- name: Macrocephaly
  category: Neurological
  description: >-
    Enlargement of the head, driven both by hydrocephalus and by the mass of the
    dilated venous pouch itself. It is one of the two commonest features at
    diagnosis and, in an infant presenting outside the neonatal cardiac window,
    often the finding that prompts imaging.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
    explanation: >-
      Macrocephaly in 48 per cent of probands at diagnosis, equal with
      hydrocephalus and consistent with the two sharing a cause.
- name: Prominent scalp veins
  category: Cardiovascular
  description: >-
    Dilated, visible veins over the scalp and face, the outward sign of a venous
    system carrying arterialised flow at arterial pressure. It is a physical-exam
    clue that may accompany a cranial bruit and an enlarging head.
  phenotype_term:
    preferred_term: Prominent scalp veins
    term:
      id: HP:0001043
      label: Prominent scalp veins
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
    explanation: >-
      PARTIAL because the source counts prominent face AND/OR scalp vasculature
      together at 45 per cent, while the HPO term available covers scalp veins
      alone. The composite proportion is therefore only upper-bound context for
      this term and does not justify assigning it a frequency category.
- name: Cutaneous vascular lesions
  category: Dermatological
  description: >-
    Capillary malformations, telangiectasias, or other skin vascular lesions occur
    in a gene-associated subset and may provide a clue to overlapping CM-AVM or
    HHT biology. The cohort grouped heterogeneous lesions, so the entry does not
    force them onto a single narrower HPO term.
  phenotype_term:
    preferred_term: Cutaneous vascular lesions
  frequency: OCCASIONAL
  notes: >-
    The 22% frequency applies to the cohort's combined category of cutaneous
    vascular lesions, not specifically to capillary malformation or cutaneous
    telangiectasia.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salient features at diagnosis included developmental delay (54%), macrocephaly (48%), hydrocephalus (48%), prominent face and/or scalp vasculature (45%), cutaneous vascular lesions (22%), and congestive heart failure (40%)."
    explanation: >-
      The combined category occurred in 22% of 114 VOGM probands, supporting the
      OCCASIONAL band while not resolving lesion subtype.
- name: Intracranial hemorrhage
  category: Neurological
  description: >-
    Bleeding into or around the brain, the least predictable of the neurological
    consequences and the one that can convert a stable child into an emergency.
    Recorded here at low strength: it is documented in individual patients in the
    cited work rather than quantified across a cohort.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, both patients had intracranial hemorrhage, progressive macrocephaly, and shunt-dependent hydrocephalus."
    explanation: >-
      PARTIAL: two ITGB1-variant patients, which establishes that the phenotype
      occurs but says nothing about how often. No frequency is asserted.
genetic:
- name: EPHB4
  gene_term:
    preferred_term: EPHB4
    term:
      id: hgnc:3395
      label: EPHB4
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Ephrin receptor B4 is one of the best-supported susceptibility genes.
    Heterozygous loss-of-function and damaging missense variants occur in affected
    individuals, transmitted variants are enriched, and patient alleles have
    functional effects in cell and animal assays. Unaffected carriers and the
    second-allele requirement in mouse experiments argue against treating a
    single germline variant as sufficient to cause the focal malformation.
  evidence:
  - reference: PMID:29444212
    reference_title: "Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a cohort of 51 patients, we found five affected individuals with heterozygous mutations in EPHB4 including de novo frameshift"
    explanation: >-
      Reports the variant findings in a defined cohort, including a de novo
      frameshift, which is the strongest form of genetic evidence available in a
      sporadic malformation.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development."
    explanation: >-
      Quantifies the enrichment rather than asserting it, and names the
      functional relationship with RASA1 that makes the two genes one mechanism
      rather than two coincidences.
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "on the contrary, EPHB4 variants were only seen in genuine vein of Galen aneurysmal malformation."
    explanation: >-
      A genotype-phenotype distinction with direct management consequences: an
      EPHB4 variant argues for a true malformation rather than a pial fistula
      draining into the vein of Galen, and the two are treated differently.
- name: RASA1
  gene_term:
    preferred_term: RASA1
    term:
      id: hgnc:9871
      label: RASA1
  relationship_type: SUSCEPTIBILITY
  notes: >-
    RAS p21 protein activator 1, a negative regulator of Ras signalling and a
    recognised cause of capillary malformation-arteriovenous malformation
    syndrome. Loss of this negative regulator is expected to increase downstream
    Ras/ERK/MAPK activity. The strong de novo loss-of-function burden supports
    susceptibility, but incomplete penetrance and occurrence across several
    cerebral high-flow shunt types preclude treating RASA1 as sufficient or
    lesion-specific.
  evidence:
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RASA1 variants were identified in all types of shunts."
    explanation: >-
      Establishes that RASA1 variation spans shunt types, which is the basis for
      treating endothelial Ras dysregulation as the shared upstream node rather
      than assigning genotypes to lesion subtypes.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7)."
    explanation: >-
      The single strongest genetic statement in this disease. A two-thousand-fold
      de novo burden reaching genome-wide significance is not a candidate-gene
      association; it is close to the ceiling of what exome burden testing can
      show.
- name: ACVRL1
  gene_term:
    preferred_term: ACVRL1
    term:
      id: hgnc:175
      label: ACVRL1
  relationship_type: SUSCEPTIBILITY
  notes: >-
    A probable susceptibility gene rather than an established monogenic cause.
    Evidence includes segregation of a damaging allele in a multigenerational
    VOGM/HHT2 pedigree and failure of the patient allele to rescue venous dilation
    in an acvrl1-depleted zebrafish assay. The overlap with HHT2 also complicates
    attribution of the focal cerebral lesion to ACVRL1 alone.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree."
    explanation: >-
      Names the gene directly in probands and, more tellingly, in a
      multi-generational pedigree, which is the segregation evidence a single
      proband cannot give.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These phenotypes were rescued by mRNA co-injection of wild-type human ACVRL1 but not of VOGM-mutant human ACVRL1 Cys344Tyr"
    explanation: >-
      Allele-specific rescue supports functional impairment of the VOGM-associated
      ACVRL1 variant, while the zebrafish phenotype remains an analog rather than
      the human lesion.
- name: NOTCH1
  gene_term:
    preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  relationship_type: UNKNOWN
  notes: >-
    Candidate association only. A damaging variant was reported in a proband and
    NOTCH1 is biologically relevant to arterial identity, but no VOGM-specific
    burden, segregation, or allele-functional evidence establishes susceptibility.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree."
    explanation: >-
      Names the gene among those carrying damaging variants in probands.
- name: ITGB1
  gene_term:
    preferred_term: ITGB1
    term:
      id: hgnc:6153
      label: ITGB1
  relationship_type: UNKNOWN
  notes: >-
    Candidate association only. Damaging variants were reported in two probands,
    both with severe vascular and neurological features, but this small
    genotype-phenotype observation does not establish a causal or susceptibility
    relationship.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree."
    explanation: >-
      Names the gene among those carrying damaging variants in probands.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, both patients had intracranial hemorrhage, progressive macrocephaly, and shunt-dependent hydrocephalus."
    explanation: >-
      PARTIAL: describes the phenotype of the two carriers, which is a
      genotype-phenotype observation in two people rather than an established
      correlation.
- name: PTPN11
  gene_term:
    preferred_term: PTPN11
    term:
      id: hgnc:9644
      label: PTPN11
  relationship_type: UNKNOWN
  notes: >-
    Candidate association only. A de novo gain-of-function PTPN11 variant was
    reported in one proband and is mechanistically coherent because it activates
    Ras signaling, but a first single-case report cannot establish VOGM
    susceptibility.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree."
    explanation: >-
      Names the gene among those carrying damaging variants in probands.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "p.Tyr63Cys disrupts SHP2 autoinhibition and causes constitutive Ras signaling activation"
    explanation: >-
      Supports the activating direction of the reported allele while the
      candidate-level disease relationship remains UNKNOWN.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, this is the first report of a de novo PTPN11 variant in a VOGM patient."
    explanation: >-
      PARTIAL because a first single-patient report identifies a candidate but
      cannot establish a gene-disease relationship.
animal_models:
- name: EPHB4 p.Phe867Leu knock-in mouse
  species: Mouse
  genotype: Ephb4 kinase-domain missense p.Phe867Leu, with a second-hit allele
  publication: PMID:37978175
  description: >-
    The mechanistic centrepiece of the current genetics, and the model that
    explains why a dominantly inherited variant produces a sporadic-looking
    disease. Mice carrying a patient-derived EPHB4 kinase-domain missense change
    develop disordered angiogenesis and fail to build a proper
    artery-capillary-vein hierarchy, which is the developmental process this
    entry places at the top of its pathograph. The finding that matters most is
    conditional: the phenotype appeared only when a second-hit allele was also
    present. That converts incomplete penetrance from a shrug into a testable
    two-hit requirement, and it is the reason an inherited variant can sit
    silently in a parent.
  modeled_mechanisms:
  - target: Impaired Developmental Angiogenesis and Arteriovenous Specification
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the developmental process this node asserts is disturbed,
      disordered angiogenesis and loss of arterial-capillary-venous hierarchy,
      using a variant taken from a patient rather than a null allele.
    limitations: >-
      The mice show disrupted developmental angiogenesis, not a vein of Galen
      aneurysmal malformation, so the model supports the upstream node and not
      the lesion itself. The phenotype also requires a second-hit allele, which
      means the model demonstrates a sensitised genetic context rather than the
      sufficiency of the patient variant alone.
    readouts:
    - name: Hierarchical development of arterial-capillary-venous networks
      target: Impaired Developmental Angiogenesis and Arteriovenous Specification
      direction: ALTERED
      interpretation: >-
        Structural correlate of disordered endothelial development, observed only
        in the presence of a second-hit allele.
      evidence:
      - reference: PMID:37978175
        reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: 'Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele.'
        explanation: >-
          Reports the measurement and, critically, its condition.
    evidence:
    - reference: PMID:37978175
      reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 'Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele.'
      explanation: >-
        Supports treating this model as informative for the endothelial
        developmental node, with the second-hit condition carried alongside
        rather than dropped.
- name: acvrl1a/b-depleted zebrafish with human allele rescue
  species: Zebrafish
  genotype: acvrl1a/b depletion in the Tg(kdr:gfp)zn1 reporter line, rescued with wild-type or Cys344Tyr human ACVRL1 mRNA
  publication: PMID:37978175
  description: >-
    The functional test behind the ACVRL1 assignment, built on the same rescue
    logic as the EPHB4 fish model. Depleting the two zebrafish acvrl1 paralogues
    produced massive dilation of a cranial vein, and the defect was corrected by
    wild-type human ACVRL1 messenger RNA but not by the patient Cys344Tyr form.
    That asymmetry is the whole argument: it shows the human variant is not
    merely rare but functionally deficient.
  modeled_mechanisms:
  - target: Impaired Developmental Angiogenesis and Arteriovenous Specification
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Wild-type human ACVRL1 rescues the venous dilation while the patient allele
      does not, establishing the variant as loss of function.
    limitations: >-
      The dilated vessel is the primordial hindbrain channel, not a median
      prosencephalic vein of Markowski, which zebrafish do not have. The model
      therefore tests allele function against a broadly analogous venous
      phenotype rather than reproducing the human lesion, and depletion is not
      the heterozygous state patients carry.
    readouts:
    - name: Calibre of the venous primordial hindbrain channel and posterior connecting segment
      target: Impaired Developmental Angiogenesis and Arteriovenous Specification
      direction: RESTORED
      interpretation: >-
        Restored by wild-type human ACVRL1 and not by the patient allele, which
        is what converts the variant into a demonstrated loss of function.
      evidence:
      - reference: PMID:37978175
        reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "These phenotypes were rescued by mRNA co-injection of wild-type human ACVRL1 but not of VOGM-mutant human ACVRL1 Cys344Tyr"
        explanation: >-
          States the rescue result and its allele specificity.
    evidence:
    - reference: PMID:37978175
      reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we found that Acvrl1a/b depletion in the Tg(kdr:gfp)zn1 reporter fish line (see Methods) resulted in VOGM-like massive dilation of the venous primordial hindbrain channel and posterior connecting segment"
      explanation: >-
        Establishes the model and the vascular phenotype it produces.
- name: EPHB4-knockdown zebrafish with human allele rescue
  species: Zebrafish
  genotype: ephb4 morpholino knockdown, rescued with wild-type or truncated human EPHB4
  publication: PMID:29444212
  description: >-
    A knockdown model used as a functional assay rather than as a phenocopy of
    the human malformation. Its value is the rescue design: wild-type human EPHB4
    corrects the brain vascular defect and the truncated disease-associated form
    does not, which converts a candidate variant into a demonstrated
    loss-of-function.
  modeled_mechanisms:
  - target: Impaired Developmental Angiogenesis and Arteriovenous Specification
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Establishes that the patient alleles are functionally deficient, by showing
      that wild-type protein rescues the vascular defect while the truncated
      variant fails to.
    limitations: >-
      The zebrafish defect is a general brain vascular abnormality rather than a
      vein of Galen malformation; no median prosencephalic vein of Markowski
      exists to persist, so the model tests allele function rather than
      reproducing the human lesion. It is also a morpholino knockdown rather than
      a germline mutant.
    evidence:
    - reference: PMID:29444212
      reference_title: "Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This model allowed us to investigate EPHB4 loss-of-function mutations in this disease by the ability to rescue the brain vascular defect in knockdown zebrafish co-injected with wild-type, but not truncated EPHB4"
      explanation: >-
        States the rescue design and its result, which is what makes the model a
        functional test of the human alleles.
  evidence:
  - reference: PMID:29444212
    reference_title: "Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This model allowed us to investigate EPHB4 loss-of-function mutations in this disease by the ability to rescue the brain vascular defect in knockdown zebrafish co-injected with wild-type, but not truncated EPHB4"
    explanation: >-
      Supports treating this model as informative for the functional consequence
      of the patient variants.
experimental_models:
- name: COS-7 cells expressing VOGM-associated EPHB4 kinase-domain variants
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: African green monkey
    term:
      id: NCBITaxon:9534
      label: Chlorocebus aethiops
  cell_source: COS-7 immortalized cell line
  culture_system: Transient expression of wild-type or mutant EPHB4 followed by immunoblotting and immunoprecipitation
  conditions:
  - Wild-type EPHB4
  - EPHB4 p.Lys650Asn
  - EPHB4 p.Arg838Trp
  - EPHB4 p.Phe867Leu
  publication: PMID:37978175
  description: >-
    A reductionist cell-line assay used to separate mutant-protein abundance from
    kinase function. The three VOGM-associated kinase-domain variants had
    abundance and decay comparable to wild type but lacked detectable
    phosphotyrosine, supporting impaired EPHB4 kinase-dependent signaling rather
    than protein instability.
  modeled_mechanisms:
  - target: Dysregulated Endothelial Developmental Signaling
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Measures stability and phosphorylation of patient-associated EPHB4 variants
      to define the proximal molecular defect.
    limitations: >-
      COS-7 is a nonhuman, non-endothelial immortalized cell line and does not
      reproduce fetal cerebrovascular development or the anatomical shunt. The
      assay distinguishes protein stability from phosphorylation but cannot alone
      resolve whether absent phosphotyrosine reflects blocked kinase activity or
      faster dephosphorylation.
    readouts:
    - name: EPHB4 steady-state abundance and protein decay
      target: Dysregulated Endothelial Developmental Signaling
      direction: UNCHANGED
      interpretation: >-
        Comparable abundance and decay indicate that the kinase-domain variants
        do not primarily act by destabilizing EPHB4 protein.
      evidence:
      - reference: PMID:37978175
        reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Cycloheximide block of protein translation revealed polypeptide decay rates of EPHB4 VOGM mutants similar to that of WT EPHB4"
        explanation: >-
          Direct comparison of mutant and wild-type decay rates in transfected
          COS-7 cells.
    - name: EPHB4 phosphotyrosine signal
      target: Dysregulated Endothelial Developmental Signaling
      direction: ABOLISHED
      interpretation: >-
        Absence of detectable phosphotyrosine supports compromised
        kinase-dependent signaling while leaving increased dephosphorylation as
        an alternative interpretation.
      evidence:
      - reference: PMID:37978175
        reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "none of the VOGM-associated EPHB4 kinase domain mutants contained detectable phosphotyrosine as detected by anti-pTyr immunoblotting of whole-cell lysates and anti-EPHB4 immunoprecipitates"
        explanation: >-
          Direct assay result for the mutant proteins.
    evidence:
    - reference: PMID:37978175
      reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings strongly suggest that VOGM-associated EPHB4 D-mis variants block the protein tyrosine kinase activity of EPHB4 or render EPHB4 phospho-sites more susceptible to dephosphorylation."
      explanation: >-
        States the mechanistic interpretation and retains the source's alternative
        explanation rather than resolving it beyond the assay.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The steady-state abundance of Lys650Asn, Arg838Trp, and Phe867Leu EPHB4 variants expressed in Cos-7 cells approximated that of WT EPHB4"
    explanation: >-
      Establishes the cell-line expression experiment and the preserved-abundance
      result.
inheritance:
- name: Autosomal dominant susceptibility in a gene-associated subset
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    This inheritance pattern applies to the subset associated with genes such as
    EPHB4, RASA1, and ACVRL1, not to every person with VOGM. A heterozygous allele
    can be transmitted in an autosomal dominant manner, but unaffected carriers
    demonstrate incomplete penetrance and variable expressivity; Mendelian allele
    transmission must not be presented as the child's probability of developing
    VOGM. That disease recurrence risk is not quantified. The EPHB4 mouse work
    supports a possible second-hit mechanism, but it does not prove that every
    human lesion requires a somatic second event.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings together show incomplete penetrance and variable expressivity of transmitted variants in the related CM-AVM genes RASA1 and EPHB4 in VOGM."
    explanation: >-
      Direct human family evidence that transmitted EPHB4 and RASA1 variants do
      not determine the focal lesion with complete penetrance.
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: 'Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele.'
    explanation: >-
      PARTIAL and deliberately so. This is a mouse result offered as a candidate
      explanation for incomplete penetrance in humans, not a demonstration that
      human non-penetrance is caused by a second hit.
diagnosis:
- name: Prenatal ultrasonography
  diagnosis_term:
    preferred_term: Fetal Ultrasound Imaging
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  description: >-
    Prenatal ultrasound can reveal deep cerebral arteriovenous shunts when the
    venous drainage is markedly dilated. Cortical cerebral fistulas can be more
    difficult to identify with this modality.
  evidence:
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A likely reason is that most AV-shunts caused by HHT-associated or RASA1 variants are related to cortical cerebral fistulas, difficult to identify in prenatal imaging, especially by ultrasound, compared to deep cerebral AV-shunts with large dilatations of the venous drainage."
    explanation: >-
      Supports prenatal ultrasound as an imaging modality for the deep,
      dilated-venous-drainage pattern while preserving the source's contrast with
      less conspicuous cortical fistulas.
- name: Fetal magnetic resonance imaging
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    Establishes the prenatal diagnosis, evaluates the brain and venous anatomy,
    and measures the falcine sinus. Falcine-sinus width is a prognostic marker,
    not a standalone definition of the lesion.
  evidence:
  - reference: PMID:40171650
    reference_title: "Mediolateral Diameter of the Falcine Sinus as a Predictor of Clinical Outcomes in Fetal Vein of Galen Malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, 59 patients (55% male and 45% female) diagnosed with vein of Galen malformation via fetal magnetic resonance imaging from 2002 to 2024 were included."
    explanation: >-
      Directly documents fetal MRI as the modality by which this clinical cohort
      was diagnosed.
- name: Fetal echocardiography
  diagnosis_term:
    preferred_term: Echocardiography Test
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: >-
    Assesses the fetal haemodynamic burden of the shunt by measuring cardiac
    output and its change around intervention. It complements neurovascular
    imaging rather than defining the cerebral anatomy.
  evidence:
  - reference: PMID:40788723
    reference_title: "In Utero Embolization for Fetal Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fetal echocardiography showed a mean 33.4% reduction (range, 16%-46%) in cardiac output."
    explanation: >-
      Directly documents fetal echocardiography measuring cardiac output in the
      VOGM intervention cohort.
- name: Magnetic resonance angiography
  diagnosis_term:
    preferred_term: Magnetic Resonance Angiography
    term:
      id: NCIT:C190557
      label: Magnetic Resonance Angiography
  description: >-
    Defines the shunt and deep venous drainage anatomy needed to distinguish a
    true VOGM from a fistula that drains into an enlarged mature vein of Galen.
    The defining finding is disconnection from normal deep cerebral venous
    drainage, which instead uses alternative routes.
  evidence:
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A true VGAM corresponded to a choroidal arteriovenous shunt draining directly into the embryonic precursor of the vein of Galen with normal deep cerebral venous drainage via alternative venous delivery routes, and without identifiable connection between the vascular malformation and the deep venous drainage on angiography, or on MRI or MRA."
    explanation: >-
      Directly states the vascular and deep-venous anatomy that MRI or MRA can
      demonstrate to classify a genuine VOGM.
- name: Catheter angiography
  diagnosis_term:
    preferred_term: Angiography
    term:
      id: NCIT:C190556
      label: Angiography
  description: >-
    Confirms the direct shunt and delineates arterial feeders and venous drainage
    before endovascular treatment. Angiographic anatomy also distinguishes a true
    malformation, whose deep cerebral veins use alternative drainage routes, from
    a pial or choroidal fistula that drains into an enlarged mature vein of Galen.
  evidence:
  - reference: PMID:38747605
    reference_title: "Endoluminal Biopsy for Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis was confirmed by catheter angiography."
    explanation: >-
      Direct statement that catheter angiography confirmed VOGM in the prospective
      endoluminal-sampling cohort.
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A true VGAM corresponded to a choroidal arteriovenous shunt draining directly into the embryonic precursor of the vein of Galen with normal deep cerebral venous drainage via alternative venous delivery routes, and without identifiable connection between the vascular malformation and the deep venous drainage on angiography, or on MRI or MRA."
    explanation: >-
      Defines the anatomy that angiography or MR angiography must establish to
      separate a genuine VOGM from a fistula draining into the mature vein.
- name: Bicêtre score assessment
  diagnosis_term:
    preferred_term: Bicêtre neonatal evaluation score
  description: >-
    A clinical assessment used to judge suitability for intervention in
    neonates and infants with VOGM. The cited six-patient cohort reports that the
    score supported intervention, but does not supply score components,
    thresholds, or independent performance validation; none are inferred here.
  evidence:
  - reference: PMID:38747605
    reference_title: "Endoluminal Biopsy for Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients were seemed suitable for clinical intervention based on Bicetre score."
    explanation: >-
      PARTIAL because it directly documents use of the score for intervention
      suitability but does not define or validate the scoring system.
imaging_findings:
- name: Wide falcine sinus on fetal MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Wide falcine sinus
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  description: >-
    Increased mediolateral falcine-sinus diameter on fetal MRI is a prognostic
    marker associated with mortality, cardiac dysfunction, brain parenchymal
    abnormalities, ventriculomegaly, and developmental delay. It helps stratify
    risk but does not by itself define VOGM.
  diagnostic: false
  notes: >-
    No sufficiently specific HP or NCIT imaging-finding term for falcine-sinus
    width was verified; the precise preferred term is retained without a forced
    broader code.
  evidence:
  - reference: PMID:40171650
    reference_title: "Mediolateral Diameter of the Falcine Sinus as a Predictor of Clinical Outcomes in Fetal Vein of Galen Malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A wide FS is robustly predictive of a high risk for mortality, cardiac dysfunction, brain parenchymal abnormalities at birth, and short- and intermediate-term neurodevelopmental delay."
    explanation: >-
      Directly supports the fetal MRI finding and its prognostic rather than
      pathognomonic role.
  - reference: PMID:40171650
    reference_title: "Mediolateral Diameter of the Falcine Sinus as a Predictor of Clinical Outcomes in Fetal Vein of Galen Malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FS predicted mortality (P=8.04×10-9), right ventricular systolic dysfunction at discharge (P=0.02), brain parenchymal abnormalities at birth (P=0.02) and discharge (P=0.02), ventriculomegaly at birth (P=0.03), and developmental delay at 1 month (P=0.001), 6 months (P=0.001), and 12 months (P=0.002)."
    explanation: >-
      Supplies the measured associations, including ventriculomegaly, without
      converting predictive associations into causal effects.
- name: Direct cerebral arteriovenous shunt to the median prosencephalic vein
  modality: ANGIOGRAPHY
  imaging_finding_term:
    preferred_term: Direct cerebral arteriovenous shunt to the median prosencephalic vein
  located_in:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  description: >-
    Angiography demonstrates primitive choroidal or subependymal arterial supply
    entering the median prosencephalic vein without an intervening capillary
    network. The collector and deep-venous drainage pattern define a genuine
    VOGM and separate it from a fistula draining into the mature vein of Galen.
  diagnostic: true
  notes: >-
    Generic cerebral arteriovenous-malformation terms are broader than this
    defining anatomy, so the imaging finding is kept as a precise preferred term
    without an ontology code.
  evidence:
  - reference: PMID:37978175
    reference_title: "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vein of Galen malformations (VOGMs), the most common and severe arteriovenous malformations (AVMs) of the human neonatal brain11,12, directly connect primitive choroidal or subependymal cerebral arteries to the MPV without an intervening capillary network."
    explanation: >-
      States the defining vascular anatomy represented by the angiographic
      finding.
clinical_trials:
- name: NCT04434729
  phase: NOT_APPLICABLE
  status: ACTIVE_NOT_RECRUITING
  description: >-
    First-in-human single-group fetal embolization study. Seven pregnancies were
    enrolled and five procedures succeeded. Three embolized children were alive
    without neurodevelopmental delay at reported follow-up, but overall mortality
    was 43%; five pregnancies had unscheduled delivery and three of those were
    preterm. These early data establish feasibility, not comparative efficacy.
  target_phenotypes:
  - preferred_term: High-output congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  notes: >-
    Registered as not applicable for phase because it is a device and procedure
    feasibility study rather than a drug trial.
  review_notes: >-
    ClinicalTrials.gov reported
    ACTIVE_NOT_RECRUITING when checked on 2026-08-24, with actual primary
    completion in 2024, estimated overall completion in 2026, and posted results;
    publication of the first seven cases does not by itself change the registry
    recruitment/status field to COMPLETED.
  evidence:
  - reference: clinicaltrials:NCT04434729
    reference_title: "Fetal Treatment of Galenic Malformations"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a prospective, single-arm non-randomized interventional study of fetuses to assess the safety and efficacy of fetal embolization of Vein of Galen Malformation (VOGM)."
    explanation: >-
      States the design and the intervention.
  - reference: PMID:40788723
    reference_title: "In Utero Embolization for Fetal Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients were enrolled; 5 underwent successful embolization."
    explanation: >-
      Reports enrollment and technical success in the first published study
      cohort.
  - reference: PMID:40788723
    reference_title: "In Utero Embolization for Fetal Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall mortality was 43%, and 43% were meeting milestones at 6 months. Three embolized patients (aged 8, 18, and 24 months) survived, all without neurodevelopmental delay."
    explanation: >-
      Gives the reported early survival and neurodevelopmental outcomes without
      implying a controlled treatment effect.
  - reference: PMID:40788723
    reference_title: "In Utero Embolization for Fetal Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five of 7 patients (71.4%) had unscheduled deliveries and 3 of these 5 were preterm, at a mean of 3.2 days after intervention."
    explanation: >-
      Captures the principal procedural safety trade-off reported in the trial.
- name: NCT07483255
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Follow-on interventional study planning enrollment of twenty pregnancies and
    fetal embolization at or after thirty-four weeks of gestation.
  target_phenotypes:
  - preferred_term: High-output congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  notes: >-
    ClinicalTrials.gov records the intervention model without an FDA drug phase;
    the schema therefore uses NOT_APPLICABLE even though "Phase II" appears in
    the study title.
  review_notes: >-
    Status RECRUITING and phase NOT_APPLICABLE were checked against the live
    ClinicalTrials.gov record on 2026-08-24.
  evidence:
  - reference: clinicaltrials:NCT07483255
    reference_title: "A Phase II Trial of Fetal Embolization for Vein of Galen Malformation"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects will receive a one-time study intervention of fetal embolization, at or after 34 weeks of gestation."
    explanation: >-
      States the intervention and the gestational threshold that defines the
      trial's risk trade-off.
treatments:
- name: Endovascular Embolization
  description: >-
    The primary treatment closes arterial feeders or the venous side of the shunt
    with liquid embolic material and/or coils, often across staged procedures.
    Timing balances neonatal cardiopulmonary instability against procedural risk.
    Outcomes have improved, but long-term results remain worse than medium-term
    follow-up implies.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Endovascular embolization
    term:
      id: NCIT:C15230
      label: Embolization Therapy
  target_mechanisms:
  - target: Persistent Embryonic Arteriovenous Shunt
    treatment_effect: INHIBITS
    description: >-
      Occludes the arteriovenous connection directly, which is why it addresses
      the cardiac, venous and steal consequences together rather than one at a
      time.
    evidence:
    - reference: PMID:38747605
      reference_title: "Endoluminal Biopsy for Vein of Galen Malformation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Current methods for closing the AV shunt rely on percutaneous transarterial or transvenous access with microcatheters, followed by vascular occlusion with liquid embolics and/or coils."
      explanation: >-
        Directly supports the procedure's route and mechanism at the shunt.
    - reference: PMID:35547535
      reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "While endovascular embolization has clearly improved the outcome, several recent case series (7, 8) have shown that the long-term prognosis in this malformation is more severe than the usually described medium-term prognosis (9-11)."
      explanation: >-
        States both halves honestly: embolization has clearly improved outcome,
        and long-term prognosis is nonetheless more severe than medium-term
        reports suggest.
  evidence:
  - reference: PMID:38747605
    reference_title: "Endoluminal Biopsy for Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endovascular embolization represents the primary treatment but typically requires several procedures, staged over months to years."
    explanation: >-
      Establishes embolization as primary treatment and documents the commonly
      staged treatment course.
  - reference: PMID:31713850
    reference_title: "Long-term outcome of vein of Galen malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth."
    explanation: >-
      PARTIAL and recorded as a limit on the treatment rather than support for it.
      Survivors of successful treatment still do worse than earlier follow-up
      predicted, which is what a family needs told.
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is lethal in almost 100% of cases if left untreated."
    explanation: >-
      The comparator that gives the previous caveat its proportion. Long-term
      outcomes after treatment are worse than medium-term follow-up implies, and
      the alternative is near-certain death.
- name: Long-term neurodevelopmental rehabilitation
  description: >-
    School-age survivors can have neuropsychological disorders that affect
    learning even when earlier outcome was classified as good, and may require
    appropriate rehabilitation or medical management. The cited cohort does not
    specify a rehabilitation protocol or drug regimen and does not establish
    treatment efficacy, so none is asserted here.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Neurodevelopmental rehabilitation
  evidence:
  - reference: PMID:31713850
    reference_title: "Long-term outcome of vein of Galen malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Even patients with good outcome often have neuropsychological disorders that may have repercussions on learning and requiring appropriate rehabilitation or medical management."
    explanation: >-
      PARTIAL because the cohort supports the need for individualized supportive
      rehabilitation or medical management but does not test a specific
      intervention or quantify its benefit.
progression:
- phase: Long-term outcome after treatment
  notes: >-
    School-age follow-up shows that survival and an initially reassuring scan do
    not guarantee normal function. In a VOGM-specific cohort, 33 of 52 patients
    were alive at long-term assessment; 14 of the 33 survivors had a poor outcome,
    and neurodevelopmental alterations were common even among those classified as
    having a good outcome. Results were less favorable than short- and
    medium-term reports, including among children without encephalomalacia at
    birth.
  evidence:
  - reference: PMID:31713850
    reference_title: "Long-term outcome of vein of Galen malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the long-term evaluation time-point, 33 patients were alive and 19 patients had died."
    explanation: >-
      Gives the VOGM-specific long-term survival count.
  - reference: PMID:31713850
    reference_title: "Long-term outcome of vein of Galen malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among survivors, 19 had a good outcome with normal schooling and 14 had a poor outcome."
    explanation: >-
      Supports the outcome split stated for the 33 survivors.
  - reference: PMID:31713850
    reference_title: "Long-term outcome of vein of Galen malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term outcome of patients with VGAM appears to be less favourable than outcome described at the short- and medium-term, even in the absence of encephalomalacia at birth."
    explanation: >-
      The counterweight: later assessment is worse than earlier assessment, and a
      normal neonatal brain does not exclude it.
discussions:
- discussion_id: vogm_second_hit_requirement
  prompt: >-
    Does vein of Galen malformation require a somatic second hit on top of an
    inherited variant, and if so what and where is it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated Endothelial Developmental Signaling
  rationale: >-
    Mice carrying a patient-derived EPHB4 kinase-domain variant developed the
    angiogenic defect only when a second-hit allele was present. That single
    conditional clause reconciles inherited susceptibility alleles with a disease
    that often appears only once in a family. If a second event is required, the
    identity of that event is unknown in humans. It could
    be a somatic mutation confined to the developing cerebral endothelium, in
    which case it would be invisible to blood-derived sequencing and would explain
    both the non-penetrant carrier parents and the focal, single-lesion anatomy of
    a disease whose germline variant is present in every cell. It could equally be
    a second germline variant elsewhere, or a non-genetic developmental
    contingency. Endoluminal coil sampling has now recovered lesional endothelial
    cells safely enough for single-cell RNA sequencing, but the published study
    presents somatic and second-hit DNA analysis as future work rather than a
    completed result. The biological question therefore remains open while the
    sampling barrier has become experimentally tractable.
  evidence:
  - reference: PMID:38747605
    reference_title: "Endoluminal Biopsy for Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No periprocedural complications related to ETS were encountered, and no subjects were lost to follow-up."
    explanation: >-
      Supports feasibility and observed procedural safety of lesion-cell sampling
      in the six-patient cohort, not the unperformed second-hit analysis.
  - reference: PMID:38747605
    reference_title: "Endoluminal Biopsy for Vein of Galen Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pedigrees were assembled to eventually compare germline DNA against EC's retrieved by ETS to identify somatic and second-hit mutations."
    explanation: >-
      The word "eventually" makes the evidence boundary explicit: matched DNA
      analysis was planned, not reported as a positive finding.
  proposed_experiments:
  - experiment_id: vogm_lesion_somatic_sequencing
    name: Matched deep DNA sequencing of coil-sampled lesional endothelium and blood
    description: >-
      During clinically indicated embolization, use endoluminal coils to obtain
      lesional endothelial cells and sequence their DNA against matched blood from
      patients carrying a germline EPHB4 or RASA1 variant, with methods validated
      for picogram input and low variant fractions. Recurrent second hits present
      in lesion and absent from blood would support the two-hit model in humans;
      adequate negative results across a series would weaken it. Single-cell RNA
      clusters alone cannot adjudicate this DNA-level question.
    evidence:
    - reference: PMID:38747605
      reference_title: "Endoluminal Biopsy for Vein of Galen Malformation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All 6 families that were solicited to participate in the study agreed and provided informed consent. ETS was performed a total of 10 times (owing to staged procedures involving the same subject), in 3 arteries and 7 veins."
      explanation: >-
        Demonstrates repeated in situ sampling in the exact patient population and
        therefore supports feasibility of the proposed matched-DNA experiment.
- discussion_id: vogm_long_term_deterioration
  prompt: >-
    Why do children with vein of Galen malformation do worse at school age than
    medium-term follow-up predicts, even when no encephalomalacia was present at
    birth?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Cerebral Arterial Steal
  - pathophysiology#Cerebral Venous Hypertension
  rationale: >-
    The outcome literature states plainly that long-term results are less
    favourable than short- and medium-term assessment suggests, and that this
    holds even in the absence of encephalomalacia at birth. That combination is
    the interesting part: a normal-looking neonatal brain does not guarantee a
    normal-functioning school-age child. Several explanations are compatible with
    it and none is established. Chronic hypoperfusion and venous hypertension may
    injure developing tissue in ways that structural imaging does not show; the
    cognitive demands that reveal impairment may simply not exist in infancy; or
    residual shunting after treatment may continue to affect a brain that is
    still developing. Distinguishing them matters directly for what families are
    told at discharge and for how long children are followed.
  proposed_experiments:
  - experiment_id: vogm_school_age_imaging_correlation
    name: School-age neurocognitive outcome against neonatal and follow-up imaging
    description: >-
      Follow a treated cohort to school age with formal neurocognitive assessment
      and serial imaging, testing whether later impairment is predicted by
      residual shunt, by interval imaging change, or by neither. If neither
      predicts it, the injury is occurring below the resolution of structural
      imaging, which is itself the finding.
differential_diagnoses:
- name: Pial arteriovenous fistula draining into an enlarged vein of Galen
  description: >-
    The critical differential, and the reason the distinction is curated rather
    than assumed. A pial arteriovenous fistula or malformation may drain into a
    secondarily dilated vein of Galen and look similar on imaging, but it is a
    different lesion with different anatomy, different genetics, and a different
    risk profile for intervention. Calling it a vein of Galen malformation would
    import the wrong treatment expectations.
  evidence:
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Misclassifications of AVFs or arteriovenous malformations that drain into a dilated vein of Galen as true VGAMs are also frequent"
    explanation: >-
      Directly identifies the recurrent diagnostic misclassification represented
      by this differential.
- name: Dural arteriovenous fistula of infancy
  description: >-
    Another high-flow shunt presenting with cardiac failure and venous
    hypertension in infancy, arising in dural rather than pial or choroidal
    vessels. Distinguished angiographically by the feeding vessels and the site
    of the shunt.
  evidence:
  - reference: PMID:35547535
    reference_title: "Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the shunt is located in the torcular, and the arterial feeders belong to the dural branches, suggesting a dural sinus malformation."
    explanation: >-
      A case-level example shows the angiographic features that redirect a
      presumed VOGM diagnosis to a dural lesion; graded PARTIAL because it is not
      a cohort-wide diagnostic study.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 30 citations 2026-08-16T20:16:53.115924

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: Vein of Galen Aneurysm
  • MONDO ID: (if available)
  • Category: Congenital

Research Objectives

Please provide a comprehensive research report on Vein of Galen Aneurysm 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

  • 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

Vein of Galen aneurysmal malformation: disease-characteristics report

Executive summary

Vein of Galen aneurysmal malformation (VGAM; increasingly VOGM, “vein of Galen malformation”) is a congenital, high-flow cerebral arteriovenous shunt. Primitive choroidal/subependymal arteries connect directly to the persistent median prosencephalic vein of Markowski, without an intervening capillary bed. It is therefore neither a true aneurysm nor usually a lesion of the mature vein of Galen. The resulting low-resistance circuit can produce fetal or neonatal high-output heart failure, pulmonary hypertension, systemic and cerebral steal, venous hypertension, hydrocephalus, and irreversible brain injury. True VOGM must be separated from a pial AV fistula or AVM that secondarily drains into an enlarged vein of Galen because anatomy, genetics, and treatment risk differ. (tas2022arteriovenouscerebralhigh pages 4-5, tas2022arteriovenouscerebralhigh pages 2-3, zhao2023mutationofkey pages 1-2)

The most important recent advance is the 2023 demonstration that VOGM is partly a disorder of developing endothelial Ras-regulatory networks. Analysis of 310 proband-family exomes and 336,326 cerebrovascular single-cell transcriptomes implicated RASA1, EPHB4, ACVRL1, NOTCH1, ITGB1, and PTPN11 and localized susceptibility to fetal endothelial cells. Endovascular embolization remains standard treatment; fetal embolization is investigational. (zhao2023mutationofkey pages 7-8, zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 13-14)

Domain Established finding Quantitative evidence/examples Evidence type and year Certainty/gap
Disease definition / embryology Vein of Galen aneurysmal malformation (VGAM/VOGM) is a congenital high-flow brain arteriovenous shunt between primitive choroidal or subependymal arteries and the median prosencephalic vein of Markowski, without an intervening capillary bed; it arises during fetal cerebrovascular development and is anatomically distinct from pial AV fistulas that merely drain into the vein of Galen. Development reported during fetal weeks 6-11; true VGAM defined by drainage into the embryonic median prosencephalic vein with normal brain venous drainage rerouted through alternative pathways. (singh2022recurrentveinof pages 1-2, zhao2023mutationofkey pages 1-2, tas2022arteriovenouscerebralhigh pages 2-3) Human clinical/review evidence, 2022-2023 High certainty for definition and embryologic concept; exact embryologic timing varies slightly across sources.
Epidemiology VGAM is rare but is among the most important vascular malformations in fetuses and infants. Reported incidence ranges in available sources from ~1:25,000 to ~1:50,000; accounts for ~30% of pediatric vascular malformations; male predominance reported around 3:1 in one source. (singh2022recurrentveinof pages 1-2, vivanti2018lossoffunction pages 1-2) Human clinical/review evidence, 2018-2022 Moderate certainty; incidence and sex-ratio estimates vary by source and older literature.
Major phenotypes The major morbidity drivers are neonatal high-output cardiac failure, hydrocephalus/venous congestion, intracranial hemorrhage risk, seizures, developmental delay, and neurologic deficits. Presentation varies by age and shunt anatomy. In a pediatric cohort of 115 children with cerebral high-flow shunts, good outcome occurred in 62% and poor outcome in 38%; median follow-up 27 months among survivors. Antenatal cardiac failure has been associated with very high mortality in older literature summarized by recent sources. (tas2022arteriovenouscerebralhigh pages 2-3, singh2022recurrentveinof pages 1-2, tas2022arteriovenouscerebralhigh pages 4-5, zhao2023mutationofkey pages 1-2) Human cohort/review evidence, 2022-2023 High certainty for phenotype spectrum; precise phenotype frequencies by subtype are incompletely standardized in currently available context.
Genetics: overall architecture VGAM is often sporadic, but a substantial minority of patients carry rare damaging germline variants in vascular-development genes; both de novo and inherited variants contribute. 310 proband-family exomes analyzed in the largest available study; de novo variants estimated to contribute to ~12% of cases; 115-child cohort found pathogenic/likely relevant variants in 39% overall. (zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 13-14, tas2022arteriovenouscerebralhigh pages 1-2) Human genomic cohort evidence, 2022-2023 High certainty that genetics contributes in a subset; overall attributable fraction remains incomplete.
Genetics: RASA1 RASA1 is the strongest currently supported VGAM gene, with loss-of-function de novo and transmitted germline variants implicating dysregulated Ras suppression. Genome-wide significant burden of de novo loss-of-function variants: 2042.5-fold enrichment, p=4.79×10^-7; case-control enrichment versus gnomAD Fisher p=2.20×10^-8, OR=67.50; example variants include p.Arg427, p.Val527Mfs16, p.Arg709, p.Tyr695/p.Tyr872* and frameshift alleles. (zhao2023mutationofkey pages 1-2, zhao2023geneticdysregulationof pages 6-8, zhao2023geneticdysregulationof pages 30-35) Human exome study and prior cohort, 2023 High certainty for association; penetrance is incomplete and phenotype can include other vascular anomalies.
Genetics: EPHB4 EPHB4 is strongly associated with true VGAM and appears especially informative for distinguishing genuine VGAM from other cerebral AV shunts. Most disease alleles impair receptor function rather than simply destabilizing protein. Rare damaging transmitted variants enriched 17.5-fold, p=1.22×10^-5; in one 115-child cohort EPHB4 variants represented 8% of identified variants and were observed only in genuine VGAM; example kinase-domain missense variant p.Phe867Leu. (zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 7-8, tas2022arteriovenouscerebralhigh pages 1-2, zhao2023mutationofkey pages 5-7) Human genomic cohort and functional studies, 2018-2023 High certainty for association with genuine VGAM; exact penetrance and full allelic spectrum remain incompletely defined.
Genetics: ACVRL1, NOTCH1, ITGB1, PTPN11 Additional genes affecting vascular development/signaling are implicated in smaller numbers of patients, broadening VGAM biology beyond the core RASA1-EPHB4 axis. ACVRL1 variants identified including p.Cys344Tyr and p.Arg484Gln; PTPN11 example p.Tyr63Cys; NOTCH1 and ITGB1 damaging variants also reported. ACVRL1 variants occurred in a multigenerational pedigree. (zhao2023mutationofkey pages 7-8, zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 13-14, zhao2023geneticdysregulationof pages 30-35) Human exome cohort evidence, 2023 Moderate certainty; gene-specific case counts are small and some genes remain candidate-level compared with RASA1/EPHB4.
Inheritance / penetrance The best-supported inherited forms show autosomal dominant transmission with incomplete penetrance and variable expressivity; some carriers have capillary malformations or other vascular phenotypes rather than VGAM. A two-hit mechanism is hypothesized for some families. Inherited RASA1/EPHB4 variants showed nonpenetrance or alternate phenotypes in family studies; prior cohort estimated inherited damaging ephrin-signaling variants accounted collectively for ~30% of cases in a 55-proband exome series. (zhao2023mutationofkey pages 5-7, duran2019mutationsinchromatin pages 1-3, zhao2023geneticdysregulationof pages 12-14) Human family-based genomic evidence, 2019-2023 Moderate-to-high certainty for incomplete penetrance/variable expressivity; direct proof of second-hit somatic events in VGAM remains limited in current context.
Endothelial Ras/MAPK mechanism The central mechanistic model is dysregulation of an endothelial Ras/ERK/MAPK signaling network during cerebrovascular development, impairing arterial-capillary-venous hierarchy formation and vascular remodeling. Developing endothelial cells emerged as the likely spatiotemporal disease locus from analysis of 336,326 cerebrovascular single-cell transcriptomes; VOGM genes showed endothelial enrichment (p=6.43×10^-6) and vascular-development pathway enrichment including 11.4-fold enrichment for positive regulation of vascular development, p=7.95×10^-8. (zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 7-8, zhao2023mutationofkey pages 13-14, zhao2023geneticdysregulationof pages 12-14) Human genomics + single-cell transcriptomics, 2023 High certainty for endothelial developmental locus and Ras-network involvement; downstream hemodynamic injury pathways are less finely quantified.
Diagnostics Diagnosis relies primarily on prenatal ultrasound and fetal MRI, then postnatal neurovascular imaging and hemodynamic assessment to define anatomy, organ dysfunction, and treatment timing. Prenatal detection is commonly in late 2nd or 3rd trimester in summarized sources; fetal trials use MRI markers such as straight/falcine sinus width ≥7 mm to identify high-risk fetuses. (singh2022recurrentveinof pages 1-2, NCT07483255 chunk 1, NCT04434729 chunk 1) Human clinical and trial-protocol evidence, 2022-2026 Moderate certainty; detailed modern sensitivity/specificity data and formal scoring-system thresholds were not available in current context.
Standard treatment: endovascular embolization Staged endovascular embolization is the current treatment standard for symptomatic or high-risk VGAM, typically performed after stabilization and tailored to angioarchitecture. Multiple current sources describe endovascular embolization as prognosis-improving standard care; untreated disease has been described as nearly uniformly fatal in severe infantile presentations. (vivanti2018lossoffunction pages 1-2, tas2022arteriovenouscerebralhigh pages 1-2, zhao2023mutationofkey pages 1-2) Human clinical/review evidence, 2018-2023 High certainty for standard-of-care status; precise pooled success/complication rates were not available in current retrievable context.
Experimental fetal embolization trials Fetal embolization is an emerging strategy for fetuses predicted to decompensate immediately after birth, aiming to reduce urgent neonatal intervention and early mortality. NCT04434729: prospective single-arm fetal embolization study, enrollment 7, active/not recruiting; NCT07483255: Phase II recruiting trial, planned enrollment 20. Both use maternal transuterine, fetal transcranial torcular puncture with median prosencephalic vein coil embolization; inclusion requires falcine/straight sinus width ≥7 mm and preserved brain parenchyma. (NCT04434729 chunk 1, NCT07483255 chunk 1) Interventional trial protocol evidence, 2022-2026 Moderate certainty for feasibility research; efficacy and long-term safety remain investigational.
Prognosis Prognosis is driven by timing/severity of cardiac failure, brain injury, hydrocephalus/venous congestion, and feasibility of staged embolization; modern outcomes are markedly better than historical natural history. 115-child cohort: 62% good vs 38% poor outcome overall; severe antenatal cardiac failure has been associated with very high mortality in summarized literature. (tas2022arteriovenouscerebralhigh pages 2-3, singh2022recurrentveinof pages 1-2) Human cohort/review evidence, 2022-2023 Moderate certainty; contemporary multicenter long-term neurodevelopmental rates were not fully available in current context.
Prevention There is no established primary prevention for sporadic VGAM. Secondary prevention focuses on prenatal detection and early referral; in familial forms, genetic counseling and targeted testing are relevant. Familial syndromic associations include RASA1/EPHB4-related capillary malformation-AVM and HHT genes such as ACVRL1/ENG; pregnancy surveillance in known carriers has been advocated in review/case literature. (vivanti2018lossoffunction pages 1-2, singh2022recurrentveinof pages 1-2, zhao2023mutationofkey pages 13-14) Human genetic and clinical evidence, 2018-2023 Moderate certainty for counseling/surveillance; no proven environmental or pharmacologic preventive factors identified.
Model organisms Functional animal models support causality and mechanism, especially for endothelial signaling genes. Mouse model expressing EPHB4 p.Phe867Leu showed disrupted developmental angiogenesis and impaired arterial-capillary-venous hierarchy, particularly with a second-hit allele; zebrafish Acvrl1a/b depletion produced VOGM-like venous dilation rescued by wild-type but not mutant ACVRL1. (zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 7-8, zhao2023geneticdysregulationof pages 30-35, duran2019mutationsinchromatin pages 1-3) Mouse and zebrafish functional studies, 2019-2023 High certainty that these models recapitulate key vascular-development features; no well-established natural nonhuman disease species identified in current context.

Table: This table summarizes the strongest currently available evidence for vein of Galen aneurysmal malformation across definition, epidemiology, clinical features, genetics, mechanisms, diagnosis, treatment, prognosis, prevention, and models. It is designed as a concise knowledge-base matrix that distinguishes established findings from current evidence gaps.

1. Disease information

Definition and terminology

Preferred terms are vein of Galen aneurysmal malformation, vein of Galen malformation, VGAM, and VOGM. Other names include aneurysmal malformation of the vein of Galen, Galenic arteriovenous malformation, and median prosencephalic arteriovenous fistula. “Vein of Galen aneurysm” is clinically common but anatomically misleading.

A genuine VOGM drains into the embryonic median prosencephalic vein, which drains the shunt while normal deep cerebral venous blood is rerouted through alternative channels. It should not be conflated with “vein of Galen aneurysmal dilatation,” in which another AVM/AVF drains into the mature Galenic system. (tas2022arteriovenouscerebralhigh pages 4-5, tas2022arteriovenouscerebralhigh pages 2-3, vivanti2018lossoffunction pages 1-2)

Identifiers

  • MONDO: a stable disease-specific MONDO identifier could not be verified from the retrieved primary literature; validate directly against the current MONDO release before ingestion.
  • OMIM: no single, universally accepted disease-specific OMIM entry was established in the retrieved evidence. Relevant Mendelian disorders include RASA1/EPHB4-related capillary malformation–AVM and ACVRL1/ENG-related hereditary hemorrhagic telangiectasia.
  • MeSH: generally indexed under Arteriovenous Malformations and related cerebral vascular-malformation terms rather than a unique VGAM descriptor.
  • ICD-10/ICD-11: no uniquely specific code was verified; cases are generally coded under congenital cerebral/circulatory-system vascular malformations. Local coding rules should be checked.
  • Orphanet: a disease-specific number was not independently verified in the retrieved evidence.

The evidence summarized here is aggregated disease-level evidence from family exomes, clinical cohorts, single-cell atlases, functional studies, and trial registries—not individual EHR-derived data.

2. Etiology, risk, and protective factors

VOGM originates during embryonic cerebrovascular development, approximately gestational weeks 6–11. Persistence of abnormal primitive arteriovenous connections prevents normal capillary and arterial–venous hierarchy formation. (singh2022recurrentveinof pages 1-2, zhao2023mutationofkey pages 1-2)

Genetic factors

The disease is usually apparently sporadic, but rare damaging germline variants explain an important subset. In a 115-child high-flow-shunt cohort, variants were found in 39% overall; RASA1, EPHB4, and HHT-associated genes represented 25%, 8%, and 5%, respectively. Those percentages describe that mixed referral cohort and should not be treated as population-wide VOGM frequencies. (tas2022arteriovenouscerebralhigh pages 2-3, tas2022arteriovenouscerebralhigh pages 1-2)

Established or strongly supported genes are RASA1 and EPHB4; additional evidence implicates ACVRL1, NOTCH1, ITGB1, and PTPN11. Rare ENG/SMAD4-associated presentations have been reported, but some may represent phenotypically related cerebral AV shunts rather than anatomically genuine VOGM. (singh2022recurrentveinof pages 1-2, zhao2023mutationofkey pages 7-8, zhao2023mutationofkey pages 1-2)

Environmental, infectious, and lifestyle factors

No reproducible maternal toxin, infection, medication, diet, smoking, alcohol, occupational exposure, or lifestyle risk factor is established. No protective genetic allele, diet, medication, or behavior is validated. The malformation is congenital and developmental, not infectious or contagious. Consequently, evidence for gene–environment interaction is presently insufficient.

3. Phenotypes

Presentation varies with shunt flow, venous restriction, brain injury, and age.

  • Fetal: cardiomegaly, tricuspid regurgitation, hydrops, enlarged neck vessels, and abnormal intracranial flow; severe antenatal cardiac failure is an adverse sign. Detection is usually in the late second or third trimester. Suggested HPO labels: fetal cardiomegaly, hydrops fetalis, arteriovenous malformation, abnormal fetal ultrasonography. (singh2022recurrentveinof pages 1-2)
  • Neonatal: high-output congestive heart failure, pulmonary hypertension, respiratory distress, hypotension/systemic hypoperfusion, multiorgan dysfunction, and encephalopathy. Severity ranges from compensated to rapidly fatal. Suggested HPO: high-output cardiac failure, pulmonary hypertension, respiratory distress, hypotension, encephalopathy. (singh2022recurrentveinof pages 1-2, zhao2023mutationofkey pages 1-2)
  • Infant/child: macrocephaly, hydrocephalus, prominent scalp veins, seizures, developmental delay, focal neurologic deficit, and failure to thrive. These may evolve progressively through venous hypertension or prior ischemic/hemorrhagic injury. Suggested HPO: hydrocephalus, macrocephaly, seizure, global developmental delay, abnormality of cerebral veins. (singh2022recurrentveinof pages 1-2, zhao2023mutationofkey pages 1-2)
  • Older child/adult: uncommon; headache, seizures, hemorrhage, hydrocephalus, cognitive difficulty, or incidental detection may occur.

In the 115-child mixed cerebral high-flow-shunt cohort, 62% had a good and 38% a poor outcome at a median 27-month survivor follow-up. This is not a phenotype-frequency survey of unselected VOGM. (tas2022arteriovenouscerebralhigh pages 2-3)

Quality-of-life effects can include motor, language, cognitive, educational, and caregiver burdens. Disease-specific validated patient-reported outcome data are sparse; formal long-term neuropsychological follow-up is preferable to survival or gross motor status alone.

4. Genetic and molecular information

RASA1

RASA1 encodes p120 RasGAP, a negative regulator of RAS. In the 2023 study, de novo loss-of-function variants showed 2,042.5-fold enrichment (p=4.79×10⁻⁷); case-control enrichment versus gnomAD had OR 67.5 (p=2.20×10⁻⁸). Reported protein variants include p.Arg427, p.Val527Mfs16, p.Arg709, p.Tyr872, and p.His743Thrfs*24. These are germline nonsense/frameshift variants expected to cause loss of function, often through nonsense-mediated decay and excessive Ras/ERK/MAPK activity. (zhao2023geneticdysregulationof pages 6-8, zhao2023geneticdysregulationof pages 30-35)

EPHB4

EPHB4 encodes a venous endothelial receptor tyrosine kinase. Rare damaging transmitted variants were enriched 17.5-fold (p=1.22×10⁻⁵). Examples include p.Lys650Asn, p.Arg838Trp, and p.Phe867Leu. Functional assays found preserved protein stability but reduced or absent phosphotyrosine signal, supporting impaired kinase function. EPHB4 variants appeared specific to genuine VOGM in one comparative cohort. (tas2022arteriovenouscerebralhigh pages 1-2, zhao2023mutationofkey pages 1-2, zhao2023geneticdysregulationof pages 30-35, zhao2023mutationofkey pages 5-7)

Additional genes

  • ACVRL1/ALK1: reported p.Cys344Tyr and p.Arg484Gln kinase-domain variants; multigenerational segregation and zebrafish rescue experiments support pathogenicity.
  • PTPN11/SHP2: p.Tyr63Cys is an example; activating PTPN11 variation can increase RAS signaling.
  • NOTCH1 and ITGB1: rare damaging variants implicate arterial specification and focal-adhesion/PI3K-AKT biology, but evidence is less mature than for RASA1/EPHB4. (zhao2023mutationofkey pages 7-8, zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 13-14, zhao2023geneticdysregulationof pages 30-35)

Variants are usually heterozygous germline, de novo or inherited. Inherited disease behaves as autosomal dominant with incomplete penetrance and variable expressivity; relatives may have capillary malformations, other AVMs, or no detected VOGM. A local postzygotic “second hit” is biologically plausible and supported by model data, but direct demonstration in human VOGM tissue remains limited. Population allele frequencies must be retrieved variant-by-variant from the current gnomAD release; no meaningful carrier frequency exists for VOGM as a whole. (zhao2023geneticdysregulationof pages 12-14, duran2019mutationsinchromatin pages 1-3, zhao2023mutationofkey pages 5-7)

No recurrent chromosomal abnormality, repeat expansion, mitochondrial variant, epigenetic signature, or validated modifier gene is established. Chromatin-modifier de novo variants were enriched in an earlier 55-proband study, but a clinically actionable epigenetic classification has not emerged. (duran2019mutationsinchromatin pages 1-3)

5. Environmental information

No validated environmental, lifestyle, or infectious cause is known. VOGM is not attributable to postnatal behavior, and there is no evidence that diet or exercise changes occurrence. Maternal exposures should therefore not be represented as causal without case-specific evidence. CTD/toxicogenomic associations would be hypothesis-generating rather than disease-defining.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream developmental susceptibility: damaging variants disturb EPHB4–RASA1, ACVRL1/TGF-β-BMP, NOTCH, integrin/focal-adhesion, or PTPN11-RAS signaling in fetal endothelial cells.
  2. Arteriovenous specification failure: endothelial identity, angiogenic sprouting, remodeling, and arterial-capillary-venous hierarchy formation are impaired.
  3. Anatomic lesion: primitive choroidal arteries retain direct connections to the median prosencephalic vein.
  4. Hemodynamic amplification: the low-resistance shunt causes extreme venous flow/pressure and arterial steal.
  5. Downstream organ injury: high cardiac preload produces high-output failure and pulmonary hypertension; systemic steal causes renal/hepatic/gut hypoperfusion; cerebral venous hypertension and reduced effective perfusion cause edema, hydrocephalus, ischemia, calcification, atrophy, or hemorrhage. (zhao2023mutationofkey pages 1-2, zhao2023geneticdysregulationof pages 12-14)

The 2023 integrated analysis found endothelial-cell enrichment (p=6.43×10⁻⁶), 11.4-fold enrichment for positive regulation of vascular development (p=7.95×10⁻⁸), and involvement of focal-adhesion–PI3K–AKT–mTOR pathways. Its abstract states: “Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology.” (zhao2023mutationofkey pages 7-8, zhao2023mutationofkey pages 1-2)

Suggested GO biological-process labels include blood-vessel development, angiogenesis, artery morphogenesis, vein morphogenesis, endothelial-cell differentiation, RAS protein signal transduction, ERK1/ERK2 cascade, and regulation of vascular permeability. Suggested CL labels are endothelial cell, vascular endothelial cell, arterial endothelial cell, and venous endothelial cell. These labels should be mapped to the current ontology release before ingestion.

Single-cell transcriptomics is currently the strongest molecular-profiling evidence. Disease-specific proteomic, metabolomic, lipidomic, spatial-transcriptomic, and validated circulating biomarker signatures are not established. No VOGM-specific CRISPR screen or patient-organoid platform is yet standard.

7. Anatomical structures affected

The primary lesion occupies the midline deep cerebral venous compartment, involving the median prosencephalic vein, primitive choroidal/subependymal arterial feeders, falcine/straight sinus outflow, and associated dural sinuses. Normal deep veins may use alternative drainage. The lesion is midline rather than meaningfully unilateral. (tas2022arteriovenouscerebralhigh pages 4-5, vivanti2018lossoffunction pages 1-2, zhao2023mutationofkey pages 1-2)

Secondary structures include cerebral white matter and cortex, ventricles, heart, pulmonary vasculature, and—through systemic steal—the kidneys, liver, and gastrointestinal tract. Relevant tissue is vascular endothelium and vessel wall; the principal subcellular components are the plasma membrane receptor-signaling complex and cytoplasmic RAS/MAPK machinery.

Suggested UBERON labels: brain, cerebral blood vessel, cerebral vein, diencephalon, ventricular system of brain, heart, and pulmonary artery. Exact identifiers require current-release validation. Suggested GO cellular-component labels include plasma membrane, receptor complex, and cytoplasm.

8. Temporal development

The lesion forms prenatally, classically during weeks 6–11, but may not become sonographically conspicuous until late gestation. Clinical course is driven by physiology rather than a formal stage system. (singh2022recurrentveinof pages 1-2)

A practical sequence is: fetal compensated shunt → fetal cardiac strain/hydrops in severe disease → abrupt neonatal decompensation as placental resistance disappears → later compensated infancy with hydrocephalus or neurodevelopmental sequelae. Untreated severe neonatal disease can progress rapidly; treated disease remains chronic until durable shunt closure and surveillance are achieved. Spontaneous thrombosis is reported but is unpredictable and not a prevention strategy.

The principal therapeutic window is before irreversible brain or multiorgan injury. Stable infants are often allowed to grow before staged embolization; refractory neonatal failure demands earlier intervention. Experimental fetal treatment targets selected late-gestation fetuses expected to decompensate after birth. (NCT07483255 chunk 1, NCT04434729 chunk 1)

9. Inheritance and population

Published incidence estimates vary from approximately 1 in 25,000 to 1 in 50,000 births. One source reports a male:female ratio near 3:1 and approximately 30% of pediatric vascular malformations, but referral and definitional differences limit generalization. No well-established ethnic or endemic geographic concentration exists. (singh2022recurrentveinof pages 1-2, vivanti2018lossoffunction pages 1-2)

Most cases remain isolated. Mendelian cases are generally autosomal dominant with incomplete penetrance and variable expressivity. Anticipation, founder effects, consanguinity dependence, carrier frequency, and germline mosaicism have not been established. A report of recurrent severe fetal disease in a consanguineous family with parental ENG p.Asp264Asn proposed biallelic fetal disease, but fetal DNA was unavailable; this remains a case-level hypothesis rather than a general inheritance model. (singh2022recurrentveinof pages 1-2)

10. Diagnostics

Imaging and physiological assessment

  • Prenatal Doppler ultrasound: midline cystic-appearing structure with turbulent high-velocity flow; assesses cardiomegaly, hydrops, and umbilical/cerebral hemodynamics.
  • Fetal MRI: confirms anatomy, falcine/straight sinus dimensions, venous outflow, and pre-existing ischemic, hemorrhagic, or atrophic brain injury.
  • Postnatal cranial Doppler and echocardiography: quantify shunt physiology, ventricular function, pulmonary hypertension, systemic steal, and venous congestion.
  • MRI/MRA/MRV: define brain integrity, arterial supply, venous drainage, hydrocephalus, and treatment planning.
  • Catheter digital-subtraction angiography: definitive angioarchitecture and procedural roadmap; generally performed when intervention is intended.
  • CT: useful in emergencies for hemorrhage/calcification but avoided when MRI/ultrasound suffice because of radiation.

No diagnostic blood biomarker, enzyme assay, biopsy, histopathologic criterion, EEG signature, or newborn-screening analyte exists. ECG, blood gases, lactate, renal/hepatic tests, BNP/troponin, and EEG are supportive measures of organ injury, not disease-specific diagnostics.

Clinical triage and differential diagnosis

Multidisciplinary teams integrate cardiac, cerebral, respiratory, hepatic, and renal status—often using the Bicêtre neonatal evaluation score—to distinguish candidates for stabilization/delayed treatment, urgent embolization, or palliation where irreversible brain injury makes intervention futile. Exact cutoffs should be taken from the institution’s validated protocol rather than reconstructed from secondary summaries.

Differentials include arachnoid cyst, porencephalic cyst, Dandy–Walker-spectrum lesion, dural sinus malformation, pial AVF, cerebral AVM draining into the Galenic system, and other causes of neonatal high-output failure. Demonstration of internal blood flow separates VOGM from a simple cyst.

Genetic testing

Testing is reasonable when there are capillary malformations, telangiectases, multiple AVMs, family history, recurrent fetal disease, or syndromic findings. A vascular-malformation panel should include RASA1, EPHB4, ACVRL1, ENG, SMAD4, GDF2, NOTCH1, ITGB1, and PTPN11, with phenotype-directed interpretation. Trio WES/WGS is appropriate for unexplained disease and improves de novo-variant detection; the largest study explicitly demonstrates WES utility. CMA/karyotype is reserved for additional congenital anomalies and is not a primary VOGM test. FISH, mtDNA, and repeat-expansion tests have no routine role. A negative blood test does not exclude low-level lesion-restricted mosaicism. (zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 13-14)

11. Outcome and prognosis

Adverse prognostic factors include antenatal hydrops/cardiac failure, severe neonatal multiorgan dysfunction, extensive pre-treatment brain injury, uncontrolled pulmonary hypertension, restrictive venous outflow, and ischemic/hemorrhagic procedural complications. Favorable factors include preserved brain parenchyma, successful physiologic stabilization, and staged flow reduction at an expert center.

Historical untreated severe infantile disease was described as nearly uniformly fatal; this should not be used as a modern treated mortality estimate. One recent source summarized approximately 80% mortality with antenatal cardiac failure. In the mixed 115-child cohort, 62% had a good outcome and 38% a poor outcome. Contemporary center-specific survival is better, but no defensible universal 5- or 10-year survival percentage was available in the retrieved evidence. (singh2022recurrentveinof pages 1-2, tas2022arteriovenouscerebralhigh pages 2-3, tas2022arteriovenouscerebralhigh pages 1-2)

Survivors may have normal development or persistent epilepsy, motor impairment, cerebral palsy, language/cognitive deficits, behavioral/educational difficulty, hydrocephalus, or visual impairment. Long-term Bayley/Vineland-type testing is more informative than discharge neurological examination. Disease-specific EQ-5D/SF-36 norms and validated molecular prognostic biomarkers are unavailable.

12. Treatment

Standard strategy

Staged endovascular embolization is standard disease-modifying therapy. A transarterial approach commonly uses n-butyl cyanoacrylate or another liquid embolic to occlude selected fistulous connections progressively while avoiding abrupt venous thrombosis and perfusion shifts. Transvenous coil techniques may be used in selected anatomy or as a final curative procedure at specialized centers. Open surgery and radiosurgery have little routine role because of deep location, high flow, and treatment latency. Improved antenatal detection and endovascular treatment have improved prognosis. (vivanti2018lossoffunction pages 1-2, tas2022arteriovenouscerebralhigh pages 1-2)

A practical algorithm is:

  1. Deliver at a tertiary fetal/neonatal cardiac and neurointerventional center.
  2. Stabilize ventilation, pulmonary pressure, perfusion, and heart failure.
  3. Image brain and angioarchitecture; assess reversibility of organ injury.
  4. If stable, defer/stage embolization to permit growth; if refractory failure persists, perform urgent partial flow reduction.
  5. Repeat staged embolization until physiological control or angiographic cure; continue cardiac, imaging, and neurodevelopmental surveillance.

Supportive treatment includes cautious ventilation, inotropes/vasoactive therapy, diuretics when appropriate, pulmonary-hypertension management, nutrition, seizure treatment, and physical/occupational/speech therapy. Drugs do not close the malformation. There is no validated pharmacogenomic, gene, cell, RNA, immunologic, or RAS-targeted therapy for VOGM.

Important embolization complications include cerebral ischemia, hemorrhage, venous thrombosis, non-target embolization, vessel perforation, contrast/radiation exposure, and acute hemodynamic instability. NCIT label suggestions include Endovascular Embolization, Transarterial Embolization, Coil Embolization, Magnetic Resonance Imaging, Ultrasonography, Physical Therapy, Occupational Therapy, and Speech Therapy; exact NCIT codes require release validation.

Experimental fetal treatment

NCT04434729 enrolled seven pregnancies in a prospective single-arm study using maternal transuterine, fetal transcranial torcular puncture and coil embolization of the median prosencephalic vein. Eligibility included preserved brain parenchyma and a straight/falcine sinus ≥7 mm; outcomes included fetal safety, neonatal death, urgent neonatal embolization, brain injury, and two-year neurodevelopment. ClinicalTrials.gov, registered study information retrieved as 2022. (NCT04434729 chunk 1)

NCT07483255 is a planned/recruiting Phase II study of 20 pregnancies using a related technique at ≥34 weeks, with 30-day mortality and 24-month safety/neurodevelopmental outcomes. Its registry start is 2026, so it is a future/current-development item rather than 2023–2024 evidence. ClinicalTrials.gov. (NCT07483255 chunk 1)

13. Prevention

There is no established primary prevention, vaccine, prophylactic drug, or lifestyle intervention. Secondary prevention consists of prenatal detection, referral before delivery, planned delivery at an expert center, and rapid postnatal assessment. Tertiary prevention includes timely embolization before irreversible injury, management of heart failure/pulmonary hypertension, seizure control, rehabilitation, and developmental surveillance.

For a pathogenic familial variant, genetic counseling should explain autosomal-dominant transmission but incomplete penetrance and unpredictable expression. Targeted prenatal or preimplantation testing can establish fetal genotype but cannot reliably predict whether or how severely VOGM will develop. Serial targeted fetal ultrasound/MRI is therefore relevant in known RASA1/EPHB4/HHT families. (vivanti2018lossoffunction pages 1-2, zhao2023mutationofkey pages 13-14, zhao2023mutationofkey pages 5-7)

14. Other species and natural disease

No reproducible naturally occurring homologous VGAM syndrome was identified in companion animals, livestock, or wildlife. There is no zoonotic potential or transmission. Orthologues of RASA1, EPHB4, ACVRL1, NOTCH1, ITGB1, and PTPN11 are evolutionarily conserved, but database-specific NCBI Gene and VBO identifiers should be populated directly from NCBI/Alliance releases rather than inferred from the human literature.

15. Model organisms

  • Mouse: endothelial conditional expression of VOGM-associated EPHB4 p.Phe867Leu, particularly with a second-hit allele, impaired fetal angiogenesis, vascular-plexus remodeling, VEGF-regulated sprouting, and hierarchical arterial-capillary-venous development. It models developmental mechanism better than the full human cardiocerebral syndrome. (zhao2023mutationofkey pages 1-2, zhao2023mutationofkey pages 13-14)
  • Zebrafish: acvrl1a/b depletion caused enlarged vessels and supernumerary AV connections/VOGM-like venous dilation; wild-type but not mutant ACVRL1 mRNA rescued the phenotype. Advantages are live vascular imaging and rapid functional testing; limitations include species-specific cerebral venous anatomy and hemodynamics. (zhao2023mutationofkey pages 7-8, zhao2023geneticdysregulationof pages 30-35)
  • Cellular assays: COS-7 transfection, cycloheximide chase, immunoblotting, and phosphotyrosine assays showed that EPHB4 domain-missense variants can preserve stability while impairing kinase activity. These assays establish protein dysfunction but do not reproduce organ-level shunting. (zhao2023mutationofkey pages 5-7)

Key recent source and evidence notes

The principal 2023 primary paper is Zhao et al., “Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations,” Nature Communications, published November 2023, DOI 10.1038/s41467-023-43062-z. Its abstract reports: “We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants,” and that developing endothelial cells were the likely spatiotemporal locus. (zhao2023mutationofkey pages 1-2)

Other key sources are Tas et al., Frontiers in Pediatrics, April 2022, DOI 10.3389/fped.2022.871565; Vivanti et al., Brain, April 2018, DOI 10.1093/brain/awy020; and Duran et al., Neuron, February 2019, DOI 10.1016/j.neuron.2018.11.041. (tas2022arteriovenouscerebralhigh pages 2-3, vivanti2018lossoffunction pages 1-2, duran2019mutationsinchromatin pages 1-3)

PMIDs were not exposed in the retrieved records and therefore are not guessed. The most important evidence gaps are contemporary population epidemiology, standardized long-term quality-of-life data, lesion-tissue somatic sequencing, validated prognostic biomarkers, disease-specific multi-omics, and controlled evidence for fetal intervention.

References

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  9. (zhao2023geneticdysregulationof pages 6-8): Shujuan Zhao, Kedous Y. Mekbib, Martijn A. van der Ent, Garrett Allington, Andrew Prendergast, Jocelyn E. Chau, Hannah Smith, John Shohfi, Jack Ocken, Daniel Duran, Charuta G. Furey, Hao Thi Le, Phan Q. Duy, Benjamin C. Reeves, Junhui Zhang, Carol Nelson-Williams, Di Chen, Boyang Li, Timothy Nottoli, Suxia Bai, Myron Rolle, Xue Zeng, Weilai Dong, Po-Ying Fu, Yung-Chun Wang, Shrikant Mane, Paulina Piwowarczyk, Katie Pricola Fehnel, Alfred Pokmeng See, Bermans J. Iskandar, Beverly Aagaard-Kienitz, Adam J. Kundishora, Tyrone DeSpenza, Ana B.W. Greenberg, Seblewengel M. Kidanemariam, Andrew T. Hale, James M. Johnston, Eric M. Jackson, Phillip B. Storm, Shih-Shan Lang, William E. Butler, Bob S. Carter, Paul Chapman, Christopher J. Stapleton, Aman B. Patel, Georges Rodesch, Stanislas Smajda, Alejandro Berenstein, Tanyeri Barak, E. Zeynep Erson-Omay, Hongyu Zhao, Andres Moreno-De-Luca, Mark R. Proctor, Edward R. Smith, Darren B. Orbach, Seth L. Alper, Stefania Nicoli, Titus J. Boggon, Richard P. Lifton, Murat Gunel, Philip D. King, Sheng Chih Jin, and Kristopher T. Kahle. Genetic dysregulation of an endothelial ras signaling network in vein of galen malformations. BioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.18.532837, doi:10.1101/2023.03.18.532837. This article has 3 citations.

  10. (zhao2023geneticdysregulationof pages 30-35): Shujuan Zhao, Kedous Y. Mekbib, Martijn A. van der Ent, Garrett Allington, Andrew Prendergast, Jocelyn E. Chau, Hannah Smith, John Shohfi, Jack Ocken, Daniel Duran, Charuta G. Furey, Hao Thi Le, Phan Q. Duy, Benjamin C. Reeves, Junhui Zhang, Carol Nelson-Williams, Di Chen, Boyang Li, Timothy Nottoli, Suxia Bai, Myron Rolle, Xue Zeng, Weilai Dong, Po-Ying Fu, Yung-Chun Wang, Shrikant Mane, Paulina Piwowarczyk, Katie Pricola Fehnel, Alfred Pokmeng See, Bermans J. Iskandar, Beverly Aagaard-Kienitz, Adam J. Kundishora, Tyrone DeSpenza, Ana B.W. Greenberg, Seblewengel M. Kidanemariam, Andrew T. Hale, James M. Johnston, Eric M. Jackson, Phillip B. Storm, Shih-Shan Lang, William E. Butler, Bob S. Carter, Paul Chapman, Christopher J. Stapleton, Aman B. Patel, Georges Rodesch, Stanislas Smajda, Alejandro Berenstein, Tanyeri Barak, E. Zeynep Erson-Omay, Hongyu Zhao, Andres Moreno-De-Luca, Mark R. Proctor, Edward R. Smith, Darren B. Orbach, Seth L. Alper, Stefania Nicoli, Titus J. Boggon, Richard P. Lifton, Murat Gunel, Philip D. King, Sheng Chih Jin, and Kristopher T. Kahle. Genetic dysregulation of an endothelial ras signaling network in vein of galen malformations. BioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.18.532837, doi:10.1101/2023.03.18.532837. This article has 3 citations.

  11. (zhao2023mutationofkey pages 5-7): Shujuan Zhao, Kedous Y. Mekbib, Martijn A. van der Ent, Garrett Allington, Andrew Prendergast, Jocelyn E. Chau, Hannah Smith, John Shohfi, Jack Ocken, Daniel Duran, Charuta G. Furey, Le Thi Hao, Phan Q. Duy, Benjamin C. Reeves, Junhui Zhang, Carol Nelson-Williams, Di Chen, Boyang Li, Timothy Nottoli, Suxia Bai, Myron Rolle, Xue Zeng, Weilai Dong, Po-Ying Fu, Yung-Chun Wang, Shrikant Mane, Paulina Piwowarczyk, Katie Pricola Fehnel, Alfred Pokmeng See, Bermans J. Iskandar, Beverly Aagaard-Kienitz, Quentin J. Moyer, Evan Dennis, Emre Kiziltug, Adam J. Kundishora, Tyrone DeSpenza, Ana B. W. Greenberg, Seblewengel M. Kidanemariam, Andrew T. Hale, James M. Johnston, Eric M. Jackson, Phillip B. Storm, Shih-Shan Lang, William E. Butler, Bob S. Carter, Paul Chapman, Christopher J. Stapleton, Aman B. Patel, Georges Rodesch, Stanislas Smajda, Alejandro Berenstein, Tanyeri Barak, E. Zeynep Erson-Omay, Hongyu Zhao, Andres Moreno-De-Luca, Mark R. Proctor, Edward R. Smith, Darren B. Orbach, Seth L. Alper, Stefania Nicoli, Titus J. Boggon, Richard P. Lifton, Murat Gunel, Philip D. King, Sheng Chih Jin, and Kristopher T. Kahle. Mutation of key signaling regulators of cerebrovascular development in vein of galen malformations. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-43062-z, doi:10.1038/s41467-023-43062-z. This article has 32 citations and is from a highest quality peer-reviewed journal.

  12. (duran2019mutationsinchromatin pages 1-3): Daniel Duran, Xue Zeng, Sheng Chih Jin, Jungmin Choi, Carol Nelson-Williams, Bogdan Yatsula, Jonathan Gaillard, Charuta Gavankar Furey, Qiongshi Lu, Andrew T. Timberlake, Weilai Dong, Michelle A. Sorscher, Erin Loring, Jennifer Klein, August Allocco, Ava Hunt, Sierra Conine, Jason K. Karimy, Mark W. Youngblood, Jinwei Zhang, Michael L. DiLuna, Charles C. Matouk, Shrikant Mane, Irina R. Tikhonova, Christopher Castaldi, Francesc López-Giráldez, James Knight, Shozeb Haider, Mariya Soban, Seth L. Alper, Masaki Komiyama, Andrew F. Ducruet, Joseph M. Zabramski, Alan Dardik, Brian P. Walcott, Christopher J. Stapleton, Beverly Aagaard-Kienitz, Georges Rodesch, Eric Jackson, Edward R. Smith, Darren B. Orbach, Alejandro Berenstein, Kaya Bilguvar, Miikka Vikkula, Murat Gunel, Richard P. Lifton, and Kristopher T. Kahle. Mutations in chromatin modifier and ephrin signaling genes in vein of galen malformation. Neuron, 101:429-443.e4, Feb 2019. URL: https://doi.org/10.1016/j.neuron.2018.11.041, doi:10.1016/j.neuron.2018.11.041. This article has 90 citations and is from a highest quality peer-reviewed journal.

  13. (zhao2023geneticdysregulationof pages 12-14): Shujuan Zhao, Kedous Y. Mekbib, Martijn A. van der Ent, Garrett Allington, Andrew Prendergast, Jocelyn E. Chau, Hannah Smith, John Shohfi, Jack Ocken, Daniel Duran, Charuta G. Furey, Hao Thi Le, Phan Q. Duy, Benjamin C. Reeves, Junhui Zhang, Carol Nelson-Williams, Di Chen, Boyang Li, Timothy Nottoli, Suxia Bai, Myron Rolle, Xue Zeng, Weilai Dong, Po-Ying Fu, Yung-Chun Wang, Shrikant Mane, Paulina Piwowarczyk, Katie Pricola Fehnel, Alfred Pokmeng See, Bermans J. Iskandar, Beverly Aagaard-Kienitz, Adam J. Kundishora, Tyrone DeSpenza, Ana B.W. Greenberg, Seblewengel M. Kidanemariam, Andrew T. Hale, James M. Johnston, Eric M. Jackson, Phillip B. Storm, Shih-Shan Lang, William E. Butler, Bob S. Carter, Paul Chapman, Christopher J. Stapleton, Aman B. Patel, Georges Rodesch, Stanislas Smajda, Alejandro Berenstein, Tanyeri Barak, E. Zeynep Erson-Omay, Hongyu Zhao, Andres Moreno-De-Luca, Mark R. Proctor, Edward R. Smith, Darren B. Orbach, Seth L. Alper, Stefania Nicoli, Titus J. Boggon, Richard P. Lifton, Murat Gunel, Philip D. King, Sheng Chih Jin, and Kristopher T. Kahle. Genetic dysregulation of an endothelial ras signaling network in vein of galen malformations. BioRxiv, Mar 2023. URL: https://doi.org/10.1101/2023.03.18.532837, doi:10.1101/2023.03.18.532837. This article has 3 citations.

  14. (NCT07483255 chunk 1): Darren Orbach. A Phase II Trial of Fetal Embolization for Vein of Galen Malformation. Darren Orbach. 2026. ClinicalTrials.gov Identifier: NCT07483255

  15. (NCT04434729 chunk 1): Darren Orbach. Fetal Treatment of Galenic Malformations. Darren Orbach. 2022. ClinicalTrials.gov Identifier: NCT04434729

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