Blue Rubber Bleb Nevus Syndrome

MONDO:0007203 Pathograph 38 Show in embeddings browser venous malformation

Blue rubber bleb nevus syndrome (BRBNS; Bean syndrome) is a multifocal venous malformation disorder, usually caused by postzygotic activating TEK variants. Recurrent double mutations in cis activate the endothelial TIE2 receptor. Cutaneous lesions are soft, blue and compressible; gastrointestinal lesions, often involving the small bowel, can cause occult or overt bleeding and iron-deficiency anemia. Typical skin lesions may be sparse or absent, and diagnosis can be delayed. Lesions may also affect deeper tissues and other organs, and localized intravascular coagulopathy can accompany extensive disease. Management combines correction of iron deficiency, lesion-directed endoscopic or surgical treatment, and specialist-directed systemic sirolimus when appropriate. Much of the downstream signaling model derives from other TEK-mutant venous malformations and must be distinguished from direct BRBNS evidence.

Ask OpenScientist

Ask a research question about Blue Rubber Bleb Nevus Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

👪

Inheritance

Somatic Mosaic HP:0001442

The usual molecularly defined disorder is postzygotic somatic mosaicism. GeneReviews reports no confirmed vertical transmission or sibling recurrence and considers recurrence risk comparable to the general population; this does not establish a literally zero risk. An apparent dominant family history warrants reassessment for familial TEK-related cutaneomucosal malformations or other vascular disorders. Historical familial cases labeled BRBNS often lack molecular confirmation.

somatic mosaicism

Show evidence (2 references)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene."

Double cis alleles predominate in multifocal disease; this is not a requirement demonstrated in every clinically diagnosed patient.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"No confirmed vertical transmission or sib recurrence has been reported to date."

Describes the observed inheritance evidence for somatic TEK-related phenotypes, including BRBN syndrome.

Discussions and Knowledge Gaps

Which downstream effects are shared by BRBN double variants and other TEK-mutant malformations?

KNOWLEDGE GAP brbns_model_transfer

Attached to

pathophysiology#Reduced Endothelial PDGFB Expression

Direct BRBN-allele HUVEC evidence establishes activation and survival phenotypes. Much of the FOXO1, PDGFB, mural-cell and drug-combination work instead uses L914F, while older AKT experiments use R849W. Allele-specific differences and cell context limit transfer. Molecular links are therefore scoped as related-model evidence rather than complete demonstrations of human BRBN pathogenesis.

Show evidence (2 references)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT In Vitro

"... both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells."

The recurrent alleles were functionally expressed in HUVECs; the cellular results are distinguished from clinical sequencing.

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"VMs with TIE2-L914F mutation showed lower expression of PDGFB and α-SMA than normal veins."

Five L914F-positive VM tissues had reduced PDGFB and mural-cell staining; these were not a BRBN-specific cohort.

Can PI3K inhibition or combination therapy improve durable control of BRBNS?

KNOWLEDGE GAP brbns_emerging_inhibition

Attached to

treatments#Systemic Sirolimus

Alpelisib corrects cellular phenotypes in TEK- and PIK3CA-mutant HUVECs, and ponatinib plus rapamycin regresses established L914F xenografts. The 2026 rapamycin-alpelisib mouse experiment used cells pretreated for 48 hours before implantation, with a DMSO comparator; it demonstrates reduced lesion formation rather than systemic treatment of established lesions. Its in vivo comparison did not establish superiority over another drug combination. p53 changes are associated readouts, not a demonstrated necessary mediator. These results do not establish a BRBNS regimen or long-term clinical safety.

Show evidence (2 references)

PMID:26637981 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The p110α-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways."

Cellular pharmacology of related venous-malformation models.

PMID:42411503 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"The results demonstrated a marked reduction in vessel sprouting in the 3D model and inhibited both lesion size and angiogenesis in the xenograft mouse model."

The full methods specify cell pretreatment before implantation; no systemic treatment of established mouse lesions was tested.

How should familial CNS-predominant cases labeled BRBNS be classified?

KNOWLEDGE GAP brbns_familial_cns_boundary

Attached to

inheritance#Somatic Mosaic

A reported father-son pair had skin venous malformations, seizures and cerebral vascular lesions, but lacked genetic assessment; the son had no significant colonoscopic abnormality and the father had non-cavernomatous arteriovenous lesions at autopsy. Such reports warrant molecular differential diagnosis rather than establishing dominant transmission, a uniform cerebral phenotype or a KRIT1 modifier for molecularly defined BRBNS.

Show evidence (1 reference)

PMID:32318009 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Unfortunately, no genetic assessment was performed due to the lack of this specific testing in our hospital."

The familial report does not establish an inherited TEK variant or a molecular BRBN diagnosis.

⚙

Pathophysiology

Somatic Activating TEK Variants

Activating TEK variants are present in affected tissues, often at low mosaic allele fractions. Double mutations in cis predominate in BRBNS and other multifocal TEK-related malformations. Identical variants across sampled lesions support a shared mutant lineage; the developmental timing and precise founding cell cannot be reconstructed from sequencing alone.

vein endothelial cell CL:0002543

TEK hgnc:11724

transmembrane receptor protein tyrosine kinase activity GO:0004714 ↑ INCREASED

Downstream

Ligand-Independent TIE2 Activation The recurrent double-mutant receptor has ligand-independent activity.

Show evidence (2 references)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome."

Lesional sequencing establishes TEK as the principal identified cause in this series; the two unsolved individuals are not assigned an unobserved genotype.

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Double cis alleles predominate in multifocal disease; this is not a requirement demonstrated in every clinically diagnosed patient.

Ligand-Independent TIE2 Activation

BRBN-associated T1105N-T1106P and the multifocal-VM-associated Y897C-R915C allele activate TIE2 without ligand in transduced endothelial cells. Their downstream phenotypes differ from normal ligand-regulated receptor signaling.

vein endothelial cell CL:0002543

Tie signaling pathway GO:0048014 ↑ INCREASED

Experimental models

BRBN-associated double-mutant TIE2 in HUVECs PRIMARY CELL CULTURE

Downstream

PI3K-AKT-mTOR Pathway Activation Related TIE2-mutant endothelial models support activation of the downstream kinase pathway.

Show evidence (1 reference)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT In Vitro

"... both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells."

The recurrent alleles were functionally expressed in HUVECs; the cellular results are distinguished from clinical sequencing.

PI3K-AKT-mTOR Pathway Activation

Activating TIE2 signals through PI3K-AKT-mTOR. Constitutive AKT phosphorylation and rapamycin responses support this route in L914F endothelial models; R849W familial-VM experiments also link AKT to cell survival. These are related-variant models, not direct demonstrations of every pathway step in BRBN double-mutant lesions.

vein endothelial cell CL:0002543

phosphatidylinositol 3-kinase/protein kinase B signal transduction GO:0043491 ↑ INCREASED

Animal models

HUVEC-TIE2-L914F xenograft Mouse (Mus musculus) perturbs Used to test pharmacological suppression of the pathway node, reading out lesion regression.

Downstream

Endothelial Apoptosis Suppression AKT supports endothelial survival in a related-variant assay.

Reduced Endothelial PDGFB Expression AKT/FOXO1 signaling is associated with reduced PDGFB transcription and secretion.

Show evidence (2 references)

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"However, only TIE2-L914F mutant ECs showed abnormal phosphorylation of AKT (ser 473) which is downstream of TIE2."

L914F-transduced endothelial cells support the pathway model; this is indirect evidence for BRBN double-mutant alleles.

PMID:15526080 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Dominant-negative Akt inhibited the pro-survival activity of mutant Tie2."

The tested receptor was R849W, associated with familial VM; the result supports the survival pathway by analogy.

Endothelial Apoptosis Suppression

BRBN-associated TIE2 double-mutant expression increases endothelial survival, invasion and colony formation. Reduced apoptosis and AKT dependence are demonstrated in related R849W and L914F models. Persistence of poorly supported vascular channels is a mechanistic interpretation rather than a directly traced cellular history in patients.

vein endothelial cell CL:0002543

negative regulation of apoptotic process GO:0043066 ↑ INCREASED

Downstream

Ectatic Mural-Cell-Poor Venous Channels Enhanced cell survival may permit persistence of dysmorphic channels; this transition is not directly traced in BRBNS.

Show evidence (2 references)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT In Vitro

"... both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells."

The recurrent alleles were functionally expressed in HUVECs; the cellular results are distinguished from clinical sequencing.

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"TIE2-L914F mutant ECs showed lower apoptosis rate than the group of GFP or TIE2-WT, suggesting their enhanced anti-apoptotic ability, consistent with the above speculation."

Flow-cytometric apoptosis results in the related L914F model support the survival mechanism.

Reduced Endothelial PDGFB Expression

In L914F-expressing HUVECs, increased AKT/FOXO1 phosphorylation accompanies reduced nuclear FOXO1 and reduced PDGFB output. Rapamycin restores nuclear FOXO1 and PDGFB expression and secretion. This provides a candidate paracrine mechanism for TEK-related malformations, but it has not been directly established for the recurrent BRBN double allele.

vein endothelial cell CL:0002543

Experimental models

TIE2-L914F endothelial and smooth-muscle co-culture CO CULTURE

Downstream

Reduced Mural Cell Recruitment and Coverage Reduced paracrine support is a candidate explanation for impaired mural-cell recruitment in related TEK-mutant models.

Show evidence (2 references)

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"FOXO1 expression in nucleus significantly reduced in TIE2-L914F mutant ECs, whereas there was an increased expression of FOXO1 after the addition of RAPA"

The L914F model shows reduced nuclear FOXO1 and rapamycin-associated restoration; transfer to BRBN remains indirect.

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"As PDGFB function as an identity of secretory protein, we detected the expression of its subtype PDGFBB in the supernatant of cell culture, and the result of ELISA assay is consistent with that obtained by real-time quantitative PCR (Fig. 5h)."

Secreted PDGFBB and transcriptional assays support an endothelial paracrine defect in the L914F model.

Reduced Mural Cell Recruitment and Coverage

L914F endothelial cells support less smooth-muscle-cell migration in co-culture; L914F venous-malformation tissues show reduced α-SMA coverage. PDGFB deficiency may contribute, but the experiments do not isolate its necessity for BRBN lesion formation.

smooth muscle cell CL:0000192

Downstream

Ectatic Mural-Cell-Poor Venous Channels Reduced mural support accompanies ectatic channels; human tissue association does not by itself prove causal sufficiency.

Show evidence (2 references)

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Compared to NC and WT groups, TIE2 mutation group showed a decreased migration of SMCs, whereas no significant differentiation between NC and WT (Fig. 6a, b)."

Co-culture shows reduced smooth-muscle-cell migration. It does not independently prove that PDGFB loss is necessary or sufficient for BRBN lesions.

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"VMs with TIE2-L914F mutation showed lower expression of PDGFB and α-SMA than normal veins."

Five L914F-positive VM tissues had reduced PDGFB and mural-cell staining; these were not a BRBN-specific cohort.

Ectatic Mural-Cell-Poor Venous Channels

Malformed, dilated blood-filled venous channels occur in skin, bowel and sometimes other tissues. Direct BRBNS histology shows thin or flattened endothelium, intralesional thrombosis and calcification. Variable mural-cell investment is described across TEK-related malformations; cellular signaling experiments provide an indirect explanation for the tissue architecture.

vein endothelial cell CL:0002543

blood vessel morphogenesis GO:0048514 ⚠ ABNORMAL

skin of body UBERON:0002097 small intestine UBERON:0002108

Animal models

Mosaic TIE2-L914F transgenic mouse Mouse (Mus musculus) recapitulates

Endothelial TEK overexpression in zebrafish embryos Zebrafish (Danio rerio) recapitulates

Downstream

Chronic Gastrointestinal Blood Loss Gastrointestinal lesions cause recurrent blood loss.

Localised Intravascular Coagulopathy Intralesional thrombus organization and clinical coagulation findings support local clot turnover; the precise hemodynamic sequence is inferred.

Cutaneous Venous Malformations The venous-channel abnormality is expressed as cutaneous lesions; the exact tissue morphogenesis is unresolved.

Gastrointestinal Venous Malformations The abnormal channels constitute the intestinal lesions.

Hepatic Venous Malformations Similar malformations can occur in other organs; organ distribution depends on the mosaic lesion pattern.

Intramuscular Venous Malformations The same venous-malformation process can involve this organ. The organ distribution and local mural-cell phenotype were not mechanistically established in this series.

Ocular Venous Malformations The same venous-malformation process can involve this organ. The organ distribution and local mural-cell phenotype were not mechanistically established in this series.

Thyroid Venous Malformations The same venous-malformation process can involve this organ. The organ distribution and local mural-cell phenotype were not mechanistically established in this series.

Splenic Venous Malformations The same venous-malformation process can involve this organ. The organ distribution and local mural-cell phenotype were not mechanistically established in this series.

Intraosseous Venous Malformations The same venous-malformation process can involve this organ. The organ distribution and local mural-cell phenotype were not mechanistically established in this series.

Pulmonary Venous Malformations The same venous-malformation process can involve this organ. The organ distribution and local mural-cell phenotype were not mechanistically established in this series.

Show evidence (2 references)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The surgery slices showed that there were proliferative and dilated cavernous vascular cavities under the mucosa lined by normal or thin or flat endothelium with varying amounts, the cavities were full of red blood cells, some of which could be seen thrombus organization and calcification in..."

Direct histology of resected BRBNS lesions shows dilated blood-filled channels and intralesional thrombus organization.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Enlarged venous-like channels with walls of smooth muscle of variable thickness are observed"

Describes the histology of TEK-related venous malformations; mural investment is variable rather than uniformly absent.

Chronic Gastrointestinal Blood Loss

Gastrointestinal venous malformations can bleed intermittently or continuously, producing occult blood loss, melena or hematochezia. Severe overt bleeding can occur; chronic iron deficiency is common but not every patient is transfusion dependent.

Downstream

Gastrointestinal Hemorrhage Blood loss manifests as occult or overt gastrointestinal hemorrhage.

Iron Deficiency Anemia Persistent blood loss depletes iron stores and can cause anemia.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Gastrointestinal lesions cause bleeding, iron deficiency, and intestinal complications (volvulus and infarction)."

Summarizes the BRBN-specific gastrointestinal manifestations.

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Serum iron and transferrin saturation were lower, total iron binding capacity were higher, which indicated IDA."

Iron studies in the pediatric series establish iron deficiency, beyond a nonspecific anemia description.

Localised Intravascular Coagulopathy

Clot formation and fibrinolysis within malformed venous channels can elevate D-dimer; more severe consumption can lower fibrinogen and increase procedural bleeding risk. Sluggish flow is the proposed initiating condition. D-dimer is not a specific test for BRBNS, and normal values do not exclude small venous malformations.

blood coagulation GO:0007596 ↕ DYSREGULATED

Downstream

Elevated D-Dimer Fibrin formation and breakdown are reflected by elevated circulating D-dimer.

Phleboliths Long-standing localized thrombosis can become calcified, forming phleboliths.

Show evidence (2 references)

PMID:19917952 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients with multifocal venous malformations (5 with sporadic multifocal VM and 2 with BRBN) had very high D-dimer levels (≥5.649μg/ml)."

Both BRBN patients had high D-dimer; this small subgroup does not estimate disease-wide prevalence.

PMID:19917952 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In one of the BRBN patients, the high D-dimers were associated with low fibrinogen level (95mg/dl), similar to two reported BRBN patients, who had acute or chronic disseminated intravascular coagulopathy13, 14."

Documents low fibrinogen in one BRBN participant; the cited prior reports are background, not extra participants.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 4

Gastrointestinal Hemorrhage HP:0002239

Show evidence (1 reference)

PMID:39426903 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Gastrointestinal bleeding is the most common complication (54.3 %), requiring endoscopic treatment (36.4 %) by various techniques."

Reports the cohort-specific complication frequency.

Iron Deficiency Anemia HP:0001891

Sequelae: Fatigue

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Serum iron and transferrin saturation were lower, total iron binding capacity were higher, which indicated IDA."

Iron studies in the pediatric series establish iron deficiency, beyond a nonspecific anemia description.

Elevated D-Dimer Elevated circulating D-dimer concentration HP:0033106

Show evidence (3 references)

PMID:19917952 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients with multifocal venous malformations (5 with sporadic multifocal VM and 2 with BRBN) had very high D-dimer levels (≥5.649μg/ml)."

Both BRBN patients had high D-dimer; this small subgroup does not estimate disease-wide prevalence.

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In our study, 87.5% of patients had elevated D-dimer levels of greater than 0.5 mg/L"

Seven of eight children had an elevated value; no population-wide frequency is inferred.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"This elevation of D-dimers is observed in approximately 40% of individuals with isolated VM and in more than 80% of individuals with VMCM and BRBN syndrome."

The chapter supplies a broader clinical frequency statement covering VMCM and BRBN together.

Phleboliths HP:6000661

Show evidence (2 references)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Abdominal CT scan showed multiple spotted calcification in liver and scattered nodular low density shadow in bowel wall with multiple punctate calcifications (patient # 1, Figure 2A,2B)."

Calcified lesions in one child, interpreted with the histologic thrombus and calcification findings.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Palpation can reveal pathognomonic phleboliths that develop due to long-standing localized thrombosis."

The TEK-related venous-malformation chapter explains phlebolith formation; the pediatric BRBN series independently documents calcified lesions.

Cardiovascular 9

Cutaneous Venous Malformations HP:0012721

These are venous malformations (HP:0012721). The historical name does not denote the melanocytic lesion represented by HP:0100814 Blue nevus.

Show evidence (4 references)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cutaneous lesions were present in 7/8 patients (87.5%), it appeared as the initial symptom in 6 patients (Figure 1), 1 patient (#2) skin lesions occurred in the 7th year of the course of disease."

Skin lesions can be absent initially or entirely; this pediatric referral series is not a population-frequency estimate.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Affected individuals often have a congenital single large VM, a so-called dominant VM ... which represents the first manifestation of BRBN syndrome."

The congenital dominant lesion is a recognized initial manifestation; the intervening parenthesis defines its size as greater than ten times the other visible lesions.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"They occur on any surface of the skin and mucosa and tend to aggregate and become hyperkeratotic, with a predilection for the palms and soles."

BRBN lesions can show characteristic palmoplantar clustering and hyperkeratosis.

+ 1 more reference

Gastrointestinal Venous Malformations HP:0012721

Sequelae: Intussusception Volvulus Intestinal Infarction

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Gastrointestinal lesions cause bleeding, iron deficiency, and intestinal complications (volvulus and infarction)."

Summarizes the BRBN-specific gastrointestinal manifestations.

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients underwent gastroscopy and ileo-colonoscopy, and 6 patients finished the whole GI screening with capsule endoscopy (CE) examinations"

Documents the gastrointestinal assessment in the eight-patient series.

Hepatic Venous Malformations Hepatic vascular malformations HP:0006576

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other organs involvement included hepatic in 3 (37.5%), intra-muscular in 2 (25.0%), ocular, thyroid, splenic, intraosseous, pulmonary in 1 (12.5%) respectively."

The small referral series documents additional organ involvement; several rare sites occurred together in one extensively affected child.

Intramuscular Venous Malformations HP:0012721

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other organs involvement included hepatic in 3 (37.5%), intra-muscular in 2 (25.0%), ocular, thyroid, splenic, intraosseous, pulmonary in 1 (12.5%) respectively."

The small referral series documents additional organ involvement; several rare sites occurred together in one extensively affected child.

Ocular Venous Malformations HP:0012721

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other organs involvement included hepatic in 3 (37.5%), intra-muscular in 2 (25.0%), ocular, thyroid, splenic, intraosseous, pulmonary in 1 (12.5%) respectively."

The small referral series documents additional organ involvement; several rare sites occurred together in one extensively affected child.

Thyroid Venous Malformations HP:0012721

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other organs involvement included hepatic in 3 (37.5%), intra-muscular in 2 (25.0%), ocular, thyroid, splenic, intraosseous, pulmonary in 1 (12.5%) respectively."

The small referral series documents additional organ involvement; several rare sites occurred together in one extensively affected child.

Splenic Venous Malformations HP:0012721

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other organs involvement included hepatic in 3 (37.5%), intra-muscular in 2 (25.0%), ocular, thyroid, splenic, intraosseous, pulmonary in 1 (12.5%) respectively."

The small referral series documents additional organ involvement; several rare sites occurred together in one extensively affected child.

Intraosseous Venous Malformations HP:0012721

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other organs involvement included hepatic in 3 (37.5%), intra-muscular in 2 (25.0%), ocular, thyroid, splenic, intraosseous, pulmonary in 1 (12.5%) respectively."

The small referral series documents additional organ involvement; several rare sites occurred together in one extensively affected child.

Pulmonary Venous Malformations HP:0012721

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other organs involvement included hepatic in 3 (37.5%), intra-muscular in 2 (25.0%), ocular, thyroid, splenic, intraosseous, pulmonary in 1 (12.5%) respectively."

The small referral series documents additional organ involvement; several rare sites occurred together in one extensively affected child.

Digestive 3

Intussusception HP:0002576

Show evidence (1 reference)

PMID:32664167 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"There were 3 segments of intussusceptions without necrosis in the ileum and a segment of intussusception that was unable to be reset at a distance from the ileocecal region and was excised."

Direct operative findings in a 33-year-old man with BRBNS.

Volvulus HP:0002580

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Gastrointestinal lesions cause bleeding, iron deficiency, and intestinal complications (volvulus and infarction)."

Summarizes the BRBN-specific gastrointestinal manifestations.

Intestinal Infarction Gastrointestinal infarctions HP:0005244

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"These are commonly located in the small intestine and can cause hemorrhage, intussusception, volvulus, and intestinal infarction"

The BRBN section identifies complications caused by gastrointestinal venous malformations.

Constitutional 1

Fatigue HP:0012378

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients (100%) presented with chronic recurring anemia manifesting as pallor, fatigue or poor exercise tolerance."

Describes symptoms accompanying anemia in the selected pediatric series; it does not mean every child had each listed symptom.

🧬

Genetic Associations

TEK (Gain of Function)

Gene: TEK hgnc:11724 relationship_type: CAUSATIVE variant_origin: SOMATIC

Show evidence (2 references)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome."

Lesional sequencing establishes TEK as the principal identified cause in this series; the two unsolved individuals are not assigned an unobserved genotype.

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Double cis alleles predominate in multifocal disease; this is not a requirement demonstrated in every clinically diagnosed patient.

Variants (1)

T1105N-T1106P

The recurrent BRBN-associated double allele p.Thr1105Asn-p.Thr1106Pro occurs in cis. Its enrichment differs from the p.Tyr897Cys-p.Arg915Cys allele recurrent in multifocal sporadic VM; genotype does not replace clinical assessment of the syndrome boundary.

Show evidence (1 reference)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation"

Identifies the recurrent alleles in their respective clinical groups.

💊

Medical Actions

Systemic Sirolimus

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Platform: Small molecule

Specialist-directed off-label mTOR inhibition can reduce bleeding and lesion burden in diffuse or difficult-to-treat BRBNS. The prospective eleven-patient study reported improvement over twelve months; longer-term response varies and relapse may follow withdrawal. Oral ulcers and other adverse effects require monitoring. No cure, uniform response or site-independent efficacy is established.

Mechanism Target:

INHIBITS PI3K-AKT-mTOR Pathway Activation — mTOR inhibition targets the signaling pathway. Clinical benefit is supported separately from the related-variant molecular assays.

Show evidence (1 reference)

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Our results showed that RAPA down-regulated the phosphorylation of AKT, FOXO1, and mTOR, especially in the TIE2-L914F mutant group (Fig. 5a, b)."

A molecular response in L914F HUVECs supports pathway inhibition, indirectly for BRBN.

Show evidence (4 references)

PMID:33416235 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The average lesion size was reduced by 7.4% (P < 0.001), 9.3% (P < 0.001), and 13.0% (P < 0.05) at 3, 6, and 12 months of sirolimus treatment, respectively."

Eleven patients were followed in a single-arm prospective study; there was no randomized comparator.

PMID:33416235 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Only 1 patient received blood transfusion once during the study."

Reports observed transfusion use during the study, not guaranteed lifelong transfusion independence.

PMID:33416235 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Grade 1-2 adverse effects including oral ulcers (81.8%), acne (27.3%), transient elevation of liver enzymes (18.2%), and hair loss (9.1%) were observed."

Adverse effects in this small cohort were mild, but this does not establish long-term safety.

+ 1 more reference

Iron Replacement

Action: Pharmacotherapy NCIT:C15986

Agent: Iron supplement

Replaces iron lost through chronic gastrointestinal bleeding; it does not stop the bleeding or remove venous malformations.

Mechanism Target:

INHIBITS Iron Deficiency Anemia — Replenishes iron and treats the resulting anemia; it does not inhibit gastrointestinal blood loss.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Iron replacement or transfusions in case of anemia from chronic bleeding"

GeneReviews separates supportive correction of anemia from treatment of the lesions.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Iron replacement or transfusions in case of anemia from chronic bleeding"

GeneReviews separates supportive correction of anemia from treatment of the lesions.

Blood Transfusion

Action: Blood Transfusion NCIT:C15192

Corrects severe or symptomatic anemia when clinically indicated. Transfusion requirements vary with disease severity and response to lesion-directed or systemic treatment.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Iron replacement or transfusions in case of anemia from chronic bleeding"

GeneReviews separates supportive correction of anemia from treatment of the lesions.

Endoscopic Treatment of Bowel Lesions

Action: Endoscopic Procedure NCIT:C16546

Accessible mucosal or submucosal lesions can be treated by sclerotherapy, resection or other endoscopic methods. Depth and extent guide selection; transmural lesions may require surgery because of perforation risk. Combined sirolimus and lauromacrogol success in a single case cannot isolate each treatment effect.

Mechanism Target:

INHIBITS Chronic Gastrointestinal Blood Loss — Removing or obliterating selected bleeding lesions can reduce blood loss; incomplete treatment can leave other active lesions.

Show evidence (1 reference)

PMID:36277742 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Through a combination of methylene blue-hetastarch injection for lifting and snare resection with a 1.5 cm Cook AcuSnare (ENDO CUT Q-3), removal of the gastric and colon lesions was achieved successfully by EMR."

Documents actual endoscopic treatment rather than inferring efficacy from bleeding alone.

Show evidence (2 references)

PMID:36277742 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Documents actual endoscopic treatment rather than inferring efficacy from bleeding alone.

PMID:39867693 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"After 1 year of treatment, the patient showed no signs of anemia or gastrointestinal tract bleeding."

One child received both sirolimus and endoscopic lauromacrogol; benefit cannot be attributed separately to either intervention.

Surgical Treatment of Gastrointestinal Lesions

Action: Surgical Procedure NCIT:C15329

Resection or ligation can control bleeding from focal or extensive lesions in selected patients. Planning aims to preserve bowel length and account for transmural disease. A ten-patient series used extensive combined procedures with durable control in most patients; morbidity, incomplete removal and recurrence remain considerations. Obstruction or intussusception can require urgent surgery.

Mechanism Target:

INHIBITS Chronic Gastrointestinal Blood Loss — Removing or obliterating selected bleeding lesions can reduce blood loss; incomplete treatment can leave other active lesions.

Show evidence (1 reference)

PMID:15729077 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Only 1 patient who had a less extensive procedure developed recurrent GI bleeding. The mean follow-up period was 5.0 years (range 2.9-10.3 years)."

Selected surgical series of ten patients; mean 137 lesions removed per operation, not evidence that all BRBNS is surgically curable.

Show evidence (2 references)

PMID:15729077 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Only 1 patient who had a less extensive procedure developed recurrent GI bleeding. The mean follow-up period was 5.0 years (range 2.9-10.3 years)."

Selected surgical series of ten patients; mean 137 lesions removed per operation, not evidence that all BRBNS is surgically curable.

PMID:32664167 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"An emergency laparotomy was performed, and postoperative management included blood transfusions and oral iron supplementation for 2 weeks."

Direct treatment of an acute intussusception complication.

Management of Localized Intravascular Coagulopathy

Action: Pharmacotherapy NCIT:C15986

Agent: Low molecular weight heparin NCIT:C2578

A vascular-anomalies and hematology team assesses coagulation before invasive procedures. Low-molecular-weight heparin can be used for painful intralesional thrombosis or perioperative coagulopathy, with the plan individualized to lesion burden, fibrinogen and active bleeding.

Mechanism Target:

INHIBITS Localised Intravascular Coagulopathy — Anticoagulation reduces intralesional thrombotic activity and aims to prevent worsening consumption around procedures.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Low-molecular-weight heparin (LMWH) should be administered prior to any invasive procedure (sclerotherapy and/or surgery) to avoid disseminated intravascular coagulopathy."

GeneReviews recommends procedural prophylaxis for TEK-related venous malformations; timing depends on fibrinogen and D-dimer results and the specialist assessment of bleeding risk.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"If lesions are painful and D-dimers are elevated, LMWH can also be used to treat the associated pain."

Expert guidance for TEK-related venous malformations; treatment must account for the individual bleeding context.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Low-molecular-weight heparin (LMWH) should be administered prior to any invasive procedure (sclerotherapy and/or surgery) to avoid disseminated intravascular coagulopathy."

GeneReviews recommends procedural prophylaxis for TEK-related venous malformations; timing depends on fibrinogen and D-dimer results and the specialist assessment of bleeding risk.

Clinical and Laboratory Surveillance

Review lesions and symptoms with a vascular-anomalies team. Follow blood count and iron indices for gastrointestinal bleeding, and D-dimer/fibrinogen for coagulation risk, especially before procedures. Sirolimus requires clinical and laboratory monitoring for toxicity and dose adjustment. Consider neurological assessment and appropriate imaging when symptoms or lesion distribution suggest CNS involvement.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Individuals on sirolimus should be closely followed at the beginning and throughout the course of their treatment, in order to modify the dosage as well as manage adverse events."

Expert monitoring recommendation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Annually or more frequently in case of symptoms (fatigue, bloody stools)"

The gastrointestinal surveillance table recommends at least annual review, intensified by symptoms.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Explain the usual postzygotic mosaic origin, limits of negative blood testing and low expected family recurrence. Do not apply the 50% transmission estimate for germline TEK-related VMCM to typical somatic BRBNS; an apparent familial presentation needs reassessment.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Counseling for recurrence risk in ... -related unifocal VM, MSVM, and BRBN syndrome should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk of recurrence for these disorders is not increased compared to the general population."

Disease-specific counseling distinguishes somatic BRBN from inherited VMCM.

Avoidance of High-Estrogen Contraceptive Pills

Platform: Other

Avoid high-estrogen contraceptive pills because venous malformations can enlarge or become symptomatic with estrogen exposure; contraceptive selection requires individual clinical assessment.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Contraceptive pills with high estrogen concentration should be avoided, as VM are estrogen responsive."

GeneReviews identifies high-estrogen contraceptive pills as a circumstance to avoid in TEK-related venous malformations.

Sclerotherapy of Symptomatic Cutaneous and Soft-Tissue Lesions

Action: Sclerotherapy NCIT:C62732

Sclerotherapy can reduce symptomatic venous-malformation volume, either alone or before surgery. Selection depends on anatomy and procedural coagulation assessment. This recommendation comes from TEK-related venous-malformation guidance, rather than a BRBN-specific comparative trial.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Sclerotherapy is the first-line treatment for VM. It is performed to decrease the volume of the VM before surgery or as monotherapy in individuals in whom surgery is not technically feasible."

TEK-related venous-malformation guidance supports lesion-directed sclerotherapy, including symptomatic skin and soft-tissue disease.

Excision of Selected Cutaneous and Soft-Tissue Lesions

Action: Surgical Procedure NCIT:C15329

Small lesions can be excised when complete removal is feasible without functional or anatomic harm. Extensive disease may be inaccessible or incompletely treated.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"If the lesion is small and complete resection is possible without anatomic or functional consequences, surgical excision should be performed as the treatment of choice."

Small accessible lesions may be excised; incomplete cure and anatomic limitations remain possible.

🔬

Diagnosis

Clinical assessment of multifocal venous malformations

Evaluate cutaneous, mucosal and gastrointestinal lesions with attention to sparse or late-appearing skin findings. Clinical phenotype and lesional molecular testing distinguish BRBNS from other multifocal vascular disorders.

Show evidence (2 references)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cutaneous lesions were present in 7/8 patients (87.5%), it appeared as the initial symptom in 6 patients (Figure 1), 1 patient (#2) skin lesions occurred in the 7th year of the course of disease."

Skin lesions can be absent initially or entirely; this pediatric referral series is not a population-frequency estimate.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Gastrointestinal lesions (grape-like mucosal venous nodules), documented by endoscopy, colonoscopy, or magnetic resonance imaging, are pathognomonic of BRBN syndrome."

Gastrointestinal lesion morphology is a central diagnostic clue; atypical or familial presentations require differential diagnosis.

Lesional TEK sequencing

Prioritize affected vascular tissue and sequencing sensitive to low-level mosaicism; a negative blood test does not exclude a lesional variant. A TEK variant of uncertain significance alone does not establish the diagnosis.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from the vascular lesion, requiring a surgical or skin biopsy ‒ should be prioritized for genetic testing."

GeneReviews recommends affected tissue because of mosaicism.

Endoscopic assessment including the small bowel

Upper/lower endoscopy and capsule endoscopy map gastrointestinal lesions. Capsule studies can detect small-bowel lesions missed on other tests; the selected six positive examinations in one series do not establish 100% diagnostic sensitivity. Consider patency assessment or imaging when obstruction is suspected. Endoscopic ultrasound helps determine depth before treating a large lesion.

Endoscopic Procedure NCIT:C16546

Show evidence (2 references)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients underwent gastroscopy and ileo-colonoscopy, and 6 patients finished the whole GI screening with capsule endoscopy (CE) examinations"

Documents the gastrointestinal assessment in the eight-patient series.

PMID:36277742 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"An initial endoscopic ultrasound was performed to evaluate the gastric lesions because of concern of transmural involvement given their size, but the lesions were found to arise from the submucosa."

EUS established lesion depth before endoscopic resection.

MRI assessment of lesion extent

MRI evaluates deeper extension and multiorgan lesion burden; whole-body imaging can be considered for multifocal disease. Imaging complements rather than replaces gastrointestinal endoscopy.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Consider whole-body MRI. ... To evaluate risk of internal lesions"

The multifocal-VM assessment table recommends considering whole-body MRI.

Blood count and iron studies

Measure hemoglobin and iron status and investigate occult gastrointestinal loss when anemia is unexplained.

Show evidence (1 reference)

PMID:34976762 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Serum iron and transferrin saturation were lower, total iron binding capacity were higher, which indicated IDA."

Iron studies in the pediatric series establish iron deficiency, beyond a nonspecific anemia description.

Coagulation assessment

D-dimer and fibrinogen help identify localized intravascular coagulopathy and inform procedural planning. The reported 96.5% D-dimer specificity concerns venous components among vascular-anomaly referrals, not BRBNS in the general population; normal values do not rule out a venous malformation.

Coagulation Study NCIT:C62662

Markers: D-dimer; fibrinogen

Show evidence (2 references)

PMID:19917952 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All patients with multifocal venous malformations (5 with sporadic multifocal VM and 2 with BRBN) had very high D-dimer levels (≥5.649μg/ml)."

Both BRBN patients had high D-dimer; this small subgroup does not estimate disease-wide prevalence.

PMID:19917952 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Among the 85 patients without VM, D-dimer levels were elevated only in 3 patients; the specificity of the dosage was 96.5% (95% confidence interval, 92.5%-100%)."

Specifies the comparator group underlying the specificity estimate.

📊

Prevalence

Worldwide

Population prevalence is unknown. Published case counts and specialist cohorts do not provide a population denominator.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"BRBN syndrome is rarely reported, with around 250 individuals reported to date"

The chapter reports an approximate historical literature count, not a population prevalence estimate.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Blue Rubber Bleb Nevus Syndrome:

Maffucci syndrome

Overlapping Features Multiple enchondromas support Maffucci syndrome in a person with cutaneous and gastrointestinal vascular lesions. Gastrointestinal involvement alone is not an absolute discriminator.

Show evidence (1 reference)

PMID:15670176 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"However, after recognition of the characteristic enchondromata, this diagnosis has been revised to Maffucci's syndrome."

A child previously labeled BRBNS was reclassified after skeletal findings.

Glomuvenous malformation

Overlapping Features Glomuvenous lesions have distinct morphology and mural glomus cells. D-dimer is often normal, but this test is an adjunct rather than a sole diagnostic rule.

Show evidence (1 reference)

PMID:19917952 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Venous malformations: 69/172 patients (40.1%); 5/5 with multifocal sporadic VM, 2/2 with BRBN, 62/149 with a solitary VM, and 0/16 with GVM."

Reports the different D-dimer findings across subgroups in this referral cohort.

🔬

Clinical Trials

NCT03767660 PHASE_IV UNKNOWN

Prospective single-arm sirolimus study for BRBNS and other venous malformations, with 20 participants planned. Registry status was UNKNOWN on 2026-10-01; the last known status was recruiting and the last posted update was 2018-12-19. Estimated completion dates do not establish completion or current recruitment. The phase IV label is the registry designation, not evidence of a BRBNS marketing authorization.

Show evidence (1 reference)

clinicaltrials:NCT03767660 SUPPORT DIRECT Other

"A prospective, nonrandomized, open-label, single-arm clinical trial to study efficacy of rapamycin (sirolimus) in the treatment of Blue Rubber Bleb Nevus Syndrome, hereditary or sporadic venous malformation"

Direct disease-relevant registry description; not an efficacy result.

NCT06642051 ACTIVE_NOT_RECRUITING

Sonablate HIFU safety/feasibility study of peripheral venous lesions; BRBNS is explicitly listed among examples. Adults and superficial peripheral lesions are eligible, while visceral/internal-organ lesions are excluded, so this is not a trial for gastrointestinal bleeding. Thirty participants are planned across conditions. Status verified 2026-10-01 against the registry update of 2026-02-19.

Show evidence (1 reference)

clinicaltrials:NCT06642051 SUPPORT DIRECT Other

"Examples of CVI are varicose veins, vascular congestion, venous ulcer, venous clusters, venous anomalies, mixed malformation, Klippel-Trenaunay Syndrome, CLOVES, Syndrome, Blue Rubber bleb Nevus Syndrome."

BRBNS is named in the registry; enrollment and benefit for BRBNS are not demonstrated.

NCT02399527 RECRUITING

Observational outcome registry that lists BRBNS among conditions but requires a significant lymphatic component in eligibility. It does not imply every patient with a pure venous BRBNS phenotype qualifies. Planned enrollment is 1,000 across conditions. Status verified 2026-10-01 against the 2026-09-10 registry update; no treatment effect is inferred.

Show evidence (1 reference)

clinicaltrials:NCT02399527 SUPPORT DIRECT Other

"the investigators are conducting an observational study of patients with lymphatic anomalies, including an annual follow-up questionnaire to gather prospective data on mortality, morbidity, treatments, and functionality as well as quality of life."

An observational natural-history registry, with broader eligibility restrictions.

🧫

Experimental Models

BRBN-associated double-mutant TIE2 in HUVECs PRIMARY_CELL_CULTURE

T1105N-T1106P expression tests ligand-independent activation and endothelial survival, invasion and colony formation, alongside the multifocal-VM-associated Y897C-R915C allele. It does not reproduce tissue mosaicism or gastrointestinal anatomy.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Human umbilical vein endothelial cells expressing TEK variants

Publication

PMID:27519652

Pathograph links

Ligand-Independent TIE2 Activation recapitulates fidelity: moderate

Show evidence (1 reference)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT In Vitro

"... both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells."

The recurrent alleles were functionally expressed in HUVECs; the cellular results are distinguished from clinical sequencing.

Show evidence (1 reference)

PMID:27519652 SUPPORT DIRECT PRIMARY RESULT In Vitro

"... both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells."

The recurrent alleles were functionally expressed in HUVECs; the cellular results are distinguished from clinical sequencing.

TIE2-L914F endothelial and smooth-muscle co-culture CO_CULTURE

Related-variant model of AKT/FOXO1 signaling, PDGFB secretion and paracrine mural-cell migration. Rapamycin rescues several readouts, but the double-mutant BRBN context was not tested.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Primary umbilical endothelial and smooth-muscle cells; endothelial lentiviral TEK expression

Publication

PMID:32867785

Pathograph links

Reduced Endothelial PDGFB Expression recapitulates fidelity: low

Limitations: L914F rather than recurrent BRBN cis variants; no PDGFB-specific necessity experiment in BRBN.

Show evidence (1 reference)

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

Secreted PDGFBB and transcriptional assays support an endothelial paracrine defect in the L914F model.

Show evidence (2 references)

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"FOXO1 expression in nucleus significantly reduced in TIE2-L914F mutant ECs, whereas there was an increased expression of FOXO1 after the addition of RAPA"

The L914F model shows reduced nuclear FOXO1 and rapamycin-associated restoration; transfer to BRBN remains indirect.

PMID:32867785 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Compared to NC and WT groups, TIE2 mutation group showed a decreased migration of SMCs, whereas no significant differentiation between NC and WT (Fig. 6a, b)."

Co-culture shows reduced smooth-muscle-cell migration. It does not independently prove that PDGFB loss is necessary or sufficient for BRBN lesions.

🐁

Animal Models

HUVEC-TIE2-L914F xenograft Xenograft

Subcutaneous HUVEC-TIE2-L914F xenografts in immunodeficient mice form ectatic vascular channels. Systemic ponatinib plus rapamycin induced regression of established lesions; withdrawal caused rebound that topical rapamycin suppressed. L914F models common TEK-mutant VM rather than the recurrent BRBN double allele or its gastrointestinal distribution.

Species

Mouse (Mus musculus)

Genotype

TIE2-mutant human endothelial cell xenograft

Genes

TEK hgnc:11724

Pathograph links

PI3K-AKT-mTOR Pathway Activation perturbs fidelity: moderate Used to test pharmacological suppression of the pathway node, reading out lesion regression.

Limitations: Single L914F overexpression in implanted cells, immunodeficient host, short follow-up and subcutaneous lesions. It does not establish treatment efficacy or safety in BRBNS patients.

Show evidence (1 reference)

PMID:30626204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Combination treatment with the ABL kinase inhibitor ponatinib and rapamycin caused VM regression in a xenograft model based on injection of HUVEC-TIE2-L914F."

Lesion regression under pathway inhibition is the readout that grounds this model link.

Show evidence (1 reference)

PMID:30626204 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Combination treatment with the ABL kinase inhibitor ponatinib and rapamycin caused VM regression in a xenograft model based on injection of HUVEC-TIE2-L914F."

A result from the model itself - lesion regression in the HUVEC-TIE2-L914F xenograft under combined pathway inhibition.

Mosaic TIE2-L914F transgenic mouse Transgenic

Variable CMV-Cre recombination activates the L914F transgene during development. Mutant offspring show partial embryonic lethality; survivors develop enlarged venous/capillary lesions and increased D-dimer. This models mosaic TEK-driven VM, with no demonstrated BRBN double-cis genotype or gastrointestinal bleeding phenotype.

Species

Mouse (Mus musculus)

Genotype

CMV-Cre; Rosa26-TIE2-L914F transgene

Pathograph links

Ectatic Mural-Cell-Poor Venous Channels recapitulates fidelity: moderate

Limitations: Transgenic L914F model with a broadly active mosaic Cre driver; not an endogenous BRBN double-variant knock-in.

Show evidence (1 reference)

PMID:42059767 SUPPORT DIRECT PRIMARY RESULT Model Organism

"surviving CMV-Cre;TIE2L914F mice developed massively enlarged venous/capillary vessels in various tissues, reminiscent of the VM phenotype."

The mosaic transgenic model produces VM-like lesions, not a demonstrated BRBN-specific phenotype.

Show evidence (1 reference)

PMID:42059767 SUPPORT DIRECT PRIMARY RESULT Model Organism

"surviving CMV-Cre;TIE2L914F mice developed massively enlarged venous/capillary vessels in various tissues, reminiscent of the VM phenotype."

The mosaic transgenic model produces VM-like lesions, not a demonstrated BRBN-specific phenotype.

Endothelial TEK overexpression in zebrafish embryos Transgenic

Patient-derived TEK variant overexpression induces venous malformations, and tested cis double variants have additive effects. Sirolimus suppresses lesion development. This is a developmental functional assay rather than a model of chronic gastrointestinal bleeding.

Species

Zebrafish (Danio rerio)

Pathograph links

Ectatic Mural-Cell-Poor Venous Channels recapitulates fidelity: moderate

Limitations: Embryonic overexpression and variant testing; the abstract does not report a BRBN organ distribution or chronic coagulopathy.

Show evidence (1 reference)

PMID:34254124 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Endothelium-specific overexpression of TEK mutations leads to robust induction of VMs, whereas MAP2K1 mutations cause AVMs in our zebrafish model."

Embryonic overexpression assay of TEK variants; the abstract does not establish that every tested variant is BRBN-associated.

Show evidence (2 references)

PMID:34254124 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Endothelium-specific overexpression of TEK mutations leads to robust induction of VMs, whereas MAP2K1 mutations cause AVMs in our zebrafish model."

Embryonic overexpression assay of TEK variants; the abstract does not establish that every tested variant is BRBN-associated.

PMID:34254124 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The clinically established mTOR-inhibitor sirolimus (rapamycin) efficiently abrogates the development of VMs in this zebrafish model."

Prevention of VM development in embryos, not human treatment evidence.

{ }

Source YAML

click to show

name: Blue Rubber Bleb Nevus Syndrome
creation_date: '2026-08-31T12:00:00Z'
synonyms:
- Bean syndrome
- blue rubber bleb naevus syndrome
- BRBNS
description: >-
  Blue rubber bleb nevus syndrome (BRBNS; Bean syndrome) is a multifocal venous malformation
  disorder, usually
  caused by postzygotic activating TEK variants. Recurrent double mutations in cis
  activate the endothelial
  TIE2 receptor. Cutaneous lesions are soft, blue and compressible; gastrointestinal
  lesions, often involving
  the small bowel, can cause occult or overt bleeding and iron-deficiency anemia.
  Typical skin lesions may
  be sparse or absent, and diagnosis can be delayed. Lesions may also affect deeper
  tissues and other organs,
  and localized intravascular coagulopathy can accompany extensive disease. Management
  combines correction
  of iron deficiency, lesion-directed endoscopic or surgical treatment, and specialist-directed
  systemic sirolimus
  when appropriate. Much of the downstream signaling model derives from other TEK-mutant
  venous malformations
  and must be distinguished from direct BRBNS evidence.
categories:
- Vascular Anomaly
- Venous Malformation
- Somatic Mosaic Disorder
parents:
- venous malformation
prevalence:
- population: Worldwide
  notes: >-
    Population prevalence is unknown. Published case counts and specialist cohorts
    do not provide a population
    denominator.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      BRBN syndrome is rarely reported, with around 250 individuals reported to date
    explanation: >-
      The chapter reports an approximate historical literature count, not a population
      prevalence estimate.
    quote_role: REVIEW_SYNTHESIS
inheritance:
- name: Somatic Mosaic
  description: >-
    The usual molecularly defined disorder is postzygotic somatic mosaicism. GeneReviews
    reports no confirmed
    vertical transmission or sibling recurrence and considers recurrence risk comparable
    to the general population;
    this does not establish a literally zero risk. An apparent dominant family history
    warrants reassessment
    for familial TEK-related cutaneomucosal malformations or other vascular disorders.
    Historical familial
    cases labeled BRBNS often lack molecular confirmation.
  inheritance_term:
    preferred_term: somatic mosaicism
    term:
      id: HP:0001442
      label: Typified by somatic mosaicism
  evidence:
  - &id001
    reference: PMID:27519652
    reference_title: Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In contrast to common unifocal venous malformation, which is most often caused
      by the somatic L914F TIE2
      mutation, multifocal forms are predominantly caused by double (cis) mutations,
      that is, two somatic mutations
      on the same allele of the gene.
    explanation: >-
      Double cis alleles predominate in multifocal disease; this is not a requirement
      demonstrated in every
      clinically diagnosed patient.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      No confirmed vertical transmission or sib recurrence has been reported to date.
    explanation: >-
      Describes the observed inheritance evidence for somatic TEK-related phenotypes,
      including BRBN syndrome.
    quote_role: REVIEW_SYNTHESIS
pathophysiology:
- name: Somatic Activating TEK Variants
  description: >-
    Activating TEK variants are present in affected tissues, often at low mosaic allele
    fractions. Double mutations
    in cis predominate in BRBNS and other multifocal TEK-related malformations. Identical
    variants across sampled
    lesions support a shared mutant lineage; the developmental timing and precise
    founding cell cannot be reconstructed
    from sequencing alone.
  biological_scale: MOLECULAR
  evidence:
  - &id007
    reference: PMID:27519652
    reference_title: Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17
      individuals with blue rubber
      bleb nevus syndrome.
    explanation: >-
      Lesional sequencing establishes TEK as the principal identified cause in this
      series; the two unsolved
      individuals are not assigned an unobserved genotype.
    quote_role: PRIMARY_RESULT
  - *id001
  downstream:
  - target: Ligand-Independent TIE2 Activation
    description: >-
      The recurrent double-mutant receptor has ligand-independent activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27519652
      reference_title: Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        ... both cause ligand-independent activation of TIE2, and increase survival,
        invasion, and colony formation when expressed in human umbilical vein endothelial
        cells.
      explanation: >-
        The recurrent alleles were functionally expressed in HUVECs; the cellular
        results are distinguished
        from clinical sequencing.
      quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: TEK
    term:
      id: hgnc:11724
      label: TEK
  molecular_functions:
  - preferred_term: transmembrane receptor protein tyrosine kinase activity
    term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    modifier: INCREASED
  cell_types:
  - preferred_term: vein endothelial cell
    term:
      id: CL:0002543
      label: vein endothelial cell
- name: Ligand-Independent TIE2 Activation
  description: >-
    BRBN-associated T1105N-T1106P and the multifocal-VM-associated Y897C-R915C allele
    activate TIE2 without
    ligand in transduced endothelial cells. Their downstream phenotypes differ from
    normal ligand-regulated
    receptor signaling.
  biological_scale: MOLECULAR
  evidence:
  - &id002
    reference: PMID:27519652
    reference_title: Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      ... both cause ligand-independent activation of TIE2, and increase survival,
      invasion, and colony formation when expressed in human umbilical vein endothelial
      cells.
    explanation: >-
      The recurrent alleles were functionally expressed in HUVECs; the cellular results
      are distinguished from
      clinical sequencing.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: PI3K-AKT-mTOR Pathway Activation
    description: >-
      Related TIE2-mutant endothelial models support activation of the downstream
      kinase pathway.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32867785
      reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        However, only TIE2-L914F mutant ECs showed abnormal phosphorylation of AKT
        (ser 473) which is downstream
        of TIE2.
      explanation: >-
        L914F-transduced endothelial cells support the pathway model; this is indirect
        evidence for BRBN double-mutant
        alleles.
      quote_role: PRIMARY_RESULT
  biological_processes:
  - preferred_term: Tie signaling pathway
    term:
      id: GO:0048014
      label: Tie signaling pathway
    modifier: INCREASED
  cell_types:
  - preferred_term: vein endothelial cell
    term:
      id: CL:0002543
      label: vein endothelial cell
- name: PI3K-AKT-mTOR Pathway Activation
  description: >-
    Activating TIE2 signals through PI3K-AKT-mTOR. Constitutive AKT phosphorylation
    and rapamycin responses
    support this route in L914F endothelial models; R849W familial-VM experiments
    also link AKT to cell survival.
    These are related-variant models, not direct demonstrations of every pathway step
    in BRBN double-mutant
    lesions.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:32867785
    reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      However, only TIE2-L914F mutant ECs showed abnormal phosphorylation of AKT (ser
      473) which is downstream
      of TIE2.
    explanation: >-
      L914F-transduced endothelial cells support the pathway model; this is indirect
      evidence for BRBN double-mutant
      alleles.
    quote_role: PRIMARY_RESULT
  - reference: PMID:15526080
    reference_title: Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Dominant-negative Akt inhibited the pro-survival activity of mutant Tie2.
    explanation: >-
      The tested receptor was R849W, associated with familial VM; the result supports
      the survival pathway
      by analogy.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Endothelial Apoptosis Suppression
    description: >-
      AKT supports endothelial survival in a related-variant assay.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15526080
      reference_title: Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Dominant-negative Akt inhibited the pro-survival activity of mutant Tie2.
      explanation: >-
        The tested receptor was R849W, associated with familial VM; the result supports
        the survival pathway
        by analogy.
      quote_role: PRIMARY_RESULT
  - target: Reduced Endothelial PDGFB Expression
    description: >-
      AKT/FOXO1 signaling is associated with reduced PDGFB transcription and secretion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32867785
      reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        FOXO1 expression in nucleus significantly reduced in TIE2-L914F mutant ECs,
        whereas there was an increased
        expression of FOXO1 after the addition of RAPA
      explanation: >-
        The L914F model shows reduced nuclear FOXO1 and rapamycin-associated restoration;
        transfer to BRBN
        remains indirect.
      quote_role: PRIMARY_RESULT
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  cell_types:
  - preferred_term: vein endothelial cell
    term:
      id: CL:0002543
      label: vein endothelial cell
- name: Endothelial Apoptosis Suppression
  description: >-
    BRBN-associated TIE2 double-mutant expression increases endothelial survival,
    invasion and colony formation.
    Reduced apoptosis and AKT dependence are demonstrated in related R849W and L914F
    models. Persistence of
    poorly supported vascular channels is a mechanistic interpretation rather than
    a directly traced cellular
    history in patients.
  biological_scale: CELLULAR
  evidence:
  - *id002
  - reference: PMID:32867785
    reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      TIE2-L914F mutant ECs showed lower apoptosis rate than the group of GFP or TIE2-WT,
      suggesting their
      enhanced anti-apoptotic ability, consistent with the above speculation.
    explanation: >-
      Flow-cytometric apoptosis results in the related L914F model support the survival
      mechanism.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Ectatic Mural-Cell-Poor Venous Channels
    description: >-
      Enhanced cell survival may permit persistence of dysmorphic channels; this transition
      is not directly
      traced in BRBNS.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27519652
      reference_title: Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        ... both cause ligand-independent activation of TIE2, and increase survival,
        invasion, and colony formation when expressed in human umbilical vein endothelial
        cells.
      explanation: >-
        The recurrent alleles were functionally expressed in HUVECs; the cellular
        results are distinguished
        from clinical sequencing.
      quote_role: PRIMARY_RESULT
  biological_processes:
  - preferred_term: negative regulation of apoptotic process
    term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    modifier: INCREASED
  cell_types:
  - preferred_term: vein endothelial cell
    term:
      id: CL:0002543
      label: vein endothelial cell
- name: Reduced Endothelial PDGFB Expression
  description: >-
    In L914F-expressing HUVECs, increased AKT/FOXO1 phosphorylation accompanies reduced
    nuclear FOXO1 and reduced
    PDGFB output. Rapamycin restores nuclear FOXO1 and PDGFB expression and secretion.
    This provides a candidate
    paracrine mechanism for TEK-related malformations, but it has not been directly
    established for the recurrent
    BRBN double allele.
  biological_scale: MOLECULAR
  evidence:
  - &id015
    reference: PMID:32867785
    reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      FOXO1 expression in nucleus significantly reduced in TIE2-L914F mutant ECs,
      whereas there was an increased
      expression of FOXO1 after the addition of RAPA
    explanation: >-
      The L914F model shows reduced nuclear FOXO1 and rapamycin-associated restoration;
      transfer to BRBN remains
      indirect.
    quote_role: PRIMARY_RESULT
  - &id017
    reference: PMID:32867785
    reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      As PDGFB function as an identity of secretory protein, we detected the expression
      of its subtype PDGFBB
      in the supernatant of cell culture, and the result of ELISA assay is consistent
      with that obtained by
      real-time quantitative PCR (Fig. 5h).
    explanation: >-
      Secreted PDGFBB and transcriptional assays support an endothelial paracrine
      defect in the L914F model.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Reduced Mural Cell Recruitment and Coverage
    description: >-
      Reduced paracrine support is a candidate explanation for impaired mural-cell
      recruitment in related TEK-mutant
      models.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32867785
      reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Compared to NC and WT groups, TIE2 mutation group showed a decreased migration
        of SMCs, whereas no
        significant differentiation between NC and WT (Fig. 6a, b).
      explanation: >-
        Co-culture shows reduced smooth-muscle-cell migration. It does not independently
        prove that PDGFB loss
        is necessary or sufficient for BRBN lesions.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: vein endothelial cell
    term:
      id: CL:0002543
      label: vein endothelial cell
- name: Reduced Mural Cell Recruitment and Coverage
  description: >-
    L914F endothelial cells support less smooth-muscle-cell migration in co-culture;
    L914F venous-malformation
    tissues show reduced α-SMA coverage. PDGFB deficiency may contribute, but the
    experiments do not isolate
    its necessity for BRBN lesion formation.
  biological_scale: CELLULAR
  evidence:
  - &id016
    reference: PMID:32867785
    reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Compared to NC and WT groups, TIE2 mutation group showed a decreased migration
      of SMCs, whereas no significant
      differentiation between NC and WT (Fig. 6a, b).
    explanation: >-
      Co-culture shows reduced smooth-muscle-cell migration. It does not independently
      prove that PDGFB loss
      is necessary or sufficient for BRBN lesions.
    quote_role: PRIMARY_RESULT
  - &id018
    reference: PMID:32867785
    reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      VMs with TIE2-L914F mutation showed lower expression of PDGFB and α-SMA than
      normal veins.
    explanation: >-
      Five L914F-positive VM tissues had reduced PDGFB and mural-cell staining; these
      were not a BRBN-specific
      cohort.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Ectatic Mural-Cell-Poor Venous Channels
    description: >-
      Reduced mural support accompanies ectatic channels; human tissue association
      does not by itself prove
      causal sufficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32867785
      reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        VMs with TIE2-L914F mutation showed lower expression of PDGFB and α-SMA than
        normal veins.
      explanation: >-
        Five L914F-positive VM tissues had reduced PDGFB and mural-cell staining;
        these were not a BRBN-specific
        cohort.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
- name: Ectatic Mural-Cell-Poor Venous Channels
  description: >-
    Malformed, dilated blood-filled venous channels occur in skin, bowel and sometimes
    other tissues. Direct
    BRBNS histology shows thin or flattened endothelium, intralesional thrombosis
    and calcification. Variable
    mural-cell investment is described across TEK-related malformations; cellular
    signaling experiments provide
    an indirect explanation for the tissue architecture.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The surgery slices showed that there were proliferative and dilated cavernous
      vascular cavities under
      the mucosa lined by normal or thin or flat endothelium with varying amounts,
      the cavities were full of
      red blood cells, some of which could be seen thrombus organization and calcification
      in different degrees,
      suggesting VMs.
    explanation: >-
      Direct histology of resected BRBNS lesions shows dilated blood-filled channels
      and intralesional thrombus
      organization.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Enlarged venous-like channels with walls of smooth muscle of variable thickness
      are observed
    explanation: >-
      Describes the histology of TEK-related venous malformations; mural investment
      is variable rather than
      uniformly absent.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Chronic Gastrointestinal Blood Loss
    description: >-
      Gastrointestinal lesions cause recurrent blood loss.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
      reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Gastrointestinal lesions cause bleeding, iron deficiency, and intestinal complications
        (volvulus and
        infarction).
      explanation: >-
        Summarizes the BRBN-specific gastrointestinal manifestations.
      quote_role: REVIEW_SYNTHESIS
  - target: Localised Intravascular Coagulopathy
    description: >-
      Intralesional thrombus organization and clinical coagulation findings support
      local clot turnover; the
      precise hemodynamic sequence is inferred.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The surgery slices showed that there were proliferative and dilated cavernous
        vascular cavities under
        the mucosa lined by normal or thin or flat endothelium with varying amounts,
        the cavities were full
        of red blood cells, some of which could be seen thrombus organization and
        calcification in different
        degrees, suggesting VMs.
      explanation: >-
        Direct histology of resected BRBNS lesions shows dilated blood-filled channels
        and intralesional thrombus
        organization.
      quote_role: PRIMARY_RESULT
  - target: Cutaneous Venous Malformations
    description: >-
      The venous-channel abnormality is expressed as cutaneous lesions; the exact
      tissue morphogenesis is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Cutaneous lesions were present in 7/8 patients (87.5%), it appeared as the
        initial
        symptom in 6 patients
        (Figure 1), 1 patient (#2) skin lesions occurred in the 7th year of the course
        of disease.
      explanation: >-
        Skin lesions can be absent initially or entirely; this pediatric referral
        series
        is not a population-frequency
        estimate.
      quote_role: PRIMARY_RESULT
  - target: Gastrointestinal Venous Malformations
    description: >-
      The abnormal channels constitute the intestinal lesions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        The surgery slices showed that there were proliferative and dilated cavernous
        vascular cavities under
        the mucosa lined by normal or thin or flat endothelium with varying amounts,
        the cavities were full
        of red blood cells, some of which could be seen thrombus organization and
        calcification in different
        degrees, suggesting VMs.
      explanation: >-
        Direct histology of resected BRBNS lesions shows dilated blood-filled channels
        and intralesional thrombus
        organization.
      quote_role: PRIMARY_RESULT
  - target: Hepatic Venous Malformations
    description: >-
      Similar malformations can occur in other organs; organ distribution depends
      on the mosaic lesion pattern.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Other organs involvement included hepatic in 3 (37.5%), intra-muscular in
        2 (25.0%), ocular, thyroid,
        splenic, intraosseous, pulmonary in 1 (12.5%) respectively.
      explanation: >-
        The small referral series documents additional organ involvement; several
        rare sites occurred together
        in one extensively affected child.
      quote_role: PRIMARY_RESULT
  - target: Intramuscular Venous Malformations
    description: >-
      The same venous-malformation process can involve this organ. The organ distribution and local mural-cell
      phenotype were not mechanistically established in this series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Other organs involvement included hepatic in 3 (37.5%), intra-muscular in
        2 (25.0%), ocular, thyroid,
        splenic, intraosseous, pulmonary in 1 (12.5%) respectively.
      explanation: >-
        The small referral series documents additional organ involvement; several
        rare sites occurred together
        in one extensively affected child.
      quote_role: PRIMARY_RESULT
  - target: Ocular Venous Malformations
    description: >-
      The same venous-malformation process can involve this organ. The organ distribution and local mural-cell
      phenotype were not mechanistically established in this series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Other organs involvement included hepatic in 3 (37.5%), intra-muscular in
        2 (25.0%), ocular, thyroid,
        splenic, intraosseous, pulmonary in 1 (12.5%) respectively.
      explanation: >-
        The small referral series documents additional organ involvement; several
        rare sites occurred together
        in one extensively affected child.
      quote_role: PRIMARY_RESULT
  - target: Thyroid Venous Malformations
    description: >-
      The same venous-malformation process can involve this organ. The organ distribution and local mural-cell
      phenotype were not mechanistically established in this series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Other organs involvement included hepatic in 3 (37.5%), intra-muscular in
        2 (25.0%), ocular, thyroid,
        splenic, intraosseous, pulmonary in 1 (12.5%) respectively.
      explanation: >-
        The small referral series documents additional organ involvement; several
        rare sites occurred together
        in one extensively affected child.
      quote_role: PRIMARY_RESULT
  - target: Splenic Venous Malformations
    description: >-
      The same venous-malformation process can involve this organ. The organ distribution and local mural-cell
      phenotype were not mechanistically established in this series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Other organs involvement included hepatic in 3 (37.5%), intra-muscular in
        2 (25.0%), ocular, thyroid,
        splenic, intraosseous, pulmonary in 1 (12.5%) respectively.
      explanation: >-
        The small referral series documents additional organ involvement; several
        rare sites occurred together
        in one extensively affected child.
      quote_role: PRIMARY_RESULT
  - target: Intraosseous Venous Malformations
    description: >-
      The same venous-malformation process can involve this organ. The organ distribution and local mural-cell
      phenotype were not mechanistically established in this series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Other organs involvement included hepatic in 3 (37.5%), intra-muscular in
        2 (25.0%), ocular, thyroid,
        splenic, intraosseous, pulmonary in 1 (12.5%) respectively.
      explanation: >-
        The small referral series documents additional organ involvement; several
        rare sites occurred together
        in one extensively affected child.
      quote_role: PRIMARY_RESULT
  - target: Pulmonary Venous Malformations
    description: >-
      The same venous-malformation process can involve this organ. The organ distribution and local mural-cell
      phenotype were not mechanistically established in this series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Other organs involvement included hepatic in 3 (37.5%), intra-muscular in
        2 (25.0%), ocular, thyroid,
        splenic, intraosseous, pulmonary in 1 (12.5%) respectively.
      explanation: >-
        The small referral series documents additional organ involvement; several
        rare sites occurred together
        in one extensively affected child.
      quote_role: PRIMARY_RESULT
  biological_processes:
  - preferred_term: blood vessel morphogenesis
    term:
      id: GO:0048514
      label: blood vessel morphogenesis
    modifier: ABNORMAL
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  cell_types:
  - preferred_term: vein endothelial cell
    term:
      id: CL:0002543
      label: vein endothelial cell
- name: Chronic Gastrointestinal Blood Loss
  description: >-
    Gastrointestinal venous malformations can bleed intermittently or continuously,
    producing occult blood
    loss, melena or hematochezia. Severe overt bleeding can occur; chronic iron deficiency
    is common but not
    every patient is transfusion dependent.
  biological_scale: ORGANISM
  evidence:
  - &id004
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gastrointestinal lesions cause bleeding, iron deficiency, and intestinal complications
      (volvulus and
      infarction).
    explanation: >-
      Summarizes the BRBN-specific gastrointestinal manifestations.
    quote_role: REVIEW_SYNTHESIS
  - &id003
    reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Serum iron and transferrin saturation were lower, total iron binding capacity
      were higher, which indicated
      IDA.
    explanation: >-
      Iron studies in the pediatric series establish iron deficiency, beyond a nonspecific
      anemia description.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Gastrointestinal Hemorrhage
    description: >-
      Blood loss manifests as occult or overt gastrointestinal hemorrhage.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
      reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Gastrointestinal lesions cause bleeding, iron deficiency, and intestinal complications
        (volvulus and
        infarction).
      explanation: >-
        Summarizes the BRBN-specific gastrointestinal manifestations.
      quote_role: REVIEW_SYNTHESIS
  - target: Iron Deficiency Anemia
    description: >-
      Persistent blood loss depletes iron stores and can cause anemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Serum iron and transferrin saturation were lower, total iron binding capacity
        were higher, which indicated
        IDA.
      explanation: >-
        Iron studies in the pediatric series establish iron deficiency, beyond a nonspecific
        anemia description.
      quote_role: PRIMARY_RESULT
- name: Localised Intravascular Coagulopathy
  description: >-
    Clot formation and fibrinolysis within malformed venous channels can elevate D-dimer;
    more severe consumption
    can lower fibrinogen and increase procedural bleeding risk. Sluggish flow is the
    proposed initiating condition.
    D-dimer is not a specific test for BRBNS, and normal values do not exclude small
    venous malformations.
  biological_scale: TISSUE
  evidence:
  - &id005
    reference: PMID:19917952
    reference_title: Elevated D-dimer level in the differential diagnosis of venous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      All patients with multifocal venous malformations (5 with sporadic multifocal
      VM and 2 with BRBN) had
      very high D-dimer levels (≥5.649μg/ml).
    explanation: >-
      Both BRBN patients had high D-dimer; this small subgroup does not estimate disease-wide
      prevalence.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19917952
    reference_title: Elevated D-dimer level in the differential diagnosis of venous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In one of the BRBN patients, the high D-dimers were associated with low fibrinogen
      level (95mg/dl), similar
      to two reported BRBN patients, who had acute or chronic disseminated intravascular
      coagulopathy13, 14.
    explanation: >-
      Documents low fibrinogen in one BRBN participant; the cited prior reports are
      background, not extra participants.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Elevated D-Dimer
    description: >-
      Fibrin formation and breakdown are reflected by elevated circulating D-dimer.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19917952
      reference_title: Elevated D-dimer level in the differential diagnosis of venous malformations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        All patients with multifocal venous malformations (5 with sporadic multifocal
        VM and 2 with BRBN) had
        very high D-dimer levels (≥5.649μg/ml).
      explanation: >-
        Both BRBN patients had high D-dimer; this small subgroup does not estimate
        disease-wide prevalence.
      quote_role: PRIMARY_RESULT
  - target: Phleboliths
    causal_link_type: DIRECT
    description: Long-standing localized thrombosis can become calcified, forming phleboliths.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
      reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Palpation can reveal pathognomonic phleboliths that develop due to long-standing
        localized thrombosis.
      explanation: >-
        The TEK-related venous-malformation chapter explains phlebolith formation; the
        pediatric BRBN series independently documents calcified lesions.
      quote_role: REVIEW_SYNTHESIS
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: DYSREGULATED
phenotypes:
- name: Cutaneous Venous Malformations
  description: >-
    Blue, soft, compressible papules or rubbery nodules may be present at birth or appear later. A congenital
    dominant venous malformation, over ten times the area of the other visible lesions, often presents first.
    Smaller lesions can cluster and become hyperkeratotic on palms and soles. Lesions can enlarge during puberty
    or pregnancy. Some patients have few visible skin lesions or none.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - &id008
    reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Cutaneous lesions were present in 7/8 patients (87.5%), it appeared as the initial
      symptom in 6 patients
      (Figure 1), 1 patient (#2) skin lesions occurred in the 7th year of the course
      of disease.
    explanation: >-
      Skin lesions can be absent initially or entirely; this pediatric referral series
      is not a population-frequency
      estimate.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Affected individuals often have a congenital single large VM, a so-called dominant VM ... which represents the first manifestation of BRBN syndrome.
    explanation: The congenital dominant lesion is a recognized initial manifestation; the intervening parenthesis defines its size as greater than ten times the other visible lesions.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: They occur on any surface of the skin and mucosa and tend to aggregate and become hyperkeratotic, with a predilection for the palms and soles.
    explanation: BRBN lesions can show characteristic palmoplantar clustering and hyperkeratosis.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Rapid expansion in the size of the lesions can be observed after trauma or hormonal modulation (e.g., during puberty or pregnancy).
    explanation: The chapter describes hormonal enlargement across TEK-related venous malformations.
  category: Dermatologic
  notes: These are venous malformations (HP:0012721). The historical name does not denote the melanocytic lesion represented by HP:0100814 Blue nevus.
- name: Gastrointestinal Hemorrhage
  description: >-
    Occult or overt gastrointestinal bleeding ranges from intermittent loss to severe
    hemorrhage. In the European
    44-patient cohort, bleeding was the most frequent reported complication (54.3%);
    this is a selected clinical
    cohort.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:39426903
    reference_title: 'Blue rubber bleb nevus syndrome: A European multicenter cohort study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gastrointestinal bleeding is the most common complication (54.3 %), requiring
      endoscopic treatment (36.4
      %) by various techniques.
    explanation: >-
      Reports the cohort-specific complication frequency.
    quote_role: PRIMARY_RESULT
  category: Gastrointestinal
- name: Iron Deficiency Anemia
  description: >-
    Chronic gastrointestinal bleeding can cause marked iron deficiency, with transfusion
    requirements varying
    by severity and treatment. Refractory anemia may be the presenting manifestation.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - *id003
  category: Hematologic
  sequelae:
  - target: Fatigue
    causal_link_type: DIRECT
    description: Chronic recurring anemia can cause fatigue.
    evidence:
    - reference: PMID:34976762
      reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        All patients (100%) presented with chronic recurring anemia manifesting as pallor,
        fatigue or poor exercise
        tolerance.
      explanation: >-
        Describes symptoms accompanying anemia in the selected pediatric series; it
        does not mean every child
        had each listed symptom.
      quote_role: PRIMARY_RESULT
- name: Gastrointestinal Venous Malformations
  description: >-
    Multifocal mucosal or deeper venous lesions commonly involve the small bowel,
    but may occur throughout
    the gastrointestinal tract. Presence and depth are evaluated endoscopically and
    with imaging; superficial
    lesions can be missed by cross-sectional imaging.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - *id004
  - &id009
    reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      All patients underwent gastroscopy and ileo-colonoscopy, and 6 patients finished
      the whole GI screening
      with capsule endoscopy (CE) examinations
    explanation: >-
      Documents the gastrointestinal assessment in the eight-patient series.
    quote_role: PRIMARY_RESULT
  category: Gastrointestinal
  sequelae:
  - target: Intussusception
    causal_link_type: DIRECT
    description: Gastrointestinal venous malformations can cause this intestinal complication.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
      reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: These are commonly located in the small intestine and can cause hemorrhage, intussusception, volvulus, and intestinal infarction
      explanation: The BRBN section identifies complications caused by gastrointestinal venous malformations.
  - target: Volvulus
    causal_link_type: DIRECT
    description: Gastrointestinal venous malformations can cause this intestinal complication.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
      reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: These are commonly located in the small intestine and can cause hemorrhage, intussusception, volvulus, and intestinal infarction
      explanation: The BRBN section identifies complications caused by gastrointestinal venous malformations.
  - target: Intestinal Infarction
    causal_link_type: DIRECT
    description: Gastrointestinal venous malformations can cause this intestinal complication.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
      reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: These are commonly located in the small intestine and can cause hemorrhage, intussusception, volvulus, and intestinal infarction
      explanation: The BRBN section identifies complications caused by gastrointestinal venous malformations.
- name: Elevated D-Dimer
  description: >-
    A marker of local intravascular clot turnover. It is common in extensive venous malformations but neither
    unique to BRBNS nor obligatory in every patient. GeneReviews reports elevated D-dimer in more than 80%
    of individuals with VMCM and BRBN syndrome; this combined clinical summary is not a BRBN-specific population
    estimate.
  phenotype_term:
    preferred_term: Elevated circulating D-dimer concentration
    term:
      id: HP:0033106
      label: Elevated circulating D-dimer concentration
  evidence:
  - *id005
  - reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In our study, 87.5% of patients had elevated D-dimer levels of greater than
      0.5 mg/L
    explanation: >-
      Seven of eight children had an elevated value; no population-wide frequency
      is inferred.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: This elevation of D-dimers is observed in approximately 40% of individuals with isolated VM and in more than 80% of individuals with VMCM and BRBN syndrome.
    explanation: The chapter supplies a broader clinical frequency statement covering VMCM and BRBN together.
  category: Hematologic
- name: Intussusception
  description: >-
    Bowel lesions can act as lead points for intussusception, presenting with acute
    pain and obstruction and
    sometimes requiring urgent surgery.
  phenotype_term:
    preferred_term: Intussusception
    term:
      id: HP:0002576
      label: Intussusception
  evidence:
  - reference: PMID:32664167
    reference_title: 'Blue rubber bleb nevus syndrome with the complication of intussusception: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      There were 3 segments of intussusceptions without necrosis in the ileum and
      a segment of intussusception
      that was unable to be reset at a distance from the ileocecal region and was
      excised.
    explanation: >-
      Direct operative findings in a 33-year-old man with BRBNS.
    quote_role: PRIMARY_RESULT
  category: Gastrointestinal
- name: Volvulus
  description: >-
    A reported intestinal complication of gastrointestinal venous malformations; frequency
    is not well quantified.
  phenotype_term:
    preferred_term: Volvulus
    term:
      id: HP:0002580
      label: Volvulus
  evidence:
  - *id004
  category: Gastrointestinal
- name: Fatigue
  description: >-
    Fatigue and reduced exercise tolerance can accompany chronic anemia.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      All patients (100%) presented with chronic recurring anemia manifesting as pallor,
      fatigue or poor exercise
      tolerance.
    explanation: >-
      Describes symptoms accompanying anemia in the selected pediatric series; it
      does not mean every child
      had each listed symptom.
    quote_role: PRIMARY_RESULT
- name: Hepatic Venous Malformations
  description: >-
    Hepatic lesions were documented in three of eight children in one series. Lesions
    need not cause liver
    dysfunction.
  phenotype_term:
    preferred_term: Hepatic vascular malformations
    term:
      id: HP:0006576
      label: Hepatic vascular malformations
  evidence:
  - &id006
    reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Other organs involvement included hepatic in 3 (37.5%), intra-muscular in 2
      (25.0%), ocular, thyroid,
      splenic, intraosseous, pulmonary in 1 (12.5%) respectively.
    explanation: >-
      The small referral series documents additional organ involvement; several rare
      sites occurred together
      in one extensively affected child.
    quote_role: PRIMARY_RESULT
  category: Hepatic
- name: Intramuscular Venous Malformations
  description: >-
    Intramuscular lesions were seen in two of eight children, including lesions assessed
    by MRI.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - *id006
  category: Musculoskeletal
- name: Phleboliths
  description: >-
    Calcified intralesional thrombi can be visible on imaging.
  phenotype_term:
    preferred_term: Phlebolith
    term:
      id: HP:6000661
      label: Phlebolith
  evidence:
  - reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Abdominal CT scan showed multiple spotted calcification in liver and scattered
      nodular low density shadow
      in bowel wall with multiple punctate calcifications (patient  # 1, Figure 2A,2B).
    explanation: >-
      Calcified lesions in one child, interpreted with the histologic thrombus and
      calcification findings.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Palpation can reveal pathognomonic phleboliths that develop due to long-standing
      localized thrombosis.
    explanation: >-
      The TEK-related venous-malformation chapter explains phlebolith formation; the
      pediatric BRBN series independently documents calcified lesions.
    quote_role: REVIEW_SYNTHESIS
- name: Ocular Venous Malformations
  description: >-
    Reported at this site in one extensively affected child in the eight-patient series.
    The observation establishes
    possible involvement, not a general population frequency.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - *id006
  category: Ophthalmologic
- name: Thyroid Venous Malformations
  description: >-
    Reported at this site in one extensively affected child in the eight-patient series.
    The observation establishes
    possible involvement, not a general population frequency.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - *id006
  category: Endocrine
- name: Splenic Venous Malformations
  description: >-
    Reported at this site in one extensively affected child in the eight-patient series.
    The observation establishes
    possible involvement, not a general population frequency.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - *id006
  category: Hematologic
- name: Intraosseous Venous Malformations
  description: >-
    Reported at this site in one extensively affected child in the eight-patient series.
    The observation establishes
    possible involvement, not a general population frequency.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - *id006
  category: Musculoskeletal
- name: Pulmonary Venous Malformations
  description: >-
    Reported at this site in one extensively affected child in the eight-patient series.
    The observation establishes
    possible involvement, not a general population frequency.
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - *id006
  category: Respiratory
- name: Intestinal Infarction
  category: Gastrointestinal
  description: A reported complication of gastrointestinal venous malformations; its frequency in BRBN is not quantified.
  phenotype_term:
    preferred_term: Intestinal infarction
    term:
      id: HP:0005244
      label: Gastrointestinal infarctions
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: These are commonly located in the small intestine and can cause hemorrhage, intussusception, volvulus, and intestinal infarction
    explanation: The BRBN section identifies complications caused by gastrointestinal venous malformations.
genetic:
- name: TEK
  gene_term:
    preferred_term: TEK
    term:
      id: hgnc:11724
      label: TEK
  relationship_type: CAUSATIVE
  variant_origin: SOMATIC
  association: Gain of Function
  variants:
  - name: T1105N-T1106P
    description: >-
      The recurrent BRBN-associated double allele p.Thr1105Asn-p.Thr1106Pro occurs
      in cis. Its enrichment differs
      from the p.Tyr897Cys-p.Arg915Cys allele recurrent in multifocal sporadic VM;
      genotype does not replace
      clinical assessment of the syndrome boundary.
    evidence:
    - reference: PMID:27519652
      reference_title: Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C
        is recurrent in sporadically
        occurring multifocal venous malformation
      explanation: >-
        Identifies the recurrent alleles in their respective clinical groups.
      quote_role: PRIMARY_RESULT
  notes: >-
    TEK encodes TIE2. Lesional somatic gain-of-function variants, often paired in
    cis, are the principal established
    cause. Variant identity, mosaic burden and lesion distribution contribute to phenotypic
    diversity; a single
    recurrent allele does not define every clinical case.
  evidence:
  - *id007
  - *id001
diagnosis:
- name: Clinical assessment of multifocal venous malformations
  description: >-
    Evaluate cutaneous, mucosal and gastrointestinal lesions with attention to sparse
    or late-appearing skin
    findings. Clinical phenotype and lesional molecular testing distinguish BRBNS
    from other multifocal vascular
    disorders.
  evidence:
  - *id008
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Gastrointestinal lesions (grape-like mucosal venous nodules), documented by
      endoscopy, colonoscopy, or
      magnetic resonance imaging, are pathognomonic of BRBN syndrome.
    explanation: >-
      Gastrointestinal lesion morphology is a central diagnostic clue; atypical or
      familial presentations require
      differential diagnosis.
    quote_role: REVIEW_SYNTHESIS
- name: Lesional TEK sequencing
  description: >-
    Prioritize affected vascular tissue and sequencing sensitive to low-level mosaicism;
    a negative blood test
    does not exclude a lesional variant. A TEK variant of uncertain significance alone
    does not establish the
    diagnosis.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably
      from the vascular
      lesion, requiring a surgical or skin biopsy ‒ should be prioritized for genetic
      testing.
    explanation: >-
      GeneReviews recommends affected tissue because of mosaicism.
    quote_role: REVIEW_SYNTHESIS
- name: Endoscopic assessment including the small bowel
  description: >-
    Upper/lower endoscopy and capsule endoscopy map gastrointestinal lesions. Capsule
    studies can detect small-bowel
    lesions missed on other tests; the selected six positive examinations in one series
    do not establish 100%
    diagnostic sensitivity. Consider patency assessment or imaging when obstruction
    is suspected. Endoscopic
    ultrasound helps determine depth before treating a large lesion.
  diagnosis_term:
    preferred_term: Endoscopic Procedure
    term:
      id: NCIT:C16546
      label: Endoscopic Procedure
  evidence:
  - *id009
  - reference: PMID:36277742
    reference_title: Endoscopic and Surgical Management of Blue Rubber Bleb Nevus Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      An initial endoscopic ultrasound was performed to evaluate the gastric lesions
      because of concern of
      transmural involvement given their size, but the lesions were found to arise
      from the submucosa.
    explanation: >-
      EUS established lesion depth before endoscopic resection.
    quote_role: PRIMARY_RESULT
- name: MRI assessment of lesion extent
  description: >-
    MRI evaluates deeper extension and multiorgan lesion burden; whole-body imaging
    can be considered for multifocal
    disease. Imaging complements rather than replaces gastrointestinal endoscopy.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Consider whole-body MRI. ... To evaluate risk of internal lesions
    explanation: >-
      The multifocal-VM assessment table recommends considering whole-body MRI.
    quote_role: REVIEW_SYNTHESIS
- name: Blood count and iron studies
  description: >-
    Measure hemoglobin and iron status and investigate occult gastrointestinal loss
    when anemia is unexplained.
  evidence:
  - *id003
- name: Coagulation assessment
  description: >-
    D-dimer and fibrinogen help identify localized intravascular coagulopathy and
    inform procedural planning.
    The reported 96.5% D-dimer specificity concerns venous components among vascular-anomaly
    referrals, not
    BRBNS in the general population; normal values do not rule out a venous malformation.
  diagnosis_term:
    preferred_term: Coagulation Study
    term:
      id: NCIT:C62662
      label: Coagulation Study
  markers: D-dimer; fibrinogen
  evidence:
  - *id005
  - reference: PMID:19917952
    reference_title: Elevated D-dimer level in the differential diagnosis of venous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Among the 85 patients without VM, D-dimer levels were elevated only in 3 patients;
      the specificity of
      the dosage was 96.5% (95% confidence interval, 92.5%-100%).
    explanation: >-
      Specifies the comparator group underlying the specificity estimate.
    quote_role: PRIMARY_RESULT
treatments:
- name: Systemic Sirolimus
  description: >-
    Specialist-directed off-label mTOR inhibition can reduce bleeding and lesion burden
    in diffuse or difficult-to-treat
    BRBNS. The prospective eleven-patient study reported improvement over twelve months;
    longer-term response
    varies and relapse may follow withdrawal. Oral ulcers and other adverse effects
    require monitoring. No
    cure, uniform response or site-independent efficacy is established.
  evidence:
  - reference: PMID:33416235
    reference_title: 'Efficacy and Safety of Sirolimus for Blue Rubber Bleb Nevus Syndrome: A Prospective Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The average lesion size was reduced by 7.4% (P < 0.001), 9.3% (P < 0.001), and
      13.0% (P < 0.05) at 3,
      6, and 12 months of sirolimus treatment, respectively.
    explanation: >-
      Eleven patients were followed in a single-arm prospective study; there was no
      randomized comparator.
    quote_role: PRIMARY_RESULT
  - reference: PMID:33416235
    reference_title: 'Efficacy and Safety of Sirolimus for Blue Rubber Bleb Nevus Syndrome: A Prospective Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Only 1 patient received blood transfusion once during the study.
    explanation: >-
      Reports observed transfusion use during the study, not guaranteed lifelong transfusion
      independence.
    quote_role: PRIMARY_RESULT
  - reference: PMID:33416235
    reference_title: 'Efficacy and Safety of Sirolimus for Blue Rubber Bleb Nevus Syndrome: A Prospective Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Grade 1-2 adverse effects including oral ulcers (81.8%), acne (27.3%), transient
      elevation of liver enzymes
      (18.2%), and hair loss (9.1%) were observed.
    explanation: >-
      Adverse effects in this small cohort were mild, but this does not establish
      long-term safety.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34976762
    reference_title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Patient  # 1 received sirolimus for more than 8 years with limited success,
      still experienced intermittent
      GI bleeding and severe anemia
    explanation: >-
      Documents incomplete response despite prolonged treatment.
    quote_role: PRIMARY_RESULT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: PI3K-AKT-mTOR Pathway Activation
    treatment_effect: INHIBITS
    description: >-
      mTOR inhibition targets the signaling pathway. Clinical benefit is supported
      separately from the related-variant
      molecular assays.
    evidence:
    - reference: PMID:32867785
      reference_title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Our results showed that RAPA down-regulated the phosphorylation of AKT, FOXO1,
        and mTOR, especially
        in the TIE2-L914F mutant group (Fig. 5a, b).
      explanation: >-
        A molecular response in L914F HUVECs supports pathway inhibition, indirectly
        for BRBN.
      quote_role: PRIMARY_RESULT
- name: Iron Replacement
  description: >-
    Replaces iron lost through chronic gastrointestinal bleeding; it does not stop
    the bleeding or remove venous
    malformations.
  evidence:
  - &id010
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Iron replacement or transfusions in case of anemia from chronic bleeding
    explanation: >-
      GeneReviews separates supportive correction of anemia from treatment of the
      lesions.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Iron supplement
  target_mechanisms:
  - target: Iron Deficiency Anemia
    treatment_effect: INHIBITS
    description: Replenishes iron and treats the resulting anemia; it does not inhibit gastrointestinal blood loss.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
      reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Iron replacement or transfusions in case of anemia from chronic bleeding
      explanation: >-
        GeneReviews separates supportive correction of anemia from treatment of the
        lesions.
      quote_role: REVIEW_SYNTHESIS
- name: Blood Transfusion
  description: >-
    Corrects severe or symptomatic anemia when clinically indicated. Transfusion requirements
    vary with disease
    severity and response to lesion-directed or systemic treatment.
  evidence:
  - *id010
  treatment_term:
    preferred_term: Blood Transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
- name: Endoscopic Treatment of Bowel Lesions
  description: >-
    Accessible mucosal or submucosal lesions can be treated by sclerotherapy, resection
    or other endoscopic
    methods. Depth and extent guide selection; transmural lesions may require surgery
    because of perforation
    risk. Combined sirolimus and lauromacrogol success in a single case cannot isolate
    each treatment effect.
  evidence:
  - &id011
    reference: PMID:36277742
    reference_title: Endoscopic and Surgical Management of Blue Rubber Bleb Nevus Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Through a combination of methylene blue-hetastarch injection for lifting and
      snare resection with a 1.5
      cm Cook AcuSnare (ENDO CUT Q-3), removal of the gastric and colon lesions was
      achieved successfully by
      EMR.
    explanation: >-
      Documents actual endoscopic treatment rather than inferring efficacy from bleeding
      alone.
    quote_role: PRIMARY_RESULT
  - reference: PMID:39867693
    reference_title: 'Case Report: Combination of sirolimus and endoscopic lauromacrogol sclerotherapy in the management of blue rubber bleb nevus syndrome with gastric tract bleeding.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      After 1 year of treatment, the patient showed no signs of anemia or gastrointestinal
      tract bleeding.
    explanation: >-
      One child received both sirolimus and endoscopic lauromacrogol; benefit cannot
      be attributed separately
      to either intervention.
    quote_role: PRIMARY_RESULT
  treatment_term:
    preferred_term: Endoscopic Procedure
    term:
      id: NCIT:C16546
      label: Endoscopic Procedure
  target_mechanisms:
  - target: Chronic Gastrointestinal Blood Loss
    treatment_effect: INHIBITS
    description: >-
      Removing or obliterating selected bleeding lesions can reduce blood loss; incomplete
      treatment can leave
      other active lesions.
    evidence:
    - *id011
- name: Surgical Treatment of Gastrointestinal Lesions
  description: >-
    Resection or ligation can control bleeding from focal or extensive lesions in
    selected patients. Planning
    aims to preserve bowel length and account for transmural disease. A ten-patient
    series used extensive combined
    procedures with durable control in most patients; morbidity, incomplete removal
    and recurrence remain considerations.
    Obstruction or intussusception can require urgent surgery.
  evidence:
  - &id012
    reference: PMID:15729077
    reference_title: 'Blue rubber bleb nevus syndrome: surgical eradication of gastrointestinal bleeding.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Only 1 patient who had a less extensive procedure developed recurrent GI bleeding.
      The mean follow-up
      period was 5.0 years (range 2.9-10.3 years).
    explanation: >-
      Selected surgical series of ten patients; mean 137 lesions removed per operation,
      not evidence that all
      BRBNS is surgically curable.
    quote_role: PRIMARY_RESULT
  - reference: PMID:32664167
    reference_title: 'Blue rubber bleb nevus syndrome with the complication of intussusception: A case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      An emergency laparotomy was performed, and postoperative management included
      blood transfusions and oral
      iron supplementation for 2 weeks.
    explanation: >-
      Direct treatment of an acute intussusception complication.
    quote_role: PRIMARY_RESULT
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Chronic Gastrointestinal Blood Loss
    treatment_effect: INHIBITS
    description: >-
      Removing or obliterating selected bleeding lesions can reduce blood loss; incomplete
      treatment can leave
      other active lesions.
    evidence:
    - *id012
- name: Management of Localized Intravascular Coagulopathy
  description: >-
    A vascular-anomalies and hematology team assesses coagulation before invasive
    procedures. Low-molecular-weight
    heparin can be used for painful intralesional thrombosis or perioperative coagulopathy,
    with the plan individualized
    to lesion burden, fibrinogen and active bleeding.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      If lesions are painful and D-dimers are elevated, LMWH can also be used to treat
      the associated pain.
    explanation: >-
      Expert guidance for TEK-related venous malformations; treatment must account
      for the individual bleeding
      context.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Low-molecular-weight heparin (LMWH) should be administered prior to any invasive procedure (sclerotherapy and/or surgery) to avoid disseminated intravascular coagulopathy.
    explanation: GeneReviews recommends procedural prophylaxis for TEK-related venous malformations; timing depends on fibrinogen and D-dimer results and the specialist assessment of bleeding risk.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Low molecular weight heparin
      term:
        id: NCIT:C2578
        label: Low Molecular Weight Heparin
  target_mechanisms:
  - target: Localised Intravascular Coagulopathy
    treatment_effect: INHIBITS
    description: Anticoagulation reduces intralesional thrombotic activity and aims to prevent worsening consumption around procedures.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
      reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: Low-molecular-weight heparin (LMWH) should be administered prior to any invasive procedure (sclerotherapy and/or surgery) to avoid disseminated intravascular coagulopathy.
      explanation: GeneReviews recommends procedural prophylaxis for TEK-related venous malformations; timing depends on fibrinogen and D-dimer results and the specialist assessment of bleeding risk.
- name: Clinical and Laboratory Surveillance
  description: >-
    Review lesions and symptoms with a vascular-anomalies team. Follow blood count
    and iron indices for gastrointestinal
    bleeding, and D-dimer/fibrinogen for coagulation risk, especially before procedures.
    Sirolimus requires
    clinical and laboratory monitoring for toxicity and dose adjustment. Consider
    neurological assessment and
    appropriate imaging when symptoms or lesion distribution suggest CNS involvement.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Individuals on sirolimus should be closely followed at the beginning and throughout
      the course of their
      treatment, in order to modify the dosage as well as manage adverse events.
    explanation: >-
      Expert monitoring recommendation.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Annually or more frequently in case of symptoms (fatigue, bloody stools)
    explanation: >-
      The gastrointestinal surveillance table recommends at least annual review, intensified
      by symptoms.
    quote_role: REVIEW_SYNTHESIS
- name: Genetic Counseling
  description: >-
    Explain the usual postzygotic mosaic origin, limits of negative blood testing
    and low expected family recurrence.
    Do not apply the 50% transmission estimate for germline TEK-related VMCM to typical
    somatic BRBNS; an apparent
    familial presentation needs reassessment.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Counseling for recurrence risk in ... -related unifocal VM, MSVM, and BRBN syndrome
      should emphasize that, while no pregnancy is at zero risk, all evidence suggests
      that the risk of recurrence for these disorders is not increased compared to
      the general population.
    explanation: >-
      Disease-specific counseling distinguishes somatic BRBN from inherited VMCM.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Avoidance of High-Estrogen Contraceptive Pills
  description: Avoid high-estrogen contraceptive pills because venous malformations can enlarge or become symptomatic with estrogen exposure; contraceptive selection requires individual clinical assessment.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Contraceptive pills with high estrogen concentration should be avoided, as VM are estrogen responsive.
    explanation: GeneReviews identifies high-estrogen contraceptive pills as a circumstance to avoid in TEK-related venous malformations.
- name: Sclerotherapy of Symptomatic Cutaneous and Soft-Tissue Lesions
  description: Sclerotherapy can reduce symptomatic venous-malformation volume, either alone or before surgery. Selection depends on anatomy and procedural coagulation assessment. This recommendation comes from TEK-related venous-malformation guidance, rather than a BRBN-specific comparative trial.
  treatment_term:
    preferred_term: Sclerotherapy
    term:
      id: NCIT:C62732
      label: Sclerotherapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: Sclerotherapy is the first-line treatment for VM. It is performed to decrease the volume of the VM before surgery or as monotherapy in individuals in whom surgery is not technically feasible.
    explanation: TEK-related venous-malformation guidance supports lesion-directed sclerotherapy, including symptomatic skin and soft-tissue disease.
- name: Excision of Selected Cutaneous and Soft-Tissue Lesions
  description: Small lesions can be excised when complete removal is feasible without functional or anatomic harm. Extensive disease may be inaccessible or incompletely treated.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
    reference_title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: If the lesion is small and complete resection is possible without anatomic or functional consequences, surgical excision should be performed as the treatment of choice.
    explanation: Small accessible lesions may be excised; incomplete cure and anatomic limitations remain possible.
animal_models:
- name: HUVEC-TIE2-L914F xenograft
  species: Mouse (Mus musculus)
  genotype: TIE2-mutant human endothelial cell xenograft
  category: Xenograft
  description: >-
    Subcutaneous HUVEC-TIE2-L914F xenografts in immunodeficient mice form ectatic
    vascular channels. Systemic
    ponatinib plus rapamycin induced regression of established lesions; withdrawal
    caused rebound that topical
    rapamycin suppressed. L914F models common TEK-mutant VM rather than the recurrent
    BRBN double allele or
    its gastrointestinal distribution.
  genes:
  - preferred_term: TEK
    term:
      id: hgnc:11724
      label: TEK
  associated_phenotypes:
  - Venous malformation
  modeled_mechanisms:
  - target: PI3K-AKT-mTOR Pathway Activation
    relationship: PERTURBS
    description: >-
      Used to test pharmacological suppression of the pathway node, reading out lesion
      regression.
    fidelity: MODERATE
    limitations: >-
      Single L914F overexpression in implanted cells, immunodeficient host, short
      follow-up and subcutaneous
      lesions. It does not establish treatment efficacy or safety in BRBNS patients.
    evidence:
    - reference: PMID:30626204
      reference_title: Ponatinib Combined With Rapamycin Causes Regression of Murine Venous Malformation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Combination treatment with the ABL kinase inhibitor ponatinib and rapamycin caused VM regression in a xenograft model based on injection of HUVEC-TIE2-L914F.
      explanation: Lesion regression under pathway inhibition is the readout that grounds this model link.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:30626204
    reference_title: Ponatinib Combined With Rapamycin Causes Regression of Murine Venous Malformation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Combination treatment with the ABL kinase inhibitor ponatinib and rapamycin caused VM regression in a xenograft model based on injection of HUVEC-TIE2-L914F.
    explanation: A result from the model itself - lesion regression in the HUVEC-TIE2-L914F xenograft under combined pathway inhibition.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Mosaic TIE2-L914F transgenic mouse
  species: Mouse (Mus musculus)
  genotype: CMV-Cre; Rosa26-TIE2-L914F transgene
  category: Transgenic
  description: >-
    Variable CMV-Cre recombination activates the L914F transgene during development.
    Mutant offspring show
    partial embryonic lethality; survivors develop enlarged venous/capillary lesions
    and increased D-dimer.
    This models mosaic TEK-driven VM, with no demonstrated BRBN double-cis genotype
    or gastrointestinal bleeding
    phenotype.
  evidence:
  - &id013
    reference: PMID:42059767
    reference_title: Constitutive, Mosaic Expression of TIE2 p.L914F During Mouse Development Causes Venous Malformation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      surviving CMV-Cre;TIE2L914F mice developed massively enlarged venous/capillary
      vessels in various tissues,
      reminiscent of the VM phenotype.
    explanation: >-
      The mosaic transgenic model produces VM-like lesions, not a demonstrated BRBN-specific
      phenotype.
    quote_role: PRIMARY_RESULT
  modeled_mechanisms:
  - target: Ectatic Mural-Cell-Poor Venous Channels
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      Transgenic L914F model with a broadly active mosaic Cre driver; not an endogenous
      BRBN double-variant
      knock-in.
    evidence:
    - *id013
- name: Endothelial TEK overexpression in zebrafish embryos
  species: Zebrafish (Danio rerio)
  category: Transgenic
  description: >-
    Patient-derived TEK variant overexpression induces venous malformations, and tested
    cis double variants
    have additive effects. Sirolimus suppresses lesion development. This is a developmental
    functional assay
    rather than a model of chronic gastrointestinal bleeding.
  evidence:
  - &id014
    reference: PMID:34254124
    reference_title: Functional assessment of two variants of unknown significance in TEK by endothelium-specific expression in zebrafish embryos.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Endothelium-specific overexpression of TEK mutations leads to robust induction
      of VMs, whereas MAP2K1
      mutations cause AVMs in our zebrafish model.
    explanation: >-
      Embryonic overexpression assay of TEK variants; the abstract does not establish
      that every tested variant
      is BRBN-associated.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34254124
    reference_title: Functional assessment of two variants of unknown significance in TEK by endothelium-specific expression in zebrafish embryos.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      The clinically established mTOR-inhibitor sirolimus (rapamycin) efficiently
      abrogates the development
      of VMs in this zebrafish model.
    explanation: >-
      Prevention of VM development in embryos, not human treatment evidence.
    quote_role: PRIMARY_RESULT
  modeled_mechanisms:
  - target: Ectatic Mural-Cell-Poor Venous Channels
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      Embryonic overexpression and variant testing; the abstract does not report a
      BRBN organ distribution
      or chronic coagulopathy.
    evidence:
    - *id014
clinical_trials:
- name: NCT03767660
  phase: PHASE_IV
  status: UNKNOWN
  description: >-
    Prospective single-arm sirolimus study for BRBNS and other venous malformations,
    with 20 participants planned.
    Registry status was UNKNOWN on 2026-10-01; the last known status was recruiting
    and the last posted update
    was 2018-12-19. Estimated completion dates do not establish completion or current
    recruitment. The phase
    IV label is the registry designation, not evidence of a BRBNS marketing authorization.
  evidence:
  - reference: clinicaltrials:NCT03767660
    reference_title: Efficacy of Rapamycin (Sirolimus) in the Treatment of Blue Rubber Bleb Nevus Syndrome, Hereditary or Sporadic Venous Malformation
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      A prospective, nonrandomized, open-label, single-arm clinical trial to study
      efficacy of rapamycin (sirolimus)
      in the treatment of Blue Rubber Bleb Nevus Syndrome, hereditary or sporadic
      venous malformation
    explanation: >-
      Direct disease-relevant registry description; not an efficacy result.
- name: NCT06642051
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Sonablate HIFU safety/feasibility study of peripheral venous lesions; BRBNS is
    explicitly listed among
    examples. Adults and superficial peripheral lesions are eligible, while visceral/internal-organ
    lesions
    are excluded, so this is not a trial for gastrointestinal bleeding. Thirty participants
    are planned across
    conditions. Status verified 2026-10-01 against the registry update of 2026-02-19.
  evidence:
  - reference: clinicaltrials:NCT06642051
    reference_title: Safety of the Sonablate System for the High-Intensity Focused Ultrasound (HIFU) Ablation of Incompetent Veins of the Periphery
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Examples of CVI are varicose veins, vascular congestion, venous ulcer, venous
      clusters, venous anomalies,
      mixed malformation, Klippel-Trenaunay Syndrome, CLOVES, Syndrome, Blue Rubber
      bleb Nevus Syndrome.
    explanation: >-
      BRBNS is named in the registry; enrollment and benefit for BRBNS are not demonstrated.
- name: NCT02399527
  status: RECRUITING
  description: >-
    Observational outcome registry that lists BRBNS among conditions but requires
    a significant lymphatic component
    in eligibility. It does not imply every patient with a pure venous BRBNS phenotype
    qualifies. Planned enrollment
    is 1,000 across conditions. Status verified 2026-10-01 against the 2026-09-10
    registry update; no treatment
    effect is inferred.
  evidence:
  - reference: clinicaltrials:NCT02399527
    reference_title: Lymphatic Anomalies Registry for the Assessment of Outcome Data
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      the investigators are conducting an observational study of patients with lymphatic
      anomalies, including
      an annual follow-up questionnaire to gather prospective data on mortality, morbidity,
      treatments, and
      functionality as well as quality of life.
    explanation: >-
      An observational natural-history registry, with broader eligibility restrictions.
disease_term:
  preferred_term: blue rubber bleb nevus
  term:
    id: MONDO:0007203
    label: blue rubber bleb nevus
differential_diagnoses:
- name: Other TEK-related venous malformations
  description: >-
    Germline cutaneomucosal VMCM, somatic multifocal VM and BRBN share TEK involvement
    but differ in inheritance,
    lesion distribution and typical alleles. A somatic TEK result alone does not resolve
    every boundary presentation.
  evidence:
  - reference: PMID:41327934
    reference_title: A Case of Multifocal Venous Malformation With Two Somatic Pathogenic Variants in the TEK Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Clinically, this case resembled multifocal sporadic VM; however, the genetic
      profile was consistent with
      blue rubber bleb nevus syndrome, suggesting this case may represent an intermediate
      phenotype between
      the two entities.
    explanation: >-
      A tissue-genotyped case illustrates a boundary phenotype; no anemia was reported.
    quote_role: PRIMARY_RESULT
- name: Maffucci syndrome
  description: >-
    Multiple enchondromas support Maffucci syndrome in a person with cutaneous and
    gastrointestinal vascular
    lesions. Gastrointestinal involvement alone is not an absolute discriminator.
  evidence:
  - reference: PMID:15670176
    reference_title: Maffucci's syndrome with extensive gastrointestinal involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      However, after recognition of the characteristic enchondromata, this diagnosis
      has been revised to Maffucci's
      syndrome.
    explanation: >-
      A child previously labeled BRBNS was reclassified after skeletal findings.
    quote_role: PRIMARY_RESULT
- name: Glomuvenous malformation
  description: >-
    Glomuvenous lesions have distinct morphology and mural glomus cells. D-dimer is
    often normal, but this
    test is an adjunct rather than a sole diagnostic rule.
  evidence:
  - reference: PMID:19917952
    reference_title: Elevated D-dimer level in the differential diagnosis of venous malformations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Venous malformations: 69/172 patients (40.1%); 5/5 with multifocal sporadic
      VM, 2/2 with BRBN, 62/149
      with a solitary VM, and 0/16 with GVM.
    explanation: >-
      Reports the different D-dimer findings across subgroups in this referral cohort.
    quote_role: PRIMARY_RESULT
- name: PIK3CA-related venous malformations
  description: >-
    PIK3CA can drive other venous malformations through overlapping AKT signaling.
    It is not established as
    a BRBNS diagnostic biomarker by the cited study, and gene-specific clinical and
    histologic differences
    were observed.
  evidence:
  - reference: PMID:26637981
    reference_title: Somatic Activating PIK3CA Mutations Cause Venous Malformation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Nevertheless, significant genotype-phenotype correlations in lesion localization
      and histology are observed
      between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific
      effects.
    explanation: >-
      Contradicts an assertion that these lesions are clinically and histologically
      indistinguishable.
    quote_role: PRIMARY_RESULT
experimental_models:
- name: BRBN-associated double-mutant TIE2 in HUVECs
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human umbilical vein endothelial cells expressing TEK variants
  description: >-
    T1105N-T1106P expression tests ligand-independent activation and endothelial survival,
    invasion and colony
    formation, alongside the multifocal-VM-associated Y897C-R915C allele. It does
    not reproduce tissue mosaicism
    or gastrointestinal anatomy.
  publication: PMID:27519652
  evidence:
  - *id002
  modeled_mechanisms:
  - target: Ligand-Independent TIE2 Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    evidence:
    - *id002
  experimental_model_type: PRIMARY_CELL_CULTURE
- name: TIE2-L914F endothelial and smooth-muscle co-culture
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Primary umbilical endothelial and smooth-muscle cells; endothelial lentiviral TEK expression
  description: >-
    Related-variant model of AKT/FOXO1 signaling, PDGFB secretion and paracrine mural-cell
    migration. Rapamycin
    rescues several readouts, but the double-mutant BRBN context was not tested.
  publication: PMID:32867785
  evidence:
  - *id015
  - *id016
  modeled_mechanisms:
  - target: Reduced Endothelial PDGFB Expression
    relationship: RECAPITULATES
    fidelity: LOW
    limitations: >-
      L914F rather than recurrent BRBN cis variants; no PDGFB-specific necessity experiment
      in BRBN.
    evidence:
    - *id017
  experimental_model_type: CO_CULTURE
discussions:
- discussion_id: brbns_model_transfer
  prompt: Which downstream effects are shared by BRBN double variants and other TEK-mutant malformations?
  rationale: >-
    Direct BRBN-allele HUVEC evidence establishes activation and survival phenotypes.
    Much of the FOXO1, PDGFB,
    mural-cell and drug-combination work instead uses L914F, while older AKT experiments
    use R849W. Allele-specific
    differences and cell context limit transfer. Molecular links are therefore scoped
    as related-model evidence
    rather than complete demonstrations of human BRBN pathogenesis.
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Reduced Endothelial PDGFB Expression
  evidence:
  - *id002
  - *id018
- discussion_id: brbns_emerging_inhibition
  prompt: Can PI3K inhibition or combination therapy improve durable control of BRBNS?
  rationale: >-
    Alpelisib corrects cellular phenotypes in TEK- and PIK3CA-mutant HUVECs, and ponatinib
    plus rapamycin regresses
    established L914F xenografts. The 2026 rapamycin-alpelisib mouse experiment used
    cells pretreated for 48
    hours before implantation, with a DMSO comparator; it demonstrates reduced lesion
    formation rather than
    systemic treatment of established lesions. Its in vivo comparison did not establish
    superiority over another
    drug combination. p53 changes are associated readouts, not a demonstrated necessary
    mediator. These results
    do not establish a BRBNS regimen or long-term clinical safety.
  kind: KNOWLEDGE_GAP
  attaches_to:
  - treatments#Systemic Sirolimus
  evidence:
  - reference: PMID:26637981
    reference_title: Somatic Activating PIK3CA Mutations Cause Venous Malformation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      The p110α-specific inhibitor BYL719 restores all abnormal phenotypes tested,
      in PIK3CA- as well as TEK-mutant
      HUVECs, demonstrating that they operate via the same pathogenic pathways.
    explanation: >-
      Cellular pharmacology of related venous-malformation models.
    quote_role: PRIMARY_RESULT
  - reference: PMID:42411503
    reference_title: AKT-mTOR/P53 PathwayDriven RapamycinAlpelisib Efficacy in Animal Models of TIE2Mutant Venous Malformations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      The results demonstrated a marked reduction in vessel sprouting in the 3D model
      and inhibited both lesion
      size and angiogenesis in the xenograft mouse model.
    explanation: >-
      The full methods specify cell pretreatment before implantation; no systemic
      treatment of established
      mouse lesions was tested.
    quote_role: PRIMARY_RESULT
- discussion_id: brbns_familial_cns_boundary
  prompt: How should familial CNS-predominant cases labeled BRBNS be classified?
  rationale: >-
    A reported father-son pair had skin venous malformations, seizures and cerebral
    vascular lesions, but lacked
    genetic assessment; the son had no significant colonoscopic abnormality and the
    father had non-cavernomatous
    arteriovenous lesions at autopsy. Such reports warrant molecular differential
    diagnosis rather than establishing
    dominant transmission, a uniform cerebral phenotype or a KRIT1 modifier for molecularly
    defined BRBNS.
  kind: KNOWLEDGE_GAP
  attaches_to:
  - inheritance#Somatic Mosaic
  evidence:
  - reference: PMID:32318009
    reference_title: 'Blue Rubber Bleb Nevus Syndrome With Multiple Cavernoma-Like Lesions on MRI: A Familial Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Unfortunately, no genetic assessment was performed due to the lack of this specific
      testing in our hospital.
    explanation: >-
      The familial report does not establish an inherited TEK variant or a molecular
      BRBN diagnosis.
    quote_role: PRIMARY_RESULT
references:
- reference: PMID:15526080
  title: Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations.
- reference: PMID:15670176
  title: Maffucci's syndrome with extensive gastrointestinal involvement.
- reference: PMID:15729077
  title: 'Blue rubber bleb nevus syndrome: surgical eradication of gastrointestinal bleeding.'
- reference: PMID:19917952
  title: Elevated D-dimer level in the differential diagnosis of venous malformations.
- reference: PMID:26637981
  title: Somatic Activating PIK3CA Mutations Cause Venous Malformation.
- reference: PMID:27519652
  title: Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
- reference: PMID:30626204
  title: Ponatinib Combined With Rapamycin Causes Regression of Murine Venous Malformation.
- reference: PMID:32318009
  title: 'Blue Rubber Bleb Nevus Syndrome With Multiple Cavernoma-Like Lesions on MRI: A Familial Case Report and Literature Review.'
- reference: PMID:32664167
  title: 'Blue rubber bleb nevus syndrome with the complication of intussusception: A case report and literature review.'
- reference: PMID:32867785
  title: AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations.
- reference: PMID:33416235
  title: 'Efficacy and Safety of Sirolimus for Blue Rubber Bleb Nevus Syndrome: A Prospective Study.'
- reference: PMID:34254124
  title: Functional assessment of two variants of unknown significance in TEK by endothelium-specific expression in zebrafish embryos.
- reference: PMID:34976762
  title: 'Blue rubber bleb nevus syndrome: a single-center case series in 12 years.'
- reference: PMID:36277742
  title: Endoscopic and Surgical Management of Blue Rubber Bleb Nevus Syndrome.
- reference: PMID:39426903
  title: 'Blue rubber bleb nevus syndrome: A European multicenter cohort study.'
- reference: PMID:39867693
  title: 'Case Report: Combination of sirolimus and endoscopic lauromacrogol sclerotherapy in the management of blue rubber bleb nevus syndrome with gastric tract bleeding.'
- reference: PMID:41327934
  title: A Case of Multifocal Venous Malformation With Two Somatic Pathogenic Variants in the TEK Gene.
- reference: PMID:42059767
  title: Constitutive, Mosaic Expression of TIE2 p.L914F During Mouse Development Causes Venous Malformation.
- reference: PMID:42411503
  title: AKT-mTOR/P53 PathwayDriven RapamycinAlpelisib Efficacy in Animal Models of TIE2Mutant Venous Malformations.
- reference: clinicaltrials:NCT02399527
  title: Lymphatic Anomalies Registry for the Assessment of Outcome Data
- reference: clinicaltrials:NCT03767660
  title: Efficacy of Rapamycin (Sirolimus) in the Treatment of Blue Rubber Bleb Nevus Syndrome, Hereditary or Sporadic Venous Malformation
- reference: clinicaltrials:NCT06642051
  title: Safety of the Sonablate System for the High-Intensity Focused Ultrasound (HIFU) Ablation of Incompetent Veins of the Periphery
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1967/?report=reader
  title: TEK-Related Venous Malformations - GeneReviews&reg; - NCBI Bookshelf
  tags:
  - GeneReviews

📚

References & Deep Research

References

PMID:15526080

Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations.