Blue rubber bleb nevus

Summary

Blue rubber bleb nevus (MONDO:0007203) is a disease with 2 cohort genes and 3 clinical trials. Top therapeutic interventions include sirolimus.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 4
• Phenotypes (HPO): 13
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated
Point prevalence	1-9 / 100 000	7	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000988	Skin rash	Very frequent (80-99%)
HP:0001048	Cavernous hemangioma	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0003010	Prolonged bleeding time	Very frequent (80-99%)
HP:0100026	Arteriovenous malformation	Very frequent (80-99%)
HP:0100761	Visceral angiomatosis	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0002580	Volvulus	Frequent (30-79%)
HP:0002584	Intestinal bleeding	Frequent (30-79%)
HP:0002597	Abnormality of the vasculature	Frequent (30-79%)
HP:0001935	Microcytic anemia	Occasional (5-29%)
HP:0005244	Gastrointestinal infarctions	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	blue rubber bleb nevus
Mondo ID	MONDO:0007203
MeSH	C536240
OMIM	112200
Orphanet	1059
NCIT	C4486
SNOMED CT	254784002
UMLS	C0346072
MedGen	83401
GARD	0005940
NORD	865
Is cancer (heuristic)	no

Also known as: bean syndrome · blue rubber bleb nevus · Blue Rubber Bleb Nevus syndrome · blue rubber bleb nevus syndrome · BRBN · BRBNS

Data availability: 4 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › blue rubber bleb nevus

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
549853	NM_053274.3(GLMN):c.1630G>T (p.Glu544Ter)	GLMN	Pathogenic	criteria provided, single submitter
30053	NM_000459.5(TEK):c.2690A>G (p.Tyr897Cys)	TEK	Pathogenic	criteria provided, multiple submitters, no conflicts
9294	NM_000459.5(TEK):c.2690A>C (p.Tyr897Ser)	TEK	Likely pathogenic	criteria provided, single submitter
298140	NM_053274.3(GLMN):c.761C>G (p.Pro254Arg)	GLMN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TEK	Orphanet:1059	Blue rubber bleb nevus
TEK	Orphanet:2451	Mucocutaneous venous malformations
TEK	Orphanet:714806	Multifocal sporadic venous malformation
TEK	Orphanet:98976	Congenital glaucoma
GLMN	Orphanet:83454	Glomuvenous malformation

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TEK	HGNC:11724	ENSG00000120156	Q02763	Angiopoietin-1 receptor	clinvar
GLMN	HGNC:14373	ENSG00000174842	Q92990	Glomulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TEK	Angiopoietin-1 receptor	Tyrosine-protein kinase that acts as a cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskelet…
GLMN	Glomulin	Regulatory component of cullin-RING-based SCF (SKP1-Cullin-F-box protein) E3 ubiquitin-protein ligase complexes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TEK	Kinase	yes	2.7.10.1	Prot_kinase_dom, EGF, Ser-Thr/Tyr_kinase_cat_dom
GLMN	Other/Unknown	no		YAP-bd/ALF4/Glomulin, Glomulin/ALF4

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
right lung	1
visceral pleura	1
cerebellar hemisphere	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TEK	223	broad	marker	right lung, diaphragm, visceral pleura
GLMN	257	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TEK	2,762
GLMN	1,566

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TEK	Q02763	17
GLMN	Q92990	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tie2 Signaling	1	300.5×	0.027	TEK
MAPK1/MAPK3 signaling	1	65.6×	0.042	TEK
MAPK family signaling cascades	1	51.4×	0.042	TEK
Cell surface interactions at the vascular wall	1	47.6×	0.042	TEK
RAF/MAP kinase cascade	1	30.5×	0.052	TEK
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.063	GLMN
Hemostasis	1	18.0×	0.063	TEK
Signal Transduction	1	5.1×	0.187	TEK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of endothelial cell apoptotic process	1	4213.0×	0.005	TEK
glomerulus vasculature development	1	2106.5×	0.005	TEK
regulation of establishment or maintenance of cell polarity	1	1685.2×	0.005	TEK
Tie signaling pathway	1	1685.2×	0.005	TEK
cell surface receptor signaling pathway	2	64.1×	0.005	TEK, GLMN
regulation of proteasomal ubiquitin-dependent protein catabolic process	1	561.7×	0.009	GLMN
regulation of vascular permeability	1	561.7×	0.009	TEK
heart trabecula formation	1	561.7×	0.009	TEK
definitive hemopoiesis	1	468.1×	0.009	TEK
positive regulation of phosphorylation	1	421.3×	0.009	GLMN
muscle cell differentiation	1	421.3×	0.009	GLMN
positive regulation of Rac protein signal transduction	1	324.1×	0.009	TEK
positive regulation of focal adhesion assembly	1	324.1×	0.009	TEK
positive regulation of intracellular signal transduction	1	324.1×	0.009	TEK
positive regulation of Rho protein signal transduction	1	290.6×	0.009	TEK
endothelial cell proliferation	1	271.8×	0.009	TEK
negative regulation of endothelial cell apoptotic process	1	247.8×	0.009	TEK
sprouting angiogenesis	1	240.7×	0.009	TEK
positive regulation of interleukin-2 production	1	234.1×	0.009	GLMN
epigenetic regulation of gene expression	1	191.5×	0.010	GLMN
substrate adhesion-dependent cell spreading	1	172.0×	0.011	TEK
negative regulation of T cell proliferation	1	165.2×	0.011	GLMN
positive regulation of cytokine production	1	135.9×	0.013	GLMN
vasculogenesis	1	127.7×	0.013	GLMN
positive regulation of endothelial cell migration	1	125.8×	0.013	TEK
positive regulation of endothelial cell proliferation	1	115.4×	0.013	TEK
cellular response to mechanical stimulus	1	108.0×	0.014	TEK
neural tube closure	1	93.6×	0.015	GLMN
cell surface receptor protein tyrosine kinase signaling pathway	1	86.9×	0.016	TEK
negative regulation of angiogenesis	1	84.3×	0.016	TEK

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TEK	CETIRIZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TEK	46	4
GLMN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	TEK
FEDRATINIB	4	TEK
TIVOZANIB	4	TEK
AXITINIB	4	TEK
SORAFENIB	4	TEK
NICLOSAMIDE	4	TEK
AMPICILLIN	4	TEK
NERATINIB	4	TEK
INFIGRATINIB PHOSPHATE	4	TEK
INFIGRATINIB	4	TEK
REGORAFENIB	4	TEK
CABOZANTINIB	4	TEK
VANDETANIB	4	TEK
NILOTINIB	4	TEK
BOSUTINIB	4	TEK
PAZOPANIB	4	TEK
NINTEDANIB	4	TEK
QUIZARTINIB	4	TEK
CRIZOTINIB	4	TEK
MIDOSTAURIN	4	TEK
LOPERAMIDE	4	TEK
LINIFANIB	3	TEK
BRIVANIB	3	TEK
CEDIRANIB	3	TEK
LESTAURTINIB	3	TEK
DORAMAPIMOD	2	TEK
FORETINIB	2	TEK
REBASTINIB	2	TEK
CEP-11981	2	TEK
DEFOSBARASERTIB	2	TEK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TEK	707	Binding:701, Functional:4, ADMET:2
GLMN	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TEK	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TEK	707

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CETIRIZINE	4	TEK
FEDRATINIB	4	TEK
TIVOZANIB	4	TEK
AXITINIB	4	TEK
SORAFENIB	4	TEK
NICLOSAMIDE	4	TEK
AMPICILLIN	4	TEK
NERATINIB	4	TEK
INFIGRATINIB PHOSPHATE	4	TEK
INFIGRATINIB	4	TEK
REGORAFENIB	4	TEK
CABOZANTINIB	4	TEK
VANDETANIB	4	TEK
NILOTINIB	4	TEK
BOSUTINIB	4	TEK
PAZOPANIB	4	TEK
NINTEDANIB	4	TEK
QUIZARTINIB	4	TEK
CRIZOTINIB	4	TEK
MIDOSTAURIN	4	TEK
LOPERAMIDE	4	TEK
LINIFANIB	3	TEK
BRIVANIB	3	TEK
CEDIRANIB	3	TEK
LESTAURTINIB	3	TEK
DORAMAPIMOD	2	TEK
FORETINIB	2	TEK
REBASTINIB	2	TEK
CEP-11981	2	TEK
DEFOSBARASERTIB	2	TEK

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TEK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GLMN

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GLMN	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03767660	PHASE4	UNKNOWN	Efficacy of Rapamycin (Sirolimus) in the Treatment of BRBNS, Hereditary or Sporadic Venous Malformation
NCT02399527	Not specified	RECRUITING	Lymphatic Anomalies Registry for the Assessment of Outcome Data
NCT06642051	Not specified	ACTIVE_NOT_RECRUITING	Safety of the Sonablate HIFU System for the Ablation of Incompetent Veins of the Periphery

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SIROLIMUS	4	1