Blue Rubber Bleb Nevus Syndrome is a rare systemic vascular disease characterized by multiple venous malformations (VMs) in the skin and internal organs, most often the gastrointestinal tract. It is also called Bean syndrome.
It was first reported by Gascoyen in 1860, and Bean gave it its current name in 1958.
Epidemiologically, it is extremely rare, with only about 200 to 350 cases reported in the literature4)10). It has been reported in all races, with no clear sex difference4).
Skin symptoms become apparent from birth to early infancy, and internal organ lesions often become clear in early adulthood. The proportion diagnosed in adulthood has been reported to be less than 4%4). Most cases are sporadic, but autosomal dominant inheritance (9p linkage) has been reported in some.
An extremely rare disease, with only about 200 to 350 cases reported in the world literature. Fewer than 4% are reported to be diagnosed in adulthood, and most begin in infancy or childhood.
Skin lesions
Appearance: Bluish-red, thin-walled cystic lesions. They have a rubbery texture.
Compression response: They collapse (empty) when pressed and slowly refill after the pressure is released. This finding is diagnostically characteristic.
Size/number: 1–30 mm. Ranges from 1 lesion to hundreds. At organ involvement frequency (120 cases), skin involvement was 93%.
Gastrointestinal lesions
Common sites: The small intestine is most common. Multiple lesions also occur in the stomach, duodenum, and colon.
Endoscopic findings: Bluish-purple nodular lesions. Lesions measuring 8, 10, and 14 mm in the stomach, 15 mm in the duodenum, and 6–8 mm in the colon have been reported3).
Special cases: An isolated gastrointestinal form without skin lesions has been reported in fewer than 7% of cases4)8).
Ophthalmic findings
Frequency of involvement: Eye lesions are rare, but venous malformations, including those of the conjunctiva, have been reported.
Lesion sites: Hemangiomas of the periorbital region, eyelids, conjunctiva, iris, and retina. Reports of conjunctival venous malformations exist7).
Clinical symptoms: Proptosis, enophthalmos, ptosis, miosis, increased intraocular pressure, subconjunctival hemorrhage, and orbital hemorrhage. Orbital lesions show imaging findings similar to cavernous hemangioma.
Kasabach-Merritt syndrome: A severe complication in which platelets are trapped within the hemangioma and disseminated intravascular coagulation (DIC) occurs. Cases have been reported in which thrombocytopenia, fibrin degradation products (FDP) > 150 μg/mL, and fibrinogen 32 mg/dL were reached, with severe anemia with hemoglobin 2 g/dL5).
It is possible. A small number of cases of isolated gastrointestinal disease without skin lesions have been reported. In unexplained gastrointestinal bleeding or refractory iron-deficiency anemia, it is important to consider BRBNS in the differential diagnosis even when there are no skin symptoms.
Rarely, venous malformations can occur in the orbit, eyelid, conjunctiva, iris, or retina and may cause proptosis, ptosis, decreased vision, or elevated intraocular pressure. Orbital lesions may also need to be distinguished from cavernous hemangioma on imaging.
The main cause of BRBNS is a somatic activating mutation in the TEK gene (which encodes the TIE2 receptor tyrosine kinase)2).
The diagnosis is based mainly on combining characteristic skin lesions (blue-red, rubbery nodules that collapse with pressure) with gastrointestinal bleeding or involvement of other organs.
Characteristic findings are blood-filled spaces lined by a single layer of endothelial cells, fibrous septa, and dystrophic calcification8). Dilated thin-walled vascular spaces centered in the submucosa are seen.
Severe iron-deficiency anemia is often present. A case with hemoglobin 1.7 g/dL, ferritin 2.0 ng/mL, and iron 16 mg/dL has been reported3).
It is important to differentiate this from similar diseases.
| Disease name | Key differential points |
|---|---|
| Osler-Weber-Rendu disease | Mainly telangiectasias and arteriovenous malformations |
| Klippel-Trenaunay syndrome | Triad of varicose veins, soft tissue overgrowth, and bone overgrowth |
| Maffucci syndrome | Hemangiomas with enchondromas |
| Sturge-Weber syndrome | Facial hemangioma, leptomeningeal hemangioma, and glaucoma |
| Kaposi sarcoma | HHV-8-associated angiosarcoma |
A curative treatment for BRBNS has not been established, and multidisciplinary treatment is provided according to the severity of symptoms and the distribution of lesions.
Iron supplementation and blood transfusion are the basis for managing anemia. Some cases can be managed with observation alone3)10).
The following drug treatments have been reported.
| Drug | Features and evidence |
|---|---|
| Sirolimus (mTOR inhibitor) | Reports describe lesion shrinkage and reduced bleeding, mainly in gastrointestinal and skin lesions1)3)10). |
| Lanreotide (once monthly) | Reported to suppress recurrent bleeding for 7 months4) |
| Octreotide | Bleeding suppression through reduced visceral blood flow and anti-angiogenic effects |
| Others | Interferon α, beta blockers, vincristine, bevacizumab, thalidomide, and others10) |
Sirolimus is an inhibitor of the PI3K/AKT/mTOR pathway and acts directly on the main molecular pathogenesis of BRBNS. Its effectiveness has been reported mainly for gastrointestinal and skin lesions, and it is currently considered the most promising drug therapy.
Somatostatin analogs (lanreotide, octreotide) suppress bleeding by reducing visceral blood flow and through anti-angiogenic effects. Monthly administration of lanreotide has been reported to suppress recurrent bleeding for 7 months4).
The following endoscopic treatments are selected for gastrointestinal lesions.
Surgical resection is used for multiple lesions or massive bleeding when endoscopic treatment is difficult.
There is no established management. For orbital and conjunctival lesions, assess whether there is visual impairment or increased intraocular pressure, and coordinate ophthalmology and internal medicine alongside the treatment plan for systemic lesions.
Sirolimus may reduce lesions and help control bleeding by inhibiting the PI3K/AKT/mTOR pathway, which is a key molecular abnormality in BRBNS. Reports have accumulated mainly for gastrointestinal and skin lesions. However, the standard dose and treatment duration have not been established, and it should be used under specialist supervision.
The core pathology of BRBNS is constitutive activation of the TIE2 receptor caused by somatic activating mutations in the TEK gene2).
Xing et al. (2025) identified a TEK c.596A>C mutation (including the T1105N-T1106P double cis mutation) in BRBNS cases by whole-exome analysis, showing that constitutive activation of the PI3K/AKT/mTOR pathway drives abnormal angiogenesis2). In addition, about 20% of solitary venous malformations have been reported to involve PIK3CA mutations.
TIE2 is a receptor tyrosine kinase for angiopoietins (Ang-1, Ang-2) and plays an essential role in maintaining vascular endothelial homeostasis. TEK mutations cause ligand-independent signal activation, leading to abnormally dilated, thin-walled vascular spaces lacking vascular smooth muscle.
Genes identified as associated with BRBNS include mucous membrane pemphigoid 9, NOTCH3, CCM2, PDGFRA, and TSC22). In particular, TSC2 mutations are upstream regulators of the mTOR pathway and suggest a shared molecular mechanism in cases with both tuberous sclerosis and BRBNS6).
Mechanical trapping of platelets within the hemangioma triggers chronic consumptive coagulopathy. It is also thought that DIC progresses when a second hit, such as inflammation, is added5).
Jitsuiki et al. (2022) reported a case of BRBNS complicated by Kasabach-Merritt syndrome and heart failure 5). The patient had severe findings of hemoglobin 2 g/dL, platelets 107,000, fibrin degradation products > 150 μg/mL, and fibrinogen 32 mg/dL, and after treatment the left ventricular ejection fraction recovered from 30% to 55%. A coexisting aneurysm of the vein of Galen was also confirmed.
Somatostatin analogues are thought to suppress bleeding from gastrointestinal lesions through both a splanchnic blood flow-reducing effect and an anti-angiogenic effect 4).
The main cause is a somatic activating mutation in the TEK gene (which encodes the TIE2 receptor). The mutation constitutively activates the PI3K/AKT/mTOR pathway and causes abnormal vascular formation. Related genes such as mucous membrane pemphigoid 9, NOTCH3, and TSC2 have also been identified, suggesting genetic diversity.
Case reports and small studies using sirolimus have accumulated. Knowledge about dosage, treatment duration, and recurrence prevention continues to accumulate toward standardizing mTOR inhibitor therapy for control of gastrointestinal bleeding and severe anemia 2)10).
Xing et al. (2025) performed whole-exome sequencing in several BRBNS cases and identified broad genetic abnormalities beyond TEK mutations, including mucous membrane pemphigoid 9, NOTCH3, PRSS1, PDGFRA, CCM2, and TNFAIP62). As understanding of the genetic heterogeneity of BRBNS advances, its application to personalized medicine is expected.
Mithanthaya et al. (2023) raised a new concern about the risk of venous thromboembolism in a BRBNS patient who developed gastrointestinal bleeding despite anticoagulant therapy4). In this patient with more than 200 small-bowel lesions, monthly lanreotide was effective in suppressing recurrent bleeding for 7 months. Anticoagulation and antithrombotic management in BRBNS remain topics for future study.
Cases of coexisting tuberous sclerosis and BRBNS have been reported6), which may help guide treatment strategies focused on the mTOR pathway.
Lekamalage et al. (2024) reported a case in which intraoperative endoscopy confirmed BRBNS small-bowel lesions, and small-bowel ischemia occurred due to mesenteric venous embolism after cyanoacrylate injection9). Further study is needed on indications for endoscopic treatment and the safety of the procedure.
Yuan D, Xie Y, Liang Q.. Blue rubber bleb nevus syndrome: A case report and literature review. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024;49(10):1706-1710. doi:10.11817/j.issn.1672-7347.2024.240163. PMID:40074320; PMCID:PMC11897967.
Yueyi Xing, Han Liu, Hua Liu, Xueli Ding, Xue Jing. Genetic mutation and blue rubber bleb nevus syndrome: case reports and literature review. Front. Genet. 2025;16. doi:10.3389/fgene.2025.1516562.
Zoilo K. Suarez, Daniel Castaneda, Adalberto Gonzalez, Fernando J. Castro, Tolga Erim. Endoscopic and Surgical Management of Blue Rubber Bleb Nevus Syndrome. ACG Case Rep J. 2022;9(10):e00890. doi:10.14309/crj.0000000000000890.
Mithanthaya A, Ismail AGM, et al. BRBNS in a patient on anticoagulation. BMJ Case Rep. 2023;16:e256702.
Kei Jitsuiki, Michika Hamada, Soichiro Ota, Ken-ichi Muramatsu, Youichi Yanagawa. A Case of Blue Rubber Bleb Nevus Syndrome With Kasabach-Merritt Syndrome and Heart Failure. Cureus. 2022. doi:10.7759/cureus.25589.
Alreefi H, AlKhateeb M. BRBNS associated with TSC and CNS involvement. Neurosciences. 2021;26(2):207-211.
Nagahama M, Chigusa Y, et al. Delivery management of pregnant blue rubber bleb nevus syndrome patients: a case report and literature review. Nagoya J Med Sci. 2024;86(3):507-513. PMID: 39355358. PMCID: PMC11439602. doi:10.18999/nagjms.86.3.507.
Reddy YK, Bayoumi M, et al. Isolated gastrointestinal BRBNS. Transl Gastroenterol Hepatol. 2022;7:12.
Binura Buwaneka Wijesinghe Lekamalage, Lucinda Duncan-Were, John Llewelyn, David McGouran, Daniel Mafi, Barnaby Smith, Jeremy Rossaak. Intraoperative Enteroscopy: A Rare Case of Blue Rubber Bleb Nevus Syndrome and a Rare Complication of Cyanoacrylate Glue. Cureus. 2024. doi:10.7759/cureus.58655.
Chen LC, Yeung CY, et al. Blue Rubber Bleb Nevus Syndrome (BRBNS): A Rare Cause of Refractory Anemia in Children. Children (Basel). 2023;10(1):3. PMID: 36670554. PMCID: PMC9856356. doi:10.3390/children10010003.
