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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Gastroenterology · Blue Rubber Bleb Nevus Syndrome

Diagnosis and Evaluating Your Tests

At a Glance

Blue Rubber Bleb Nevus Syndrome (BRBNS) is diagnosed using physical exams, advanced imaging like capsule endoscopy to find internal malformations, and tissue biopsies. Genetic tests look for somatic mutations in the TEK (or TIE2) gene to officially confirm the condition.

Getting a diagnosis for Blue Rubber Bleb Nevus Syndrome (BRBNS) requires a combination of physical examination, advanced internal imaging, and precise genetic testing. Because the condition is so rare, it is often misdiagnosed as more common conditions, such as simple birthmarks or “sporadic” venous malformations (isolated issues that don’t involve the whole body) [1][2].

The Clinical Starting Point

Doctors typically begin with a physical exam. They are looking for the “hallmark” signs of BRBNS:

  • The “Button” Test: Lesions are usually bluish, nodular, and feel like soft rubber [3][4].
  • Compression: A key feature is that these spots can often be flattened with pressure and will slowly refill with blood when the pressure is released [3].
  • Location: While they can appear anywhere, finding these rubbery blue spots on the palms of the hands or soles of the feet is highly suggestive of BRBNS [3][4].

Finding Hidden Lesions

Since BRBNS often involves the internal organs—especially the digestive tract—doctors use specialized imaging to “see” where the skin cannot reach.

Capsule Endoscopy
This is often considered the “gold standard” for finding GI lesions in BRBNS [5][6].

  • What it is: You swallow a large pill that contains a tiny wireless camera [5].
  • Why it’s used: Unlike a traditional colonoscopy or upper endoscopy, which only see the ends of the digestive tract, the capsule camera travels through the entire small intestine. This is where many BRBNS malformations hide [5][6].

Advanced Imaging
For lesions deep in the muscles, bones, or other organs, standard X-rays or ultrasounds may not be enough.

  • MRI: Magnetic Resonance Imaging is excellent for seeing the “architecture” of blood vessels [7].
  • Scintigraphy (SPECT/CT): This involves a small amount of a safe “tracer” injected into the blood. A special scanner then tracks where blood pools in the body, which can highlight hidden malformations [8][7].

Genetic Confirmation

The most definitive way to confirm BRBNS is through genetic testing, but the type of test matters. Because the mutation is somatic (only in the abnormal vessels), a standard blood test may come back negative [9][10]. Doctors often need to take a small tissue biopsy of a skin lesion to find the mutation [10][11].

Completeness Checklist for Your Reports
When you receive a genetic or pathology report, look for these specific details to ensure the diagnosis is thorough:

  • Gene Name: The report should specifically mention the TEK (or TIE2) gene [9][10].
  • Mutation Type: Look for terms like “cis-double” or “compound” mutations. Finding two separate glitches on the same gene is a classic genetic “fingerprint” for BRBNS [12][13].
  • Sequencing Depth: Because the mutation might only be present in a small percentage of the cells in the sample, the test needs to be “deep” enough to find it.
  • Tissue Source: Check that the sample was taken from an affected area (like a skin lesion) rather than just a general blood draw [10].

Common Misdiagnoses

If your diagnosis is still uncertain, it may be because BRBNS can look like:

  • Sporadic Venous Malformations: These are single, isolated lesions. BRBNS is different because it is multifocal (occurring in many places) [9][10].
  • VMCM (Venous Malformation Cutaneous and Mucosal): This is a similar condition but is inherited (passed down through families) and usually involves different genetic patterns [11][14].
  • Hemangiomas: These are common “strawberry” birthmarks that usually go away over time, whereas BRBNS lesions are permanent and grow with the patient [15][16].

Common questions in this guide

How is Blue Rubber Bleb Nevus Syndrome diagnosed?
Doctors diagnose BRBNS using a combination of physical exams, advanced imaging like capsule endoscopy or MRI, and specialized genetic testing. They look for signature rubbery blue lesions on the skin and check for hidden vascular malformations in internal organs.
Why do I need a capsule endoscopy for BRBNS?
A capsule endoscopy allows doctors to see the entire small intestine by having you swallow a tiny pill containing a wireless camera. This is critical because BRBNS malformations frequently hide deep in the digestive tract where standard endoscopies cannot reach.
What does the TEK gene mean on my genetic report?
The TEK (or TIE2) gene is where the specific genetic mutation causing BRBNS occurs. A thorough pathology report will mention this gene and look for a 'cis-double' or 'compound' mutation, which is the classic genetic fingerprint for the syndrome.
Can a normal blood test detect the BRBNS genetic mutation?
Typically, a standard blood test cannot detect BRBNS. Because the genetic mutation is somatic—meaning it only exists within the abnormal blood vessels—doctors usually need to perform a tissue biopsy on an actual skin lesion to find the genetic error.
What is the button test for BRBNS?
The button test is a physical exam technique where a doctor presses on a suspected skin lesion. In BRBNS, these bluish, rubbery spots typically flatten under pressure and then slowly refill with blood once the pressure is released.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does my genetic report mention a 'cis-double' or 'compound' mutation in the TEK gene?
  2. 2.What was the 'sequencing depth' of my genetic test? Is it high enough to catch low-level somatic mutations?
  3. 3.Is a capsule endoscopy necessary to check for silent bleeding in my small intestine?
  4. 4.Should we consider a SPECT/CT or a whole-body MRI to look for malformations that aren't visible on the skin?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (16)
  1. 1

    Case Report: Combination of sirolimus and endoscopic lauromacrogol sclerotherapy in the management of blue rubber bleb nevus syndrome with gastric tract bleeding.

    Liu L, Wang L, Hu F

    Frontiers in pediatrics 2024; (12()):1488466 doi:10.3389/fped.2024.1488466.

    PMID: 39867693
  2. 2

    Bean's syndrome (blue rubber bleb nevus syndrome - BRBNS) as a gastrointestinal bleeding - case report and review of the literature.

    Lenarcik M, Pachlewski J, Mróz A

    Polish journal of pathology : official journal of the Polish Society of Pathologists 2021; (72(2)):190-194 doi:10.5114/pjp.2021.109524.

    PMID: 34706529
  3. 3

    Blue rubber bleb nevus syndrome: Presentation of a case and review of the literature.

    Lasso Andrade FA, Cadena Arteaga JA, Echeverry Morillo VL, et al.

    Radiology case reports 2021; (16(8)):2003-2006 doi:10.1016/j.radcr.2021.04.086.

    PMID: 34158881
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    Blue bleb rubber nevus syndrome.

    Ballieux F, Boon LM, Vikkula M

    Handbook of clinical neurology 2015; (132()):223-30.

    PMID: 26564083
  5. 5

    Blue rubber bleb nevus syndrome: a single-center case series in 12 years.

    Xia H, Wu J, Huang Y

    Translational pediatrics 2021; (10(11)):2960-2971 doi:10.21037/tp-21-238.

    PMID: 34976762
  6. 6

    A 10-year delayed diagnosis of blue rubber bleb nevus syndrome characterized by refractory iron-deficiency anemia: A case report and literature review.

    Tang X, Gao J, Yang X, Guo X

    Medicine 2018; (97(22)):e10873 doi:10.1097/MD.0000000000010873.

    PMID: 29851802
  7. 7

    Essentials for parathyroid imaging and intervention: what radiologists need to know.

    Choi HJ, Kim JH

    Ultrasonography (Seoul, Korea) 2025; (44(5)):324-345 doi:10.14366/usg.25102.

    PMID: 40935596
  8. 8

    99mTc-Labeled Blood Pool Scintigraphy and SPECT/CT Findings in a Rare Case of Blue Rubber Bleb Nevus Syndrome.

    Wakankar R, Dharmashaktu Y, Kumar R

    Clinical nuclear medicine 2025; (50(4)):e234-e235 doi:10.1097/RLU.0000000000005627.

    PMID: 40029800
  9. 9

    Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

    Soblet J, Kangas J, Nätynki M, et al.

    The Journal of investigative dermatology 2017; (137(1)):207-216 doi:10.1016/j.jid.2016.07.034.

    PMID: 27519652
  10. 10

    Blue rubber bleb nevus syndrome: A European multicenter cohort study.

    Becq A, Bisdorff A, Riccioni ME, et al.

    Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2025; (57(2)):603-608 doi:10.1016/j.dld.2024.10.001.

    PMID: 39426903
  11. 11

    Blue Nodules in a 2-Year-Old Female With Chronic Severe Anemia.

    Ross KR, Throckmorton SK, Haley KM, et al.

    International journal of dermatology 2026; (65(4)):703-705 doi:10.1111/ijd.70202.

    PMID: 41369117
  12. 12

    Double Jeopardy: The Rubber Ball Bounces Twice.

    Arbiser JL, Gilbert LC

    The Journal of investigative dermatology 2017; (137(1)):15-17 doi:10.1016/j.jid.2016.08.011.

    PMID: 28010758
  13. 13

    Genetic mutation and blue rubber bleb nevus syndrome: case reports and literature review.

    Xing Y, Liu H, Liu H, et al.

    Frontiers in genetics 2025; (16()):1516562 doi:10.3389/fgene.2025.1516562.

    PMID: 40584829
  14. 14

    Glomovenous malformation secondary to a heterozygous nonsense variant in GLMN: a clinical mimicker of blue rubber bleb naevus syndrome.

    Ramessur R, Fadhli T, Tripathi B, et al.

    Clinical and experimental dermatology 2023; (49(1)):108-110 doi:10.1093/ced/llad302.

    PMID: 37655781
  15. 15

    Blue Rubber Bleb Nevus Syndrome Presenting as Anemia, Hemorrhage, and Hemangiomas: A Rare Case Report.

    Khan QA, Farkouh C, Khan A, et al.

    Clinical medicine insights. Case reports 2023; (16()):11795476231173503 doi:10.1177/11795476231173503.

    PMID: 37205005
  16. 16

    Endoscopic Band Ligation in Blue Rubber Bleb Nevus Syndrome: A Report of Two Children.

    Samanta A, Poddar U, Sarma MS, et al.

    JPGN reports 2023; (4(4)):e344 doi:10.1097/PG9.0000000000000344.

    PMID: 38034424

This page explains diagnostic tests and genetic reports for Blue Rubber Bleb Nevus Syndrome for educational purposes only. Always consult your healthcare provider or genetic counselor to interpret your specific medical results.

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