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

Aymeric Becq, Annouk Bisdorff, Maria Elena Riccioni, Sophie Blaise, Stéphanie Mallet, Ervin Toth, Annabel Maruani, Edward Despott, Christine Labreze, Pablo Cortegoso Valdivia, et al.

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## To cite this version:

Aymeric Becq, Annouk Bisdorff, Maria Elena Riccioni, Sophie Blaise, Stéphanie Mallet, et al. Blue rubber bleb nevus syndrome: A European multicenter cohort study. Digestive and Liver Disease, 2024, 57 (2), pp.603 - 608. 10.1016/j.dld.2024.10.001. hal-05122055

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Alimentary Tract

Blue rubber bleb nevus syndrome: A European multicenter cohort study

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Aymeric Becq<sup>a,∗</sup>, Annouk Bisdorff<sup>b</sup>, Maria Elena Riccioni<sup>c,d</sup>, Sophie Blaise<sup>e</sup>,
Stéphanie Mallet<sup>f</sup>, Ervin Toth<sup>g</sup>, Annabel Maruani<sup>h,i</sup>, Edward Despott<sup>j</sup>, Christine Labreze<sup>k</sup>,
Pablo Cortegoso Valdivia<sup>l</sup>, Emmanuele Rondonotti<sup>m</sup>, Cristina Carrretero Ribón<sup>n</sup>,
Laetitia Goffinet<sup>o</sup>, Elise Coffin<sup>p</sup>, Bruno Rosa<sup>q</sup>, Cynthia Medlij<sup>r</sup>, Jean-Christophe Saurin<sup>s</sup>,
Xavier Dray<sup>t</sup>, on behalf of the iCARE group and FAVA-Multi

ARTICLE INFO

Article history:
Received 28 June 2024
Accepted 1 October 2024
Available online 18 October 2024

Keywords:
Blue rubber bleb nevus syndrome
Vascular malformations
Gastrointestinal bleeding
Gastrointestinal endoscopy
Sirolimus

A B S T R A C T

**Background and aim:** Blue Rubber Bleb Nevus Syndrome (BRBNS) is a rare congenital vascular entity, mainly characterized by cutaneous and gastrointestinal venous malformations. BRBNS remains relatively unexplored and only limited descriptive data is available. The aim of this study was to evaluate the clinical features, diagnostic work-up and therapeutic management in current practice.

**Methods:** A multicenter, European, cohort study was performed to investigate the BRBNS population. Patient demographics, clinical presentation and management data were collected.

**Results:** In this multicenter cohort study including 44 patients, BRBNS is diagnosed at a median age of 12 years, mainly based on clinical presentation (65.9 %). The majority of patients present cutaneous (68.2 %) and digestive (79.5 %) lesions, mainly in the colon and small bowel. D-dimer and fibrinogen levels are checked in <50 % of patients at diagnosis. Tie2/TEK mutation testing is rarely performed. Gastrointestinal bleeding is the most common complication (54.3 %), requiring endoscopic treatment (36.4 %) by various techniques.

**Conclusions:** This is the largest cohort study on BRBNS. Diagnosis is mainly based on clinical presentation. D-dimer, fibrinogen and Tie2/TEK mutation testing should be performed in case of suspected BRBNS as it could help confirm the diagnosis.

© 2024 The Author(s). Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))

<footnote><sup>a</sup> Gastroenterology Department, APHP, Henri Mondor Hospital, Paris Est Créteil University, 1 Rue Gustave Eiffel, Créteil 94000, France</footnote>

<footnote><sup>b</sup> Neuroradiology Department, Lariboisière Hospital, Center of Vascular Anomalies Clinic VASCERN VASCA European Reference Centre, Paris, France</footnote>

<footnote><sup>c</sup> Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy</footnote>

<footnote><sup>d</sup> Dipartimento di Scienze Medico-Chirurgiche e Gastroenterologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy</footnote>

<footnote><sup>e</sup> Vascular Medicine Department, HP2 Laboratory, University Grenoble Alpes, CHU Grenoble Alpes, Grenoble 38000, France</footnote>

<footnote><sup>f</sup> Department of Dermatology, University Hospital Center of Marseille, Marseille, France</footnote>

<footnote><sup>g</sup> Department of Gastroenterology, Malmö and Department of Clinical Sciences Malmö, Skåne University Hospital, Lund University, Sweden</footnote>

<footnote><sup>h</sup> University of Tours, University of Nantes, Institut National de la Santé et de la Recherche Médicale, SPHERE U1246, Tours, France</footnote>

<footnote><sup>i</sup> Department of Dermatology, Center of Reference for rare Vascular Anomalies MAGEC, University Hospital Center of Tours, Tours, France</footnote>

<footnote><sup>j</sup> Royal Free Unit for Endoscopy, The Royal Free Hospital and UCL Institute for Liver and Digestive Health, London, UK</footnote>

<footnote><sup>k</sup> Department of Dermatology, Pellegrin Hospital, CHU de Bordeaux, Bordeaux, France</footnote>

<footnote><sup>l</sup> Gastroenterology and Endoscopy Unit, University Hospital of Parma, University of Parma, Parma, Italy</footnote>

<footnote><sup>m</sup> Gastroenterology Unit, Valduce Hospital, Como, Italy</footnote>

<footnote><sup>n</sup> Department of Gastroenterology, University of Navarre Clinic, Healthcare Research Institute of Navarre, Pamplona, Spain</footnote>

<footnote><sup>o</sup> Pediatric Surgery Department, University Hospital of Nancy, Lorraine University, France</footnote>

<footnote><sup>p</sup> Endoscopy Department, Foch Hospital, Suresnes, France</footnote>

<footnote><sup>q</sup> Department of Gastroenterology, Hospital da Senhora da Oliveira, Guimarães, Portugal</footnote>

<footnote><sup>r</sup> Gastroenterology Department, Saint Joseph Hospital, Paris, France</footnote>

<footnote><sup>s</sup> Department of Hepatology and Gastroenterology, Edouard Herriot Hospital, Lyon, France</footnote>

<footnote><sup>t</sup> Centre for Digestive Endoscopy, Sorbonne University, Saint Antoine Hospital, APHP, Paris, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: aymeric.becq@aphp.fr (A. Becq).</footnote>
# 1. Introduction

Blue Rubber Bleb Nevus Syndrome (BRBNS), also known as BEAN syndrome, is a rare congenital vascular entity, mainly characterized by cutaneous and gastrointestinal venous malformations. Cutaneous lesions consist of multiple blue or purplish, soft and elastic (hence the term rubber) blebs, either on the skin or mucosal tissue (oral, genital). Subcutaneous, mucosal or hyperkeratotic lesions typically on palms and soles are frequent. The small intestine is the most affected location of the digestive tract. Digestive bleeding and iron-deficiency anemia (IDA) can occur [1,2]. These malformations can be seen in other organs as well such as the liver, spleen, heart, eyes and central nervous system. BRBNS is a sporadic disorder in most cases although autosomal dominant transmission has been reported (chromosome 9p locus) [3–5]. Somatic mutations in Tie2/TEK, an endothelial cell tyrosine kinase receptor for angiopoietins, have recently been discovered to cause the disorder [6]. Somatic mutations occurring late in development lead to mosaicism, accounting for the heterogeneity of the clinical presentation which, combined to the rarity of the disease, explains the lack of well-established diagnostic criteria.

BRBNS remains relatively unexplored and little descriptive data is available, consisting mainly of clinical cases and case series. Thus, diagnosis and management depend on the caring physicians and their specialty. The different degrees of severity, including diagnostic involvement and its impact on quality of life are also unknown. Thus, an in-depth description of BRBNS is warranted.

The aim of this study was to describe the clinical features, diagnostic work-up, and therapeutic management of this population of patients.

# 2. Patients and methods

A multicenter, European, retrospective cohort study was performed to describe the clinical features, diagnostic work-up and therapeutic management of patients with a diagnosis of BRBNS.

## 2.1. Study population

Patients with a definitive diagnosis of BRBNS, whatever the age, were eligible for inclusion in the study between 2022 and 2023. Although there are no formally defined criteria, BRBNS diagnosis usually relies on the presence of typical skin lesions and/or gastrointestinal lesions and/or involvement of another organ (3,5). Physician participating in the present study were members of either the International CAPsule endoscopy REsearch (iCARE) group (specialized in small bowel disease) or the Rare Vascular Disease research network. Subjects were defined as BRBNS patients and included in the present study if the clinical presentation was consistent with previously mentioned clinical criteria and the following conditions were ruled out. Differential diagnosis, characterized by different forms of vascular malformations, such as Hereditary Hemorrhagic Telangiectasia [6], Maffucci syndrome [7], Combined capillary-veno-lymphatic Malformations (CVLM) syndrome [8], sporadic multifocal venous malformations, Venous Malformation Cutaneous Mucosal (VMCM) and combined capillary-veno-lymphatic malformations were excluded. All potential patients that did not object to participating were included in the study. The study was approved by our Institutional Review Board (#00,011,558 – 2023–153).

## 2.2. Data collection

A secured computerized data collection sheet was sent out to a group of experts in small bowel pathologies and a group of experts in vascular diseases, comprising various medical specialties.

Out of 113 specialists, 42 answered to our invitation (i.e. followed patient(s) with BRBNS. In fine, 18 participated in the study. The following variables were collected from the medical records: patient demographics, referring physician specialty, follow-up duration, diagnostic workup (diagnosis age, onset, first organ involved, biological markers, sporadic vs genetic syndrome, genetic testing, family history), clinical characteristics and complications: skin lesions (number, largest, location, symptoms), gastrointestinal lesions (number, location, symptoms, complications, endoscopic appearance and management, blood transfusion and iron supplementation needs), other organ involvement, extra-digestive complications, death and cause of death, as well as endoscopic and pharmacological treatment. The investigators collected all the data pertinent to the study, from November 2022 to September 2023, using an a priori designed form.

## 2.3. Outcomes

The outcomes of the study were the clinical characteristics, diagnostic workup, complications, endoscopic and pharmacological management of BRBNS.

## 2.4. Statistical analysis

The statistical analysis included a description of the study population with frequency evaluation for categorical variables, and median [1st and 3rd quartile] for quantitative variables.

# 3. Results

During the study period, a total of 44 patients with a diagnosis of BRBNS were included for analysis, 28 from France (63.8 %), 9 from Italy (20.5 %), 3 from Sweden (6.8 %), 2 from the United Kingdom (4.5 %), one from Spain (2.3 %) and one from Portugal (2.3 %). Twenty five patients were males (56.8 %), 5 were children (11.4 %). The median age was 40 years-old (IQR 20–58). The referring physicians were gastroenterologists in 22 cases (50.0 %), dermatologists in 10 cases (22.7 %), vascular surgeons/radiologists in 10 cases (22.7 %), pediatricians in 3 cases (6.8 %) and a plastic surgeon in one case (2.3 %). The median age at diagnosis was 12.0 years old (IQR 3.3–46.5). The median follow-up duration was 8 years (IQR 3.3–25.5). The onset of the first lesion was at birth (0 up to 6 months) in 11 patients (25.0 %), during childhood (7 months up to 11 years) in 15 patients (34.1 %), during adolescence (12 up to 18 years) in 5 patients (11.4 %), and during adulthood (> 18 years) in 13 patients (29.5 %). The first organ involved was the skin in 22 patients (50.0 %), followed by the digestive tract in 13 patients (29.5 %). Twenty-nine patients (65.9 %) were diagnosed because of typical skin lesions or because of signs/symptoms related to vascular lesions, while family history and genetic testing served as diagnostic criteria in 4 (9.1 %) and 11 (25.0 %) patients, respectively. D-dimer at diagnosis was documented in 14 patients, and was elevated in 11 (25.0 %) of these patients. Fibrinogen at diagnosis was documented in 23 patients, and was low in 6 (13.6 %) of these patients. Cross-sectional imaging was performed for diagnostic purposes in 16 patients (36.4 %) (Table 1).

## 3.1. Cutaneous lesions

Thirty patients (68.2 %) had cutaneous malformations. The number of lesions was between 1 and 5 in 10 of these patients (33.3 %), 6 and 10 in 8 patients (26.7 %), 11 and 20 in 3 patients (10.0 %), 21 and 50 in 3 patients (10.0 %) and over 51 in 6 patients (20.0 %). The median largest lesion measured 20 mm (13–68). Lesions were seen at the level of the cervico-facial area in 7 patients (23.3 %), the trunk in 17 patients (56.7 %), and the upper and lower
<caption>**Table 1**</caption>

Characteristics and diagnosis criteria of 44 patients with blue rubber bleb nevus syndrome.

<table><thead><tr><th></th><th>Total n = 44 (%)</th></tr></thead><tbody><tr><td>Country of origin</td><td></td></tr><tr><td>France</td><td>28 (63.6)</td></tr><tr><td>Italy</td><td>9 (20.5)</td></tr><tr><td>Sweden</td><td>3 (6.8)</td></tr><tr><td>UK</td><td>2 (4.5)</td></tr><tr><td>Spain</td><td>1 (2.3)</td></tr><tr><td>Portugal</td><td>1 (2.3)</td></tr><tr><td>Male</td><td>25 (56.8)</td></tr><tr><td>Age (median (IQR))</td><td>40 (20–58)</td></tr><tr><td>Referring physician</td><td></td></tr><tr><td>Gastroenterologist</td><td>22 (50.0)</td></tr><tr><td>Dermatologist</td><td>10 (22.7)</td></tr><tr><td>Vascular surgeon/radiologist</td><td>10 (22.7)</td></tr><tr><td>Pediatrician</td><td>3 (6.8)</td></tr><tr><td>Plastic surgeon</td><td>1 (2.3)</td></tr><tr><td>Age at diagnosis (median (IQR))</td><td>12 (3.3–46.5)</td></tr><tr><td>Follow-up (median (IQR))</td><td>8 (3.3–25.5)</td></tr><tr><td>Onset of first lesion</td><td></td></tr><tr><td>0 to 6 months</td><td>11 (25.0)</td></tr><tr><td>7 months to 11 years</td><td>15 (34.1)</td></tr><tr><td>12 to 18 years</td><td>5 (11.4)</td></tr><tr><td>&gt; 18 years</td><td>13 (29.5)</td></tr><tr><td>First organ involved</td><td></td></tr><tr><td>Skin</td><td>22 (50.0)</td></tr><tr><td>Digestive tract</td><td>13 (29.5)</td></tr><tr><td>Mouth</td><td>3 (6.8)</td></tr><tr><td>Muscle</td><td>1 (2.3)</td></tr><tr><td>Eyes</td><td>1 (2.3)</td></tr><tr><td>Brain</td><td>1 (2.3)</td></tr><tr><td>Lungs</td><td>1 (2.3)</td></tr><tr><td>Multiple</td><td>2 (4.5)</td></tr><tr><td>Diagnostic criteria</td><td></td></tr><tr><td>Clinical presentation</td><td>29 (65.9)</td></tr><tr><td>Family case (Autosomal Dominant) associated with chromosome 9p</td><td>4 (9.1)</td></tr><tr><td>Enhanced c-kit expression</td><td>0 (0.0)</td></tr><tr><td>Somatic TEK mutation (Tie2/TEK)</td><td>2 (4.5)</td></tr><tr><td>Genetic (unspecified)</td><td>9 (20.5)</td></tr><tr><td>Biologic marker levels at diagnosis</td><td></td></tr><tr><td>D-Dimers</td><td></td></tr><tr><td>Not checked</td><td>30 (68.2)</td></tr><tr><td>Normal</td><td>3 (6.8)</td></tr><tr><td>High</td><td>11 (25.0)</td></tr><tr><td>Fibrinogen</td><td></td></tr><tr><td>Not checked</td><td>21 (47.7)</td></tr><tr><td>Normal</td><td>20 (45.5)</td></tr><tr><td>Low</td><td>6 (13.6)</td></tr><tr><td>Imaging</td><td></td></tr><tr><td>Diagnostic</td><td>16 (36.4)</td></tr><tr><td>Interventional</td><td>7 (15.9)</td></tr><tr><td>None</td><td>21 (47.7)</td></tr></tbody></table>

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** A: Multiple cutaneous blebs. Edward Despott, Royal Free Unit for Endoscopy, The Royal Free Hospital and UCL Institute for Liver and Digestive Health, London, UK. B: Resected specimen of the small bowel. Ervin Toth, Department of Gastroenterology, Skåne University Hospital, Malmö, Sweden.</figcaption></figure>

<caption>**Table 2**</caption>

Cutaneous lesions of 30 patients with Blue Rubber Bleb Nevus Syndrome.

<table><thead><tr><th></th><th>Total n = 30 (%)</th></tr></thead><tbody><tr><td>Number of cutaneous malformations</td><td></td></tr><tr><td>1 to 5</td><td>10 (33.3)</td></tr><tr><td>6 to 10</td><td>8 (26.7)</td></tr><tr><td>11 to 20</td><td>3 (10.0)</td></tr><tr><td>21 to 50</td><td>3 (10.0)</td></tr><tr><td>&gt; 51</td><td>6 (20.0)</td></tr><tr><td>Largest lesion (mm) (median (IQR))</td><td>20 (13–68)</td></tr><tr><td>Location</td><td></td></tr><tr><td>Cervico-facial</td><td>7 (23.3)</td></tr><tr><td>Trunk</td><td>17 (56.7)</td></tr><tr><td>Upper Limbs</td><td>10 (33.3)</td></tr><tr><td>Lower Limbs</td><td>8 (26.7)</td></tr><tr><td>Multiple areas</td><td>19 (63.3)</td></tr><tr><td>Symptoms</td><td></td></tr><tr><td>None</td><td>15 (50.0)</td></tr><tr><td>Pain</td><td>12 (40.0)</td></tr><tr><td>Perspiration</td><td>0 (0.0)</td></tr><tr><td>Other</td><td>5 (16.7)</td></tr><tr><td>Other skin lesions</td><td></td></tr><tr><td>None</td><td>24 (80.0)</td></tr><tr><td>Large cavernous and disfiguring lesions</td><td>1 (3.3)</td></tr><tr><td>Irregular blue or black pimples or papules</td><td>1 (3.3)</td></tr><tr><td>Cosmetic treatment of skin lesions</td><td></td></tr><tr><td>None</td><td>18 (60.0)</td></tr><tr><td>Laser</td><td>3 (10.0)</td></tr><tr><td>Surgery</td><td>7 (23.3)</td></tr><tr><td>Electrodessication</td><td>0 (0.0)</td></tr><tr><td>Cryotherapy</td><td>0 (0.0)</td></tr><tr><td>Sclerotherapy</td><td>4 (13.3)</td></tr></tbody></table>

limbs in 10 (33.3 %) and 8 (26.7 %) patients, respectively (Fig. 1.A). Lesions were found in multiple areas in 19 (63.6 %) patients. Lesions were asymptomatic in 15 patients (50.0 %). Pain was noted in 12 (40.0 %) patients. Other symptoms were bleeding (3 patients), swelling (1 patient) and visual disturbance (1 patient). Cosmetic treatment such as laser, surgery and sclerotherapy was performed in 3 (10.0 %), 7 (23.3 %) and 4 (13.3 %) of patients, respectively (Table 2).

## 3.2. Gastrointestinal lesions

Thirty-five patients (79.5 %) had gastrointestinal malformations. Amongst these patients, upper endoscopy, small bowel capsule endoscopy (SB-CE), device assisted enteroscopy (DAE) and colonoscopy were performed at least once in 18 (51.4 %), 29 (82.9 %), 9 (25.7 %) and 19 (54.3 %) of patients, respectively. The number of lesions was between 1 and 5 in 6 patients (17.1 %), 6 and 10 in 6 patients (17.1 %), 11 and 20 in 5 patients (14.3 %), 21 and 50 in 6 patients (17.1 %) and over 51 in 6 patients (17.1 %). Lesions were most commonly located in the jejunum (21 patients, 60.0 %) and ileum (18 patients, 51.4 %) (Fig. 1.B). Lesions appeared as homogeneous, dark blue and discreetly elevated in 27 patients (77.1 %) and as hypervascular, wide and polyp-shaped with central invagination in 6 patients (17.1 %) (Table 3). Complications of gastrointestinal lesions were: overt digestive bleeding in 19 patients (6 with hematochezia, 12 with melena, and one patient with hematemesis) (54.3 %), iron deficiency in 15 patients (42.9 %) and intussusception in 2 patient (5.7 %).

Amongst the 29 patients who had a SB-CE, lesions were found in 27 patients (93.1 %). The number of lesions was between 1 and 5 in 4 patients (13.4 %), 6 and 10 in 7 patients (24.1 %), 11 and 20 in 6 patients (20.7 %), 21 and 50 in 5 patients (17.2 %) and over 51 in 3 patients (10.3 %). The jejunum was the localization with the highest burden (19 patients, 65.5 %). Lesions appeared as homogeneous, dark blue and discreetly elevated in 24 patients (82.8 %) and as hypervascular, wide and polyp-shaped with central invagin-
<table><caption>**Table 3**
Endoscopic findings in 35 patients with Blue Rubber Bleb Nevus Syndrome.</caption><thead><tr><th></th><th>Total n = 35 (%)</th></tr></thead><tbody><tr><td>Endoscopy performed at least once</td><td></td></tr><tr><td>Upper endoscopy</td><td>18 (51.4)</td></tr><tr><td>Push enteroscopy with colonoscope</td><td>2 (4.5)</td></tr><tr><td>Small bowel Capsule endoscopy</td><td>29 (82.9)</td></tr><tr><td>Device assisted Enteroscopy</td><td>9 (25.7)</td></tr><tr><td>Colonoscopy</td><td>19 (54.3)</td></tr><tr><td>None</td><td>7 (20.0)</td></tr><tr><td>Number of gastrointestinal hemangiomas</td><td></td></tr><tr><td>1 to 5</td><td>6 (17.1)</td></tr><tr><td>6 to 10</td><td>6 (17.1)</td></tr><tr><td>11 to 20</td><td>5 (14.3)</td></tr><tr><td>21 to 50</td><td>6 (17.1)</td></tr><tr><td>> 51</td><td>6 (17.1)</td></tr><tr><td>Unknown</td><td>3 (8.6)</td></tr><tr><td>Location</td><td></td></tr><tr><td>Oral cavity</td><td>1 (2.9)</td></tr><tr><td>Hypopharynx</td><td>1 (2.9)</td></tr><tr><td>Esophagus</td><td>5 (14.3)</td></tr><tr><td>Stomach</td><td>8 (22.9)</td></tr><tr><td>D1</td><td>1 (2.9)</td></tr><tr><td>D2</td><td>4 (11.4)</td></tr><tr><td>Jejunum</td><td>21 (60.0)</td></tr><tr><td>Ileum</td><td>18 (51.4)</td></tr><tr><td>Caecum</td><td>2 (4.5)</td></tr><tr><td>Right colon</td><td>5 (14.3)</td></tr><tr><td>Transverse colon</td><td>3 (8.6)</td></tr><tr><td>Left colon</td><td>3 (8.6)</td></tr><tr><td>Sigmoid colon</td><td>4 (11.4)</td></tr><tr><td>Rectum</td><td>3 (8.6)</td></tr><tr><td>Colon unspecified</td><td>6 (17.1)</td></tr><tr><td>Unknown</td><td>2 (4.5)</td></tr><tr><td>Endoscopic appearance*</td><td></td></tr><tr><td>Homogeneous, dark blue – discreetly elevated, purple</td><td>27 (77.1)</td></tr><tr><td>Wide and polyp-shaped with central invagination and hypervascular</td><td>6 (17.1)</td></tr><tr><td>Stigma of recent bleeding</td><td>4 (11.4)</td></tr></tbody></table>

<table><caption>**Table 4**
Extra digestive / cutaneous lesions of 44 patients with Blue Rubber Bleb Nevus Syndrome.</caption><thead><tr><th></th><th>Total n = 44 (%)</th></tr></thead><tbody><tr><td>Other organs involved</td><td></td></tr><tr><td>Liver</td><td>3 (6.8)</td></tr><tr><td>Parotids and sub mandibular glands</td><td>1 (2.3)</td></tr><tr><td>Brain</td><td>2 (4.5)</td></tr><tr><td>Pleura</td><td>1 (2.3)</td></tr><tr><td>Spleen</td><td>1 (2.3)</td></tr><tr><td>Lungs</td><td>1 (2.3)</td></tr><tr><td>Skeleton</td><td>2 (4.5)</td></tr><tr><td>Muscles</td><td>1 (2.3)</td></tr><tr><td>Peritoneum</td><td>1 (2.3)</td></tr><tr><td>Joints</td><td>1 (2.3)</td></tr></tbody></table>

In 4 patients (13.8 %). Active bleeding was seen in 12 patients (41.4 %).

### 3.3. Extra-digestive and extra-cutaneous lesions

Organs involved other than the gastrointestinal tract and skin were the liver in 3 patients (6.8 %), the brain and skeleton in 2 patients (4.5 %), the parotids and sub mandibular glands, pleura, spleen, lungs, muscles, peritoneum and joints in one patient (2.3 %) (Table 4). Neurological extra-digestive complications occurred in 5 patients (11.4 %). Two patients had other complications (parotitis, hemarthrosis). Complication-related death occurred in one patient (2.3 %), due to a decompensated respiratory failure, triggered by a GI bleeding. Of note, 100 % of patients had a cutaneous and/or gastrointestinal lesion.

<table><caption>**Table 5**
Endoscopic management of gastrointestinal bleeding in 16 patients with Blue Rubber Bleb Nevus Syndrome.</caption><thead><tr><th></th><th>Total n = 16 (%)</th></tr></thead><tbody><tr><td>Type of procedure</td><td></td></tr><tr><td>Upper endoscopy</td><td>4 (25)</td></tr><tr><td>Push enteroscopy with colonoscope</td><td>2 (12.5)</td></tr><tr><td>Device assisted Enteroscopy</td><td>13 (81.25)</td></tr><tr><td>Colonoscopy</td><td>6 (37.5)</td></tr><tr><td>Treatment</td><td></td></tr><tr><td>Endoscopic mucosal resection</td><td>2 (12.5)</td></tr><tr><td>Endoscopic submucosal dissection</td><td>1 (6.3)</td></tr><tr><td>Argon Plasma Coagulation</td><td>6 (37.5)</td></tr><tr><td>Laser photocoagulation</td><td>1 (6.3)</td></tr><tr><td>Sclerotherapy</td><td>6 (37.5)</td></tr><tr><td>Band ligation</td><td>2 (12.5)</td></tr><tr><td>Other</td><td>3 (18.8)</td></tr></tbody></table>

### 3.4. Management

A total of 13 patients (29.5 %) required red blood cell (RBC) transfusion and 30 patients (68.2 %) required iron supplementation. Hospitalization in internal medicine was warranted in 29 patients (65.9 %), and in the intensive care unit in one patient (2.3 %). Endoscopic management of digestive bleeding was required in 16 patients (36.4 %). Upper endoscopy was performed in 4 of these patients (25 %), push enteroscopy with a colonoscope was performed in 2 patients (12.5 %), DAE was performed in 13 patients (81.25 %) and colonoscopy was performed in 6 patients (37.5 %). Endoscopic treatment consisted in endoscopic mucosal resection in 2 of these patients (12.5 %), endoscopic submucosal dissection in one patient (6.3 %), argon plasma coagulation (APC) in 6 patients (37.5 %), laser photocoagulation in one patient (6.3 %), sclerotherapy in 6 patients (37.5 %) and band ligation in 2 patients (12.5 %) (Table 5). The only reported adverse event was a hemoperitoneum. One perforation occurred during an enteroscopy and did not require surgery. Four patients underwent surgery due to intussusception (2) and GI bleeding (2) and three patients underwent cosmetic surgery. Pharmacological treatment was prescribed in 15 patients (34.1 %). Octreotide was prescribed in 4 patients (9.1 %), Thalidomide in one patient (2.3 %) and Sirolimus in 10 patients (22.7 %).

### 4. Discussion

In this multicenter cohort study, we describe the clinical features, diagnostic workup, complications and management of 44 patients diagnosed with BRBNS. Published data regarding BRBNS mostly consists of clinical cases, small case series [9] and systematic reviews pooling together case reports [7,10,11]. Therefore, to the best of our knowledge, our study represents the largest case series on BRBNS. Our study shows that this syndrome is diagnosed at a median age of 12 years, mainly based on clinical presentation (65.9 %). Moreover, our study confirms that the majority of patients present cutaneous (68.2 %) and digestive (79.5 %) lesions, in various locations and numbers. Gastrointestinal bleeding is the most common complication (54.3 %), requiring RBC transfusion (29.5 %), iron supplementation (68.2 %) and hospitalization (65.9 %) in many cases. Various endoscopic hemostatic techniques are used for bleeding control. Finally, pharmacological treatment is prescribed in 34.1 % of patients.

Our study shows BRBNS is mainly diagnosed based on clinical characteristics. About 70 % of patients have clinical manifestations before 18 years of age. However, the median age at diagnosis is 12 years. All patients had cutaneous or gastrointestinal (and sometimes both) involvement, in about the same proportion as reported in a systematic review on clinical characteristics of this syn-

<footnote>* largest lesion or cause of complication.</footnote>
drome [11]. Biological markers such as D-dimer and fibrinogen are not checked in most cases when diagnosis is suspected. Associated intravascular coagulation disorder (elevated D-dimer and low fibrinogen) should be sought out. Localized intravascular coagulopathy (LIC) is the most common form of coagulopathy in the setting of vascular malformations. Low fibrinogen levels, because of a high consumption, is due to clotting. It is associated with high fibrinolysis and an increased risk for bleeding. Preventive management by low molecular weight heparin (LMWH) [12] is the most effective agent to normalize coagulation, preventing progression of severe LIC to disseminated intra vascular coagulopathy (DIC) [13] and thus reducing the risk of bleeding [14]. There is no data specific to the effect of this prophylaxis on the risk of GIB however given the knowledge on coagulopathies associated with vascular malformations [15] it could constitute an interesting option. A study evaluating LMWH prophylaxis would be of interest.

Sirolimus also helps reduce the risk of bleeding and lowers D-dimer levels. D-dimer surveillance could thus be useful as well [15]. In our study, the majority of cases are sporadic which concurs with published data [2]. Somatic mutations in Tie2/TEK, an endothelial cell tyrosine kinase receptor for angiopoietins, is described in two patients only. This mutation, leading to unregulated angiogenesis, has been discovered recently. In a study by Soblet et al., 15 out of 17 patients with BRBNS had a somatic mutation of Tie2/TEK 6. It is known that autosomal dominant modes of inheritance exist as well (chromosome 9p) despite being much less frequent [3–5]. Our better understanding of the etiology of BRBNS in recent years could be helpful when it comes to a challenging diagnosis, given the shortcomings of the clinical presentation. Tie2/TEK mutation testing in case of suspected BRBNS could help confirm the diagnosis, and seems to be overlooked.

The majority (68.2 %) of patients had cutaneous lesions. An even higher proportion (79.5 %) of patients had gastrointestinal malformations, although the fact that 50.0 % of referring physicians were gastroenterologists could participate to a selection bias. The number and location of these lesions varied greatly between patients. Other organs were involved as well. Our data concurs with what has been published to this date, and goes an extra step in the description of the predominant lesions associated with BRBNS. Regarding gastrointestinal lesions, many prior reports are outdated, mainly from the 1990s and early 2000s [16,17]. SB CE did not exist at the time. Most recent reviews do not go into these details [2,7,11]. One systematic review, published in 2023, including 106 cases, showed jejunum, ileum and colon involvement in 68.6 %, 73.5 % and 62.6 % of cases, respectively [10]. Our study confirms these numbers.

Gastrointestinal bleeding was the most common complication (54.3 %) and enteroscopy was the most frequently required type of endoscopic procedure. The chosen method of hemostasis varies greatly, APC and sclerotherapy being the most commonly used. In the previously described systematic review [10], 37 patients (34.9 %) had an endoscopic treatment of BRBNS bleeding lesions. The most used hemostatic techniques were snare mucosectomy (21.6 %), followed by APC and sclerotherapy (16.2 % each). Our results differ. Only a large-scale prospective comparative study could determine which endoscopic techniques is best suited for BRBNS lesions. However, given the rarity of this syndrome, such a study would be difficult to implement. Endoscopic management should be tailored to the endoscopists' expertise and to the patients' needs.

Several strengths and weaknesses of this study can be highlighted. To our knowledge, this is the largest cohort regarding BRBNS, a rare affliction. Also, patients were followed by a diverse panel of specialties making this cohort representative of BRBNSs clinical features and diagnostic work-up. In the future, this study could help develop a consensual diagnostic work-up algorithm as

well as raise awareness on the potential impact of BRBNS, especially in terms of complications. Given that, in clinical practice, communication between the different physicians and specialties involved in patient care is lacking, this study could also promote a multidisciplinary approach, involving pediatricians, gastroenterologists, dermatologists, radiologists (diagnostic and interventional) as well as adult or pediatric surgeons. This study is limited by its retrospective nature. Diagnostic relies on clinician's opinion, and is debatable in essence. Large series such as ours is helpful in defining diagnostic criteria. Also, many patients were followed by gastroenterologists and dermatologists, possibly accounting for the high rates of gastrointestinal and cutaneous lesions, and the majority were followed in French centers. Regarding endoscopic management, we did not have sufficient data on the follow-up such as efficiency, recurrence, repeat endoscopy. Finally, only 18 specialists included patients out of the 42 who responded initially (113 were solicited), introducing a participation bias. Probably, a majority of the 24 specialists who did not provide data had patients with BRBNS, which could have been included in this study.

In conclusion, this is the largest published cohort study to this date, including 44 patients with BRBNS. We show that the diagnosis remains mainly based on clinical features. Cutaneous and/or gastrointestinal signs are major diagnostic criterion as they were always present at diagnosis. Involvement of other organs was less consistent, but could help confirm the diagnosis. Associated intravascular coagulopathy (D-dimer and fibrinogen levels) and testing for somatic Tie2/TEK mutation should be performed when diagnosis is suspected.

Declaration of competing interest

Aymeric Becq: The Author declares that there is no conflict of interest.

Annouk Bisdorff: The Author declares that there is no conflict of interest.

Maria Elena Riccioni: The Author declares that there is no conflict of interest.

Sophie Blaise: The Author declares that there is no conflict of interest.

Stéphanie Mallet: The Author declares that there is no conflict of interest.

Ervin Toth: Medtronic, Norgine, Olympus

Annabel Maruani: The Author declares that there is no conflict of interest.

Edward Despott: The Author declares that there is no conflict of interest.

Labreze Christine: The Author declares that there is no conflict of interest.

Pablo Cortegoso Valdivia: The Author declares that there is no conflict of interest.

Emmanuele Rondonotti: The Author declares that there is no conflict of interest.

Cristina Carretero Ribón: The Author declares that there is no conflict of interest.

Laetitia Goffinet: The Author declares that there is no conflict of interest.

Elise Coffin: The Author declares that there is no conflict of interest.

Bruno Rosa: The Author declares that there is no conflict of interest.

Cynthia Medlij: The Author declares that there is no conflict of interest.

Jean-Christophe Saurin: The Author declares that there is no conflict of interest.

Xavier Dray: Abbvie, Augmented Endoscopy, Fujifilm, Medtronic, Norgine, Provepharma, Sandoz.
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