Blue rubber bleb nevus: a rare cause of GI bleeding—review of management

Abstract

Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital vascular anomaly syndrome characterised by multifocal venous vascular malformations. It involves skin, central nervous systems, liver, muscles and gastrointestinal (GI) tract resulting in intestinal haemorrhage and anaemia. Patients with BRBNS experience severe chronic anaemia without any diagnosis requiring multiple transfusions and hospitalisations. BRBNS has a propensity for severe life-threatening bleeding. Skin and GI tract are the most commonly affected organs.

Background

Blue rubber bleb nevus syndrome (BRBNS) is a rare syndrome with only 200 cases reported to date is characterised by multiple vascular malformations in the skin (93%) and gastrointestinal (GI) tract (76%). Other organs, such as central nervous system (13%), liver (11%) and muscle (9%), can be involved as well.¹ This syndrome was first recognised by Gascoyen in 1860 who found it in the parotid gland.² Later William Bennett Bean further described this syndrome in 1958, and giving it the name BRBNS or Bean syndrome.^{3 4} We are presenting a rare case of GI bleeding due to BRBNS without cutaneous involvement.

Case presentation

A 55-year-old man with no significant medical history was initially seen in the emergency department for palpitations and shortness of breath for a few months. Physical examination showed conjunctival paleness and sinus tachycardia. Laboratory studies showed haemoglobin (Hb) 58 g/L (normal 135–175 g/L) with normal white cell count, platelets, prothrombin time (PT) and international normalised ratio (INR). A peripheral blood smear was ordered which showed microcytosis and hypochromia. Routine biochemistry values were normal. The iron panel showed decreased ferritin, iron and per cent iron saturation. He received packed red cells and iron supplementation. Although the patient denied melaena and haematochezia, the gastroenterology team was consulted for suspicion of occult GI bleeding. Abdominal imaging was unremarkable. He underwent oesophagogastroduodenoscopy and colonoscopy. Oesophagogastroduodenoscopy was unremarkable but colonoscopy showed multiple scattered venous blebs throughout the colon. They ranged in size from 2 to 8 mm. None of these blebs were actively bleeding (figure 1). These lesions were not amenable to endoscopic treatment. Treatment was conservative with proton pump inhibitors (PPI) for symptoms of gastro-oesophageal reflux disease (GORD) and blood transfusions with iron replacement for anaemia. Patient Hb improved and was subsequently discharged with outpatient GI follow-up.

Figure 1.

Colonoscopy images demonstrating venous blebs (black arrow) in the colon.

Investigations

• Complete blood count.

• Complete metabolic profile.

• Iron profile (iron level, ferritin level, total iron-binding capacity and transferrin saturation).

• PT.

• INR.

• Oesophagogastroduodenoscopy.

• Colonoscopy.

Differential diagnosis

Our differential diagnoses at this point were BRBNS, mucosal venous malformation syndrome, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), Klippel-Trenaunay syndrome, Maffucci syndrome, diffuse neonatal angiomatosis, Sturge-Weber syndrome and Fabry’s disease.

Treatment

• The patient was treated with conservative management.

• Blood transfusions (two packed red blood cells (RBCs)) and intravenous iron replacement (300 mg intravenous×3 doses) were given to the patient during inpatient hospitalisation.

• PPI were prescribed for symptoms of GORD.

Outcome and follow-up

The patient in outpatient follow-up has been doing better. Hb so far has been stable but the patient has been counselled for further management if Hb drops. The patient has been counselled for low-dose sirolimus for treatment of BRBNS. Sirolimus being the mechanistic target of rapamycin (mTOR) inhibitor can prevent angiogenesis by blocking the phosphorylation of AKT, which is responsible for activation of angiopoietin. Enterotomy with resection of the lesions, endoscopic ligation and sclerotherapy and/or surgical resection of the bowel include further options.

Discussion

BRBNS is a rare disease characterised by multiple vascular malformations present predominantly in the skin and GI tract. In the literature, the word haemangiomas have been used for these lesions. But the histological picture of haemangiomas and vascular malformation is different. Haemangiomas have hyperplastic endothelium, while vascular malformations are lined by normal endothelium. Histologically, vascular malformations of BRBNS are characterised by a collection of dilated irregular spaces lined by normal/thin endothelium with varying amounts of connective tissue.^{5 6} It can occur sporadically but can also be inherited by autosomal dominant pattern. Recent studies have identified chromosome 9 being responsible for a familial form of BRBNS.^7–9 Recently, it has also been reported that activation of TEK gene somatic mutation which encodes the TIE-2 (endothelial cell tyrosine kinase receptor for angiopoietin in humans) can also be responsible for BRBNS. These mutations also cause activation of AKT/PI3K pathway.¹⁰ Its mortality and morbidity depend on the extent of the visceral organ involvement.

The cutaneous lesions of BRBNS are usually soft, bluish and easily compressible lesions leaving an empty space when compressed and refills slowly. Unlike the cutaneous lesions, the vascular malformations in the GI tract are susceptible to bleeding causing anaemia. Many other locations can be involved, such as oropharynx, liver, spleen, parotid gland, heart, lung, pleura, peritoneum, kidney, thyroid, bone, bladder, brain, penis, vulva and eyes.^{7 9} Central nervous involvement has been reported involving different areas of the brain, such as cerebellum and diencephalon. Cases have also been presented with brain haemorrhage and dural arteriovenous fistula. Elderly patients with vascular dementia due to cavernous haemangiomas may present with ataxia and dementia.^{7 11–13}

The GI lesions of BRBNS are more significant than cutaneous and soft tissue lesions. Patients may present with upper or lower GI bleed and continue for a long period of time. These malformations can range from 1 to 10 cm. Sometimes, they can become large enough acting as a lead point for intussusception, volvulus and, subsequently, infarction. In a patient of BRBNS presenting with an acute abdomen, the possibility of one of these malformations bleeding into bowel wall must be ruled out.^{9 14} Evaluation of GI lesions is made by upper and lower endoscopy, barium swallow, nuclear imaging, CT and MRI. Comprehensive gastroscopy and colonoscopy should be done and in the case of negative findings, should prompt the management with capsule endoscopy, which is non-invasive and well-tolerated technique, that can provide complete picture of the intestine, including small intestine.^{14 15} Labelled RBC scan can be the best non-invasive method of diagnosing the lesions when there is GI bleeding and no findings on endoscopies. In patients with no active bleeding and high suspicion, the RBC scan will show pooling of radionuclide in the venous malformation. A barium swallow can only show the polyposis nature of lesion but it cannot differentiate the type of vascular malformation present. MRI is excellent for revealing lesions in the liver, spleen and pancreas.¹⁵

Several pharmacologic agents have been tried for the treatment of BRBNS. Antiangiogenic agents which are commonly used in the treatment of haemangiomas, such as interferon alpha and corticosteroids, have been tried for the treatment of BRBNS but attempts were futile.¹⁶ Patients who have mild intermitted bleeding or occult bleeding, conservative measures, such as iron supplementation and blood transfusion, is recommended along with regular follow-up.⁹ Octreotide has also been tried and believed to decrease the GI blood loss, and hence decreases the need for the blood transfusions.^{16 17} However, there is no convincing evidence for consistent beneficial effects of any pharmacologic treatment.¹⁶ The latest treatment that has been proposed for the treatment of BRBNS is low-dose sirolimus. Sirolimus is an mTOR inhibitor that has antiangiogenic properties and causes inhibition of phosphorylation of AKT responsible for activation of angiopoietin. It resulted in significant improvement of vascular lesions in an 8-year-old girl with BRBNS.^{10 18}

Surgery is also one of the therapeutic options in some cases. However, if numerous haemangiomas are spread throughout the GI tract, resection is not feasible. Multiple surgeries, such as partial gastrectomy, partial small bowel resection and ileostomy, have been done for focal lesions but are associated with significant morbidity. Non-surgical but invasive options, such as endoscopic band ligation and sclerotherapy, have been used in patients with BRBNS of stomach, oesophagus, proximal duodenum and colon. However, there is an associated risk of perforation with these procedures.^{16 18 19} Following is the table showing all the suggested therapeutic options for BRBNS throughout this time (table 1).^20–26

Table 1.

Different therapeutic options for blue rubber bleb nevus syndrome

Author	Therapeutic methods	Outcome	Reference
Maunoury et al	Nd:YAG laser and bipolar electrocoagulation	Successfully stopped bleeding but wasn’t able to avoid haemorrhagic recurrence of the lesion	20
Carr et al	Resection of haemangiomas with each enterotomy	Patient was stable with 5-year follow-up	21
Sala et al	Endoscopic treatment by sclerosis and banding ligation	Therapy was effective with no significant complication	22
Place	Multiple resectional surgeries of the bowel	Significant long-term complications	6
Ng and Kong	Argon plasma coagulation	Simple and effective treatment	23
Anzinger et al	Therapeutic double balloon enteroscopy	Effective	24
Okabayashi et al	Laproscopic surgery	No iron deficiency anaemia for a year	25
Emami et al	Endoscopic polypectomy	Useful in patients with large and polypoid lesions	26
Yuksekkaya et al	Sirolimus	Vascular lesions were reduced and completely resolved after the treatment	18

Taking into preposition that this is a rarely reported disease, clinicians should be encouraged to report and consider the diagnosis of BRBNS with symptoms of chronic anaemia and GI bleeding. When diagnosed with BRBNS, the patient should be counselled about the chronic nature of the disease.

Learning points.

• Blue rubber bleb nevus syndrome (BRBNS) should be considered when a patient presents with gastrointestinal bleeding as early diagnosis and treatment can reduce morbidity and mortality.

• Low-dose sirolimus, a new therapeutic option, is available for the non-invasive management of BRBNS.

• For widespread lesions, conservative management, such as blood transfusion and iron supplementation, remains the considerable option.