Refractory Blue Rubber Bleb Nevus Syndrome in an Adult: Limitations of Endoscopic Therapy and Sirolimus

Abstract

This case describes a 68-year-old man with recurrent gastrointestinal bleeding who was ultimately diagnosed with blue rubber bleb nevus syndrome with small-bowel predominance. Ongoing bleeding persisted despite multiple endoscopic interventions and medical therapy with sirolimus and octreotide, necessitating small-bowel resection. This case underscores the challenges in managing refractory gastrointestinal bleeding in adult late-onset blue rubber bleb nevus syndrome and highlights the potential role of early surgical intervention. The patient's sustained postoperative resolution of symptoms supports consideration of small-bowel resection in selected patients with small-bowel–predominant disease who fail endoscopic and medical therapies.

INTRODUCTION

Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular disorder with multifocal venous malformations, most commonly in the gastrointestinal tract. While usually diagnosed in childhood, adult presentations are increasingly recognized and challenging.

A subset of BRBNS cases has been linked to somatic or germline mutations in the TEK gene, which encodes the TIE2 tyrosine kinase receptor.¹ Constitutive activation of the TIE2 signaling pathway is thought to promote dysregulated angiogenesis, leading to the development of venous malformations. Gastrointestinal involvement represents a major source of morbidity, frequently manifesting as severe iron deficiency anemia or recurrent overt gastrointestinal bleeding, and less frequently as intussusception or bowel obstruction.

Management of BRBNS remains nonstandardized and is guided by disease burden and bleeding severity. Endoscopic therapies such as band ligation, sclerotherapy, and argon plasma coagulation, as well as segmental surgical resection for refractory or localized disease, have been used with variable success. Medical therapies, including octreotide and mechanistic target of rapamycin (mTOR) inhibitors, have been reported with variable efficacy.^2–6

We report a case of adult-onset BRBNS presenting with transfusion-dependent gastrointestinal bleeding refractory to endoscopic and medical therapy, ultimately requiring surgical resection with sustained clinical remission.

CASE REPORT

A 68-year-old man presented with melena, dyspnea, and fatigue, which began approximately 1 month after initiation of apixaban for newly diagnosed atrial fibrillation. His medical history was notable for obstructive sleep apnea, essential hypertension, dyslipidemia, and benign sessile colonic polyps identified on 3 previous colonoscopies.

On presentation, hemoglobin was 51 g/L (135–175 g/L) with persistent overt gastrointestinal bleeding and melena requiring near-daily transfusions despite cessation of apixaban. Esophagogastroduodenoscopy and colonoscopy revealed no identifiable source of bleeding. Arterial-phase abdominal CT showed no evidence of active hemorrhage. Technetium-99m–labeled red blood cell scintigraphy demonstrated active bleeding of the small bowel in the left hemiabdomen. Video capsule endoscopy revealed more than a dozen hemorrhagic mucosal lesions involving a long segment of the proximal small bowel.

Balloon enteroscopy showed approximately 12 blue-colored venous blebs with bleeding stigmata extending from the distal duodenum to the proximal jejunum. Three large, high-risk venous blebs were treated with argon plasma coagulation (Figure 1). Repeat enteroscopy identified additional high-risk bleeding venous blebs in the small bowel which were treated with endoscopic clip placement (Figure 2). The affected segment was tattooed to facilitate surgical localization given our inability to reach and treat all lesions seen on the video capsule endoscopy. After endoscopic therapy, transfusion needs decreased, but due to ongoing significant blood loss, sirolimus (2 mg orally once a day) was started. Despite therapeutic trough levels (12.3 ng/mL) at 2 weeks, he experienced recurrent melena with escalating transfusion requirements. At 3 weeks, subcutaneous octreotide (50 μg twice a day) was added. No clinical improvement followed.

Figure 1.

Endoscopic appearance of small-bowel venous malformations in blue rubber bleb nevus syndrome. Balloon enteroscopy demonstrating a large blue venous bleb in the distal duodenum (D3) with high-risk stigmata for bleeding (A), followed by post–argon plasma coagulation appearance of the same lesion (B). Tx, treatment.

Figure 2.

Actively bleeding small-bowel venous malformation treated with endoscopic clipping. Balloon enteroscopy demonstrating multiple venous blebs in the small bowel (A, B), including a lesion in the proximal jejunum with evidence of recent (C) or active bleeding (D, E), followed by successful mechanical hemostasis with endoscopic clip placement (F).

Given ongoing transfusion dependence and refractory diffuse small-bowel bleeding, resection of the jejunal segment harboring the largest lesions was performed, achieving definitive hemostasis. Histopathology revealed multiple submucosal vascular and lymphatic lesions consistent with BRBNS. Postoperatively, hemoglobin normalized with no further transfusion required.

DISCUSSION

Cutaneous lesions predominate in early childhood BRBNS, whereas gastrointestinal venous malformations usually appear in early adulthood.⁷ Our patient presented with gastrointestinal bleeding without cutaneous involvement, an uncommon presentation.^8,9 Small-bowel–predominant BRBNS is challenging due to limited endoscopic access, diffuse lesions, high risk of recurrent bleeding, and variable response to medical therapy.

Our case illustrates BRBNS presenting with nonspecific symptoms and diffuse distal duodenal and proximal jejunal involvement with limited endoscopic and medical therapeutic success. Endoscopic therapy can serve as a temporizing measure. In our patient, transfusion requirements decreased after argon plasma coagulation. However, vascular malformations carry an inherent risk of recurrent bleeding. Case series suggest that multiple endoscopic sessions are often needed, and surgery may be more definitive for complete hemostasis, especially for extensive small-bowel disease.²

Sirolimus was administered for a shorter duration than in pediatric studies, where the average time to hemoglobin normalization is 52 days.¹⁰ Despite achieving therapeutic drug levels, persistent bleeding in our adult patient suggests that adequate sirolimus exposure does not always translate to effective hemostasis, especially in cases with diffuse small-bowel involvement. In a systematic review of 18 children with BRBNS with gastrointestinal manifestations treated with sirolimus, 17 of 18 patients reported improvement in symptoms defined as decreased need for transfusions and bleeding.¹¹ Octreotide has been associated with reduced transfusion requirements, likely through its ability to decrease splanchnic blood flow and mitigate ongoing bleeding.¹² However, the addition of both sirolimus and octreotide did not change transfusion needs in our patient, suggesting medical therapy may be insufficient for extensive disease.

Available data suggest that medical and endoscopic therapies can provide short-term benefit, but surgical resection remains the most definitive intervention for BRBNS. In a meta-analysis of 106 patients younger than 18 years with BRBNS, all surgically treated patients achieved clinical success at 2 years, with extensive resection required in 65.5% of cases.² Endoscopic and pharmacological therapies achieved 86.4% and 92.5% success at 1 year, further supporting surgery as definitive therapy.² In our patient, surgical resection provided complete resolution of bleeding at 1-year follow-up, highlighting the importance of early surgical evaluation in adults failing endoscopic and medical management. Histopathologic confirmation postresection remains essential to establish the diagnosis and exclude alternative vascular entities. While surgical resection can achieve long-term bleeding control in localized disease, recurrence is possible from residual or newly developing venous malformations. In a series of 10 surgically treated patients with BRBNS followed for a mean of 5 years, recurrent bleeding occurred in 1 patient 2 years after surgery.¹³ Notably, this patient did not undergo intraoperative small-bowel enteroscopy, and lesions were instead resected based solely on external examination and palpation of the bowel, underscoring the importance of meticulous intraluminal lesion localization.¹³ This emphasizes the value of intraoperative enteroscopy and preoperative tattooing, as performed in our patient.

This case demonstrates the diagnostic and therapeutic challenges of adult-onset, small-bowel–predominant BRBNS. Persistent bleeding despite multiple endoscopic interventions and therapeutic sirolimus levels underscores the limitations of nonsurgical therapy in diffuse disease. Surgical resection should be considered early in adult patients with extensive small-bowel involvement to achieve durable hemostasis.

DISCLOSURES

Author contributions: Y. Pilon wrote the original draft of the manuscript. All authors reviewed and critically revised the manuscript and approved the final version for submission. C. Soulellis is the article guarantor.

Financial disclosure: None to report.

Informed consent was obtained for this case report.

ABBREVIATIONS:

BRBNS

Blue rubber bleb nevus syndrome

mTOR

Mechanistic target of rapamycin

Tx

Treatment