Oral sirolimus in blue rubber bleb naevus syndrome: Evidence of safety, efficacy, and improved quality of life

Dear Editor,

Blue rubber bleb naevus syndrome (BRBNS) is a rare condition characterised by multiple angiomatous lesions on the skin and gastrointestinal mucosa. These lesions can manifest as a gastrointestinal bleed of obscure origin. Cutaneous lesions are generally button-like with a bluish tint and have a rubber-like consistency on palpation, earning the name blue rubber naevus.¹ Rarely, the visceral parenchyma may be involved, including that of the brain, liver, spleen, and thyroid. Cutaneous lesions may cause significant disfigurement, but gastrointestinal lesions can cause chronic anaemia following prolonged bleeding, necessitating repeated blood transfusions and the need for iron administration.¹ Infrequently encountered in dermatology clinics, a high level of clinical suspicion is essential for diagnosis and successfully addressing the extreme morbidity of the patient requiring frequent blood transfusions.

A 5-year-old, fully immunised boy presented with multiple bluish-black swellings on his right lateral malleolus, wrist, soles, and trunk since birth. A similar lesion on the left parietal scalp was excised in childhood, resulting in atrophic scarring. He experienced fatigue and black stools and required blood transfusions every fortnight, affecting his school attendance. There was no other significant medical or family history.

On general examination, he had marked pallor and noticeable maxillary fullness. On cutaneous examination, multiple soft, dark bluish vascular lesions, measuring 2x2 mm to 5x5 mm, were observed on the bilateral soles, right wrist and left elbow. These swellings were tender, compressible with rubbery consistency, and a few of them had a hyperkeratotic surface [Figure 1a and b]. Systemic examination revealed non-tender, mild hepatomegaly. Laboratory findings confirmed iron deficiency anaemia with blood in the stool. Gastrointestinal endoscopy showed multiple venous malformations in the stomach and colon [Figures 2a, b and c]. Skin biopsy was deferred due to anaemia, and genetic testing could not be performed due to financial constraints. A diagnosis of BRBNS was made owing to the cutaneous and visceral lesions, and oral sirolimus was initiated at 1 mg/day. Based on the child’s weight (17kg) and body surface area (0.80 m²), this corresponded to low dose oral sirolimus (0.058 mg/kg/day or 1.25 mg/m²/day). Treatment began after a baseline assessment, including blood counts, metabolic screening, and infectious screening. Monitoring included monthly blood counts, liver and kidney function tests, serum electrolytes, fasting lipid profile and blood sugar, urinalysis, and blood pressure checks. Sirolimus trough levels were not measured due to financial constraints. Within a month after initiating treatment, haemoglobin levels increased from 7.3 g/dL to 9.1 g/dL, along with improvement in fatigue and cutaneous lesions. After three months, haemoglobin levels reached 13.4 g/dL, and sirolimus was continued. At the 24-month follow-up, haemoglobin levels were stable with no further need of blood transfusions, and the cutaneous lesions showed considerable flattening and lightening [Figures 3a and b]. The child is under regular follow-up, and the treatment is being well tolerated.

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Figure 1:

Pre-treatment image showing characteristic soft, rubbery, compressible blue vascular lesions on the a) lateral aspect of left foot and b) plantar aspect of right foot.

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Figure 2a:

Upper gastrointestinal tract endoscopy showing multiple venous malformations (black arrows) in the stomach, with the highest count in the fundus and the largest in the antrum.

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Figure 2b:

Duodenum showing large venous malformation (black arrow).

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Figure 2c:

Colonoscopy showing a large purplish lesion in the sigmoid colon (black arrow) and rectum (black circle), without active bleeding.

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Figure 3a-b:

Post treatment images at 6 months after daily oral sirolimus 1mg therapy. Clinical improvement can be appreciated by the flattening and colour change.

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BRBNS, initially described by Gascoyen in 1860 and later expanded upon by William B. Bean in 1958, is characterised by cutaneous vascular malformations with gastrointestinal tract involvement in approximately 76% of cases.^2,3 It can present with hematemesis, melena, and occult bleeding, causing iron deficiency anaemia to life-threatening complications like intussusception, volvulus, intestinal infarcts, and hypovolemic shock.³ Currently, treatment for BRBNS lacks consensus. Various modalities have been attempted, including surgery, sclerotherapy, laser photocoagulation, and endoscopic sclerosis, mainly for gastrointestinal lesions. Additionally, corticosteroids, thalidomide, propranolol, octreotide, bevacizumab, vincristine, and interferon-α have been used sporadically without sustained efficacy.^1,3,4 BRBNS is associated with somatic mutations in tyrosine kinase receptor TEK/TIE2, which trigger endothelial cell survival pathways, including phosphatidylinositol 3-kinase and mammalian target of rapamycin (mTOR), thereby promoting angiogenesis.⁵ This recent finding underlies the use of sirolimus, an mTOR inhibitor that selectively targets angiogenesis, causing decreased development of new lesions and improvement in anaemia. Since its first use in BRBNS in an 8-year-old with considerable efficacy, few case reports have reiterated its safety and efficacy in the paediatric population.⁶

Our patient demonstrated a remarkable response to sirolimus, eliminating the requirement of blood transfusions throughout the 24-month follow-up. Given this promising outcome, it is crucial to establish consensus regarding sirolimus dosage and treatment duration for BRBNS, along with the creation of international databases for comprehensive data collection. Through this case, we contribute to the literature by sharing our experience with sirolimus in the treatment of BRBNS.