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Blue rubber bleb nevus syndrome (BRBNS) commonly presents with anemia from bleeding gastrointestinal (GI) vascular malformations. Management is highly variable, as no consensus guidelines for medical treatment currently exist. Sirolimus has been used in BRBNS to decrease GI bleeding and seems well tolerated, though questions remain regarding dosing, duration of therapy, and adverse effects. Here, we report our single-center experience of four pediatric patients with BRBNS who were successfully treated with sirolimus and review the existing literature regarding sirolimus for treatment of GI bleeding in BRBNS. Further prospective studies are needed to establish optimal dosage, drug monitoring, and duration.

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RATIONALE: Blue rubber bleb nevus syndrome (BRBNS) is a rare condition with characteristic vascular malformations of the skin, most frequently lesions of the gastrointestinal tract and central nervous system, and less often, the musculoskeletal system. We report a 5-year case of BRBNS complicated with pathological femoral fracture that was successfully treated with sirolimus. PATIENT CONCERNS: We report the case of a 1-week-old girl with a diagnosis of BRBNS who had multiple venous malformations over her body. She also presented with right lower-limb swelling and complicated with a pathological femoral fracture. DIAGNOSES: BRBNS with the complication of pathological femoral fracture. INTERVENTIONS: Treatment with low-dose sirolimus as an antiangiogenic agent was administered, combined with hip spica protection. OUTCOMES: The vascular lesion was reduced after about 6 months and the fracture site had healed around 2.5 years after initiation of sirolimus therapy. There were no drug adverse effects at the 5-year follow-up point. The patient showed excellent spirit and no obvious sequelae were found. LESSONS: To the best of our knowledge, this is the first report of the successful use of sirolimus in a patient with a pathological femoral fracture related to BRBNS complications.

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INTRODUCTION: Blue rubber bleb nevus syndrome (BRBNS) is a rare systemic venous malformation (VM) disease. The characteristic gastrointestinal (GI) bleeding from multiple VM lesions causes severe chronic anemia which renders most patients depend on lifelong blood transfusion and frequent endoscopic treatment with dismayed outcomes. Although recent case reports suggest that oral sirolimus (rapamycin) is effective, a comprehensive evaluation of its efficacy and safety is in need. METHODS: A prospective study was conducted for both pediatric and adult BRBNS patients with administration of sirolimus at the dose of 1.0 mg/m2 to maintain a trough concentration of 3-10 ng/mL. Laboratory tests including complete blood count, biochemical profile, D-dimer, and whole-body magnetic resonance imaging were performed at baseline and 3, 6, and 12 months after treatment. Clinical indicators such as hemoglobin level, lesion size, and transfusion need were evaluated. Adverse effects were recorded regularly. RESULTS: A total of 11 patients (4 males and 7 females) with median age of 14 (range, 5-49) years were recruited. The average lesion size was reduced by 7.4% (P < 0.001), 9.3% (P < 0.001), and 13.0% (P < 0.05) at 3, 6, and 12 months of sirolimus treatment, respectively. Hemoglobin increased significantly after 6- and 12-month treatment (P = 0.006 and 0.019, respectively). Only 1 patient received blood transfusion once during the study. Patients' quality of life and coagulation function were improved. Grade 1-2 adverse effects including oral ulcers (81.8%), acne (27.3%), transient elevation of liver enzymes (18.2%), and hair loss (9.1%) were observed. DISCUSSION: Sirolimus reduces the size of VMs, alleviates GI bleeding, and eliminates transfusion dependence of patients with BRBNS. The drug-related adverse effects are mild and mostly self-limited. These findings support sirolimus as a first-line treatment for GI and cutaneous VMs of BRBNS (see Visual abstract, Supplementary Digital Content, http://links.lww.com/AJG/B819).

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Blue rubber bleb nevus syndrome is a rare vascular syndrome characterized by continuous eruption of vascular nodules in the skin, mucous membranes, and solid organs due to somatic activating mutations of the angiopoietin receptor TEK gene. It may be complicated by acute life-threatening hemorrhage and localized intravascular coagulation. We report an 11-year-old girl with complicated blue rubber bleb nevus syndrome treated with sirolimus since the age of 2. We review the literature on sirolimus therapy for children with blue rubber bleb nevus syndrome.

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To study the clinical effect of oral sirolimus in the treatment of children with blue rubber bleb nevus syndrome (BRBNS) in the gastrointestinal tract, a retrospective analysis was performed on the clinical data and follow-up results of two children with BRBNS treated by sirolimus. The two children with BRBNS had gastrointestinal bleeding and anemia and were treated with sirolimus at a dose of 1 mg/day as part of treatment. The plasma concentration of the drug was maintained between 2.5-12.0 ng/mL. The children showed disappearance of gastrointestinal bleeding and improvements in anemia and coagulation function, and blood transfusion could be stopped during treatment, with no obvious adverse drug reactions. PubMed, Wanfang Data, and CNKI were searched for related articles on sirolimus in the treatment of BRBNS. A total of 26 cases of children with BRBNS, aged 0-18 years, were obtained. With the addition of the 2 cases in this study, sirolimus treatment achieved a satisfactory clinical effect in all 28 cases. Sirolimus may be effective and safe in the treatment of children with BRBNS, and further prospective studies are needed to evaluate the long-term efficacy of this drug.

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Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0-1.5 mg/m2 /day with a target drug level of 5-10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.

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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.

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Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder with characteristic skin hemangiomas and vascular malformations, mostly in the gastrointestinal (GI) tract. The GI lesions are mainly located in the stomach and small intestine, usually more than a hundred, leading to gastrointestinal bleeding and severe chronic anemia. Parenteral iron infusions and scheduled transfusions are frequently necessary. We describe the case of a 21-year-old male with anemia secondary to BRBNS, who becomes unresponsive to octreotide and shows an excellent response to sirolimus (SRL), dismissing the intravenous iron supplementations and being free of transfusions. During the treatment, the patient presents avascular hip necrosis, which is adequately treated with an injection of stem cells with complete recovery, and without the suspension of SRL. Two years later, adequate response persists with no other relevant side effects.

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The aim of this study is to review sirolimus as a treatment for blue rubber bleb naevus syndrome (BRBNS). A literature search of Medline, Embase, CINAHL, SCOPUS and Google Scholar was conducted for publications reporting treatment of patients with BRBNS with sirolimus. Of 46 articles identified, 17 studies reporting 23 patients met inclusion criteria. Sirolimus was well tolerated in all but one patient who required treatment cessation; 17/18 patients noted an improvement in gastrointestinal disease where this was reported; 21/22 patients noted an improvement in cutaneous disease where this was reported. Based on these results, sirolimus may be considered a first-line treatment of BRBNS depending on patient morbidity.

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RATIONALE: Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by multiple venous malformations. The gastrointestinal bleeding and secondary iron deficiency anemia are the most common complications. There are currently no effective treatments for BRBNS. Here, we report a case of successful treatment with a small dose of sirolimus of a BRBN patient with a de novo gene mutation. PATIENT CONCERNS: A 12-year-old female was admitted to our hospital with multiple hemangiomas for 12 years. The patient often displayed melena; she recently received transfusion of 2 units of red blood cells once every 2 weeks. Multiple fist-sized hemangiomas were piled up on both sides and back of the neck, and were also noted on the arms, legs, chest, back, and on the tip of the tongue. The laboratory findings demonstrated severe anemia. Blood sample sequencing detected a heterozygous de novo mutation c.2545C > Tin the TEK gene. DIAGNOSES: Based on these findings, final diagnosis of Blue rubber bleb nevus syndrome (BRBNS) was made. INTERVENTIONS: After the diagnosis, low-dose sirolimus was orally administered. OUTCOMES: The patient's hemoglobin was increased after treatment with sirolimus for 1 month. Since the initial treatment with sirolimus, she had not received any blood transfusions. The skin and mucosal hemangioma decreased significantly, and new digestive tract hemorrhage, muscle hematoma, or adverse drug reactions were not observed. LESSONS: we report a case of a mutation in exon 15 of the TEK gene leading to BRBN. It was successfully treated with a small dose of sirolimus as an alternative to blood transfusion in order to save the of BRBN patient's life.

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BACKGROUND: Blue rubber bleb nevus syndrome is a rare disease involving venous malformations. CASE CHARACTERISTICS: We present a 6-year-old female with the syndrome, and consumptive coagulopathy. INTERVENTION/OUTCOME: After management with sirolimus, symptoms resolved. MESSAGE: Sirolimus may be a valuable option for reducing bleeding complications and cosmetic sequelae for the patients with this syndrome.

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Recently, sirolimus was demonstrated to be effective in treating vascular lesions and lessening the frequency of bleeding and secondary iron deficiency anemia. We present a child with blue rubber bleb nevus syndrome who had prolonged history of iron deficiency anemia secondary to unrecognized gastrointestinal bleeding. Treatment with propranolol, omeprazole and iron had failed. After 2.5 months of sirolimus therapy (trough levels 1 to 5 ng/mL), his hemoglobin concentration improved into the normal range and remained stable. Vascular malformations on both the patient's tongue and in the fundus of his stomach shrank within 5 months of the initiation of sirolimus. In gastrointestinal involvement of blue rubber bleb nevus syndrome sirolimus was found to be effective even in the tongue's vascular lesions.

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BACKGROUND: Blue rubber bleb nevus syndrome (BRBNS) is a rare multifocal venous malformation syndrome involving predominantly the skin and gastrointestinal tract. Traditional treatment modalities include corticosteroids, interferon-α, sclerotherapy, and aggressive surgical resection. Sirolimus has been used in several single case reports. PROCEDURE: We performed a single-institution retrospective review of four children with BRBNS, who received sirolimus as part of their treatment regimens. A diagnosis of BRBNS was based on clinical, radiologic, and pathologic criteria. RESULTS: Median age was 6.5 years (range: 2-16 years). Pathologic evaluations revealed a combined malformation with venous and lymphatic components. The novel finding of a lymphatic component was confirmed with PROX-1 immunostaining. Patients received oral sirolimus with target drug levels between 10 and 13 ng/ml. Responses to treatment were defined as stabilization/decrease in size of lesions; resolution of transfusion requirements; reduction in pain, and improvement in quality of life (QOL). Median time to response was 1.5 months (SD ± 0.96 month, range: 1-3 months). Median follow-up was 21 months (range: 18-26 months). Lesion size and characteristics improved in all patients. All patients reported decrease in pain and improvement in QOL. All three patients requiring transfusions became transfusion-independent. One patient had resolution of coagulopathy. Adverse effects of sirolimus consisted of mucositis in three patients and neutropenia in one patient. CONCLUSIONS: Sirolimus is safe and efficient for the treatment of BRBNS. Further prospective studies are needed to evaluate the long-term effectiveness of this drug. This is the first report that identifies a lymphatic component as part of BRBNS.

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