Successful Management of Blue Rubber Bleb Nevus Syndrome (BRBNS) with Sirolimus.
Vascular anomalies can be divided into two broad categories, according to the International Society for the Study of Vascular Anomalies (ISSVA) system: vascular malformations and vascular neoplasms . Vascular malformations include slow-flow malformations (with venous, capillary and/or lymphatic components) and fast-flow malformations (with arterial components); while vascular neoplasms undergo mitosis and include such lesions as infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma, tufted angioma, hemangiopericytoma, and angiosarcoma . Blue rubber bleb nevus syndrome (BRBNS) is primarily considered a slowflow venous malformation, although there has been a single case report which includes a lymphatic component . BRBNS usually presents in infancy and childhood and rarely in adulthood . Lesions are blue, rubbery, and compressible, and they occur in several organ/systems and most commonly occur within the skin and gastrointestinal (GI) tract .
2. Case Description
A Hispanic female initially presented at three years of age with a history of oropharyngeal bleeding since birth and diffuse skin vascular malformations. Upper and lower GI endoscopies revealed multiple vascular anomalies throughout the entire tract. She was subsequently diagnosed with blue rubber bleb nevus syndrome based on clinical and endoscopic findings. Due to GI bleeding, chronic iron deficiency anemia, and the increased need for blood transfusions, she underwent surgical removal of multiple blebs from her stomach, small intestine, and colon. In addition, she underwent a right colectomy, gastrostomy for tube feedings, and a tracheostomy due to multiple tracheal lesions. At the age of 6.5 years, she was referred to pediatric hematology for the management of anemia. She had long-standing iron deficiency anemia due to significant blood loss from GI bleeding, despite previous RBC transfusions, and intravenous iron therapy. To help control bleeding, she underwent frequent sclerosing therapies to multiple lesions, including the pericervical lesions. An oral aminocaproic acid (Amicar) trial of 10 days duration was not successful to reduce GI bleeding. Despite the above interventions, she remained severely anemic (hemoglobin levels 5.2 gm/dL to 7 gm/dL) and required frequent blood transfusions, as often as every 1-4 months. Due to the significant GI bleeding, her stools were black, tarry, often with bright red blood, occurring 3-4 times a week. At age 15, a trial of daily sirolimus therapy was initiated, based on a case report by Yuksekkaya et al. , at a dose of 0.05 mg/kg/dose and levels followed with a target range of 5-10 ng/ml. Within 2 months of initiating sirolimus therapy, she experienced cessation of hematochezia and melena, and her hemoglobin has since remained above 11 g/dl (Figure 1). She is now over 60 months into therapy, remains without anemia, and has not required further blood transfusions. She remains mildly iron deficient to date, most likely due to decreased ability to adequately absorb oral iron due to the blebs and prior GI surgery. No adverse drug reactions have occurred.
Blue rubber bleb nevus syndrome is a rare congenital disorder with hallmarks of venous malformations on the skin and viscera. The skin and soft tissue lesions rarely cause debilitating disease and are mostly a cosmetic concern . In contrast, the GI lesions are a major cause of morbidity. Patients usually develop severe chronic iron deficiency anemia, requiring multiple transfusions due to persistent GI losses .
To date, there is no curative treatment for BRBNS. Management options that have been attempted include iron therapy, blood transfusions, surgical interventions, and pharmacologic agents . Iron therapy and blood transfusions have been employed to alleviate anemia from GI losses. Surgery has been used to eradicate blebs from the skin, soft tissue, or GI tract; however, the blebs eventually recur. Other modalities including laser photocoagulation and sclerotherapy have been applied with limited success. Pharmaceutical agents such as propranolol, octreotide, corticosteroids, interferon alpha, thalidomide, antifibrinolytics, and most recently sirolimus have also been utilized. These have been used based on extrapolation of their efficacy in infantile hemangiomas and other vascular anomalies.
Sirolimus is an immunosuppressant drug that has both antiangiogenic and antineoplastic properties. Its mechanism of action is via pathway inhibition of the mammalian target of rapamycin (mTOR), a serine/threonine kinase regulated by phosphoinositide-3-kinase (PI3K) . It has been used successfully in the management of several vascular anomalies such as kaposiform hemangioendothelioma, tufted angioma, and lymphatic malformations . The first case report describing response of BRBNS to sirolimus was published in 2012 by Yussekkaya et al. . Following that there have been several other reports also describing response to sirolimus [3, 6-14]. Table 1 details the various reports in the literature so far that have described the use of sirolimus for BRBNS.
The exact mechanism of action of sirolimus in BRBNS remains unclear, but proposed mechanisms of action include inhibition of ligand-binding-induced signaling through VEGFR-3 (vascular endothelial growth factor receptor-3) on lymphatic endothelial surface, which would normally result in activation of the PI3K/Akt/mTOR pathway [3, 5]. In addition, c-kit (stem cell growth factor receptor) expression from small venous vessels has been described  and has been proposed as a possible mechanism of action, given that c-kit is a tyrosine kinase upstream of mTOR .
There exists a dilemma as to what constitutes appropriate duration of therapy. Our patient continues on sirolimus at a dose of 1.2 mg/day (0.024 mg/kg/dose), with target trough level of 2-4 ng/mL and has not experienced any side effects. Her hemoglobin and symptoms remained controlled. Of note, when sirolimus was held for a surgical procedure due to concerns for postsurgical wound healing, her GI bleeding returned within 3 days of discontinuation. Further studies are needed to determine if sirolimus can be safely discontinued, without disease relapse.
In conclusion, sirolimus may be used in management of patients with BRBNS. Our case report describes resolution of GI bleeding and obviation of the need for multiple blood transfusions following initiation of sirolimus therapy. We propose this as an alternative therapy for the treatment of symptomatic BRBNS, especially when other conventional therapies have proved to be unsuccessful.
Abbreviations BRBNS: blue rubber bleb nevus syndrome GI: gastrointestinal mTOR: mammalian target of rapamycin ISSVA: International Society for the Study of Vascular Anomalies PI3K: phosphoinositide-3-kinase.
The abstract was presented as a poster at the 2015 ASPHO (American Society of Pediatric Hematology/Oncology) meeting.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
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 K. L. Wang, S. F. Ma, L. Y. Pang et al., "Sirolimus alternative to blood transfusion as a life saver in blue rubber bleb nevus syndrome: a case report," Medicine (Baltimore), vol. 97, no. 8, article e9453, 2018.
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Ugochi O. Ogu, (1) Ghada Abusin, (2) Rolla F. Abu-Arja, (3) and Janice M. Staber (4)
(1) Division of Hematology, Department of Oncology, Montefiore Medical Center, Bronx, NY, USA
(2) Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
(3) Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, OH, USA
(4) Division of Pediatric Hematology/Oncology, Stead Family Department of Pediatrics,
University of Iowa Carver College of Medicine, Iowa City, IA, USA
Correspondence should be addressed to Janice M. Staber; firstname.lastname@example.org
Received 14 August 2018; Accepted 17 September 2018; Published 8 October 2018
Academic Editor: Bernhard Resch
Caption: Figure 1: Hemoglobin concentration before and after Sirolimus therapy.
Table 1: Articles on BRBNS with Sirolimus therapy. Article authors Article title Article journal Yuksekkaya H, Ozbek Blue rubber bleb Pediatrics 0, keser M, Toy H nevus syndrome:  successful treatment with Sirolimus Taddio A, Benelli E, From skin to gut J Pediatr Pierobon C, Martelossi S, Berti I, Ventura A  Ozgonenel B, Martin Low-dose sirolimus Pediatr Blood Cancer A  controls recurrent iron deficiency in a patient with blue rubber bleb nevus syndrome Ferres-Ramis L, Rapamycin in the Actas Dermo- knopfel N, Salinas- treatment of blue Sifiliograficas Sanz J, Martin- rubber bleb nevus (English Edition) Santiago A  syndrome Warner B, Butt A, Sirolimusis a J Pediatr cairns S  successful treatment Gastroenterol Nutr for recurrent iron deficiency anemia in blue rubber bleb nevus syndrome Salloum R, Fox CE, Response of blue Pediatr Blood Cancer Alvarez-Allende CR, rubber bleb nevus et al.  syndrome to sirolimus treatment. Cardoso H, Dias JA, Gastrointestinal: J Gastroenterol Silva M, et al.  successful treatment Hepatol with sirolimus of a patient with blue rubber bleb nevus syndrome Unlusoy Aksu A, Sari Favorable response J Pediatr Hematol S, Egritas Gurkan O, to sirolimus in a Oncol Dalgic B [H] child with blue rubber bleb nevus syndrome in the gastrointestinal tract Akyuz C, Susam-Sen Blue rubber bleb INDIAN Pediatr H, Aydin B  nevus syndrome: promising response to sirolimus Wang KL, Ma SF, Pang Sirolimus Medicine (Baltimore) LY, Zhang MN, Hu LY, alternative to blood Liu MJ, Zou LP  transfusion as a life saver in blue rubber bleb nevus syndrome Kizilocak H, Dikme Sirolimus experience J Pediatr Hematol G, celkan T  in blue rubber bleb Oncol nevus syndrome Article authors Article year Patient Yuksekkaya H, Ozbek 2012 8 yo F; GI bleeding, 0, keser M, Toy H not responsive to  prednisolone, propranolol, aminocaproic acid, and alpha- interferon therapy Taddio A, Benelli E, 2013 3 yo M; severe iron Pierobon C, deficiency anemia, Martelossi S, Berti large subcutaneous I, Ventura A  swelling on right ankle, and multiple skin lesions Ozgonenel B, Martin 2015 18 yo F; GI bleeding A  and iron deficiency anemia Ferres-Ramis L, 2015 8 yo with congenital knopfel N, Salinas- cutaneous and GI Sanz J, Martin- vascular Santiago A  malformations Warner B, Butt A, 2015 18 yo M; hemangioma, cairns S  tracheostomy, anemic; thalidomide-discontinued due to side effects; multiple bowel resections to remove vascular malformations Salloum R, Fox CE, 2016 2-16 yo, cutaneous, Alvarez-Allende CR, GI tract, visceral et al.  and muscular lesions Cardoso H, Dias JA, 2016 19 yo M; multiple Silva M, et al.  visceral, muscular, and subcutaneous vascular lesions, complicated with chronic local pain and GI bleeding requiring RBC transfusion (total of 74); treatment with thermal argon ablation and sclerosis and segmental jejunoileal surgical resections, propranolol and ferric carboxymaltose Unlusoy Aksu A, Sari 2017 11 yo M with S, Egritas Gurkan O, vascular Dalgic B [H] malformation in GI tract Akyuz C, Susam-Sen 2017 6 yo F with skin H, Aydin B  lesions, GI tract and consumptive coagulopathy (platelets 77K, fibrinogen 104 mg/ dL, d/dimer >40 mg/ dL); oral steroids without success; bleeding requiring transfusions (hemoglobin 6.1 gm/ dL) Wang KL, Ma SF, Pang 2018 12 yo F with LY, Zhang MN, Hu LY, multiple hemangiomas Liu MJ, Zou LP  on head and neck, limbs and trunk, tip of tongue and digestive tract. Severe anemia, requiring red cell transfusion every 2 weeks. Mutation in exon 15 of TEK gene Kizilocak H, Dikme 2018 Four children, ages G, celkan T  4-15 years. Three with GI lesions, one with respiratory tract lesions Article authors Response to Sirolimus dose Sirolimus Yuksekkaya H, Ozbek Hemoglobin improved 0.05-0.1 mg/kg 0, keser M, Toy H from 7gm/dL to 14gm/  dL (with iron supplement); Taddio A, Benelli E, Hemoglobin improved not available (NA) Pierobon C, from 6.4 gm/dL to Martelossi S, Berti 'stable ' I, Ventura A  Ozgonenel B, Martin Hemoglobin improved 1.6 mg/[m.sup.2]/ A  from 5 gm/dL to /14 day divided BID; gm/dL reduced to 0.6 mg/ [m.sup.2]/day Ferres-Ramis L, Decreased size of Initial dose 0.05 knopfel N, Salinas- lesions, normalized mg/kg, reduced to Sanz J, Martin- hemoglobin 0.02 mg/kg Santiago A  Warner B, Butt A, Hemoglobin 6.9 gm/ 4mg daily cairns S  dL, anemia resolved Salloum R, Fox CE, Decreased size of 0.8 mg/nr every 12 Alvarez-Allende CR, lesions, decreased hour et al.  pain, normalized hemoglobin Cardoso H, Dias JA, improved blood loss, 2 gm/day Silva M, et al.  asthenia, and decreased size of lesions; hemoglobin improved by 6 gm/dL Unlusoy Aksu A, Sari Normalized 0.1 mg/kg/d S, Egritas Gurkan O, hemoglobin in 2.5 Dalgic B [H] months, decreased lesions in 5 months Akyuz C, Susam-Sen improved size and 1.6 to 2 mg/nr/day H, Aydin B  number of lesions, no further GI bleeding or anemia Wang KL, Ma SF, Pang Improved hemoglobin, 1 mg/nr/d, average LY, Zhang MN, Hu LY, skin and digestive 0.7 mg/d Liu MJ, Zou LP  tract hemangiomas, no further transfusions Kizilocak H, Dikme Normalized 1.2 mg/nr/d G, celkan T  hemoglobin, decreased pain, decreased size of lesions Article authors Sirolimus level Time to improvement Yuksekkaya H, Ozbek 1-5ng/mL 2 months. Symptoms 0, keser M, Toy H returned if  sirolimus discontinued Taddio A, Benelli E, NA 6 months Pierobon C, Martelossi S, Berti I, Ventura A  Ozgonenel B, Martin 10/15 ng/mL, then "after starting A  goal levels reduced sirolimus" <2.0/3.1 ng/mL Ferres-Ramis L, Within a month knopfel N, Salinas- Sanz J, Martin- Santiago A  Warner B, Butt A, cairns S  Salloum R, Fox CE, dose titrated to less than 3 months Alvarez-Allende CR, target trough level et al.  between 10 and 13 ng/mL Cardoso H, Dias JA, about 5 months Silva M, et al.  Unlusoy Aksu A, Sari 1-5ng/mL 2.5-5 months S, Egritas Gurkan O, Dalgic B [H] Akyuz C, Susam-Sen 5-12 ng/mL Less than 1 month. H, Aydin B  Disconintued sirolimus and at 4 months off therapy- no evidence of microscopic blood in stool and normal hemaglobin levels, stable Wang KL, Ma SF, Pang 6.2-11.89 ug/L lesions 1 month LY, Zhang MN, Hu LY, Liu MJ, Zou LP  Kizilocak H, Dikme 2 months G, celkan T 
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|Title Annotation:||Case Report|
|Author:||Ogu, Ugochi O.; Abusin, Ghada; Abu-Arja, Rolla F.; Staber, Janice M.|
|Publication:||Case Reports in Pediatrics|
|Date:||Jan 1, 2018|
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