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Successful Management of Blue Rubber Bleb Nevus Syndrome (BRBNS) with Sirolimus.

1. Introduction

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 [1]. 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 [2]. 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 [3]. BRBNS usually presents in infancy and childhood and rarely in adulthood [3]. Lesions are blue, rubbery, and compressible, and they occur in several organ/systems and most commonly occur within the skin and gastrointestinal (GI) tract [4].

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. [4], 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.

3. Discussion

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 [4]. 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 [4].

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 [4]. 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) [5]. It has been used successfully in the management of several vascular anomalies such as kaposiform hemangioendothelioma, tufted angioma, and lymphatic malformations [1]. The first case report describing response of BRBNS to sirolimus was published in 2012 by Yussekkaya et al. [4]. 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 [15] and has been proposed as a possible mechanism of action, given that c-kit is a tyrosine kinase upstream of mTOR [3].

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.


Disclosure

The abstract was presented as a poster at the 2015 ASPHO (American Society of Pediatric Hematology/Oncology) meeting.

https://doi.org/10.1155/2018/7654278

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

[1] J. F. Margolin, H. M. Soni, and S. Pimpalwar, "Medical therapy for pediatric vascular anomalies," Seminars in Plastic Surgery, vol. 28, no. 2, pp. 79-86, 2014.

[2] R. Kollipara, L. Dinneen, K. E. Rentas et al., "Current classification and terminology of pediatric vascular anomalies," American Journal of Roentgenology, vol. 201, no. 5, pp. 1124-1135, 2013.

[3] R. Salloum, C. E. Fox, C. R. Alvarez-Allende et al., "Response of blue rubber bleb nevus syndrome to sirolimus treatment," Pediatric Blood and Cancer, vol. 63, no. 11, pp. 1911-1914, 2016.

[4] H. Yuksekkaya, O. Ozbek, M. Keser, and H. Toy, "Blue rubber bleb nevus syndrome: successful treatment with sirolimus," Pediatrics, vol. 129, no. 4, pp. e1080-e1084, 2012.

[5] A. M. Hammill, M. Wentzel, A. Gupta et al., "Sirolimus for the treatment of complicated vascular anomalies in children," Pediatric Blood and Cancer, vol. 57, no. 6, pp. 1018-1024,2011.

[6] A. Taddio, E. Benelli, C. Pierobon, S. Martelossi, I. Berti, and A. Ventura, "From skin to gut," Journal of Pediatrics, vol. 163, no. 2, p. 610, 2013.

[7] B. Warner, A. Butt, and S. Cairns, "Sirolimus is a successful treatment for recurrent iron deficiency anaemia in blue rubber bleb naevus syndrome," Journal of Pediatric Gastroenterology and Nutrition, vol. 61, no. 5, p. e24, 2015.

[8] L. Ferres-Ramis, N. Knopfel, J. Salinas-Sanz, and A. Martin-Santiago, "Rapamycin in the Treatment of Blue Rubber Bleb Nevus Syndrome," Actas Dermo-Sifiliograficas (English Edition), vol. 106, no. 2, pp. 137-138, 2015.

[9] B. Ozgonenel and A. Martin, "Low-dose sirolimus controls recurrent iron deficiency in a patient with blue rubber bleb nevus syndrome," Pediatric Blood and Cancer, vol. 62, no. 11, pp. 2054-2055, 2015.

[10] H. Cardoso, J. A. Dias, M. Silva et al., "Gastrointestinal: successful treatment with sirolimus of a patient with blue rubber bleb nevus syndrome," Journal of Gastroenterology and Hepatology, vol. 31, no. 3, p. 519, 2016.

[11] A. Unlusoy Aksu, S. Sari, O. E. Gurkan, and B. Dalgic, "Favorable response to sirolimus in a child with blue rubber bleb nevus syndrome in the gastrointestinal tract," Journal of Pediatric Hematology/Oncology, vol. 39, no. 2, pp. 147-149, 2017.

[12] C. Akyuz, H. Susam-Sen, and B. Aydin, "Blue rubber bleb nevus syndrome: promising response to sirolimus," Indian Pediatrics, vol. 54, no. 1, pp. 53-54, 2017.

[13] 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.

[14] H. Kizilocak, G. Dikme, and T. Celkan, "Sirolimus experience in blue rubber bleb nevus syndrome," Journal of Pediatric Hematology/Oncology, vol. 40, no. 2, pp. 168-169, 2018.

[15] C. Mogler, C. Beck, A. Kulozik, R. Penzel, P. Schirmacher, and K. Breuhahn, "Elevated expression of c-kit in small venous malformations of blue rubber bleb nevus syndrome," Rare Tumors, vol. 2, no. 2, pp. 99-100, 2010.

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; janice-staber@uiowa.edu

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:
[4]                    successful treatment
                       with Sirolimus

Taddio A, Benelli E,   From skin to gut       J Pediatr
Pierobon C,
Martelossi S, Berti
I, Ventura A [6]

Ozgonenel B, Martin    Low-dose sirolimus     Pediatr Blood Cancer
A [9]                  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 [8]         syndrome

Warner B, Butt A,      Sirolimusis a          J Pediatr
cairns S [7]           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. [3]             syndrome to
                       sirolimus treatment.

Cardoso H, Dias JA,    Gastrointestinal:      J Gastroenterol
Silva M, et al. [10]   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 [12]        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 [13]    transfusion as a
                       life saver in blue
                       rubber bleb nevus
                       syndrome

Kizilocak H, Dikme     Sirolimus experience   J Pediatr Hematol
G, celkan T [14]       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
[4]                                           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 [6]                              swelling on right
                                              ankle, and multiple
                                              skin lesions

Ozgonenel B, Martin    2015                   18 yo F; GI bleeding
A [9]                                         and iron deficiency
                                              anemia

Ferres-Ramis L,        2015                   8 yo with congenital
knopfel N, Salinas-                           cutaneous and GI
Sanz J, Martin-                               vascular
Santiago A [8]                                malformations

Warner B, Butt A,      2015                   18 yo M; hemangioma,
cairns S [7]                                  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. [3]                                    and muscular lesions

Cardoso H, Dias JA,    2016                   19 yo M; multiple
Silva M, et al. [10]                          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 [12]                               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 [13]                           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 [14]                              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/
[4]                    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 [6]

Ozgonenel B, Martin    Hemoglobin improved    1.6 mg/[m.sup.2]/
A [9]                  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 [8]

Warner B, Butt A,      Hemoglobin 6.9 gm/     4mg daily
cairns S [7]           dL, anemia resolved

Salloum R, Fox CE,     Decreased size of      0.8 mg/nr every 12
Alvarez-Allende CR,    lesions, decreased     hour
et al. [3]             pain, normalized
                       hemoglobin

Cardoso H, Dias JA,    improved blood loss,   2 gm/day
Silva M, et al. [10]   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 [12]        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 [13]    tract hemangiomas,
                       no further
                       transfusions

Kizilocak H, Dikme     Normalized             1.2 mg/nr/d
G, celkan T [14]       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
[4]                                           sirolimus
                                              discontinued

Taddio A, Benelli E,   NA                     6 months
Pierobon C,
Martelossi S, Berti
I, Ventura A [6]

Ozgonenel B, Martin    10/15 ng/mL, then      "after starting
A [9]                  goal levels reduced    sirolimus"
                       <2.0/3.1 ng/mL

Ferres-Ramis L,                               Within a month
knopfel N, Salinas-
Sanz J, Martin-
Santiago A [8]

Warner B, Butt A,
cairns S [7]

Salloum R, Fox CE,     dose titrated to       less than 3 months
Alvarez-Allende CR,    target trough level
et al. [3]             between 10 and 13
                       ng/mL

Cardoso H, Dias JA,                           about 5 months
Silva M, et al. [10]

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 [12]                               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 [13]

Kizilocak H, Dikme                            2 months
G, celkan T [14]
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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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