Blue Rubber Bleb Nevus Syndrome


Article Author:
Dana Baigrie


Article Editor:
In An


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William Gossman


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Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
4/21/2019 9:40:36 PM

Introduction

Blue Rubber Bleb Nevus Syndrome is also known as Bean syndrome. It is a rare syndrome of venous malformations which arise in the skin and gastrointestinal tract. Patients present with multiple venous malformations in various organ systems including the liver, spleen, heart, eye, and central nervous system. Blue rubber bleb nevus syndrome patients are at increased risk for gastrointestinal hemorrhage and severe iron deficiency anemia. They require a multifaceted medical management approach with hematology, dermatology, gastroenterology, and other specialties caring for the patient. Treatment is largely supportive and involves managing potential complications such as volvulus, intussusception, infarction, and gastrointestinal bleeding.[1][2][3][4]

Etiology

The syndrome is usually a sporadic disorder; however, autosomal dominant modes of inheritance are reported, specifically with a locus found on chromosome 9p.[5][6] Recently, somatic mutations in TIE2, an endothelial cell tyrosine kinase receptor for angiopoietins, has been discovered to cause the disorder. Soblet et al. studied 17 patients with blue rubber bleb nevus syndrome along with six individuals with multifocal vascular malformations.M In most of the patients with blue rubber bleb nevus syndrome had two somatic TEK mutations.[7]

Epidemiology

Blue rubber bleb nevus syndrome is a rare disorder. Approximately 200 cases have been reported in the literature.[8][9] It has been reported in all races, with Caucasians most frequently affected. The syndrome affects both males and females with equal frequency, and the cutaneous manifestations typically present at birth or early childhood. However, visceral involvement tends to present later in life in early adulthood.[10]

Histopathology

Histopathologic features of cutaneous lesions are non-specific and have features of venous malformations. Large, tortuous, dilated vessels with a single endothelial lining are noted, and smooth muscle may be present in the vessel walls. Calcification may be seen.[11]

History and Physical

Patients will present at birth or in early childhood with multiple blue to violaceous soft compressible nodules on the skin or mucous membranes. The typical skin lesions are described as rubbery in consistency and may be painful or tender when compressed. These lesions can range in size from only a few millimeters in diameter to up to 4 to 5 cm in diameter. They can increase in size with time, and more lesions may develop in the skin or gastrointestinal tract with time. Blue marks that are large and disfiguring may appear as well. The lesions have a response to dependency; therefore, they can swell when placed in a dependent position.[8]

Since venous malformations can be seen in various locations throughout the body, which can make a physical examination challenging. The venous malformations may be located in the heart, spleen, liver, central nervous system, and gastrointestinal tract. The small bowel is the most common site of gastrointestinal tract involvement; however, lesions can occur anywhere from the mouth to the anus. Patients may present with severe iron deficiency anemia from recurrent gastrointestinal hemorrhage due to malformations in the gastrointestinal tract.[12] Angiomas and venous malformations of the retina, conjunctiva, iris, and orbit may occur.[13][14]

Venous malformations are slow-flow lesions, making them prone to thrombosis. Thrombosis presents as an erythematous, warm swelling that may be tender to palpation.[8]

There are case reports of thyroid, parotid, musculoskeletal, lung, and bladder involvement as well.[8]

Evaluation

Aside from clinical diagnosis, other diagnostic modalities include imaging studies. Ultrasound would be the first study of choice as it is the least invasive. Ultrasound may be performed endoscopically if gastrointestinal venous malformations are suspected. Ultrasound should be performed by a radiologist or ultrasound technician who is experienced in vascular anomalies. Since the radiologist reading the study may not have the clinical history or benefit of seeing the patient in real-time, it is recommended by some sources to send the patient for an ultrasound at the vascular anomalies center. If ultrasound is inconclusive or not possible, then an MRI with intravenous contrast, arterial and venous phases, and fat suppression is indicated if needed for diagnostic reasons. Other diagnostic modalities include CT, barium studies, and skin biopsy. Technetium Tc-99m-labeled red blood cell imaging may help localize the source and extent of blood loss.[15]

Blue rubber bleb nevi can be examined under dermoscopy with features including superficial, light red arborizing veins, maculae with undefined borders on the palms and soles, and blue-purple nodules with lacunae divided by white linear structures.[16]

Other laboratory studies that may be helpful in evaluation and management include fecal occult blood tests, complete blood counts, iron panels, and urinalysis to screen for hematuria and bladder involvement.[17]

Treatment / Management

Treatment of blue rubber bleb nevus syndrome is largely symptomatic. The most important step is monitoring the evolution of gastrointestinal lesions and preventing severe bleeding. Patients may benefit from iron replacement or transfusions if iron deficiency anemia occurs from gastrointestinal bleeding. Other treatment options for vascular malformations include endoscopic sclerotherapy, band ligation, or laser photocoagulation. Resection of portions of the gastrointestinal tract may become necessary if there is significant involvement to prevent gastrointestinal hemorrhage, which can be life-threatening.[18] 

Pharmacologic agents have been tried with variable response.[4] Somatostatin analogs like subcutaneous octreotide can be used to decrease splanchnic blood flow in patients with gastrointestinal hemorrhage. This may be helpful in decreasing the need for blood transfusions in these patients. Other pharmacologic agents reported to prove helpful include corticosteroids, sirolimus, interferon alpha IVIG, and vincristine.[19] Sirolimus is recently reported in the literature as a successful treatment option for this condition; however, the dose and treatment duration remains uncertain. This angiogenesis inhibitor has been used to avoid blood transfusions in these patients, who often require multiple in their lifetime. In several studies, adverse drug reactions and complications from the medicine including hepatic, renal, neutropenia, systemic infection, or cholesterol levels were not observed.[19][20][21][22]]

The patient may require evaluation by an orthopedic surgeon if they develop complications from venous malformations in the bone leading to deformation such as bowing or pathologic fractures. They will also need to be managed by a gastroenterologist, hematologist, ophthalmologist, and possibly, cardiovascular or neurosurgeon if central nervous system involvement occurs.[8][14]

Differential Diagnosis

Differential diagnosis of blue rubber bleb nevus syndrome includes other congenital vascular malformation syndromes such as diffuse neonatal hemangiomatosis, familial glomangiomatosis, Klippel-Trenaunay-Weber syndrome, Maffucci syndrome, and mucosal venous malformation syndrome.[23][24]

Prognosis

Individuals with blue rubber bleb nevus syndrome usually have a normal lifespan as long as the bleeding is controlled and no serious complications such as gastrointestinal hemorrhage result. The venous malformations will persist throughout the patient’s life.[2]

Consultations

Patients with blue rubber bleb nevus syndrome will require a multispecialty approach to management. They may need evaluation by an orthopedic surgeon if they develop complications from venous malformations in the bone that lead to deformation such as bowing or pathologic fractures. They will also need monitoring by a gastroenterologist, hematologist, ophthalmologist, and possibly, cardiovascular or neurosurgeon if central nervous system involvement occurs.[8][14]

Enhancing Healthcare Team Outcomes

Blue Rubber Bleb Nevus Syndrome is also known as Bean syndrome. It is a rare syndrome of venous malformations which arise in the skin and gastrointestinal tract. Patients present with multiple venous malformations in various organ systems including the liver, spleen, heart, eye, and central nervous system. Blue rubber bleb nevus syndrome patients are at increased risk for gastrointestinal hemorrhage and severe iron deficiency anemia. They require a multifaceted medical management approach with hematology, dermatology, gastroenterology, surgery, nurse practitioners and other specialties caring for the patient.

There is no cure for the disorder and treatment is supportive. Patients do need to be monitored as they are prone to potential complications such as volvulus, intussusception, infarction, and gastrointestinal bleeding.


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Blue Rubber Bleb Nevus Syndrome - Questions

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Blue rubber bleb nevus syndrome represents a condition of significance because of the potential for which of the following?



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A patient presents with multiple soft blue compressible subcutaneous nodules on their right arm. There is the suspicion that the patient may have blue rubber bleb nevus syndrome. Which medical specialty is the most urgent referral for further workup of this patient?



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What is the gene mutation associated with blue rubber bleb nevus syndrome?



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Which imaging study would be most appropriate for initial evaluation of the vascular anomalies in blue rubber bleb nevus syndrome?



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A patient presents with multiple blue rubbery compressible tender nodules on their skin. They report dark stools. Which medication has been found to be most effective in preventing life-threatening complications related to this disorder?



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Blue Rubber Bleb Nevus Syndrome - References

References

RICE JS,FISCHER DS, Blue rubber-bleb nevus syndrome. Generalized cavernous hemangiomatosis or venous hamartoma with medulloblastoma of the cerebellum: case report and review of the literature. Archives of dermatology. 1962 Oct     [PubMed]
Nahm WK,Moise S,Eichenfield LF,Paller AS,Nathanson L,Malicki DM,Friedlander SF, Venous malformations in blue rubber bleb nevus syndrome: variable onset of presentation. Journal of the American Academy of Dermatology. 2004 May     [PubMed]
Ishii T,Asuwa N,Suzuki S,Suwa H,Shimada K, Blue rubber bleb naevus syndrome. Virchows Archiv. A, Pathological anatomy and histopathology. 1988     [PubMed]
Boente MD,Cordisco MR,Frontini MD,Asial RA, Blue rubber bleb nevus (Bean syndrome): evolution of four cases and clinical response to pharmacologic agents. Pediatric dermatology. 1999 May-Jun     [PubMed]
Liu Q,Chen YP,Li YM, Blue rubber bleb nevus syndrome: a report of one case associated with recurrent epistaxis. Chinese medical journal. 2007 Apr 20     [PubMed]
Jin XL,Wang ZH,Xiao XB,Huang LS,Zhao XY, Blue rubber bleb nevus syndrome: a case report and literature review. World journal of gastroenterology. 2014 Dec 7     [PubMed]
Zahedi MJ,Darvish Moghadam S,Seyed Mirzaei SM,Dehghani M,Shafiei Pour S,Rasti A, Blue Rubber Bleb Nevus Syndrome as a rare Cause of Iron Deficiency Anemia: a Case Report and Review of Literature. Middle East journal of digestive diseases. 2013 Oct     [PubMed]
Kaur T,Singh S, Blue rubber bleb nevus syndrome: a case report. Indian journal of dermatology. 2014 Jan     [PubMed]
Dobru D,Seuchea N,Dorin M,Careianu V, Blue rubber bleb nevus syndrome: case report and literature review. Romanian journal of gastroenterology. 2004 Sep     [PubMed]
Rodrigues D,Bourroul ML,Ferrer AP,Monteiro Neto H,Gonçalves ME,Cardoso SR, Blue rubber bleb nevus syndrome. Revista do Hospital das Clinicas. 2000 Jan-Feb     [PubMed]
Xu Y,Zhou B,Zhang M,Luo D, An unusual case of blue rubber bleb nevus syndrome with unilateral linear distribution. Indian journal of dermatology, venereology and leprology. 2013 Mar-Apr     [PubMed]
Dòmini M,Aquino A,Fakhro A,Tursini S,Marino N,Di Matteo S,Lelli Chiesa P, Blue rubber bleb nevus syndrome and gastrointestinal haemorrhage: which treatment? European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie. 2002 Apr     [PubMed]
Garzon MC,Huang JT,Enjolras O,Frieden IJ, Vascular malformations. Part II: associated syndromes. Journal of the American Academy of Dermatology. 2007 Apr     [PubMed]
Mejía-Rodríguez S,Valencia-Herrera A,Escobar-Sánchez A,Mena-Cedillos C, Dermoscopic features in Bean (blue rubber bleb nevus) syndrome. Pediatric dermatology. 2008 Mar-Apr     [PubMed]
Wynford-Thomas R,Johnston A,Halpin S,Hamandi K, Rarities in neurology: blue rubber bleb naevus syndrome. Practical neurology. 2014 Oct     [PubMed]
Aravindan U,Ganesan R,Thamarai Kannan M, Surgery for Blue Rubber Bleb Nevus Syndrome-a Case Report. The Indian journal of surgery. 2018 Jun     [PubMed]
Kassarjian A,Fishman SJ,Fox VL,Burrows PE, Imaging characteristics of blue rubber bleb nevus syndrome. AJR. American journal of roentgenology. 2003 Oct     [PubMed]
Petek B,Jones RL, The management of ophthalmic involvement in blue rubber bleb nevus syndrome. GMS ophthalmology cases. 2014     [PubMed]
Arena M,Virdis M,Morandi E,Viaggi P,Pisani A,Opocher E,Masci E, Blue rubber bleb nevus syndrome: combined surgical and endoscopic treatment. Endoscopy. 2015     [PubMed]
Martinez CA,Rodrigues MR,Sato DT,Silveira Júnior PP,Gama RF,Mattavelli CB,Pereira JA, Blue rubber bleb nevus syndrome as a cause of lower digestive bleeding. Case reports in surgery. 2014     [PubMed]
Aihara M,Konuma Y,Okawa K,Komai R,Kudo I,Morioka R,Kariya K,Takami H,Sawada Y,Munakata A, Blue rubber bleb nevus syndrome with disseminated intravascular coagulation and thrombocytopenia: successful treatment with high-dose intravenous gammaglobulin. The Tohoku journal of experimental medicine. 1991 Feb     [PubMed]
Wang KL,Ma SF,Pang LY,Zhang MN,Hu LY,Liu MJ,Zou LP, Sirolimus alternative to blood transfusion as a life saver in blue rubber bleb nevus syndrome: A case report. Medicine. 2018 Feb     [PubMed]
Akyuz C,Susam-Sen H,Aydin B, Blue Rubber Bleb Nevus Syndrome: Promising Response To Sirolimus. Indian pediatrics. 2017 Jan 15     [PubMed]
Soblet J,Kangas J,Nätynki M,Mendola A,Helaers R,Uebelhoer M,Kaakinen M,Cordisco M,Dompmartin A,Enjolras O,Holden S,Irvine AD,Kangesu L,Léauté-Labrèze C,Lanoel A,Lokmic Z,Maas S,McAleer MA,Penington A,Rieu P,Syed S,van der Vleuten C,Watson R,Fishman SJ,Mulliken JB,Eklund L,Limaye N,Boon LM,Vikkula M, Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations. The Journal of investigative dermatology. 2017 Jan     [PubMed]

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