Are You Confident of the Diagnosis?
Blue rubber bleb nevus syndrome (BRBNS) is a combination of cutaneous and visceral venous malformations. It was first described by Gascoyen in 1860 but Bean, in 1958, was the first person to use the term BRBNS.
What you should be alert for in the history
BRBNS is congenital; its name comes from the characteristic appearance of venous blebs that look like rubber nipples. These are present on the trunk and extremities (Figure 1) and may increase in size and number with time. They can also recur following surgical excision.
Characteristic findings on physical examination
The cutaneous lesions are typically small, bluish, soft, easily compressible, and nonpainful. Occasionally they are painful, usually owing to thrombosis or calcification. They are not friable and do not bleed easily (unlike the gastrointestinal [GI] tract lesions). Overlying hyperhidrosis has been described in some cases.
Besides having the characteristic cutaneous lesions, patients may present with iron-deficient anemia owing to occult GI bleeding from venous malformations in the GI tract. Less commonly, melena or hematochezia may occur.
Venous malformations may appear anywhere from the mouth to the anus (Figure 2) and all patients with suspected BRBNS should undergo upper and lower endoscopy. The most common GI tract locations include the small bowel and distal colon. Besides causing bleeding, GI lesions may lead to intussusception, volvulus, infarction, or rectal prolapse. Abdominal pain in these patients should always be taken seriously and appropriately evaluated.
Less commonly, venous malformations may occur in the brain, eyes, airway, liver, spleen, lungs, heart, genitourinary system, and skeletal muscle. Bone involvement may arise from the pressure of adjacent venous malformations, or hypertrophy may occur due to hypervascularity. Amputations of extremities have occurred in severe cases. Imaging should be pursued in symptomatic patients.
Expected results of diagnostic studies
Histologic examination reveals ectatic, branching, thin-walled vascular spaces lined with a single layer of flattened endothelial cells that may be surrounded by bundles of smooth muscle (Figure 3 and Figure 4). Proliferation of the eccrine gland has been described, which accounts for the clinical observation of hyperhidrosis.
Magnetic resonance imaging (MRI), computed tomography (CT), barium studies, and angiography have all been used as diagnostic studies, but upper and lower endoscopy remains the gold standard for evaluation of intestinal involvement because of its level of sensitivity. Endoscopy shows polypoid mucosal vascular nodules (Figure 5), and endoscopic biopsy will demonstrate endothelial-cell-lined cystic spaces containing scattered red blood cells in the mucosa.
Plain radiographs will be normal, unless calcification is present within the venous malformations.
Laboratory tests may be significant for microcytic anemia, thrombocytopenia, and low ferritin levels. Peripheral blood smear may show anisopikilocytosis.
Other conditions to include in the differential diagnosis of BRBNS are Mafucci syndrome, Osler-Weber-Rendu syndrome, multiple glomangiomas, Klippel-Trenaunay-Weber syndrome, and Kaposi sarcoma.
In Mafucci syndrome there should be enchondromas (benign cartilaginous tumors seen on the phalanges and long bones), which are not present in BRBNS. In Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia, epistaxis is prominent. Epistaxis should not be present in BRBNS. Furthermore, patients with Osler-Weber-Rendu syndrome should have telangiectasias, rather than malformations, on the skin. The telangiectasias are not present at birth but develop over time.
Glomangiomas can also be easily confused with BRBNS. In both disorders there can be similar-appearing vascular papules on the skin that can be painful or painless. However, patients with glomangiomas do not have GI involvement, and skin biopsy of a glomangioma will show glomus cells rather than endothelial-lined vessels. In Klippel-Trenaunay-Weber syndrome, there is overgrowth of an extremity due to underlying hypervascularity. There is no GI involvement.
The dermatologic manifestations of Kaposi sarcoma can appear similar to BRBNS. Red to blue nodules form diffusely through the body and can be found in the mucosa of the GI tract as well. This disease develops in the context of severe immune deficiency, which may aid in distinguishing the two disorders.
Who is at Risk for Developing this Disease?
BRBNS affects males and females equally. Most cases are sporadic but two autosomal dominant cases have been described. Due to the lack of other reports of autosomal dominant inheritance, these cases may actually represent pseudodominance (autosomal recessive inheritance in a closed population where recessive gene carriage is common).
Familial venous malformation syndrome (VMCM) has been described with autosomal dominant inheritance in a large family. Several members of the family had GI bleeding from intestinal involvement. This syndrome is caused by mutations in the TEK gene. It may be that cases of BRBNS that have been described as having autosomal dominant inheritance are really cases of VMCM. Some authors have suggested that BRBNS and VMCM are the same disease.
BRBNS is extremely rare with just over 200 cases described in the English literature. It has been described in all ages and races.
What is the Cause of the Disease?
Underlying etiology is not known. BRBNS appears to be a sporadic event (although a small number of autosomal dominant cases has been reported).
It is not known whether BRBNS occurs secondary to angiogenesis, vasculogenesis, or enlargement of dormant vessels.
Systemic Implications and Complications
The biggest concern in BRBNS is GI involvement. All patients with suspected BRBNS should undergo upper and lower endoscopy. Involvement of other organ systems may also occur and appropriate imaging should be performed when the child is symptomatic.
Some children with BRBNS may have limited ability to participate in sports due to involvement of an extremity.
The cutaneous venous malformations are generally not treated unless they are cosmetically disfiguring or impairing function. Excision or laser treatment may be pursued when necessary. Successful ablative laser treatment with the carbon dioxide laser has been reported, but the long pulse Nd:YAG laser may also be of benefit owing to its beneficial effect in treating other cutaneous venous malformations. A suggested Nd:YAG 1064 nm setting would be to use a 7 mm hand piece and start out using 100 J/cm2 with a 30 msec pulse width. Settings may need to be adjusted if ulceration occurs or if more of a response is needed.
Sclerotherapy administered by a trained interventional radiologist is a treatment option for smaller malformations. Cryotherapy has also been successfully used to treat small malformations. These two modalities should provide good cosmetic result if the lesions are solely cutaneous.
Larger venous malformations may require compression garments when possible. Etidronate has been used before in a patient with multiple painful lesions due to calcification. Calcification of the malformations of BRBNS is rare and the etiology is unknown. The rationale for using a bisphosphonate is that they inhibit the formation of calcium phosphate crystals in vitro. When GI bleeding is significant, laser treatment may be helpful. Bowel resection is an option when only a small portion of bowel is involved.
Recent trials with Sirolimus have shown cessation of GI bleeding and stabilization of hemoglobin levels, resulting in patients no longer requiring transfusions. Long-term treatment with antiangiogenic agents may cause adverse effects on renal and bone marrow function. Luckily, doses as low as 0.025 mg/kg have been shown to be effective.
If a patient begins to require blood transfusions from chronic GI bleeding, surgical intervention may be warranted. The entire GI system should be visualized to ensure complete eradication of all venous malformation lesions; any remaining lesions may multiply and spread to recreate clinical disease. In patients with excessive lesions, staged procedures can be done. Alternatively, laparotomy with intraoperative endoscopy can be used for those with refractory anemia.
Optimal Therapeutic Approach for this Disease
When BRBNS is first suspected, a skin biopsy should be performed to confirm the presence of venous malformations. Stool sample should be checked for occult blood and, if present, iron supplementation should be given. Upper and lower endoscopy should be performed even when occult bleeding is not present. Any large GI tract malformations may be ablated when possible. If the patient is symptomatic from anemia, a blood transfusion may be considered.
Patients with suspected BRBNS should have upper and lower endoscopy to look for venous malformations. If there is a large malformation confined to one segment of the GI tract, surgical resection or band ligation may be considered. In other cases, ablative laser therapy may be an option. There are also reports of using systemic corticosteroids, interferon-alpha, vincristine, propranolol, and octreotide to help stabilize bleeding. The dose and length of treatment with these agents has not been well defined and lesions may return to their pretreatment size after discontinuation of treatment. In the absence of GI bleeding, conservative treatment should suffice.
In cases of severe anemia, a blood transfusion may be necessary. Repetitive transfusions carry the risk of allosensitization or, less frequently, hepatitis. Otherwise iron replacement should be given.
Unusual Clinical Scenarios to Consider in Patient Management
As discussed earlier, confirmation of the diagnosis is essential. Often patients with glomangiomas are incorrectly diagnosed as having BRBNS.
There are two reported cases of BRBNS presenting unilaterally on a patient’s body. Other reports of atypical presentations include exclusively facial lesions, sparing the more common trunk and upper limb distribution. While these cases are rare, it demonstrates that geographic location of lesions cannot be used to rule out the disorder.
While the most common cause of death in BRBNS is GI bleeding, there has been a reported case of CNS bleeding consuming an infant. If this complication is suspected, cerebral MRI will show round vascular lesions throughout the brain parenchyma. If these lesions haemorrhage without causing death, the patient may suffer from focal neurologic signs, ataxia, or dementia.
What is the Evidence?
Agnese, M, Cipolletta, L, Bianco, MA, Quitadamo, P, Miele, E, Staiano, A. “Blue rubber bleb nevus syndrome”. Acta Paediatr. vol. 99. 2010. pp. 632-5. (The authors describe a case of a 10-year-old girl with numerous venous malformations all over her body and a lymphangioma on her right leg since birth. She had multiple venous malformations in the esophagus, stomach, duodenum, and colon. Although she had an episode of GI bleeding in the past, she was managed conservatively because of an absence of any current bleeding. The authors discuss different treatments available for treating the malformations of BRBNS.)
Shin, SH, Chae, HS, Ji, JS, Kim, HK, Cho, YS, Chang, ED. “A case of blue rubber bleb nevus syndrome”. Korean J Intern Med. vol. 23. 2008. pp. 208-12. (A 14-year-old girl is reported with a complaint of dizziness. Upon examination, she is found to have multiple malformations on the skin and in the GI tract, consistent with a diagnosis of BRBNS. She was found to be anemic due to chronic blood loss from the GI tract. She was treated with methylprednisolone for 4 months, with stabilization of the bleeding.)
Kishikawa, H, Okada, Y, Kawahara, T, Saito, K, Tanaka, Y. “A case of blue rubber bleb nevus syndrome treated by etidronate”. J Bone Miner Metab. vol. 25. 2007. pp. 38-41. (The authors present a case of a 23-year-old woman with BRBNS who developed calcification with her malformations. They discuss successful treatment of the calcifications with etidronate.)
Mittal, RR, Pure, ET. “Blue rubber bleb nevus syndrome”. Indian J Dermatol Venereol Leprol. vol. 67. 2001. pp. 41-2. (Two cases of BRBNS are presented with a short discussion.)
Lu, R, Krathen, RA, Sanchez, RL, May, NC, Hsu, S. “Multiple glomangiomas: potential for confusion with blue rubber bleb nevus syndrome”. J Am Acad Dermatol. vol. 52. 2005. pp. 731-2. (The authors provide an important reminder that multiple glomangiomas can be clinically confused with BRBNS. A biopsy showing glomus cells can help differentiate between the two diagnoses, as well as an absence of GI involvement with multiple glomangiomas.)
Massoumi, H, Patel, S. “Blue rubber bleb nevus syndrome”. Gastrointest Endosc. vol. 65. 2007. pp. 1076(The author provides clinical pictures of skin and GI involvement with a brief discussion of BRBNS.)
Bedocs, PM, Gould, JW. “Blue rubber-bleb nevus syndrome: a case report”. Cutis. vol. 71. 2003. pp. 315-8. (The authors present a case of BRBNS and provide a review and history of BRBNS.)
Ertem, D, Acar, Y, Kotiloglu, E, Yucelten, D, Pehlivanoglu, E. “Blue rubber bleb nevus syndrome”. Pediatrics. vol. 107. 2001. pp. 418-20. (A case of a 6-year-old boy with BRBNS is reported. The authors discuss different treatment options for the condition.)
Boente, MD, Cordisco, MR, Frontini, MD, Asial, RA. “Blue rubber bleb nevus (Bean syndrome): evolution of four cases and clinical response to pharmacologic agents”. Pediatr Dermatol. vol. 16. 1999. pp. 222-7. (The authors report their experience with four children with BRBNS over 5 years. They discuss different treatment options and review BRBNS.)
Stavropoulou, E, Korfitis, C, Christofidou, E, Tzilalis, VD, Rallis, E. “Blue rubber bleb nevus syndrome successfully treated with polidocanol sclerotherapy and cryosurgery”. Dermatol Surg. vol. 35. 2009. pp. 1442-4. (The authors discuss using polidocanol sclerotherapy and cryotherapy in treating some of the malformations of BRBNS.)
Ferrés-Ramis, L, Knöpfel, N, Salinas-Sanz, JA, Martín-Santiago, A. “Rapamycin in the Treatment of Blue Rubber Bleb Nevus Syndrome”. Actas Dermo-Sifiliográficas (English Edition). vol. 106.2. pp. 137-38. (The authors discuss success in treating BRBNS disease with antiangiogenic agents.)
Yuksekkaya, H, Ozbek, O, Keser, M, Toy, H. “Blue rubber bleb nevus syndrome: successful treatment with sirolimus”. Pediatrics. 2012. pp. 129.4(This article discusses treatment of BRBNS with Sirolimus.)
Li, Z, Yuan, H, Yu, D, Victor, N. “The surgery for blue rubber bleb nevus syndrome”. Annals of Medicine and Surgery. vol. 5. 2016. pp. 93-96. (This article gives an overview of BRBNS and surgical approaches to treatment.)
Sancheti, K, Podder, I, Das, A, Choudhury, S. “Unilateral, Linear Blue Rubber Bleb Nevus Syndrome (Bean's Syndrome): An Unfamiliar Presentation: First Case from India”. Indian Journal of Dermatology. Nov.-Dec. 2015. (This case report details an unusual unilateral presentation of BRBNS.)
Ocampo-Garza, J, Salas-Alanís, JC, Ponce-Camacho, MA, Rosales-Solis, GM. “Fatal Outcome from Brain Vascular Lesions in a Neonate with Blue Rubber Bleb Nevus Syndrome”. Pediatric dermatology. vol. 33. 2016. pp. e29-e31. (This case report discusses a rare complication and cause of mortality of BRBNS.)
Srinivas, SM, Premalatha, R. “Blue Rubber Bleb Nevus Syndrome in a Child”. J Clin Diagn Res. vol. 9. 2015. pp. WD03-WD04. (This case report discusses steps in diagnosing BRBNS in 13-year-old patient with refractory anemia.)
Martorano, LM, Cannella, JD, Lloyd, JR. “Mucocutaneous presentation of Kaposi sarcoma in an asymptomatic human immunodeficiency virus-positive man”. Cutis. April 2015. (This article discusses Kaposi sarcoma and its differential diagnosis.)
Korekawa, A, Nakajima, K, Aizu, T, Nakano, H, Sawamura, D. “Blue Rubber Bleb Nevus Syndrome Showing Vascular Skin Lesions Predominantly on the Face”. Case Rep Dermatol. vol. 7.2. 2015. pp. 194-98. (This case report outlines an atypical presentation appearing mostly on the face and sparing trunk and upper limbs.)
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