Blue Rubber Bleb Nevus Syndrome 

Updated: Jan 24, 2019
Author: Basil S Cherpelis, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Blue rubber bleb nevus syndrome (BRBNS) is a rare condition that is characterized by numerous malformations of the venous system that significantly involve the skin and visceral organs.[1] This condition was initially discovered in 1860 by Gascoyen.[1] However, it was later made famous in 1958, by William Bennett Bean for which the disease has been termed "bean syndrome," later referenced as blue rubber bleb nevus syndrome.[1] BRBNS is an important condition due to the potential for significant bleeding which can be fatal.

Also see the article, Dermatologic Manifestations of Gastrointestinal Disease.

Note the images below.

Multiple scattered blue to black rubbery papules a Multiple scattered blue to black rubbery papules and nodules involving the mid-chest region.
Purple to blue/black papules involving the upper a Purple to blue/black papules involving the upper and lower lips.
Multiple blue to black pigmented, rubbery, blood-f Multiple blue to black pigmented, rubbery, blood-filled sacs, which are easily compressible involving the GI tract.

Pathophysiology

Skin manifestations can typically be found at birth, whereas, organ system involvement tends to appear later in life.[1] The internal organ system most frequently involved is the GI system, for which GI bleeding is a common symptom.[2] Therefore, GI bleeding can lead to anemia and severe cases of hemorrhage may require transfusion therapy.[2] Additional complications include telescoping of the intestines, volvulus, and necrosis of the intestinal mucosa.[3] In addition, multiple vascular blebs and nodules can be found throughout the body. Case reports have demonstrated involvement of the CNS, thyroid, parotid, eyes, oral cavity, musculoskeletal, oral cavity, lungs, liver, spleen, and bladder. Although, literature suggests the coexistence of CNS with GI symptoms, they are still rare.[3]

Histopathologic examination of the lesions will reveal ecstatic vascular dilated spaces filled with endothelial cells forming a single layer, surrounded by connective tissue.[4]

Etiology

The etiology of blue rubber bleb nevus syndrome (BRBNS) remains unknown.[5] The literature suggests that this condition occurs sporadically.[5, 6] A few reported cases have been associated with an autosomal dominant inheritance pattern, for which a locus was found on chromosome 9p.[5, 7]

Epidemiology

Frequency

Blue rubber bleb nevus syndrome (BRBNS) is a rare condition with about 200 cases reported in the literature.[6] The exact etiology of this disease remains unknown.[5] Most cases occur sporadically.[5, 6] A few reported cases have been associated with an autosomal dominant inheritance pattern with a locus found on chromosome 9p.[5, 7]

One case report of BRBNS was discovered to be associated with pancreatic lymphangiomas. The systemic vascular lesions found in that case were linked to a familial germ line functional mutation (Arg849Trp) in the TIE2 gene.[8]

Race

Blue rubber bleb nevus syndrome (BRBNS) has been reported to occur in people of all races;[9] however, whites appear to be most frequently affected.

Sex

Blue rubber bleb nevus syndrome (BRBNS) affects both males and females equally.[3, 6]

Age

Skin manifestations of blue rubber bleb nevus syndrome (BRBNS) typically can be present at birth or evident in early childhood.[1] Visceral organ involvement tends to appear later in life, traditionally around early adulthood.[1]

Prognosis

The morbidity related to this condition depends on the extent of GI involvement, ranging from minimal to invasive.[1, 10] To date the literature supports no evidence of a carcinogenetic or fatal conversion of this condition.[10] Therefore, the malignancy potential has not yet been determined.[10] A complication of this condition is profound GI hemorrhage, which can lead to death.[1, 10] Serial transfusions and periodic surveillance can modify the morbidity of the disease. Lesions involving bones and joints can cause profound discomfort and loss of function, requiring amputations in some cases. Rarely, CNS involvement can be fatal.[11]

The prognosis for blue rubber bleb nevus syndrome (BRBNS) depends on the extent of visceral organ involvement and complications related to the degree of symptoms. Most patients are expected have a normal life span.

 

Presentation

History

The lesions of blue rubber bleb nevus syndrome (BRBNS) are asymptomatic; however, some may be spontaneously painful or tender to palpation. Patients with this condition may present for evaluation secondary to concerns related to its cosmetic appearance. BRBNS is characterized clinically by numerous violaceous to dark blue colored soft papules and nodules that are compressible in nature.[10] These lesions termed "blebs" contain a discriminate rubberlike consistency upon palpation.[10] Patients with BRBNS may note increased sweating on the skin overlying the lesion.

Presenting complaints and symptoms are directly related to the degree and extent of organ system involvement. Fatigue and weakness may be due to underlying occult blood loss. Other symptoms that could prompt emergent evaluation include hematemesis, melena or frank rectal bleeding. When bone is involved, symptoms may include joint pain or impaired ambulation. Extracutaneous lesions may also result in epistaxis, hemoptysis, hematuria, or menorrhagia. Other rare complications include dementia, ataxia and coagulopathy.[12] Patients may present with blindness due to cerebral or cerebellar cavernomas that may hemorrhage into the occipital lobes.[3]

Physical Examination

Physical findings in blue rubber bleb nevus syndrome (BRBNS) are divided into cutaneous and extracutaneous manifestations.

Cutaneous manifestations of BRBNS

Skin lesions are usually multiple, protuberant, dark blue, compressible blebs, a few millimeters to several centimeters in diameter and can vary in morphological shape. The lesions have a characteristic rubbery consistency upon palpation. They may range from few in number to hundreds of skin lesions. See the image below:

Lower extremity cutaneous lesions described in blu Lower extremity cutaneous lesions described in blue rubber bleb nevus syndrome, consisting of blue rubbery papules and nodules with an easily compressible smooth surface.

Three types of cutaneous lesions have been described in BRBNS: (1) blue, rubbery, blood-filled sacs with a smooth or wrinkled surface that are easily compressible and promptly refill when pressure is removed; (2) large, disfiguring, cavernous lesions that may compress vital structures; and (3) blue, irregular macules.

The color of cavernous lesions may appear red, purple-red, blue, or black, and morphology varies from flat to elevated, occasionally pedunculated, nodules.

Lesions may exhibit tenderness to palpation or underlying hyperhidrosis.

BRBNS skin lesions rarely bleed unless traumatized.

The progression in size and number of blebs may occur with advancing age.

The lesions are principally located on the upper limbs, trunk, and perineum, but they may occur anywhere.[13]

One case report has even described a unilateral configuration of linear lesions following the lines of Blaschko.[14]

Using polarized light, the dermatoscopic features reveal homogeneous macular blue to red-purple lesions that are separated by linear white bands.[4, 15]

Extracutaneous manifestations of BRBNS

The GI tract is the most common visceral organ affected. The small bowel is the most predominant region involved; however, vascular malformations can occur in any site in the body from the oral cavity to the anal mucosa. In contrast to the skin lesions, the GI lesions often have a tendency to bleed. They may spontaneously rupture, causing acute hemorrhage and death. However, most bleeding from the GI tract tends to progress relatively slowly, resulting in minor, chronic, and occult blood loss. This can eventually lead to an iron deficiency anemia from the ongoing bleeding. A case of thrombocytopenia and disseminated intravascular coagulation has been reported in association with BRBNS. Other complications include intussusception, volvulus, and bowel infarction. These diagnoses should be considered in patients with BRBNS and abdominal pain.

Orthopedic manifestations[16, 17] include skeletal bowing, pathologic fractures, bony overgrowth, and articular derangement. Bone deformities may arise as a result of pressure effects from adjacent vascular lesions. Vertebral lesions have caused spinal cord compression and vertebral collapse, and the lesions may extend into joint spaces affecting range of motion.[18] Extensive lesions also have been reported on the feet, impairing ambulation. Debilitating enlargement occasionally requires amputation of the affected limb.

Blue rubber bleb nevi have been reported in the skull, CNS, thyroid, parotid, eyes, oral cavity, lungs, pleura, pericardium, musculoskeletal system, peritoneal cavity, mesentery, kidney, liver, spleen, penis, vulva, and bladder.

Recurrent thromboembolic events from shunts in visceral lesions led to the development of pulmonary hypertension in one case,[19]  and another reported pulmonary stenosis.[20]

Complications

The rare complications of blue rubber bleb nevus syndrome (BRBNS), include, acute GI hemorrhage and central nervous system involvement, which result in death.

Pregnancy and BRBNS

Pregnancy has been shown to increase the size of vascular lesions due to the changes in the circulating hormones most evident by the third trimester.[21] Therefore, vascular malformations may manifest sporadically or increasing in size during pregnancy.[21]

In a study by Suksamanapun et al, they suggest that pregnant women, who may have the option to deliver vaginally with BRBNS, must consider the potential for underlying complications.[22] Pregnant women with BRBNS should undergo routine obstetrical care as well as obtain baseline laboratory evaluation and then monthly monitoring due to increased risk for hematological complications.[22] The studies suggest fibrinogen and D-dimers are to be monitored monthly to evaluate for associated clotting dysfunction. A thorough genital examination should also be performed in the antenatal period evaluating for genital hemangiomas or vascular malformations which may complicate the delivery process.[22]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

The following laboratory studies might be warranted:

  • Fecal occult blood test: Screen for occult blood loss from GI blue rubber bleb nevus syndrome (BRBNS) lesions.

  • CBC count: Screen for iron deficiency anemia.

  • Urinalysis: Hematuria may be caused by lesions in the bladder.

Imaging Studies

Radiographic imaging of suspected bone and joint involvement can be useful in identifying fractures, bony overgrowth, and articular abnormalities. Radiographic images in blue rubber bleb nevus syndrome (BRBNS) may be useful in suspected bone or joint involvement to detect fractures, bony overgrowth, and articular derangement. Radiographic contrast techniques may detect GI lesions, but endoscopy is considered to be superior.

MRI has been described as a useful tool for detecting extracutaneous lesions and for screening asymptomatic family members.[23]

Technetium Tc-99m–labeled red blood cell imaging may be helpful to localize or delineate the extent of bleeding in patients with blue rubber bleb nevus syndrome.[24]

CT scans can be useful to assess for underlying complications such as volvulus, intussusception, infarction, and GI bleeding.[2]

Procedures

Endoscopy may be warranted in blue rubber bleb nevus syndrome (BRBNS). GI lesions may be demonstrated by endoscopic examination or by radiographic contrast techniques. Upper GI endoscopy is more sensitive than an upper GI series and colonoscopy more useful than a barium enema. Endoscopy also provides the opportunity to treat and diagnose the lesions.[25, 26]

Histologic Findings

Histopathologic examination of skin blue rubber bleb nevus syndrome (BRBNS) lesions reveals vascular tissue with tortuous, blood-filled ectatic vessels, lined by a single layer of endothelium, with surrounding thin connective tissue. Dystrophic calcification may be present. See the image below.

Histopathology reveals blood-filled vessels, compo Histopathology reveals blood-filled vessels, composed of single layers of endothelium, surrounded by connective tissue.
 

Treatment

Medical Care

The literature suggests no standard of care or systemic treatment regimen is available for blue rubber bleb nevus syndrome (BRBNS). One report of BRBNS indicated the successful use of interferon-beta to treat the manifestations of disseminated intravascular coagulation in one patient with disseminated skin and GI venous malformations.[27] Another report describes long-term subcutaneous octreotide therapy as successful as decreasing GI bleeding in BRBNS.[28]  One report describes successful treatment with oral sirolimus.[29]

Surgical Care

Surgical treatment of cutaneous lesions in blue rubber bleb nevus syndrome (BRBNS)

The treatment of cutaneous lesions is not usually required. Treatment is rendered for cosmetic purposes or for the management of symptomatic lesions. Malignant transformation of BRBNS lesions has not been reported.

Methods to remove lesions include electrodesiccation and curettage, liquid nitrogen, and excision. These treatment options can lead to recurrent skin lesions and abnormal healing, such as hypertrophic scars. Successful treatment without scarring has been reported with the use of the carbon dioxide laser. Treatment of 225 lesions without recurrence was reported with the use of the carbon dioxide laser.[30]

Surgical treatment of extracutaneous lesions in BRBNS

Bleeding from GI lesions is usually managed conservatively with iron supplementation and blood transfusions when necessary. Endoscopic coagulation or removal is an effective modality for repeated bleeding. Experience with endoscopic sclerotherapy suggests that it is ineffective and complicated by the development of ulcerations and strictures. Other therapeutic management modalities for BRBNS include Nd:YAG laser, bipolar or argon plasma coagulation, band ligation, sclerotherapy and snare resection.[31, 32]

One study even reported the successful treatment of mucocutaneous lesions of BRBNS with NdYag.[33]

The literature suggests treatment options include glubran 2 injections, which have been successfully used in the management of gastric varices.

Other treatments described include endoscopic obliteration of cavernous hemangiomas with n-butyl-2-cyanoacrylate (Histoacryl).[31]

When traditional methods fail and the vascular lesions are confined to a segment of the GI tract, resection of the involved segment of gut may be indicated. This approach should be used with caution because recurrences may occur after excision.[34] Diffuse and scattered lesions or those where operation is not feasible should be treated conservatively.

Orthopedic lesions are managed with orthotics and supportive measures, unless impaired function necessitates surgery.

An 8-month old infant with bleeding hemangiomas of the rectum and colon was successfully treated with argon plasma coagulation. This treatment resulted in long-term success.[35]

In one report, an aggressive surgical approach to the treatment of blue rubber bleb nevus syndrome was attempted in 10 patients. GI venous malformations were identified endoscopically and then treated by wedge resection, polypectomy, suture ligation, segmental bowel resection, or band ligation. Only one patient developed recurrent GI bleeding.[36]

Multiple hemangiomas of the terminal ileum and colon were treated endoscopically in an adult female with the argon plasma coagulator.[37]

Consultations

Patients with blue rubber bleb nevus syndrome (BRBNS) should be referred to a gastroenterologist for management of GI manifestations.

Orthopedics should be consulted to assist in the care management of bone or joint related complications.

Additional referrals should be made to the appropriate specialists and treatment teams depending on the extent and nature of organ system involvement.

Genetic testing and counseling should be considered in cases with familial occurrence.

Long-Term Monitoring

The formation of new GI lesions in blue rubber bleb nevus syndrome (BRBNS) may continue to occur; therefore, periodic GI and hematologic surveillance studies should be instituted.