Blue Rubber Bleb Nevus Syndrome
- 1 Disease Entity
- 2 General Manifestations
- 3 Diagnosis
- 4 Management
- 5 Prognosis and Complications
- 6 References
Blue rubber bleb nevus syndrome (BRBNS)
Blue rubber bleb nevus syndrome is a vascular disease characterized by venous malformations and hemangiomas in the skin and visceral organs, most commonly the GI tract. Nearly 100 years after Gascoyan first described the disease in 1860, William Bennett Bean coined the term “blue rubber bleb nevus syndrome” due to the blue coloration and rubbery texture of the characteristic hemangiomas. It is extremely rare; to date, only approximately 200 cases have been reported in the literature. Presenting with a variety of signs and symptoms, BRBNS has the potential for severe or fatal bleeding.
BRBNS primarily presents at birth or in infancy and early childhood, although later onset has been reported. Caucasians appear to be more frequently affected. The disease shows no predilection for gender.
Etiology and Pathophysiology
The etiology and pathophysiology of BRBNS is unknown, however activating mutations in the angiopoietin receptor TIE2/TEK have been determined as a potential cause for BRBNS. Although some forms appear to have an autosomal dominant inheritance pattern linked to chromosome 9p, the majority of cases are sporadic.
BRBNS is characterized by cutaneous and GI lesions, but other visceral organs can be involved. In a review of 120 cases from the literature, reported prevalence of organ involvement is as follows:
- Skin: 93%
- Gastrointestinal: 76%
- CNS: 13%
- Liver: 11%
- Muscle: 9%
- Vagina, Spine, Eyes: 3%
- Uterus, Bone, Mediastinum, Lung: 2.5%
Other organs with reported BRBNS involvement include the mesentery, joints, kidneys, bladder, thyroid, parotid gland, spleen, endobronchial, gallbladder, vocal cord, pancreas, adrenal gland, peritoneum, retroperitoneum, Ampulla of Vater, nasopharynx, pleura, heart, and arytenoid cartilage.
Ocular manifestations of BRBNS are rare, and include hemangiomas of the periorbital region, lids, conjunctiva, iris, and retina. Unlike the characteristic soft, rubbery hemangiomas of BRBNS, the majority of orbital lesions resemble cavernous hemangiomas however some may take on characteristics of venous malformation.
The clinical diagnosis of BRBNS is based on the presence of characteristic cutaneous lesions with or without GI bleeding and/or the involvement of other organs. The clinical manifestations vary according to organ involvement, and can include melena, epilepsy, hemoptysis, hematuria, paralysis, or visual changes.
The characteristic cutaneous hemangiomas found in BRBNS are described as bluish red, thin-walled sacs with a soft, rubbery consistency. Digital compression will leave an empty wrinkled sack that slowly refills. They may also present as bluish macules or large, disfiguring cavernous lesions. The lesions may number from one up to several hundred and vary in size from 1-30 mm in diameter. They are typically asymptomatic, but they may be tender to palpation and can cause pain with contraction of smooth muscle fibers.
Patients with GI tract lesions most commonly present with GI bleeding and subsequent iron deficiency anemia, although severe hemorrhaging, sometimes fatal, can occur. Bone and joint involvement can present with significant discomfort and loss of function, occasionally requiring amputation. Extracutaneous lesions may cause epistaxis, hemoptysis, hematuria, or menorrhagia. CNS involvement is rare but can also lead to fatal cerebral hemorrhage.
Ocular symptoms can be acute or chronic. When ocular involvement occurs, patients may present with orbital pain, proptosis, enophthalmos, vision loss, ptosis, miosis, imbalance, occipital headaches, ecchymosis, increased intraocular pressure, and subconjunctival or intraorbital hemorrhage. Patients, particularly in younger age groups, who present with these symptoms should undergo systemic evaluation. Imaging of the brain may reveal dual arteriovenous fistulas and intraconal, nasal or orbital masses.
Diagnostic procedures include:
- Histopathologic examination, which is consistent with cavernous hemangiomas and will reveal large, blood-filled spaces separated by fibrous septa of varying thickness lined by a single layer of endothelial cells. Dystrophic calcification can be seen.
- Push or capsule endoscopy to detect GI lesions
- Magnetic resonance imaging (MRI) and computed tomography (CT) to detect lesions
- Fecal occult blood test, to screen for occult blood loss from GI lesions
- Laboratory testing for iron deficiency anemia
- Urine analysis, as the presence of hematuria may indicate lesions in the bladder
- Radiographic images for suspected bone or joint involvement
- Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
- Klippel-Trenaunay syndrome
- Maffucci syndrome
- Diffuse neonatal angiomatosis
- Sturge-Weber syndrome
- Fabry’s disease
Treatment of BRBNS depends on the number, location, size, and symptoms of the lesions. The cutaneous lesions are usually asymptomatic and do not require treatment unless they are cosmetically or functionally troublesome. If there is minor GI bleeding, conservative treatment includes blood transfusions and iron supplementation. For more extensive or symptomatic disease, a variety of therapeutic strategies have been proposed, although no particular method has demonstrated reliable efficacy. These include:
- Pharmaceutical therapy: anti-angiogenic agents, interferon-alpha, corticosteroids, sirolimus (mTOR inhibitor), beta-blockers
- Surgical resection, if conservative methods fail and the lesions are confined to a segment of the GI tract
- Endoscopic treatment: polypectomy, band ligation, clipping, argon plasma coagulation (APC), neodymium:YAG (Nd:YAG) laser photocoagulation
There is no established management for BRBNS with ophthalmic involvement. Various treatments have been reported in the literature with varying levels of success. These include observation, analgesics, endovascular embolization, and surgical excision. Some success has been achieved in treating orbital lesions with sirolimus. Sirolimus inhibits the mTOR pathway, which when hyperactive is an underlying mechanism for the abnormal angiogenesis associated with tumorigenesis. Inhibiting the mTOR pathway prevents proliferation and protein synthesis in many types of mammalian cells.
Prognosis and Complications
The prognosis for patients with BRBNS is generally good, but the quality of life can be significantly diminished due to GI bleeding, oral drug therapy, and blood transfusions. GI lesions can cause chronic and occult bleeding, and acute bleeding can lead to severe anemia (Barlas). Rare complications include volvulus, bowel infarction, suffocation from otolaryngological manifestations, hemothorax, hemopericardium, icertus, cirrhosis, chronic disseminated intravascular coagulation, acute paraparesis, ataxia, and vascular dementia. Rarely, GI bleeding and cerebral hemorrhage from BRBNS can be fatal. Early diagnosis of BRBNS is critical in order to manage these potentially life-threatening complications.
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