Blue Rubber Bleb Nevus Syndrome

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Article initiated by:

Caroline Awh, Stephen C. Dryden, M.D.

All contributors:

Andrew G. Meador, Brian T. Fowler, MD, Caroline Awh, Stephen C. Dryden, M.D., Gangadhara Sundar, MD, Jill Wells, MD, Caroline Awh, Michael T Yen, MD, Cat Nguyen Burkat, MD FACS, Carisa E. Bohnak, MD, Jan P. Ulloa-Padilla, M.D.

Assigned editor:

Gangadhara Sundar, MD, Jan P. Ulloa-Padilla, M.D.

Review:

Assigned status Up to Date

 by Gangadhara Sundar, MD on September 15, 2024.

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Contributing Editors:	add

Blue Rubber Bleb Nevus Syndrome

DiseasesDB

31379

OMIM

112200

Disease Entity

Blue rubber bleb nevus syndrome (BRBNS)

Disease

Blue rubber bleb nevus syndrome is a rare 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. The disease itself is heterogenous in nature, presenting with a variety of signs and symptoms but characteristically presents with multifocal mucocutaneous lesions While treatment is largely supportive, patients with BRBNS are at an increased risk of life-threatening hemorrhage, localized intravascular coagulation, intussusception, and severe iron deficiency. A multi-disciplinary approach involving dermatologists and gastroenterologists is recommended to best care for these complex patients.

Epidemiology

BRBNS affects about 1 in 14,000 live births. It primarily presents at birth or in infancy and early childhood, although later onset has been reported. Although it has been reported in numerous races, Caucasians appear to be most frequently affected. The disease shows no predilection for gender. Cutaneous manifestations typically present at birth or within early childhood while visceral involvement typically manifests in early adulthood.

Etiology and Pathophysiology

The etiology and pathophysiology of BRBNS is unknown, however activating mutations in the angiopoietin receptor TIE2/TEK, an endothelial cell tyrosine kinase receptor involved in multiple steps of angiogenesis, 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.

General Manifestations

Systemic Manifestations

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, pulmonary, heart, and arytenoid cartilage.

Ocular Manifestations

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.

Diagnosis

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.

Clinical Presentation

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.

GI lesions may be present along the entire alimentary tract and can be seen on gastroscopy and ileo-colonoscopy. 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 Findings

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, particularly CNS imaging. Imaging of the brain may reveal dual arteriovenous fistulas and intraconal, nasal or orbital masses.

Diagnostic Procedures

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.
• Gastrointestinal lesions are best imaged by ultrasonography by an experienced person
• Push or capsule endoscopy to detect GI lesions
• Skin lesions can be examined under dermoscopy
• Magnetic resonance imaging (MRI) and computed tomography (CT) to detect GI and CNS 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

Differential Diagnosis

The differential diagnosis for BRBNS includes other diseases that are characterized by vascular malformations. These include:

• Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
• Klippel-Trenaunay syndrome
• Maffucci syndrome
• Diffuse neonatal angiomatosis
• Sturge-Weber syndrome
• Fabry’s disease
• Kaposi's Sarcoma

Management

Treatment of BRBNS is largely supportive and depends on the number, location, size, and symptoms of the lesions. Most patients benefit from multidisciplinary evaluation and management.The cutaneous lesions are usually asymptomatic and do not require treatment unless they are cosmetically or functionally unacceptable. If there is minor GI bleeding, patients are treated conservatively with 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:

1. Pharmaceutical therapy: anti-angiogenic agents, interferon-alpha, corticosteroids, sirolimus (mTOR inhibitor), beta-blockers, subcutaneous octreotide
2. Surgical resection, if conservative methods fail and the lesions are confined to a segment of the GI tract or with severe complications such as intussusception
3. 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. There is increasing evidence in the literature to support efficacy of sirolimus in the treatment of both pediatric and adult patients; however, the majority of these studies are case reports or case series with the largest study including only 11 patients. Similar success has been achieved in treating orbital lesions with sirolimus. This is of particular interest because prior management of orbital lesions has primarily involved observation/conservative management or more aggressive invasive procedures including embolization(s) or surgical excision. 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.