Continuing Education Activity

Blue rubber bleb nevus syndrome is also known as Bean syndrome. It is a rare syndrome of venous malformations that 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. Patients with blue rubber bleb nevus syndrome are at increased risk for gastrointestinal hemorrhage and severe iron deficiency anemia. This activity reviews the evaluation and management of blue rubber bleb nevus syndrome and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Explain the etiology of blue rubber bleb nevus syndrome.
• Describe the presentation of a patient with blue rubber bleb nevus syndrome.
• Summarize the treatment considerations for patients with blue rubber bleb nevus syndrome.
• Outline the importance of collaboration and communication amongst the interprofessional team to improve outcomes for patients affected by blue rubber bleb nevus syndrome.

Introduction

Blue rubber bleb nevus syndrome is also known as Bean syndrome. It is a rare syndrome of venous malformations that 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. Patients with blue rubber bleb nevus syndrome 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 involved in their care. Treatment is largely supportive and involves managing potential complications such as volvulus, intussusception, infarction, and gastrointestinal bleeding.[1][2][3][4]

Etiology

Blue rubber bleb nevus syndrome is usually a sporadic disorder; however, autosomal dominant modes of inheritance are reported, specifically with a locus found on chromosome 9p.[5][6][7] Recently, somatic mutations in TIE2, an endothelial cell tyrosine kinase receptor for angiopoietins, have been discovered to cause the disorder. Soblet et al. studied 17 patients with blue rubber bleb nevus syndrome and six individuals with multifocal vascular malformations. The majority of patients with blue rubber bleb nevus syndrome were associated with mutations in TEK (also known as TIE2), which encodes TEK receptor tyrosine kinase. In contrast to common unifocal venous malformation, multifocal malformations are associated with two somatic activating mutations on the same allele (double [cis] mutations).[8]

Epidemiology

Blue rubber bleb nevus syndrome is a rare disorder. Approximately 200 cases have been reported in the literature.[9][10] It has been identified in all races, with Whites most frequently affected. The syndrome affects both males and females with equal frequency, and the cutaneous manifestations typically present at birth or early childhood. Visceral involvement tends to present in early adulthood.[11]

Pathophysiology

As previously mentioned, blue rubber bleb nevus syndrome is caused by double (cis) mutations in the TEK gene (otherwise known as TIE2). The TEK gene encodes a protein called TEK receptor tyrosine kinase. TEK receptor tyrosine kinase is a transmembrane receptor involved in multiple steps of angiogenesis, including destabilization of existing vessels, endothelial cell migration, tube formation, and stabilization of newly formed tubes by mesenchymal cells. When the TEK receptor is activated, it triggers a release of chemical signals that facilitates cell-cell communication between endothelial cells and smooth muscle cells. This communication leads to new blood vessel formation and safeguards the structure and integrity of these blood vessels. The TEK receptor is constitutively active in blue rubber bleb nevus syndrome due to somatic activating mutations. This leads to unregulated angiogenesis.[12][13][14]

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 also be seen.[15]

History and Physical

Patients with blue rubber bleb syndrome present at birth or in early childhood with multiple blue to violaceous soft compressible nodules on the skin or mucous membranes. They are often born with a "dominant" lesion and develop numerous venous malformations over their lifetime.[8] The typical skin lesions are described as rubbery in consistency and may be painful or tender when compressed. Pain is especially prevalent at nighttime. 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. Blue marks that are large and disfiguring may appear as well. Uniquely, lesions tend to swell in gravity-dependent positions, and patients have focal areas of hyperhidrosis overlying these lesions.[9]

Venous malformations can be seen in various locations throughout the body, which makes physical examination difficult. 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. As a result, patients may present with severe iron deficiency anemia from recurrent gastrointestinal hemorrhage.[16] Angiomas and venous malformations of the retina, conjunctiva, iris, and orbit may occur.[17][18] There are case reports of thyroid, parotid, musculoskeletal, lung, and bladder involvement as well.[9]

Venous malformations are slow-flow lesions, making them prone to thrombosis. Thrombosis presents as an erythematous, warm swelling that may be tender to palpation.[9]

Evaluation

Aside from clinical diagnosis, other diagnostic modalities include imaging studies. Ultrasound is the initial diagnostic 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 magnetic resonance imaging (MRI) with intravenous contrast, arterial and venous phases, and fat suppression is indicated. Other diagnostic modalities include computed tomography (CT), barium studies, and skin biopsy. Technetium Tc-99m-labeled red blood cell imaging may help localize the source and extent of blood loss.[19]

Blue rubber bleb nevi can be examined under dermoscopy with features of 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.[20]

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.[21]

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 intestinal involvement in order to prevent life-threatening gastrointestinal hemorrhage.[22] 

Pharmacologic agents have been tried with variable responses.[4] Somatostatin analogs like subcutaneous octreotide can be used to decrease splanchnic blood flow in patients with gastrointestinal hemorrhage. This may help decrease the need for blood transfusions in these patients. Other pharmacologic agents reported efficacious include corticosteroids, interferon-alpha, IVIG, and vincristine.[23] Sirolimus was recently reported in the literature as a successful treatment option for this condition; however, the dose and treatment duration remains uncertain. Sirolimus is an angiogenesis inhibitor that has been used to avoid blood transfusions in these patients, who often require multiple in their lifetime.[23][24][25][26]

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.[9][18]

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.[27][28]

Prognosis

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

Complications

The most concerning complications of blue rubber bleb nevus syndrome are severe gastrointestinal hemorrhage or intestinal intussusception. As a result, patients often require multiple blood transfusions throughout their lifetime.[7][29]

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 deforming venous malformations in the bone. They will also need monitoring by a gastroenterologist, hematologist, ophthalmologist, and possibly, cardiovascular or neurosurgeon if central nervous system involvement occurs.[9][18]

Deterrence and Patient Education

It is important to counsel patients and parents about the risk of severe gastrointestinal bleeding and intussusception in blue rubber bleb nevus syndrome. There should be a low threshold for patients to present for medical evaluation if they have abnormal bowel function or abdominal pain.

Enhancing Healthcare Team Outcomes

Blue Rubber Bleb Nevus Syndrome is also known as Bean syndrome. It is a rare syndrome of venous malformations that 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 an interprofessional team 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. [Level 5]