Blue Rubber Bleb Nevus Syndrome is also known as Bean syndrome. It is a rare syndrome of venous malformations which 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 a multifaceted medical management approach with hematology, dermatology, gastroenterology, and other specialties caring for the patient. Treatment is largely supportive and involves managing potential complications such as volvulus, intussusception, infarction, and gastrointestinal bleeding.
The syndrome is usually a sporadic disorder; however, autosomal dominant modes of inheritance are reported, specifically with a locus found on chromosome 9p. Recently, somatic mutations in TIE2, an endothelial cell tyrosine kinase receptor for angiopoietins, has been discovered to cause the disorder. Soblet et al. studied 17 patients with blue rubber bleb nevus syndrome along with six individuals with multifocal vascular malformations.M In most of the patients with blue rubber bleb nevus syndrome had two somatic TEK mutations.
Blue rubber bleb nevus syndrome is a rare disorder. Approximately 200 cases have been reported in the literature. It has been reported in all races, with Caucasians most frequently affected. The syndrome affects both males and females with equal frequency, and the cutaneous manifestations typically present at birth or early childhood. However, visceral involvement tends to present later in life in early adulthood.
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 be seen.
Patients will present at birth or in early childhood with multiple blue to violaceous soft compressible nodules on the skin or mucous membranes. The typical skin lesions are described as rubbery in consistency and may be painful or tender when compressed. 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 with time. Blue marks that are large and disfiguring may appear as well. The lesions have a response to dependency; therefore, they can swell when placed in a dependent position.
Since venous malformations can be seen in various locations throughout the body, which can make a physical examination challenging. The 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. Patients may present with severe iron deficiency anemia from recurrent gastrointestinal hemorrhage due to malformations in the gastrointestinal tract. Angiomas and venous malformations of the retina, conjunctiva, iris, and orbit may occur.
Venous malformations are slow-flow lesions, making them prone to thrombosis. Thrombosis presents as an erythematous, warm swelling that may be tender to palpation.
There are case reports of thyroid, parotid, musculoskeletal, lung, and bladder involvement as well.
Aside from clinical diagnosis, other diagnostic modalities include imaging studies. Ultrasound would be the first 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 an MRI with intravenous contrast, arterial and venous phases, and fat suppression is indicated if needed for diagnostic reasons. Other diagnostic modalities include CT, barium studies, and skin biopsy. Technetium Tc-99m-labeled red blood cell imaging may help localize the source and extent of blood loss.
Blue rubber bleb nevi can be examined under dermoscopy with features including 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.
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.
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 involvement to prevent gastrointestinal hemorrhage, which can be life-threatening.
Pharmacologic agents have been tried with variable response. Somatostatin analogs like subcutaneous octreotide can be used to decrease splanchnic blood flow in patients with gastrointestinal hemorrhage. This may be helpful in decreasing the need for blood transfusions in these patients. Other pharmacologic agents reported to prove helpful include corticosteroids, sirolimus, interferon alpha IVIG, and vincristine. Sirolimus is recently reported in the literature as a successful treatment option for this condition; however, the dose and treatment duration remains uncertain. This angiogenesis inhibitor has been used to avoid blood transfusions in these patients, who often require multiple in their lifetime. In several studies, adverse drug reactions and complications from the medicine including hepatic, renal, neutropenia, systemic infection, or cholesterol levels were not observed.]
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.
Individuals with blue rubber bleb nevus syndrome usually have a normal lifespan as long as the bleeding is controlled and no serious complications such as gastrointestinal hemorrhage result. The venous malformations will persist throughout the patient’s life.
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 venous malformations in the bone that lead to deformation such as bowing or pathologic fractures. They will also need monitoring by a gastroenterologist, hematologist, ophthalmologist, and possibly, cardiovascular or neurosurgeon if central nervous system involvement occurs.
Blue Rubber Bleb Nevus Syndrome is also known as Bean syndrome. It is a rare syndrome of venous malformations which 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 a multifaceted medical management 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.
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