PEDIATRICS Vol. 107 No. 2 February 2001, pp. 418-420

EXPERIENCE AND REASON:
Blue Rubber Bleb Nevus Syndrome

	ABSTRACT

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Blue rubber bleb nevus syndrome is a rare disorder characterized by distinctive cutaneous and gastrointestinal venous malformations that usually cause massive or occult gastrointestinal hemorrhage and iron deficiency anemia secondary to the bleeding episodes. It is even a rare cause of gastrointestinal hemorrhage during childhood. We describe a 6-year-old boy who had multiple venous malformations all over his body. He also suffered from several episodes of melena, chronic anemia, and growth retardation. The endoscopic examination of the gastrointestinal tract revealed multiple bluish-black sessile and polypoid venous malformations in various sizes. It was possible to remove the largest venous malformations causing massive bleeding during colonoscopy.

Blue rubber bleb nevus syndrome (BRBNS) is a rare entity consisting of distinctive venous malformations in the skin, gastrointestinal tract, and less often in other organs, leading to occult or profound gastrointestinal bleeding and chronic anemia. This association was first described by Gascoyen in 1860, and in 1958 Bean separated these venous malformations, which look like blue rubber blebs, from other vascular diseases of the skin.^1,2 Since then, less than 150 cases have been reported in the literature.³ Most cases are sporadic, although an autosomal dominant pattern of inheritance has been reported in several families.⁴ It affects all races, both sexes, adults, and children.

BRBN syndrome is generally present from birth or childhood and the evolution may be complicated by gastrointestinal bleeding and skeletal deformities.^5,6 The bleeding is usually occult and chronic or may be acute in the form of hematemesis or melena. The management of the gastrointestinal lesions depends on the extent of involvement and severity of gastrointestinal bleeding. A conservative approach usually is recommended whenever the clinical features and bleeding episodes are mild.⁷ Peroral iron supplementation is usually adequate for diffuse lesions, bleeding mildly.

Advances in endoscopy enable us to perform effective, relatively safe, and less invasive treatment modalities such as sclerotherapy, band ligation, and laser photocoagulation for these patients who suffer from recurrent or chronic gastrointestinal bleeding secondary to the venous malformations.^8-10 Because these venous malformations are usually sessile or pedunculated with a large base, endoscopic removal of them is less commonly reported in the literature.⁸

We report a 6-year-old boy with BRBNS with massive gastrointestinal hemorrhage and severe iron deficiency anemia secondary to several bleeding episodes and growth retardation. We successfully performed an endoscopic polypectomy in this patient.

	CASE REPORT

A 6-year-old boy presented with massive gastrointestinal hemorrhage at our hospital. He had a history of several hospital admissions for this problem since birth. He was born with a walnut-sized cutaneous angioma located on his right capula, and he was operated and the angioma was resected when he was 1 month old. After the operation, new pinpoint macular blue-black venous malformations became apparent on the soles of his feet, lower extremities, trunk, and gluteal region ranging in size 0.5 to 1.5 cm in diameter. By the age of 8 months, the family first noticed a pallor on his face, and the patient experienced several episodes of acute gastrointestinal bleeding in the form of melena since then. He had several blood transfusions and oral iron supplementation for iron deficiency anemia. Previously, he has been given interferon- treatment for 3 months in a local government hospital. Because he developed new venous malformations during and after the treatment and his bleeding episodes did not subside. The family denied the beneficial effect of interferon treatment on cutaneous lesions or bleeding episodes.

At admission, physical examination showed an extremely pale and growth retarded boy, his weight was 14 300 g (below the third percentile), his height was 101 cm (below the third percentile). The skin demonstrated multiple, raised, bluish-black lesions over the trunk, dorsal aspect of extremities, and gluteal region. Numerous bleb-like tumors were observed over the plantar surfaces of the feet (Fig 1). The lesions varied in size from 5 mm to 2 cm in diameter. The mucous membranes were not affected. He had a systolic cardiac murmur with a grade of 2/6. He had 2-cm liver palpable below the costal margin, and the spleen was not palpable. There was an incision scar on the right scapula and he had a scoliosis facing to the right side. The rest of the systemic examination was normal.

View larger version (107K): [in this window] [in a new window]   Fig. 1.   Multiple bluish-black lesions on the soles of the feet of the patient.

The laboratory findings included a hemoglobin level of 4.5 g/dL, hematocrit of 16.5%, mean corpuscular volume of 69 µm³, red blood cell distribution width of 24.2, and serum ferritin level of 4 ng/mL (normal:7-120 ng/mL). On peripheral blood smear, the red blood cells were microcytic and hypochromic indicating an iron deficiency anemia. Coagulation studies and routine blood biochemistry values were normal. The serologic investigation for hepatitis B and C viruses and human immunodeficiency virus were all negative. During the hospital stay, he had tarry stools several times and he had received a blood transfusion to keep the hematocrit level at 25% to 30%. Because the history and characteristics of the cutaneous lesions were typical for BRBNS, the diagnosis was made after a dermatology consultation.

To evaluate the presence of any nevus besides cutaneous lesions, thoracic and abdominal magnetic resonance imagings (MRI) were done. They showed a 38 × 25-mm hyperintense mass between the musculus latissimus dorsi and the musculus serratus anterior, and a 65 × 45 × 25-mm hyperintense mass between the acetabular part of the iliac bone and the musculus gluteus minimus and the musculus gluteus medius in T2-weighted images. The cranial MRI was normal, and the ophtalmologic examination of the patient revealed normal ophtalmologic findings. During the hospital stay, he had experienced a sudden swelling of the right knee that was later found to be secondary to the hemorrhage of the venous malformation located in the infrapatellar region. The MRI of the right knee revealed a 40 × 35 × 45-mm sized hyperintense mass in the infrapatellar region in T2-weighted images.

During the upper gastrointestinal endoscopy, several maculopapular venous malformations were discovered in the stomach, ranging in diameter from 4 to 5 mm (Fig 2A). There was also a large pink-bluish pedunculated, nonbleeding venous malformation 1 cm in diameter in the descending part of the duodenum. Colonoscopy revealed 1 papular venous malformation 5 mm in diameter in the rectum, 1 sessile venous malformation 20 mm in diameter in the splenic flexura, and 2 malformations 20 to 25 mm in diameter in the transvers colon; it was bleeding severely (Fig 2B). The bleeding colonic venous malformation in the transverse colon was removed by endoscopic polypectomy technique with a coagulation current using an electrosurgical unit (Erbotom Icc 200, Erbe Elektromedizin GmbH, Tübingen, Germany; Fig 2C). The bleeding episode was controlled after the polypectomy, and the transfusion was stopped. The histologic examination of the removed polyp showed multiple dilated capillaries engorged with red blood cells residing in the lamina propria and submucosa (Fig 3). The diagnosis of cavernous venous malformation was compatible with BRBNS.

View larger version (51K): [in this window] [in a new window]   Fig. 2.   Endoscopic view. A, Venous malformations in the stomach; B, Venous malformation in the splenic flexura; C, Polypectomised venous malformation in the colon.

View larger version (108K): [in this window] [in a new window]   Fig. 3.   Histologic appearance of a colonic polyp showing a venous malformation compatible with the blue rubber bleb nevus syndrome (hematoxylin and eosin, original magnification ×40)

	DISCUSSION

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BRBNS is a rare disorder characterized by distinctive venous malformations of the skin, gastrointestinal tract, and other internal organs.^3,7,11-14 The lesions usually appear at birth or in early childhood and tend to increase in size and number with age. Lesions may be present throughout the body, particularly predominate on the upper limbs and trunk.

In addition to the cutaneous involvement, vascular lesions can be present in the gastrointestinal tract, anywhere from mouth to anus, but the small bowel is the most frequently involved site.^7,15,16 Gastrointestinal lesions are generally multiple and, in contrast to cutaneous lesions, they tend to bleed easily, leading to massive hemorrhage and iron deficiency anemia that may be severe and require blood transfusions. BRBNS lesions are soft, blue nodules comprised of dysplastic venous channels with flat endothelium and irregularly attenuated walls with deficient smooth muscle cells.¹⁷ The course of BRBNS is intriguing. The lesions become more and more numerous as the child grows older. The pathogenesis of the disease is not clear. It is still not known whether the disease is secondary to angiogenesis or vasculogenesis or enlargement of dormant vessels.¹⁸ MRI, computed tomography, barium studies, and angiography have been used as diagnostic tools. When lesions are accessible to gastroscopy and colonoscopy, these procedures have been proven to be more sensitive than the other diagnostic techniques.^3,19-21 In our patient, gastroscopy and colonoscopy revealed multiple venous malformations in the stomach, duodenum, and colon. He also suffered from severe iron deficiency anemia since he was 1 year old, which might be the cause of growth retardation in this case.

Besides the cutaneous and gastrointestinal venous malformations, orthopedic abnormalities secondary to the pressure effects of adjacent venous malformations are often associated with BRBNS. Skeletal bowing as well as pathologic fractures have been reported.⁶ This boy was born with a big venous malformation located on the right scapula. He had a scoliosis facing to the right side after the resection of the lesion. He had had an episode of intraarticular hemorrhage in the right knee, and it was later demonstrated by an MRI that an infrapatellar venous malformation was present.

A conservative approach usually is recommended whenever the clinical features and bleeding episodes are mild. When the bleeding from the gastrointestinal tract is significant and the lesions are confined to 1 segment of the gastrointestinal tract, resection of the involved segment is recommended.^7,22 Because the venous malformations may be diffusely scattered through the gut from mouth to anus, recurrences are so common that a radical surgical approach seems to be helpful in only selected cases.^7,16 Peroral iron supplementation is usually adequate for diffuse lesions, bleeding mildly. Gastrointestinal lesions can also be treated with endoscopic techniques such as sclerotherapy, band ligation, or coagulation for accessible venous malformations involving the esophagus, stomach, proximal small intestine, and colon. Endoscopic polypectomy can be tried for the venous malformations, which are pedunculated. In our patient, one of the colonic venous malformations was rather pedunculated, and bleeding profusely, so we performed endoscopic polypectomy. The bleeding episode was controlled after the polypectomy in our patient. As new lesions may develop in different parts of the gastrointestinal tract in time, surgical intervention should be avoided if possible.

Although mentioned in the literature rarely, the pharmacologic treatment with corticosteroids, interferon-, and vincristine have been tried in some patients, but the lesions returned to their pretreatment levels soon after the treatment was discontinued.^7,18 The dose and the duration of the treatment with these agents are not defined very well. The role of pharmacotherapy in venous malformations depends on the presence of active angiogenesis, probably those showing an alarming growth and causing complications.¹⁸ The antiangiogenic or antiproliferative role of interferon might be the rationale, explaining the use of pharmacologic agents in BRBNS. Boente at al⁷ described 4 children with BRBNS 3 of whom were treated with either steroids alone or a combination of steroid and interferon-. All of the children responded to the treatment at first but relapsed as soon as the therapy stopped. The stabilization of the disease and partial remission of cutaneous lesions and bleeding episodes might be the benefits of pharmacotherapy.^7,18 Our patient received 3 months of interferon- therapy at 5 years of age, and his cutaneous lesions did not improve with this therapy. We did not try pharmacotherapy again with this patient. If one weighs the risks and benefits of long-term steroid treatment in a growing child, the value of long-term use of both steroids and interferon- remains uncertain.

	CONCLUSION

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In summary, BRBNS is a rare disorder characterized by distinctive cutaneous and gastrointestinal venous malformations. The syndrome is commonly associated with occult or life-threatening gastrointestinal bleeding and severe iron deficiency anemia. As the pathogenesis of the disease is not clear yet, it is important to evaluate patients individually according to clinical presentation, the organ systems involved, and the severity of the bleeding episodes. The role and long-term benefits of pharmacotherapy are not clear yet. In addition to conservative treatment, it is important to remove the lesions endoscopically, which have a higher bleeding tendency, whenever the venous malformations are accessible for the endoscopic procedure. Investigations that will be done on the pathogenesis of the disease may bring light into the definite treatment modalities of the disease.

Deniz Ertem, MD^*
Yesim Acar, MD^*
Esin Kotiloglu, MD
Deniz Yucelten, MD^§
Ender Pehlivanoglu, MD^*
Marmara University School of Medicine
^* Division Pediatric Gastroenterology and Nutrition
 Department of Pathology
^§ Department Dermatology
Tophanelioglu Cd. 13-15, 81190 Altunizade-Istanbul, Turkey

	FOOTNOTES

Received for publication Mar 2, 2000; accepted Jun 9, 2000.

Address correspondence to Ender Pehlivanoglu, MD, Marmara University School of Medicine, Chief, Division of Pediatric Gastroenterology and Nutrition, Tophanelioglu Cd. 13-15, 81190 Altunizade-Istanbul, Turkey. E-mail: dertem{at}hotmail.com

	ABBREVIATIONS

BRBNS, blue rubber bleb nevus syndrome; MRI, magnetic resonance imaging.

	REFERENCES

Top Abstract Introduction Discussion Conclusion References

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