• algorithm
• diagnosis
• therapy

• Child
• Humans
• Anemia/etiology
• Anemia/therapy
• Anemia/diagnosis
• Anemia/drug therapy
• Anemia, Iron-Deficiency/etiology
• Dietary Supplements
• Gastroenterology
• Gastrointestinal Diseases/complications
• Iron/therapeutic use
• Vitamins/therapeutic use

• None.
• None

• Anomalías vasculares
• Malformaciones vasculares
• Tumores vasculares
• Vascular anomalies
• Vascular malformations
• Vascular tumours

• Humans
• Vascular Malformations/diagnosis
• Vascular Malformations/therapy
• Child
• Quality of Life

• Humans
• Sirolimus/therapeutic use
• Sirolimus/adverse effects
• Infant
• Vascular Malformations/drug therapy
• Infant, Newborn

• R01 HD112886 NICHD NIH HHS

• endoscopy
• enteroscopy
• small bowel
• vascular malformation

• Humans
• Gastrointestinal Hemorrhage/diagnosis
• Gastrointestinal Hemorrhage/etiology
• Gastrointestinal Hemorrhage/therapy
• Gastrointestinal Neoplasms/complications
• Gastrointestinal Neoplasms/surgery
• Nevus, Blue/complications
• Nevus, Blue/diagnosis
• Skin Neoplasms/diagnosis
• Syndrome

• Birthmarks
• overgrowth syndrome
• vascular anomalies
• vascular malformations
• vascular tumours

• Infant, Newborn
• Child
• Humans
• Vascular Malformations/diagnosis
• Vascular Malformations/therapy
• Vascular Malformations/pathology
• Vascular Diseases
• Syndrome

• BRBNS
• Bean syndrome
• Blue rubber bleb nevus syndrome
• Compression
• Laminectomy
• Pediatric
• Rupture
• Spine

• Humans
• Child
• Hematoma, Epidural, Spinal
• Nevus, Blue/complications
• Nevus, Blue/surgery
• Nevus, Blue/pathology
• Skin Neoplasms/complications
• Skin Neoplasms/surgery
• Skin Neoplasms/pathology
• Skin/pathology

• Humans
• Glomus Tumor/diagnosis
• Glomus Tumor/surgery
• Paraganglioma, Extra-Adrenal

• GI bleeding
• blue rubber bleb nevus syndrome
• sirolimus
• vascular malformation

• CSF
• blue rubber bleb nevus syndrome
• congenital
• spontaneous intracranial hypotension
• venous malformation

• T32 HL007574 NHLBI NIH HHS

• TEK/TIE2
• genetics
• rapamycin
• vascular malformation
• venous malformation

Blue rubber bleb nevus syndrome is a very rare systemic vascular malformation frequently affecting the skin and the gastrointestinal tract. The pathogenesis of the disease is still unclear, and the standard treatment does not exist. This study reports two blue rubber bleb nevus syndrome cases, of which the second patient received the TEK gene mutations detection and got a low-dose sirolimus therapy, compared with the first patient who was not treated with sirolimus. The report shows some positive findings of TEK gene mutations and the efficacy of sirolimus treatment. We postulate that the TEK gene mutations play an important role in the pathogenesis. The mutations of different locations of the TEK gene cause a wide range of activating TIE2 mutations, which could stimulate the mammalian target of rapamycin signaling pathways to mediate angiogenesis, resulting in different clinical phenotypes of cutaneomucosal venous malformations. Sirolimus could effectively block the upstream and downstream factors of mammalian target of rapamycin signaling pathways to achieve the antiangiogenic effect. The initial dose of sirolimus can be 0.05–0.1 mg/kg/d for a trough level of 5–15 μg/L in the treatment of blue rubber bleb nevus syndrome. However, a lower-dose sirolimus is also effective while minimizing the side effects.

• Blue rubber bleb nevus syndrome
• TEK gene mutations
• mTOR
• sirolimus

• Argon plasma coagulation
• angiodysplasia
• children
• endoscopy
• gastrointestinal hemorrhage

• Blue rubber bleb nevus syndrome (BRBNS)
• anemia
• case series
• sirolimus
• venous malformations

• Anemia
• Blue rubber bleb nevus syndrome
• Double balloon enteroscopy
• Endoscopy
• Small bowel
• Submucosal dissection

Our knowledge in vascular anomalies has grown tremendously in the past decade with the identification of key molecular pathways and genetic mutations that drive the development of vascular tumors and vascular malformations. This has led us to better understand the pathogenesis of vascular lesions, refine their diagnosis and update their classification while also exploring the opportunity for a targeted molecular treatment. This paper aims to provide an overview of venous malformations (VM) in childhood. Specific entities include common VMs, cutaneo-mucosal VM, blue rubber bleb nevus syndrome or Bean syndrome, glomuvenous malformation, cerebral cavernous malformation, familial intraosseous vascular malformation and verrucous venous malformation. The clinicopathological features and the molecular basis of each entity are reviewed.

• genetics
• histopathology
• somatic and germline mutations
• targeted therapy
• vascular anomalies
• venous malformations

Blue rubber bleb naevus syndrome (BRBNS) is a rare disease that usually presents with multiple venous malformations in the skin and gastrointestinal tract. Lesions located in the gastrointestinal tract always result in chronic gastrointestinal bleeding and severe anemia. The successful management of BRBNS with sirolimus had been reported in many institutions, due to its impact on signaling pathways of angiogenesis. However, the experience in treatment of neonates with BRBNS was limited.

A 38-day-old premature female infant born with multiple skin lesions, presented to our center complaining of severe anemia and hematochezia. Laboratory examination demonstrated that hemoglobin was 5.3 g/dL and contrast-enhanced abdominal computed tomography showed multiple low-density space-occupying lesions in the right lobe of the liver. She was diagnosed as having BRBNS based on typical clinical and examination findings. The patient was treated by transfusions twice and hemostatic drugs but symptoms of anemia were difficult to alleviate. A review of BRBNS case reports found that patients had been successfully treated with sirolimus. Then the patient was treated with sirolimus at an average dose of 0.95 mg/m²/d with a target drug level of 10-15 ng/mL. During 28 mo of treatment, the lesion was reduced, hemoglobin returned to normal, and there were no adverse drug reactions.

This case highlights the dosing regimen and plasma concentration in neonates, for the current common empiric dose is high.

• Cutaneous hemangioma
• Vascular malformation
• Sirolimus
• Rapamycin
• Blue rubber bleb nevus syndrome
• Case report

Blue rubber bleb nevus syndrome (BRBNS) is a rare syndrome characterized by venous malformations of mostly skin and gastrointestinal tract. Patients present with multiple venous malformations in various organs including liver, spleen, heart, eye, and central nervous system. Few ophthalmological cases have been published in literature and at present, there are no clear guidelines on the treatment of eye hemorrhages associated with the BRBNS. We report a 3-year-old boy with the BRBNS who developed a spontaneous progressive enlarging subconjunctival hemorrhage in the left eye despite being treated with oral propranolol. The subconjunctival hemorrhage was caused by an underlying conjunctival vascular malformation. With topical treatment with timolol maleate 0.5% once a day in the affected eye, the lesion regressed completely after 4 months. This child represents the first case of the BRBNS associated with a subconjunctival progressive bleeding necessitating topical treatment despite oral propranolol effectively controlling the cutaneous lesions. We recommend ophthalmic screening of patients with BRBNS in early childhood. For patients with BRBNS-related subconjunctival vascular lesions with subsequent hemorrhage, treatment with a topical β-blocker may be an efficient and harmless treatment option.

• Blue rubber bleb nevus syndrome
• Case report
• Subconjunctival hemorrhage
• Topical β-blocker

• Angioectasias
• GI angiodysplasia Video capsule endoscopy
• Gastrointestinal bleeding
• Small bowel hemorrhagic lesions
• Small bowel tumors
• Small bowel ulcers
• Suspected small bowel bleeding

• ISSVA
• gastrointestinal tract
• skin
• vascular anomalies
• venous malformations

Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular disease, difficult to diagnose and choose a treatment method, especially in young children. There are several limiting factors to the use of enteroscopy for diagnostics and treatment in pediatric patients, in general. The literature on BRBNS cases is limited and presents various therapeutic approaches.

We present here a case of BRBNS involving a 4-year-old female, whose intestinal venous lesions were successfully treated by endoscopic sclerotherapy and aethoxysklerol foam. Skin lesions, typical for BRBNS, appeared on the 8^th d of the child’s life and their number increased over the next several months. The child also experienced episodes of critical decrease in hemoglobin level (by as much as 52 g/L) for several years, requiring iron supplementation and several blood transfusions. Video capsule endoscopy revealed numerous vascular formations in the small bowel. The combined findings of gastrointestinal venous formations and skin lesions prompted BRBNS diagnosis. Single-balloon enteroscopy was used to perform sclerotherapy, with aethoxysklerol foam. A positive effect was observed within 19 mo of follow-up. We continue to monitor the patient’s hemoglobin level, every 2 wk, and it has remained satisfactory (> 120 g/L).

Endoscopic sclerotherapy can be effective in the clinical management of gastrointestinal manifestations of BRBNS in young children.

• Blue rubber bleb nevus syndrome
• Bean syndrome
• Single-balloon enteroscopy
• Children
• Vascular malformations
• Gastrointestinal tract
• Sclerotherapy
• Aethoxysklerol foam
• Case report

• Blue rubber bleb nevus syndrome
• Malformation veineuse
• Sirolimus
• Syndrome de Bean
• Venous malformation

• blue rubber bleb nevus syndrome
• hemorrhage
• localized intravascular coagulation
• long-term therapy
• sirolimus

• complex vascular malformations
• vascular anomalies
• vascular birthmarks
• vascular malformations
• vascular tumors

The keystone flap is well known to plastic surgeons and is frequently utilized for its ease of implementation, limited donor site morbidity, and favorable aesthetic outcomes. Although keystone flaps have been described in reconstruction of myelomeningocele defects, there have been no reports of their application to infants with large vascular malformations. This case illustrates the utilization of a keystone flap in reconstruction of a large posterior trunk defect that resulted from excision of a massive venous malformation in an 8-week-old infant with blue rubber bleb nevus syndrome. The patient’s consumptive coagulopathy resolved in the early postoperative period, and long-term follow-up demonstrated a favorable aesthetic outcome. This case reiterates the power and versatility of the keystone flap technique through its novel application to an infant with a life-threatening venous malformation on the posterior trunk.

• Vascular anomalies
• Vascular malformations
• Visceral

• 蓝色橡皮疱痣综合征
• 西罗莫司
• 雷帕霉素
• 消化道出血
• 儿童
• blue rubber bleb nevus syndrome
• sirolimus
• rapamycin
• gastrointestinal bleeding
• child

• Adolescent
• Child
• Child, Preschool
• Gastrointestinal Neoplasms/drug therapy
• Humans
• Infant
• Infant, Newborn
• Nevus, Blue/drug therapy
• Prospective Studies
• Retrospective Studies
• Sirolimus/therapeutic use
• Skin Neoplasms/drug therapy