title: Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.
abstract: Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.
authors: Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors: Julie
authors: J
authors: Soblet
authors: Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors: Jaakko
authors: J
authors: Kangas
authors: Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors: Marjut
authors: M
authors: Nätynki
authors: Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors: Antonella
authors: A
authors: Mendola
authors: Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors: Raphaël
authors: R
authors: Helaers
authors: Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors: Melanie
authors: M
authors: Uebelhoer
authors: Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors: Mika
authors: M
authors: Kaakinen
authors: Department of Dermatology, Hospital Garrahan, Buenos Aires, Argentina.
authors: Maria
authors: M
authors: Cordisco
authors: Department of Dermatology, Université de Caen Basse Normandie, CHU Caen, Caen, France.
authors: Anne
authors: A
authors: Dompmartin
authors: Pediatric Vascular Clinic, Department of Maxillofacial and Plastic Surgery, Hôpital d'Enfants Armand Trousseau, Paris, France.
authors: Odile
authors: O
authors: Enjolras
authors: Department of Clinical Genetics, Addenbrooke's Hospital, Cambridge, UK.
authors: Simon
authors: S
authors: Holden
authors: Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Alan D
authors: AD
authors: Irvine
authors: Great Ormond Street Hospital, London and St Andrews Centre for Plastic Surgery, Broomfield Hospital, Chelmsford, UK.
authors: Loshan
authors: L
authors: Kangesu
authors: Dermatology Department, Hôpital Pellegrin Enfants, Bordeaux, France.
authors: Christine
authors: C
authors: Léauté-Labrèze
authors: Department of Dermatology, Hospital Garrahan, Buenos Aires, Argentina.
authors: Agustina
authors: A
authors: Lanoel
authors: Vascular Biology, Murdoch Childrens Research Institute and Pediatrics, University of Melbourne, Victoria, Australia.
authors: Zerina
authors: Z
authors: Lokmic
authors: Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Saskia
authors: S
authors: Maas
authors: Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Maeve A
authors: MA
authors: McAleer
authors: Vascular Biology, Murdoch Childrens Research Institute and Pediatrics, University of Melbourne, Victoria, Australia.
authors: Anthony
authors: A
authors: Penington
authors: Kinderchirurgie, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Paul
authors: P
authors: Rieu
authors: Great Ormond Street Hospital for Children NHS Trust, London, Birmingham, UK.
authors: Samira
authors: S
authors: Syed
authors: Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Carine
authors: C
authors: van der Vleuten
authors: Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Rosemarie
authors: R
authors: Watson
authors: Vascular Anomalies Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Steven J
authors: SJ
authors: Fishman
authors: Vascular Anomalies Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: John B
authors: JB
authors: Mulliken
authors: Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors: Lauri
authors: L
authors: Eklund
authors: Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors: Nisha
authors: N
authors: Limaye
authors: Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium; Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint-Luc and Université catholique de Louvain, Brussels, Belgium.
authors: Laurence M
authors: LM
authors: Boon
authors: Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium. Electronic address: miikka.vikkula@uclouvain.be.
authors: Miikka
authors: M
authors: Vikkula
mesh_terms: D001530:Belgium; D015331:Cohort Studies; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006801:Humans; D015994:Incidence; D008297:Male; D009154:Mutation; D018329:Nevus, Blue / Q000175:diagnosis / Q000235:genetics*; D035583:Rare Diseases; D042787:Receptor, TIE-2 / Q000235:genetics*; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics*; D054079:Vascular Malformations / Q000175:diagnosis / Q000235:genetics*
chemical_list: D042787:Receptor, TIE-2