Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations

Soblet, Julie; Kangas, J.; Nätynki, Marjut; Mendola, Antonella; Helaers, Raphaël; Uebelhoer, Mélanie; Kaakinen, Mika; Cordisco, Maria; Dompmartin, Anne; Enjolras, O; Holden, Simon; Irvine, Alan D.; Kangesu, Loshan; Léauté‐Labrèze, Christine; Lanöel, Agustina; Lokmic, Zerina; Maas, Saskia M.; McAleer, Maeve A.; Penington, Anthony; Rieu, P.N.M.A.; Syed, Samira; Vleuten, Carine van der; Watson, Rosemarie; Fishman, Steven J.; Mulliken, John B.; Eklund, Lauri; Limaye, Nisha; Boon, Laurence M.; Vikkula, Miikka

doi:10.1016/j.jid.2016.07.034

Cited by 160 publications

(147 citation statements)

References 33 publications

(44 reference statements)

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“…Both TEK mutations found in the BRBN case were present in cis . As all mutated reads contained both mutations, the same variant allele frequency was suggested . In contrast to the literature, our TEK mutated cases were histologically more heterogeneous showing also combined lesions with a venous, capillary, and/or a lympathic component.…”

Section: Discussionsupporting

confidence: 40%

Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases

Broek

Eijkelenboom

Vleuten

et al. 2019

Genes Chromosomes & Cancer

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Vascular malformations are part of overgrowth syndromes characterized by somatic mosaic mutations or rarely by germline mutations. Due to their similarities and diversity, clinicopathological classification can be challenging. A comprehensive targeted Next Generation Sequencing screen using Unique Molecular Identifiers with a technical sensitivity of 1% mutant alleles was performed for frequently mutated positions in ≥21 genes on 319 formalin‐fixed paraffin‐embedded samples. In 132 out of 319 cases pathogenic mosaic mutations were detected affecting genes previously linked to vascular malformations e.g. PIK3CA (n=80), TEK ( TIE2 ) (n=11), AKT1 (n=1), GNAQ (n=7), GNA11 (n=4), IDH1 (n=3), KRAS (n=9), and NRAS (n=1). Six cases harbored a combination of mutations in PIK3CA and in GNA11 (n=2), GNAQ (n=2), or IDH1 (n=2). Aberrations in PTEN and RASA1 with a variant allele frequency approaching 50% suggestive of germline origin were identified in six out of 102 cases tested; four contained a potential second hit at a lower allele frequency. Ninety‐one of the total 142 pathogenic mutations were present at a variant allele frequency <10% illustrating the importance of sensitive molecular analysis. Clinicopathological characteristics showed a broad spectrum and overlap when correlated with molecular data. Sensitive screening of recurrently mutated genes in vascular malformations may help to confirm the diagnosis and reveals potential therapeutic options with a significant contribution of PIK3CA/mTOR and RAS‐MAPK pathway mutations. The co‐existence of two activating pathogenic mutations in parallel pathways illustrates potential treatment challenges and underlines the importance of multigene testing. Detected germline mutations have major clinical impact.

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Section: Discussionsupporting

confidence: 40%

Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases

Broek

Eijkelenboom

Vleuten

et al. 2019

Genes Chromosomes & Cancer

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“…BRBNS is a rare sporadic disorder characterized by multiple multifocal venous malformations primarily involving the skin and gastrointestinal tract. Additionally, somatic mutations in TEK encoding TIE2 were discovered in individuals with BRBNS and determined as the cause of BRBNS [1]. …”

Section: Discussionmentioning

confidence: 99%

Blue Rubber Bleb Nevus Syndrome: A Possible Cause for Growth Retardation and Pubertal Delay

et al. 2018

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Objective: The aim of this paper was to describe a rare case of blue rubber bleb nevus (BRBNS) with growth retardation and pubertal delay. Clinical Presentation and Intervention: A 16-year-old boy with severe iron deficiency anemia was diagnosed with BRBNS, showing growth retardation and pubertal delay simultaneously. The patient was treated conservatively with intravenous iron therapy, and his puberty advanced gradually. Conclusion: Given that growth retardation and pubertal delay are rare in BRBNS patients, this case reminds us to include BRBNS in the differential diagnosis of growth retardation.

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“…These results indicate that the TIE2 receptor and the PIK3CA signal transducer participate in the same VM signalling pathway, opening new possibilities for evidence-based molecular therapies against VMs [29,31,32,150]. Recent genetic analysis have revealed that allelic TIE2 double mutations are enriched in blue rubber bleb nevous syndrome (BRBN), characterized by multiple VM lesions [151]. ECs expressing recurrent BRBN TIE2 mutation showed increased colony forming capacity in vitro assays that may contribute to the clinically distinct multifocal VM phenotype in BRBN patients [151].…”

Section: Ang–tie System In Vascular Diseasesmentioning

confidence: 99%

“…Recent genetic analysis have revealed that allelic TIE2 double mutations are enriched in blue rubber bleb nevous syndrome (BRBN), characterized by multiple VM lesions [151]. ECs expressing recurrent BRBN TIE2 mutation showed increased colony forming capacity in vitro assays that may contribute to the clinically distinct multifocal VM phenotype in BRBN patients [151]. …”

Section: Ang–tie System In Vascular Diseasesmentioning

confidence: 99%

Angiopoietin–Tie signalling in the cardiovascular and lymphatic systems

Eklund¹,

Kangas²,

2016

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Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)–Tie system is a second endothelial cell specific ligand–receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang–Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding of the Ang–Tie signalling system, including cross-talk with the vascular endothelial protein tyrosine phosphatase (VE-PTP) and the integrin cell adhesion receptors, focusing on the Ang–Tie system in vascular development and pathogenesis of vascular diseases.

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Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations

Cited by 160 publications

References 33 publications

Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases

Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases

Blue Rubber Bleb Nevus Syndrome: A Possible Cause for Growth Retardation and Pubertal Delay

Angiopoietin–Tie signalling in the cardiovascular and lymphatic systems

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