scholarly journals Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA

2021 ◽  
Vol 7 (6) ◽  
pp. a006147
Author(s):  
Sarah E. Sheppard ◽  
Victoria R. Sanders ◽  
Abhay Srinivasan ◽  
Laura S. Finn ◽  
Denise Adams ◽  
...  
Keyword(s):  
Arteriovenous Malformations ◽  
Mapk Pathway ◽  
Vascular Malformations ◽  
Lymphatic Vessels ◽  
Catalytic Subunit ◽  
Venous Malformations ◽  
Phosphatidylinositol 3 Kinase ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Cerebral Vascular Malformations

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K–RAS–MAPK pathway (Padia et al., Laryngoscope Investig Otolaryngol 4: 170–173 [2019]). Activating pathogenic variants in the gene PIK3CA, which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., Pediatr Dev Pathol 16: 51 [2013]; Luks et al., J Pediatr 166: 1048–1054.e1–5 [2015]; Al-Olabi et al., J Clin Invest 128: 1496–1508 [2018]). These vascular malformations are part of the PIK3CA-related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic PIK3CA pathogenic variants (Keppler-Noreuil et al., Am J Med Genet A 167A: 287–295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet–Dechaume–Blanc syndrome, and Wyburn–Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., Interv Neuroradiol 7: 5–17 [2001]; Krings et al., Neuroimaging Clin N Am 17: 245–258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., Am J Neuroradiol 39: 2103–2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene PIK3CA. We propose that CVMS be recognized as part of the PIK3CA-related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.

scholarly journals Somatic PIK3CA mutations as a driver of sporadic venous malformations

2016 ◽  
Vol 8 (332) ◽  
pp. 332ra42-332ra42 ◽  
Author(s):  
Pau Castel ◽  
F. Javier Carmona ◽  
Joaquim Grego-Bessa ◽  
Michael F. Berger ◽  
Agnès Viale ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Vascular Malformations ◽  
Akt Pathway ◽  
Venous Malformations ◽  
Phosphatidylinositol 3 Kinase ◽  
Pik3ca Mutations ◽  
Downstream Signaling ◽  
Clinical Challenge ◽  
Substantial Morbidity ◽  
Over Time

Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyen et al., 2014; Uebelhoer et al., 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limaye et al., 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.

Neurosurgical Issues in Pregnancy

2017 ◽  
Vol 37 (06) ◽  
pp. 689-693 ◽  
Author(s):  
Anil Can ◽  
Rose Du
Keyword(s):  
Arteriovenous Malformations ◽  
Intracranial Aneurysms ◽  
Vascular Malformations ◽  
Significant Risk ◽  
Unborn Child ◽  
Cavernous Malformations ◽  
Life Threatening ◽  
Ruptured Intracranial Aneurysms ◽  
Cerebral Vascular Malformations ◽  
Cerebral Vascular

AbstractAlthough rare, intracranial hemorrhage due to rupture of cerebral vascular malformations or intracranial aneurysms during pregnancy is a potentially devastating and life-threatening disorder, posing a diagnostic and therapeutic challenge to a multidisciplinary team of neurosurgeons, neurologists, obstetricians, and anesthesiologists. Despite the significant risk of morbidity and mortality affecting both the mother and the unborn child, knowledge of the natural history, epidemiology, and appropriate management of cerebral vascular malformations and intracranial aneurysms in pregnant women is limited. Although emergent neurosurgical concerns usually outweigh obstetric considerations, and treatment of these disorders is generally similar in pregnant and nonpregnant women, any necessary and feasible modifications to protect the unborn child should be made. This article reviews the management of ruptured intracranial aneurysms and cerebral vascular malformations, including arteriovenous malformations, cavernous malformations, and moyamoya disease, in women during pregnancy, partus, and puerperium.

Cerebral vascular malformations in hereditary hemorrhagic telangiectasia

2014 ◽  
Vol 120 (1) ◽  
pp. 87-92 ◽  
Author(s):  
M. Neil Woodall ◽  
Melissa McGettigan ◽  
Ramon Figueroa ◽  
James R. Gossage ◽  
Cargill H. Alleyne
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Vascular Malformations ◽  
Cerebral Aneurysms ◽  
Developmental Venous Anomalies ◽  
Capillary Telangiectasia ◽  
The Brain ◽  
Single Modality ◽  
Cerebral Vascular Malformations ◽  
Cerebral Vascular

Object Hereditary hemorrhagic telangiectasia (HHT) is a hereditary disorder characterized by mucocutaneous telangiectasias, frequent nosebleeds, and visceral arteriovenous malformations (AVMs). Few reports have outlined the prevalence of the various cerebral vascular malformations found in patients with HHT. The authors set out to define the prevalence of cerebral vascular malformations in a population of HHT patients who underwent imaging with 3-T imaging (MRI/MR angiography [MRA]) of the brain. Methods A retrospective review of prospectively collected data was carried out using a database of 372 HHT patients who were seen and examined at the Georgia Regents University HHT Center and screened with 3-T MRI/MRA. Data were tabulated for numbers and types of vascular malformations in this population. Results Arteriovenous malformations were identified in 7.7%, developmental venous anomalies in 4.3%, and cerebral aneurysms in 2.4% of HHT patients. The HHT AVMs tended to be supratentorial, small, and cortical in this series, findings consistent with other recent studies in the literature. An arteriovenous fistula, cavernous malformation, and capillary telangiectasia were identified in 0.5%, 1%, and 1.9% of HHT patients, respectively. Conclusions Few studies have investigated the prevalence of the various vascular malformations found in HHT patients screened with 3-T MRI/MRA of the brain. Hereditary hemorrhagic telangiectasia AVMs are more likely to be multiple and have a tendency toward small size and cortical location. As such, they are often treated using a single-modality therapy.

scholarly journals The Efficiency of Sclerotherapy in the Treatment of Vascular Malformations: A Retrospective Study of 63 Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Esko Veräjänkorva ◽  
Riitta Rautio ◽  
Salvatore Giordano ◽  
Ilkka Koskivuo ◽  
Otto Savolainen
Keyword(s):  
Retrospective Study ◽  
Growth And Development ◽  
Congenital Malformations ◽  
Arteriovenous Malformations ◽  
Vascular Malformations ◽  
High Flow ◽  
University Hospital ◽  
Venous Malformations ◽  
Duration Of Treatment ◽  
Satisfactory Clinical Response

Background and Aims. Vascular malformations are a vast group of congenital malformations that are present at birth. These malformations can cause pain, pressure, and cosmetic annoyance as well as downturn growth and development in a child in the case of high flow. Sclerotherapy has become an important tool in the treatment of vascular malformations. However, little is known about the success rate of sclerotherapy. Material and Methods. In this study, the efficiency of sclerotherapy in the treatment of vascular anomalies was investigated retrospectively in 63 patients treated in Turku University Hospital between 2003 and 2013. Results. Out of the 63 patients investigated, 83% (53) had venous malformations (VMs) and 9% (5) were defined as having arteriovenous malformations (AVMs). Patients with a VM were operated on, in 14% (8) out of all VM cases. Hence 86% (45) of patients with a VM received adequate help to their symptoms solely from sclerotherapy. The duration of treatment for the 14% of the VM patients that needed a surgical procedure was prolonged by 7–9 months, that is, by 41%. Conclusions. Sclerotherapy is an effective method in the treatment of VMs with a satisfactory clinical response in patients symptoms in 84% of cases.

scholarly journals Vascular endothelial cell specification in health and disease

Angiogenesis ◽  
2021 ◽  
Author(s):  
Corina Marziano ◽  
Gael Genet ◽  
Karen K. Hirschi
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Current Knowledge ◽  
Vascular Malformations ◽  
Immune Surveillance ◽  
Vascular Endothelial Cell ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
The Body ◽  
Vascular Networks

AbstractThere are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

scholarly journals Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

2021 ◽  
Vol 22 (11) ◽  
pp. 6141
Author(s):  
Teodora Larisa Timis ◽  
Ioan Alexandru Florian ◽  
Sergiu Susman ◽  
Ioan Stefan Florian
Keyword(s):  
Immune Cells ◽  
Arteriovenous Malformations ◽  
Intracranial Aneurysms ◽  
Immune Cell ◽  
Vascular Malformations ◽  
Cerebral Injury ◽  
Future Research ◽  
Mortality And Morbidity ◽  
The Central Nervous System ◽  
The Brain

Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their outcomes. Recent evidence suggests that activated proinflammatory microglia are implicated in the expansion of brain injury following subarachnoid hemorrhage (SAH) in both the acute and chronic phases, being also a main actor in vasospasm, considerably the most severe complication of SAH. On the other hand, anti-inflammatory microglia may be involved in the resolution of cerebral injury and hemorrhage. These immune cells have also been observed in high numbers in brain arteriovenous malformations (bAVM) and cerebral cavernomas (CCM), although their roles in these lesions are currently incompletely ascertained. The following review aims to shed a light on the most significant findings related to microglia and their roles in intracranial aneurysms and vascular malformations, as well as possibly establish the course for future research.

Unexpected Binding of Tozuleristide “Tumor Paint” to Cerebral Vascular Malformations: A Potentially Novel Application of Fluorescence-Guided Surgery

Neurosurgery ◽  
2021 ◽  
Author(s):  
Andrew J Kobets ◽  
David Nauen ◽  
Amy Lee ◽  
Alan R Cohen
Keyword(s):  
Near Infrared ◽  
Vascular Malformations ◽  
Cns Tumors ◽  
Matrix Metalloproteinase 2 ◽  
Cerebrovascular Lesions ◽  
Cavernous Malformations ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Cerebral Vascular Malformations ◽  
Cerebral Vascular

Abstract BACKGROUND Fluorescence-guided surgery (FGS) is under investigation as a means to improve the extent of resection for primary central nervous system (CNS) tumors. Tozuleristide, known also as “Tumor Paint,” is an investigational tumor-targeting agent covalently conjugated to a derivative of the fluorescent dye indocyanine green. OBJECTIVE To report the finding of avid intraoperative fluorescence of tozuleristide on cerebral vascular malformations. METHODS Our institution is participating in a phase 2/3 study of intraoperative near-infrared fluorescence detection of pediatric primary CNS tumors in patients receiving intravenous tozuleristide and imaged with the Canvas system. Our site enrolled 2 patients with intracranial lesions, suspected preoperatively of possibly being gliomas that proved to be cavernous vascular malformations after resection. RESULTS Each lesion had a dark blue mulberry appearance and each fluoresced avidly with tozuleristide. Each was completely resected, and the patients recovered without deficit. Pathological assessment showed cavernous angioma for both cases. Tozuleristide fluorescence is postulated to result from binding to matrix metalloproteinase-2 and annexin A2, and literature review demonstrates expression of both these ligands on multiple cerebrovascular lesions, including cavernous malformations. CONCLUSION This finding deserves further investigation to determine if tozuleristide “Tumor Paint” may have a wider role in the identification of non-neoplastic intracranial pathologies.

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