{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T09:20:16Z","timestamp":1770888016134,"version":"3.50.1"},"reference-count":30,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,1]]},"abstract":"<jats:sec>\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>Genetic alterations are increasingly recognized as etiologic factors linked to the pathogenesis and development of cerebrovascular anomalies. Their identification allows for advanced screening and targeted therapeutic approaches. The authors aimed to describe the role of a collaborative approach to care and genetic testing in pediatric patients with neurovascular anomalies, with the objectives of identifying what genetic testing recommendations were made, the yield of genetic testing, and the implications for familial screening and management at present and in the future.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>METHODS<\/jats:title>\n<jats:p>The authors performed a descriptive retrospective cohort study examining pediatric patients genetically screened through the Pediatric Neurovascular Program of a single treatment center. Patients 18 years of age and younger with neurovascular anomalies, diagnosed radiographically or histopathologically, were evaluated for germline genetic testing. Patient demographic data and germline genetic testing and recommendation, clinical, treatment, and outcome data were collected and analyzed.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p>Sixty patients were included; 29 (47.5%) were female. The mean age at consultation was 11.0 \u00b1 4.9 years. Diagnoses included cerebral arteriovenous malformations (AVMs) (n = 23), cerebral cavernous malformations (n = 19), non-neurofibromatosis\/non\u2013sickle cell moyamoya (n = 8), diffuse cerebral proliferative angiopathy, and megalencephaly\u2013capillary malformation. Of the 56 patients recommended to have genetic testing, 40 completed it. Genetic alterations were found in 13 (23%) patients. Four patients with AVMs had <jats:italic>RASA1, GDF2<\/jats:italic>, and <jats:italic>ACVRL1<\/jats:italic> mutations. Four patients with cavernous malformations had <jats:italic>Krit1<\/jats:italic> mutations. One with moyamoya disease had an <jats:italic>RNF213<\/jats:italic> mutation. Three patients with megalencephaly\u2013capillary malformation had <jats:italic>PIK3CA<\/jats:italic> mutations, and 1 patient with a cavernous sinus lesion had an <jats:italic>MED12<\/jats:italic> mutation. The majority of AVM patients were treated surgically. Patients with diffuse cerebral proliferative angiopathy were treated medically with sirolimus. At-risk relatives of 3 patients positive for genetic anomalies had also been tested.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CONCLUSIONS<\/jats:title>\n<jats:p>This study demonstrates a role for exploring genetic alterations in the identification and treatment of pediatric neurovascular disease pathogenesis. Germline genetic mutations were found in almost one-quarter of the patients screened in this study, results that helped to identify medically targeted treatment modalities for some pediatric neurovascular patients. Insight into the genetic etiology of vascular anomalies may provide broader clinical implications for risk assessment, family screening, follow-up surveillance, and medical management.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2022.11.peds22392","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T12:28:06Z","timestamp":1671798486000},"page":"212-220","source":"Crossref","is-referenced-by-count":6,"title":["Germline genetic mutations in pediatric cerebrovascular anomalies: a multidisciplinary approach to screening, testing, and management"],"prefix":"10.3171","volume":"31","author":[{"given":"Melissa A.","family":"LoPresti","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Northwestern University Feinberg School of Medicine, and Division of Pediatric Neurosurgery, Lurie Children\u2019s Hospital, Chicago, Illinois;"},{"name":"Department of Neurosurgery, Baylor College of Medicine; Division of Pediatric Neurosurgery, Texas Children\u2019s Hospital, Houston, Texas;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca Y.","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Northwestern University Feinberg School of Medicine, and Division of Pediatric Neurosurgery, Lurie Children\u2019s Hospital, Chicago, Illinois;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Eun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Baylor College of Medicine; Division of Pediatric Neurosurgery, Texas Children\u2019s Hospital, Houston, Texas;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ionela","family":"Iacobas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine; Section of Hematology Oncology, Vascular Anomalies Center, Texas Children\u2019s Hospital, Houston, Texas; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie","family":"Bergstrom","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics, Seattle Children\u2019s Hospital, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel G.","family":"McClugage","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Baylor College of Medicine; Division of Pediatric Neurosurgery, Texas Children\u2019s Hospital, Houston, Texas;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandi K.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Northwestern University Feinberg School of Medicine, and Division of Pediatric Neurosurgery, Lurie Children\u2019s Hospital, Chicago, Illinois;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1754","reference":[{"issue":"7","key":"b1","series-title":"Eur J Hum Genet","first-page":"860","article-title":"Hereditary haemorrhagic telangiectasia: a clinical and scientific review","volume":"17","author":"Govani FS","year":"2009","unstructured":"Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009;17(7):860\u2013871.19337313"},{"issue":"4","key":"b2","series-title":"J Clin Invest","first-page":"1496","article-title":"Mosaic RAS\/MAPK variants cause sporadic vascular malformations which respond to targeted therapy","volume":"128","author":"Al-Olabi L","year":"2018","unstructured":"Al-Olabi L, Polubothu S, Dowsett K,  Mosaic RAS\/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest. 2018;128(4):1496\u20131508.29461977"},{"issue":"6","key":"b3","series-title":"Am J Hum Genet","first-page":"1240","article-title":"Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations","volume":"73","author":"Eerola I","year":"2003","unstructured":"Eerola I, Boon LM, Mulliken JB,  Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73(6):1240\u20131249.14639529"},{"issue":"4","key":"b4","series-title":"Ann Oncol","first-page":"525","article-title":"mTOR-targeted therapy of cancer with rapamycin derivatives","volume":"16","author":"Vignot S","year":"2005","unstructured":"Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005;16(4):525\u2013537.15728109"},{"issue":"4","key":"b5","series-title":"Lymphat Res Biol","first-page":"226","article-title":"Update on the molecular genetics of vascular anomalies","volume":"3","author":"Wang QK","year":"2005","unstructured":"Wang QK. Update on the molecular genetics of vascular anomalies. Lymphat Res Biol. 2005;3(4):226\u2013233.16379592"},{"key":"b6","series-title":"J Blood Med","first-page":"191","article-title":"Optimal management of hereditary hemorrhagic telangiectasia","volume":"5","author":"Garg N","year":"2014","unstructured":"Garg N, Khunger M, Gupta A, Kumar N. Optimal management of hereditary hemorrhagic telangiectasia. J Blood Med. 2014;5:191\u2013206.25342923"},{"issue":"7","key":"b7","series-title":"Hum Mutat","first-page":"959","article-title":"Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations","volume":"29","author":"Revencu N","year":"2008","unstructured":"Revencu N, Boon LM, Mulliken JB,  Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29(7):959\u2013965.18446851"},{"issue":"2","key":"b8","series-title":"J Med Genet","first-page":"73","article-title":"International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia","volume":"48","author":"Faughnan ME","year":"2011","unstructured":"Faughnan ME, Palda VA, Garcia-Tsao G,  International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73\u201387.19553198"},{"issue":"7","key":"b9","series-title":"Neurology","first-page":"959","article-title":"Pulmonary arteriovenous malformations: cerebral ischemia and neurologic manifestations","volume":"55","author":"Moussouttas M","year":"2000","unstructured":"Moussouttas M, Fayad P, Rosenblatt M,  Pulmonary arteriovenous malformations: cerebral ischemia and neurologic manifestations. Neurology. 2000;55(7):959\u2013964.11061251"},{"issue":"5","key":"b10","series-title":"Thromb Haemost","first-page":"1031","article-title":"Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism","volume":"98","author":"Shovlin CL","year":"2007","unstructured":"Shovlin CL, Sulaiman NL, Govani FS, Jackson JE, Begbie ME. Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost. 2007;98(5):1031\u20131039.18000608"},{"issue":"10","key":"b11","series-title":"Trends Mol Med","first-page":"856","article-title":"Cancer-associated PIK3CA mutations in overgrowth disorders","volume":"24","author":"Madsen RR","year":"2018","unstructured":"Madsen RR, Vanhaesebroeck B, Semple RK. Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol Med. 2018;24(10):856\u2013870.30197175"},{"key":"b12","series-title":"GeneReviews\u00ae [Internet]","article-title":"PIK3CA-related overgrowth spectrum","author":"Mirzaa G","year":"2013","unstructured":"Mirzaa G, Graham JM Jr, Keppler-Noreuil K. PIK3CA-related overgrowth spectrum. In: Adam MP, Everman DB, Mirzaa GM, , eds. GeneReviews\u00ae [Internet]. University of Washington; 2013."},{"issue":"7","key":"b13","series-title":"Am J Med Genet A","first-page":"1713","article-title":"Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum","volume":"164A","author":"Keppler-Noreuil KM","year":"2014","unstructured":"Keppler-Noreuil KM, Sapp JC, Lindhurst MJ,  Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014;164A(7):1713-1733.24782230"},{"issue":"10","key":"b14","series-title":"AJNR Am J Neuroradiol","first-page":"1812","article-title":"Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging findings in 6 patients","volume":"32","author":"Alomari AI","year":"2011","unstructured":"Alomari AI, Chaudry G, Rodesch G,  Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging findings in 6 patients. AJNR Am J Neuroradiol. 2011;32(10):1812\u20131817.21310861"},{"issue":"10","key":"b15","series-title":"Am J Med Genet A","first-page":"2559","article-title":"Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation","volume":"170","author":"Gripp KW","year":"2016","unstructured":"Gripp KW, Baker L, Kandula V,  Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation. Am J Med Genet A. 2016;170(10):2559\u20132569.27191687"},{"key":"b16","series-title":"GeneReviews\u00ae [Internet]","article-title":"Cerebral cavernous malformation, familial","author":"Morrison L","year":"2003","unstructured":"Morrison L, Akers A. Cerebral cavernous malformation, familial. In: Adam MP, Everman DB, Mirzaa GM, , eds. GeneReviews\u00ae [Internet]. University of Washington; 2003."},{"issue":"2","key":"b17","series-title":"Surg Neurol","first-page":"167","article-title":"Vertebral and spinal cavernous angiomas associated with familial cerebral cavernous malformation","volume":"71","author":"Toldo I","year":"2009","unstructured":"Toldo I, Drigo P, Mammi I, Marini V, Carollo C. Vertebral and spinal cavernous angiomas associated with familial cerebral cavernous malformation. Surg Neurol. 2009;71(2):167\u2013171.18207546"},{"issue":"6","key":"b18","series-title":"Arch Neurol","first-page":"843","article-title":"Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation","volume":"64","author":"Battistini S","year":"2007","unstructured":"Battistini S, Rocchi R, Cerase A,  Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation. Arch Neurol. 2007;64(6):843\u2013848.17562932"},{"key":"b19","series-title":"GeneReviews\u00ae [Internet]","article-title":"Hereditary hemorrhagic telangiectasia","author":"McDonald J","year":"2000","unstructured":"McDonald J, Stevenson DA. Hereditary hemorrhagic telangiectasia. In: Adam MP, Everman DB, Mirzaa GM, , eds. GeneReviews\u00ae [Internet]. University of Washington; 2000."},{"issue":"6","key":"b20","series-title":"AJNR Am J Neuroradiol","first-page":"1016","article-title":"Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia","volume":"21","author":"Matsubara S","year":"2000","unstructured":"Matsubara S, Mandzia JL, ter Brugge K,  Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. AJNR Am J Neuroradiol. 2000;21(6):1016\u20131020.10871005"},{"issue":"1","key":"b21","series-title":"J Neurosurg Pediatr","first-page":"1","article-title":"A study of pediatric cerebral arteriovenous malformations: clinical presentation, radiological features, and long-term functional and educational outcomes with predictors of sustained neurological deficits","volume":"24","author":"Ravindra VM","year":"2019","unstructured":"Ravindra VM, Bollo RJ, Eli IM,  A study of pediatric cerebral arteriovenous malformations: clinical presentation, radiological features, and long-term functional and educational outcomes with predictors of sustained neurological deficits. J Neurosurg Pediatr. 2019;24(1):1\u20138.30952115"},{"issue":"9144","key":"b22","series-title":"Soci\u00e9t\u00e9 Fran\u00e7aise de Neurochirurgie. Lancet","first-page":"1892","article-title":"Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families","volume":"352","author":"Labauge P","year":"1998","unstructured":"Labauge P, Laberge S, Brunereau L, Levy C, Tournier-Lasserve E. Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Soci\u00e9t\u00e9 Fran\u00e7aise de Neurochirurgie. Lancet. 1998;352(9144):1892\u20131897.9863787"},{"issue":"11","key":"b23","series-title":"Neurology","first-page":"803","article-title":"Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease","volume":"78","author":"Miyatake S","year":"2012","unstructured":"Miyatake S, Miyake N, Touho H,  Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology. 2012;78(11):803\u2013810.22377813"},{"issue":"6","key":"b24","series-title":"J Neurosurg Pediatr","first-page":"673","article-title":"Antiangiogenic agent as a novel treatment for pediatric intracranial arteriovenous malformations: case report","volume":"24","author":"Maynard K","year":"2019","unstructured":"Maynard K, LoPresti M, Iacobas I, Kan P, Lam S. Antiangiogenic agent as a novel treatment for pediatric intracranial arteriovenous malformations: case report. J Neurosurg Pediatr. 2019;24(6):673\u2013679."},{"issue":"1","key":"b25","series-title":"Eur J Pediatr Surg","first-page":"86","article-title":"Sirolimus in the treatment of vascular anomalies","volume":"27","author":"Triana P","year":"2017","unstructured":"Triana P, Dore M, Cerezo VN,  Sirolimus in the treatment of vascular anomalies. Eur J Pediatr Surg. 2017;27(1):86\u201390.27723921"},{"issue":"11","key":"b26","series-title":"PLoS One","first-page":"e0188943","article-title":"Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): a retrospective study of 46 patients","volume":"12","author":"Guilhem A","year":"2017","unstructured":"Guilhem A, Fargeton AE, Simon AC,  Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): a retrospective study of 46 patients. PLoS One. 2017;12(11):e0188943.29190827"},{"issue":"5","key":"b27","series-title":"Genet Med","first-page":"1189","article-title":"Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum","volume":"21","author":"Parker VER","year":"2019","unstructured":"Parker VER, Keppler-Noreuil KM, Faivre L,  Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum. 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