Familial Cerebral Cavernous Malformations

Kelly D Flemming, Edward Smith, Douglas Marchuk, W Brent Derry, Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Anne Amemiya, Kelly D Flemming, Edward Smith, Douglas Marchuk, W Brent Derry, Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Anne Amemiya

Excerpt

Clinical characteristics: Familial cerebral cavernous malformations (FCCM) is a disorder characterized by multiple vascular lesions in the brain and spinal cord that consist of clustered, endothelial-lined caverns ranging in diameter from a few millimeters to several centimeters. Cerebral and/or spinal cavernous malformations may increase in number over time, and individual lesions may increase or decrease in size. The number of cerebral cavernous malformations (CCMs) identified in an individual ranges from one or two to hundreds of lesions (typical number 6-20 CCMs) depending on the individual's age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades of life either incidentally or associated with seizures, focal neurologic deficits, headaches, and/or cerebral hemorrhage. Cutaneous vascular lesions are found in 9% and retinal vascular lesions in almost 5% of affected individuals. Up to 50% of individuals with FCCM remain symptom free throughout their lives.

Diagnosis/testing: The diagnosis of familial cerebral cavernous malformations (FCCM) is established in a proband with multiple CCMs, one CCM and at least one other family member with one or more CCMs, or a heterozygous germline pathogenic variant in KRIT1, CCM2, or PDCD10 identified by molecular genetic testing.

Management: Treatment of manifestations: Surgical removal of symptomatic lesions may be considered in individuals with acute hemorrhage and/or a mass effect presenting with focal neurologic deficit, headache, or seizure or in those with intractable seizures (with or without associated hemorrhage). Treatment of epilepsy is symptomatic. Headaches are managed symptomatically and prophylactically. Rehabilitation may aid in management of acute and chronic neurologic deficits.

Surveillance: Brain MR imaging with susceptibility-weighted imaging (SWI) is indicated in individuals experiencing new neurologic manifestations.

Agents/circumstances to avoid: Caution is recommended with medications such as analgesics such as NSAIDs, antithrombotic medications such as heparin and warfarin (Coumadin®), thrombolytic agents, and oral female hormones. Note: When antithrombotic and thrombolytic medications are necessary for treatment of life-threatening thrombosis, careful consideration of appropriate dosage and close monitoring are warranted. Radiation to the central nervous system may lead to new lesion formation.

Evaluation of relatives at risk: Asymptomatic at-risk relatives of all ages may be evaluated by molecular genetic testing if the family-specific pathogenic variant is known to allow early diagnosis and monitoring of individuals at risk of developing CCMs. Symptomatic relatives may undergo brain MRI with SWI sequences to determine presence, size, and location of lesions.

Pregnancy management: Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or headaches require close monitoring during pregnancy. Seizures are the most common manifestations of CCM hemorrhage during pregnancy; exposure to anti-seizure medication during pregnancy may increase the risk for adverse fetal outcomes but is generally recommended, as the fetal risk is typically less than that associated with an untreated maternal seizure disorder. Any focal neurologic deficits or severe headaches during pregnancy should be evaluated and other neurologic causes (e.g., ischemic stroke, cerebral venous thrombosis) ruled out.

Genetic counseling: FCCM is inherited in an autosomal dominant manner. Many individuals diagnosed with FCCM have a symptomatic parent. The proportion of individuals with FCCM caused by a de novo pathogenic variant is unknown. Each child of an individual with FCCM has a 50% chance of inheriting an FCCM-related pathogenic variant. If a pathogenic variant has been identified in an affected family member, prenatal testing of an at-risk pregnancy and preimplantation genetic testing are possible.

Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

References

    1. Akers A, Al-Shahi Salman R, Awad IA, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E, Waggoner D, Whitehead K. Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. Neurosurgery. 2017;80:665-80.
    1. Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet. 2009;18:919-30.
    1. Alalfi MO, Lanzino G, Flemming KD. Clinical presentation, hemorrhage risk, and outcome in patients with familial cavernous malformations: a pragmatic prospective analysis of 75 patients. J Neurosurg. 2023. Epub ahead of print.
    1. Al-Shahi R, Bhattacharya JJ, Currie DG, Papanastassiou V, Ritchie V, Roberts RC, Sellar RJ, Warlow CP, et al. Prospective, population-based detection of intracranial vascular malformations in adults: the Scottish Intracranial Vascular Malformation Study (SIVMS). Stroke. 2003;34:1163-9.
    1. Battistini S, Rocchi R, Cerase A, Citterio A, Tassi L, Lando G, Patrosso MC, Galli R, Brunori P, Sgrò DL, Pitillo G, Lo Russo G, Marocchi A, Penco S. Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation. Arch Neurol. 2007;64:843-8.
    1. Bilo L, Antenora A, Peluso S, Procaccini EM, Quarantelli M, Mansueto G, Cigoli MS, Penco S, De Michele G. CCM3/PDCD10 gene mutation in cerebral cavernous malformations associated with hyperkeratotic cutaneous capillary venous malformations. J Dermatol. 2016;43:962-3.
    1. Borikova AL, Dibble CF, Sciaky N, Welch CM, Abell AN, Bencharit S, Johnson GL. Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype. J Biol Chem. 2010;285:11760-4.
    1. Brownlee WJ, Roxburgh R. Mystery case: cutaneous lesions in KRIT1-associated cerebral cavernous malformations. Neurology. 2014;83:e133-4.
    1. Brunereau L, Levy C, Laberge S, Houtteville J, Labauge P. De novo lesions in familial form of cerebral cavernous malformations: clinical and MR features in 29 non-Hispanic families. Surg Neurol. 2000;53:475-82
    1. Campione E, Diluvio L, Terrinoni A, Di Stefani A, Orlandi A, Chimenti S, Bianchi L. Progressive late-onset of cutaneous angiomatosis as possible sign of cerebral cavernous malformations. Dermatol Online J. 2013;19:2.
    1. Carrión-Penagos J, Zeineddine HA, Polster SP, Girard R, Lyne SB, Koskimäki J, Romanos S, Srinath A, Zhang D, Cao Y, Stadnik A, Piedad K, Shenkar R, Awad IA. Subclinical imaging changes in cerebral cavernous angiomas during prospective surveillance. J Neurosurg. 2020;134:1147-54.
    1. Cau M, Loi M, Melis M, Congiu R, Loi A, Meloni C, Serrenti M, Addis M, Melis MA. C329X in KRIT1 is a founder mutation among CCM patients in Sardinia. Eur J Med Genet. 2009;52:344-8.
    1. Cha YJ, Nahm JH, Ko JE, Shin HJ, Chang JH, Cho NH, Kim SH. Pathological evaluation of radiation-induced vascular lesions of the brain: distinct from de novo cavernous hemangioma. Yonsei Med J. 2015;56:1714-20.
    1. Choquet H, Nelson J, Pawlikowska L, McCulloch CE, Akers A, Baca B, Khan Y, Hart B, Morrison L, Kim H. Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation. Cerebrovasc Dis. 2014;37:57-63.
    1. Cigoli MS, Avemaria F, De Benedetti S, Gesu GP, Accorsi LG, Parmigiani S, Corona MF, Capra V, Mosca A, Giovannini S, Notturno F, Ciccocioppo F, Volpi L, Estienne M, De Michele G, Antenora A, Bilo L, Tavoni A, Zamponi N, Alfei E, Baranello G, Riva D, Penco S. PDCD10 gene mutations in multiple cerebral cavernous malformations. PLoS One. 2014;9:e110438.
    1. Corr M, Lerman I, Keubel JM, Ronacher L, Misra R, Lund F, Sarelius IH, Glading AJ. Decreased Krev interaction-trapped 1 expression leads to increased vascular permeability and modifies inflammatory responses in vivo. Arterioscler Thromb Vasc Biol. 2012;32:2702-10.
    1. D'Angelo R, Marini V, Rinaldi C, Origone P, Dorcaratto A, Avolio M, Goitre L, Forni M, Capra V, Alafaci C, Mareni C, Garrè C, Bramanti P, Sidoti A, Retta SF, Amato A. Mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation. Brain Pathol. 2011;21:215-24.
    1. Denier C, Labauge P, Brunereau L, Cavé-Riant F, Marchelli F, Arnoult M, Cecillon M, Maciazek J, Joutel A, Tournier-Lasserve E. Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. Ann Neurol. 2004;55:213-20.
    1. Denier C, Labauge P, Bergametti F, Marchelli F, Riant F, Arnoult M, Maciazek J, Vicaut E, Brunereau L, Tournier-Lasserve E, Société Française de Neurochirurgie. Genotype-phenotype correlations in cerebral cavernous malformations patients. Ann Neurol. 2006;60:550-6.
    1. DiStefano PV, Kuebel JM, Sarelius IH, Glading AJ. KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling. J Biol Chem. 2014;289:33054-65.
    1. Drigo P, Mammi I, Battistella PA, Ricchieri G, Carollo C. Familial cerebral, hepatic, and retinal cavernous angiomas: a new syndrome. Childs Nerv Syst. 1994;10:205-9.
    1. Eerola I, Plate KH, Spiegel R, Boon LM, Mulliken JB, Vikkula M. KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation. Hum Mol Genet. 2000;9:1351-5
    1. Erdur H, Scheitz JF, Tütüncü S, Fiebach JB, Endres M, Werring DJ, Nolte CH. Safety of thrombolysis in patients with acute ischemic stroke and cerebral cavernous malformations. Stroke. 2014;45:1846-8.
    1. Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E. Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends Mol Med. 2013;19:302-8.
    1. Fisher OS, Deng H, Liu D, Zhang Y, Wei R, Deng Y, Zhang F, Louvi A, Turk BE, Boggon TJ, Su B. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. Nat Commun. 2015;6:7937.
    1. Flemming KD, Chiang C, Brown RD, Lanzino G. Safety of select headache medications in patients with cerebral and spinal cavernous malformations. Cephalalgia Reports. 2021;4.
    1. Flemming KD, Graff-Radford J, Aakre J, Kantarci K, Lanzino G, Brown RD Jr, Mielke MM, Roberts RO, Kremers W, Knopman DS, Petersen RC, Jack CR Jr. Population-based prevalence of cerebral cavernous malformations in older adults: Mayo Clinic Study of Aging. JAMA Neurol. 2017;74:801-5.
    1. Flemming KD, Kumar S, Brown RD Jr, Singh RJ, Whitehead K, McCreath L, Lanzino G. Cavernous malformation hemorrhagic presentation at diagnosis associated with low 25-hydroxy-vitamin D level. Cerebrovasc Dis. 2020;49:216-22.
    1. Flemming KD, Kumar S, Lanzino G, Brinjikji W. Baseline and evolutionary radiologic features in sporadic, hemorrhagic brain cavernous malformations. AJNR Am J Neuroradiol. 2019;40:967-72.
    1. Flemming KD, Lanzino G. Cerebral cavernous malformation: what a practicing clinician should know. Mayo Clin Proc. 2020;95:2005-2020.
    1. Flemming KD, Link MJ, Christianson TJ, Brown RD Jr. Use of antithrombotic agents in patients with intracerebral cavernous malformations. J Neurosurg. 2013;118:43-6.
    1. Fox CK, Nelson J, McCulloch CE, Weinsheimer S, Pawlikowska L, Hart B, Mabray M, Zafar A, Morrison L, Zabramski JM, Akers A, Kim H. Seizure incidence rates in children and adults with familial cerebral cavernous malformations. Neurology. 2021;97:e1210-6.
    1. Gallione CJ, Detter MR, Sheline A, Christmas HM, Lee C, Marchuk DA. Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations gene. Hum Genet. 2022;141:1761-1769.
    1. Gallione CJ, Solatycki A, Awad IA, Weber JL, Marchuk DA. A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations. Genet Med. 2011;13:662-6.
    1. Gao X, Yue K, Sun J, Fang Z, Cao Y, Zhao B, Zhang H, Dai S, Zhang L, Luo P, Jiang X. A systematic review and meta-analysis of surgeries performed for cerebral cavernous malformation-related epilepsy in pediatric patients. Front Pediatr. 2022;10:892456.
    1. Geraldo AF, Alves CAPF, Luis A, Tortora D, Guimarães J, Abreu D, Reimão S, Pavanello M, de Marco P, Scala M, Capra V, Vaz R, Rossi A, Schwartz ES, Mankad K, Severino M. Natural history of familial cerebral cavernous malformation syndrome in children: a multicenter cohort study. Neuroradiology. 2023;65:401-14.
    1. Girard R, Khanna O, Shenkar R, Zhang L, Wu M, Jesselson M, Zeineddine HA, Gangal A, Fam MD, Gibson CC, Whitehead KJ, Li DY, Liao JK, Shi C, Awad IA. Peripheral plasma vitamin D and non-HDL cholesterol reflect the severity of cerebral cavernous malformation disease. Biomark Med. 2016;10:255-64.
    1. Glading A, Han J, Stockton RA, Ginsberg MH. KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol. 2007;179:247-54.
    1. Goitre L, Balzac F, Degani S, Degan P, Marchi S, Pinton P, Retta SF. KRIT1 regulates the homeostasis of intracellular reactive oxygen species. PLoS One. 2010;5:e11786.
    1. Goitre L, De Luca E, Braggion S, Trapani E, Guglielmotto M, Biasi F, Forni M, Moglia A, Trabalzini L, Retta SF. KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun. Free Radic Biol Med. 2014;68:134-47.
    1. Golden M, Saeidi S, Liem B, Marchand E, Morrison L, Hart B. Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation. J Med Imaging Radiat Oncol. 2015b;59:134-6.
    1. Golden MJ, Morrison LA, Kim H, Hart BL. Increased number of white matter lesions in patients with familial cerebral cavernous malformations. AJNR Am J Neuroradiol. 2015a;36:899-903.
    1. Gibson CC, Zhu W, Davis CT, Bowman-Kirigin JA, Chan AC, Ling J, Walker AE, Goitre L, Delle Monache S, Retta SF, Shiu YT, Grossmann AH, Thomas KR, Donato AJ, Lesniewski LA, Whitehead KJ, Li DY. Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation. 2015;131:289-99.
    1. Gross BA, Du R. Hemorrhage from cerebral cavernous malformations: a systematic pooled analysis. J Neurosurg. 2017;126:1079-87.
    1. Guclu B, Ozturk AK, Pricola KL, Bilguvar K, Shin D, O'Roak BJ, Gunel M. Mutations in apoptosis-related gene, PDCD10, cause cerebral cavernous malformation 3. Neurosurgery 2005;57:1008-13
    1. Hart BL, Mabray MC, Morrison L, Whitehead KJ, Kim H. Clin Imaging. 2021;75:55-66.
    1. He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H, Min W. Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Sci Signal. 2010;3:ra26.
    1. Heros RC, Heros DO. Principles of neurosurgery. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. Vol 1. Boston, MA: Butterworth Heinemann; 2000:931-58.
    1. Hilder TL, Malone MH, Bencharit S, Colicelli J, Haystead TA, Johnson GL, Wu CC. Proteomic identification of the cerebral cavernous malformation signaling complex. J Proteome Res. 2007;6:4343-55.
    1. Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, Maxwell SS, White P, Christianson TJ, Agid R, Cho WS, Oh CW, Wu Z, Zhang JT, Kim JE, Ter Brugge K, Willinsky R, Brown RD Jr, Murray GD, Al-Shahi Salman R, et al. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 2016;15:166-73.
    1. Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97.
    1. Huo R, Wang J, Sun YF, Weng JC, Li H, Jiao YM, Xu HY, Zhang JZ, Zhao SZ, He QH, Wang S, Zhao JZ, Cao Y. Simplex cerebral cavernous malformations with MAP3K3 mutation have distinct clinical characteristics. Front Neurol. 2022;13:946324.
    1. Johnson EW, Iyer LM, Rich SS, Orr HT, Gil-Nagel A, Kurth JH, Zabramski JM, Marchuk DA, Weissenbach J, Clericuzio CL, Davis LE, Hart BL, Gusella JF, Kosofsky BE, Louis DN, Morrison LA, Green ED, Weber JL. Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig. Genome Res. 1995;5:368-80.
    1. Johnson EW, Marchuk DA, Zabramski JM. Genetics of cerebral cavernous malformations. In: Winn HR, ed. Youman's Neurological Surgery. 5 ed. Vol 2. Philadelphia, PA: WB Saunders Co, Philadelphia; 2004:2299-304.
    1. Joseph NK, Kumar S, Brown RD Jr, Lanzino G, Flemming KD. Influence of pregnancy on hemorrhage risk in women with cerebral and spinal cavernous malformations. Stroke. 2021;52:434-41.
    1. Kalani MY, Zabramski JM. Risk for symptomatic hemorrhage of cerebral cavernous malformations during pregnancy. J Neurosurg. 2013;118:50-5.
    1. Kumar S, Brinjikji W, Lanzino G, Flemming KD. Distinguishing mimics from true hemorrhagic cavernous malformations. J Clin Neurosci. 2020;74:11-7.
    1. Kurlemann G. Neurocutaneous syndromes. Handb Clin Neurol. 2012;108:513-33.
    1. Labauge P, Brunereau L, Laberge S, Houtteville JP. Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations. Neurology. 2001;57:1825-8
    1. Labauge P, Brunereau L, Lévy C, Laberge S, Houtteville JP. The natural history of familial cerebral cavernomas: a retrospective MRI study of 40 patients. Neuroradiology. 2000;42:327-32.
    1. Labauge P, Denier C, Bergametti F, Tournier-Lasserve E. Genetics of cavernous angiomas. Lancet Neurol. 2007;6:237-44.
    1. Labauge P, Krivosic V, Denier C, Tournier-Lasserve E, Gaudric A. Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas: a clinical and genetic study. Arch Ophthalmol. 2006;124:885-6.
    1. Lanfranconi S, Piergallini L, Ronchi D, Valcamonica G, Conte G, Marazzi E, Manenti G, Bertani GA, Locatelli M, Triulzi F, Bresolin N, Scola E, Comi GP. Clinical, neuroradiological and genetic findings in a cohort of patients with multiple cerebral cavernous malformations. Metab Brain Dis. 2021;36:1871-8.
    1. Lanfranconi S, Scola E, Bertani GA, Zarino B, Pallini R, d'Alessandris G, Mazzon E, Marino S, Carriero MR, Scelzo E, Faragò G, Castori M, Fusco C, Petracca A, d'Agruma L, Tassi L, d'Orio P, Lampugnani MG, Nicolis EB, Vasamì A, Novelli D, Torri V, Meessen JMTA, Al-Shahi Salman R, Dejana E, Latini R; Treat-CCM Investigators. Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial. Trials. 2020;21:401.
    1. Lanfranconi S, Scola E, Meessen JMTA, Pallini R, Bertani GA, Al-Shahi Salman R, Dejana E, Latini R, et al. Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): a randomised, open-label, blinded-endpoint, phase 2 pilot trial. Lancet Neurol. 2023;22:35-44.
    1. Larson JJ, Ball WS, Bove KE, Crone KR, Tew JM Jr. Formation of intracerebral cavernous malformations after radiation treatment for central nervous system neoplasia in children. J Neurosurg. 1998;88:51-6.
    1. Liquori CL, Berg MJ, Squitieri F, Leedom TP, Ptacek L, Johnson EW, Marchuk DA. Deletions in CCM2 are a common cause of cerebral cavernous malformations. Am J Hum Genet. 2007;80:69-75.
    1. Liquori CL, Penco S, Gault J, Leedom TP, Tassi L, Esposito T, Awad IA, Frati L, Johnson EW, Squitieri F, Marchuk DA, Gianfrancesco F. Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics. 2008;9:25-31.
    1. Lucas M, Costa AF, Montori M, Solano F, Zayas MD, Izquierdo G. Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations. Ann Neurol. 2001;49:529-32
    1. Mabray MC, Starcevich J, Hallstrom J, Robinson M, Bartlett M, Nelson J, Zafar A, Kim H, Morrison L, Hart BL. High prevalence of spinal cord cavernous malformations in the Familial Cerebral Cavernous Malformations Type 1 Cohort. AJNR Am J Neuroradiol. 2020;41:1126-30.
    1. Macek Jilkova Z, Lisowska J, Manet S, Verdier C, Deplano V, Geindreau C, Faurobert E, Albigès-Rizo C, Duperray A. CCM proteins control endothelial β1 integrin dependent response to shear stress. Biol Open. 2014;3:1228-35.
    1. Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, Tournier-Lasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E. EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature. 2013;498:492-6.
    1. Manole AK, Forrester VJ, Zlotoff BJ, Hart BL, Morrison LA. Cutaneous findings of familial cerebral cavernous malformation syndrome due to the common Hispanic mutation. Am J Med Genet A. 2020;182:1066-72.
    1. Marchi S, Corricelli M, Trapani E, Bravi L, Pittaro A, Delle Monache S, Ferroni L, Patergnani S, Missiroli S, Goitre L, Trabalzini L, Rimessi A, Giorgi C, Zavan B, Cassoni P, Dejana E, Retta SF, Pinton P. Defective autophagy is a key feature of cerebral cavernous malformations. EMBO Mol Med. 2015;7:1403-17.
    1. Moultrie F, Horne MA, Josephson CB, Hall JM, Counsell CE, Bhattacharya JJ, Papanastassiou V, Sellar RJ, Warlow CP, Murray GD, Al-Shahi Salman R, et al. Outcome after surgical or conservative management of cerebral cavernous malformations. Neurology. 2014;83:582-9.
    1. Nikoubashman O, Di Rocco F, Davagnanam I, Mankad K, Zerah M, Wiesmann M. Prospective hemorrhage rates of cerebral cavernous malformations in children and adolescents based on MRI appearance. AJNR Am J Neuroradiol. 2015;36:2177-83.
    1. Nimjee SM, Powers CJ, Bulsara KR. Review of the literature on de novo formation of cavernous malformations of the central nervous system after radiation therapy. Neurosurg Focus. 2006;21:e4.
    1. Pagenstecher A, Stahl S, Sure U, Felbor U. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Hum Mol Genet. 2009;18:911-8
    1. Peyre M, Miyagishima D, Bielle F, Chapon F, Sierant M, Venot Q, Lerond J, Marijon P, Abi-Jaoude S, Le Van T, Labreche K, Houlston R, Faisant M, Clémenceau S, Boch AL, Nouet A, Carpentier A, Boetto J, Louvi A, Kalamarides M. Somatic PIK3CA mutations in sporadic cerebral cavernous malformations. N Engl J Med. 2021;385:996-1004.
    1. Poorthuis MHF, Rinkel LA, Lammy S, Al-Shahi Salman R. Stereotactic radiosurgery for cerebral cavernous malformations: a systematic review. Neurology. 2019;93:e1971-e1979.
    1. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL. Guidelines for the early management of patients with acute ischemic stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50:e344-e418.
    1. Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126-33.
    1. Rauschenbach L, Santos AN, Dinger TF, Darkwah Oppong M, Li Y, Tippelt S, Dohna-Schwake C, Schmidt B, Jabbarli R, Wrede KH, Sure U, Dammann P. Functional outcome after pediatric cerebral cavernous malformation surgery. Sci Rep. 2023;13:2286.
    1. Ren AA, Snellings DA, Su YS, Hong CC, Castro M, Tang AT, Detter MR, Hobson N, Girard R, Romanos S, Lightle R, Moore T, Shenkar R, Benavides C, Beaman MM, Müller-Fielitz H, Chen M, Mericko P, Yang J, Sung DC, Lawton MT, Ruppert JM, Schwaninger M, Körbelin J, Potente M, Awad IA, Marchuk DA, Kahn ML. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature. 2021;594:271-6.
    1. Riant F, Bergametti F, Ayrignac X, Boulday G, Tournier-Lasserve E. Recent insights into cerebral cavernous malformations: the molecular genetics of CCM. FEBS J. 2010;277:1070-5.
    1. Riant F, Bergametti F, Fournier HD, Chapon F, Michalak-Provost S, Cecillon M, Lejeune P, Hosseini H, Choe C, Orth M, Bernreuther C, Boulday G, Denier C, Labauge P, Tournier-Lasserve E. CCM3 Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas. Mol Syndromol. 2013;4:165-72.
    1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.
    1. Sahoo T, Johnson EW, Thomas JW, Kuehl PM, Jones TL, Dokken CG, Touchman JW, Gallione CJ, Lee-Lin SQ, Kosofsky B, Kurth JH, Louis DN, Mettler G, Morrison L, Gil-Nagel A, Rich SS, Zabramski JM, Boguski MS, Green ED, Marchuk DA. Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet. 1999;8:2325-33.
    1. Santos AN, Rauschenbach L, Saban D, Chen B, Darkwah Oppong M, Herten A, Gull HH, Rieß C, Deuschl C, Schmidt B, Jabbarli R, Wrede KH, Zhu Y, Frank B, Sure U, Dammann P.Multiple cerebral cavernous malformations: clinical course of confirmed, assumed and non-familial disease. Eur J Neurol. 2022;29:1427-34.
    1. Sarraf D, Payne AM, Kitchen ND, Sehmi KS, Downes SM, Bird AC. Familial cavernous hemangioma: An expanding ocular spectrum. Arch Ophthalmol. 2000;118:969-73.
    1. Selman WR, Tarr RW, Ratcheson RA. Arteriovenous malformation. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. Vol 1. Boston, MA: Butterworth Heinemann; 2000:1201-14.
    1. Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, Zhang L, Austin C, Akers AL, Gallione CJ, Rorrer A, Gunel M, Min W, Marcondes de Souza J, Lee C, Marchuk DA, Awad IA. Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med. 2015;17:188-96.
    1. Sirvente J, Enjolras O, Wassef M, Tournier-Lasserve E, Labauge P. Frequency and phenotypes of cutaneous vascular malformations in a consecutive series of 417 patients with familial cerebral cavernous malformations. J Eur Acad Dermatol Venereol. 2009;23:1066-72.
    1. Snellings DA, Girard R, Lightle R, Srinath A, Romanos S, Li Y, Chen C, Ren AA, Kahn ML, Awad IA, Marchuk DA. Developmental venous anomalies are a genetic primer for cerebral cavernous malformations. Nat Cardiovasc Res. 2022;1:246-52.
    1. Spiegler S, Najm J, Liu J, Gkalympoudis S, Schröder W, Borck G, Brockmann K, Elbracht M, Fauth C, Ferbert A, Freudenberg L, Grasshoff U, Hellenbroich Y, Henn W, Hoffjan S, Hüning I, Korenke GC, Kroisel PM, Kunstmann E, Mair M, Munk-Schulenburg S, Nikoubashman O, Pauli S, Rudnik-Schöneborn S, Sudholt I, Sure U, Tinschert S, Wiednig M, Zoll B, Ginsberg MH, Felbor U. High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors. Mol Genet Genomic Med. 2014;2:176-85.
    1. Stahl S, Gaetzner S, Voss K, Brackertz B, Schleider E, Sürücü O, Kunze E, Netzer C, Korenke C, Finckh U, Habek M, Poljakovic Z, Elbracht M, Rudnik-Schöneborn S, Bertalanffy H, Sure U, Felbor U. Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex. Hum Mutat. 2008;29:709-17.
    1. Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207.
    1. Stockton RA, Shenkar R, Awad IA, Ginsberg MH. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med. 2010;207:881-96.
    1. Strickland CD, Eberhardt SC, Bartlett MR, Nelson J, Kim H, Morrison LA, Hart BL. Familial cerebral cavernous malformations are associated with adrenal calcifications on CT scans: an imaging biomarker for a hereditary cerebrovascular condition. Radiology. 2017;284:443-50.
    1. Tandberg SR, Bocklage T, Bartlett MR, Morrison LA, Nelson J, Hart BL. vertebral intraosseous vascular malformations in a familial cerebral cavernous malformation population: prevalence, histologic features, and associations with CNS disease. AJR Am J Roentgenol. 2020;214:428-36.
    1. Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017;545:305-10.
    1. Tang AT, Sullivan KR, Hong CC, Goddard LM, Mahadevan A, Ren A, Pardo H, Peiper A, Griffin E, Tanes C, Mattei LM, Yang J, Li L, Mericko-Ishizuka P, Shen L, Hobson N, Girard R, Lightle R, Moore T, Shenkar R, Polster SP, Roedel CJ, Li N, Zhu Q, Whitehead KJ, Zheng X, Akers A, Morrison L, Kim H, Bittinger K, Lengner CJ, Schwaninger M, Velcich A, Augenlicht L, Abdelilah-Seyfried S, Min W, Marchuk DA, Awad IA, Kahn ML. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019;11:eaaw3521.
    1. Taslimi S, Ku JC, Modabbernia A, Macdonald RL. Hemorrhage, seizures, and dynamic changes of familial versus nonfamilial cavernous malformation: systematic review and meta-analysis. World Neurosurg. 2019;126:241-6.
    1. Taslimi S, Modabbernia A, Amin-Hanjani S, Barker FG 2nd, Macdonald RL. Natural history of cavernous malformation: systematic review and meta-analysis of 25 studies. Neurology. 2016;86:1984-91.
    1. Toldo I, Drigo P, Mammi I, Marini V, Carollo C. Vertebral and spinal cavernous angiomas associated with familial cerebral cavernous malformation. Surg Neurol. 2009;71:167-71.
    1. Uhlik MT, Abell AN, Johnson NL, Sun W, Cuevas BD, Lobel-Rice KE, Horne EA, Dell'Acqua ML, Johnson GL Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol. 2003;5:1104-10
    1. Verlaan DJ, Davenport WJ, Stefan H, Sure U, Siegel AM, Rouleau GA. Cerebral cavernous malformations: Mutations in Krit1. Neurology. 2002;58:853-7
    1. Voss K, Stahl S, Schleider E, Ullrich S, Nickel J, Mueller TD, Felbor U. CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics. 2007;8:249-56.
    1. Wang Y, Liu H, Zhang Y, Ma D. cDNA cloning and expression of an apoptosis-related gene, humanTFAR15 gene. Sci China C Life Sci. 1999;42:323-9.
    1. Weinsheimer S, Nelson J, Abla AA, Ko NU, Tsang C, Okoye O, Zabramski JM, Akers A, Zafar A, Mabray MC, Hart BL, Morrison L, McCulloch CE, Kim H, et al. Intracranial hemorrhage rate and lesion burden in patients with familial cerebral cavernous malformation. J Am Heart Assoc. 2023;12:e027572.
    1. Weng J, Yang Y, Song D, Huo R, Li H, Chen Y, Nam Y, Zhou Q, Jiao Y, Fu W, Yan Z, Wang J, Xu H, Di L, Li J, Wang S, Zhao J, Wang J, Cao Y. Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation. Am J Hum Genet. 2021;108:942-50.
    1. Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, Ling J, Mayo AH, Drakos SG, Jones CA, Zhu W, Marchuk DA, Davis GE, Li DY. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med. 2009;15:177-84.
    1. Witiw CD, Abou-Hamden A, Kulkarni AV, Silvaggio JA, Schneider C, Wallace MC. Cerebral cavernous malformations and pregnancy: hemorrhage risk and influence on obstetrical management. Neurosurgery. 2012;71:626-30.
    1. Wood MW, White RJ, Kernohan JW. Cavernous hemangiomatosis involving the brain, spinal cord, heart, skin and kidney: report of case. Proc Staff Meet Mayo Clin. 1957;32:249-54.
    1. Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A. Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A. 2010;107:12640-5.
    1. You C, Sandalcioglu IE, Dammann P, Felbor U, Sure U, Zhu Y. Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations. J Cell Mol Med. 2013;17:407-18.
    1. Zabramski JM, Wascher TM, Spetzler RF, Johnson B, Golfinos J, Drayer BP, Brown B, Rigamonti D, Brown G. The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg. 1994;80:422-32
    1. Zafar A, Quadri SA, Farooqui M, Ikram A, Robinson M, Hart BL, Mabray MC, Vigil C, Tang AT, Kahn ML, Yonas H, Lawton MT, Kim H, Morrison L.Stroke. 2019;50:1294-301.
    1. Zawistowski JS, Serebriiskii IG, Lee MF, Golemis EA, Marchuk DA. KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. Hum Mol Genet. 2002;11:389-96.
    1. Zlotoff BJ, Bang RH, Padilla RS, Morrison L. Cutaneous angiokeratoma and venous malformations in a Hispanic-American patient with cerebral cavernous malformations. Br J Dermatol. 2007;157:210-2.
    1. Zuurbier SM, Hickman CR, Tolias CS, Rinkel LA, Leyrer R, Flemming KD, Bervini D, Lanzino G, Wityk RJ, Schneble H-M, Sure U, Al-Shahi Salman R, Scottish Audit of Intracranial Vascular Malformations Steering Committee. Long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis. Lancet Neurol. 2019;18:935-41.
    1. Zuurbier SM, Santos AN, Flemming KD, Schmidt B, Jabbarli R, Lanzino G, Sure U, Dammann P. Female hormone therapy and risk of intracranial hemorrhage from cerebral cavernous malformations: a multicenter observational cohort study. Neurology. 2023;100:e1673-e1679.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera