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Cerebral cavernous malformation 4(CCM4)

MedGen UID:
1794201
Concept ID:
C5561991
Congenital Abnormality
Synonyms: Cerebral cavernous malformations 4; Familial Cerebral Cavernous Malformation 4
 
Gene (location): PIK3CA (3q26.32)
 
Monarch Initiative: MONDO:0859192
OMIM®: 619538

Disease characteristics

Excerpted from the GeneReview: Familial Cerebral Cavernous Malformations
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. [from GeneReviews]
Authors:
Kelly D Flemming  |  Edward Smith  |  Douglas Marchuk, et. al.   view full author information

Additional description

From OMIM
Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system that are composed of abnormally enlarged capillary cavities without intervening brain parenchyma. CCMs manifest primarily as subclinical bleeding, but can also lead to seizures and hemorrhagic stroke with substantial neurologic complications, especially when localized in the brainstem. More than 80% of CCMs occur sporadically (summary by Peyre et al., 2021). For a phenotypic description and discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (116860).  http://www.omim.org/entry/619538

Clinical features

From HPO
Cerebral cavernous malformation
MedGen UID:
418825
Concept ID:
C2919945
Congenital Abnormality
Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord comprising closely clustered, enlarged capillary channels (caverns) with a single layer of endothelium without mature vessel wall elements or normal intervening brain parenchyma. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase or decrease in size and increase in number over time. Hundreds of lesions may be identified, depending on the person'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 with findings such as seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with FCCM remain symptom free throughout their lives. Cutaneous vascular lesions are found in 9% of those with familial cerebral cavernous malformations (FCCM; see Diagnosis/testing) and retinal vascular lesions in almost 5%.

Professional guidelines

PubMed

Stapleton CJ, Barker FG 2nd
Stroke 2018 Apr;49(4):1029-1035. Epub 2018 Mar 13 doi: 10.1161/STROKEAHA.117.017074. PMID: 29535273
Akers A, Al-Shahi Salman R, A Awad I, 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
Neurosurgery 2017 May 1;80(5):665-680. doi: 10.1093/neuros/nyx091. PMID: 28387823Free PMC Article
Alexiou GA, Prodromou N
Neurol Sci 2011 Aug;32(4):735. Epub 2010 Jul 2 doi: 10.1007/s10072-010-0366-6. PMID: 20596740

Recent clinical studies

Etiology

Lanfranconi S, Scola E, Meessen JMTA, Pallini R, Bertani GA, Al-Shahi Salman R, Dejana E, Latini R; Treat_CCM Investigators
Lancet Neurol 2023 Jan;22(1):35-44. Epub 2022 Nov 17 doi: 10.1016/S1474-4422(22)00409-4. PMID: 36403580
Idiculla PS, Gurala D, Philipose J, Rajdev K, Patibandla P
Eur Neurol 2020;83(4):360-368. Epub 2020 Jul 30 doi: 10.1159/000508748. PMID: 32731220
Akers A, Al-Shahi Salman R, A Awad I, 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
Neurosurgery 2017 May 1;80(5):665-680. doi: 10.1093/neuros/nyx091. PMID: 28387823Free PMC Article
Gross BA, Du R
Expert Rev Neurother 2015;15(7):771-7. Epub 2015 Jun 22 doi: 10.1586/14737175.2015.1055323. PMID: 26098013
Petr O, Lanzino G
J Neurosurg Sci 2015 Sep;59(3):271-82. Epub 2015 May 6 PMID: 25943871

Diagnosis

Li Z, Lu J, Liu M, Ma L, Quan K, Zhang H, Liu P, Shi Y, Dong X, You C, Tian R, Zhu W
Int J Surg 2024 Apr 1;110(4):2217-2225. doi: 10.1097/JS9.0000000000001111. PMID: 38668661Free PMC Article
Dammann P, Santos AN, Wan XY, Zhu Y, Sure U
Neurosurg Clin N Am 2022 Oct;33(4):449-460. Epub 2022 Sep 11 doi: 10.1016/j.nec.2022.05.001. PMID: 36229132
Idiculla PS, Gurala D, Philipose J, Rajdev K, Patibandla P
Eur Neurol 2020;83(4):360-368. Epub 2020 Jul 30 doi: 10.1159/000508748. PMID: 32731220
Akers A, Al-Shahi Salman R, A Awad I, 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
Neurosurgery 2017 May 1;80(5):665-680. doi: 10.1093/neuros/nyx091. PMID: 28387823Free PMC Article
Gross BA, Du R
Expert Rev Neurother 2015;15(7):771-7. Epub 2015 Jun 22 doi: 10.1586/14737175.2015.1055323. PMID: 26098013

Therapy

Mantziaris G, Dumot C, Pikis S, Peker S, Samanci Y, Ardor GD, Nabeel AM, Reda WA, Tawadros SR, Abdel Karim K, El-Shehaby AMN, Emad Eldin RM, Elazzazi AH, Sheehan D, Sheehan K, Martínez Moreno N, Martínez Álvarez R, Liscak R, May J, Tripathi M, Rajput A, Kumar N, Kaur R, Alzate JD, Kondziolka D, Dayawansa S, Sheehan JP
J Neurosurg Pediatr 2024 Apr 1;33(4):315-322. Epub 2024 Jan 5 doi: 10.3171/2023.11.PEDS23402. PMID: 38181511
Lanfranconi S, Scola E, Meessen JMTA, Pallini R, Bertani GA, Al-Shahi Salman R, Dejana E, Latini R; Treat_CCM Investigators
Lancet Neurol 2023 Jan;22(1):35-44. Epub 2022 Nov 17 doi: 10.1016/S1474-4422(22)00409-4. PMID: 36403580
Akers A, Al-Shahi Salman R, A Awad I, 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
Neurosurgery 2017 May 1;80(5):665-680. doi: 10.1093/neuros/nyx091. PMID: 28387823Free PMC Article
Poorthuis MH, Klijn CJ, Algra A, Rinkel GJ, Al-Shahi Salman R
J Neurol Neurosurg Psychiatry 2014 Dec;85(12):1319-23. Epub 2014 Mar 25 doi: 10.1136/jnnp-2013-307349. PMID: 24667206
Nagy G, Kemeny AA
Neurosurg Clin N Am 2013 Oct;24(4):575-89. Epub 2013 Aug 2 doi: 10.1016/j.nec.2013.05.004. PMID: 24093575

Prognosis

Dammann P, Santos AN, Wan XY, Zhu Y, Sure U
Neurosurg Clin N Am 2022 Oct;33(4):449-460. Epub 2022 Sep 11 doi: 10.1016/j.nec.2022.05.001. PMID: 36229132
Hong T, Xiao X, Ren J, Cui B, Zong Y, Zou J, Kou Z, Jiang N, Meng G, Zeng G, Shan Y, Wu H, Chen Z, Liang J, Xiao X, Tang J, Wei Y, Ye M, Sun L, Li G, Hu P, Hui R, Zhang H, Wang Y
Brain 2021 Oct 22;144(9):2648-2658. doi: 10.1093/brain/awab117. PMID: 33729480
Idiculla PS, Gurala D, Philipose J, Rajdev K, Patibandla P
Eur Neurol 2020;83(4):360-368. Epub 2020 Jul 30 doi: 10.1159/000508748. PMID: 32731220
Kondziolka D, Monaco EA 3rd, Lunsford LD
Prog Neurol Surg 2013;27:141-6. Epub 2012 Dec 11 doi: 10.1159/000341774. PMID: 23258518
Batra S, Rigamonti K, Rigamonti D
Curr Atheroscler Rep 2012 Aug;14(4):360-5. doi: 10.1007/s11883-012-0261-0. PMID: 22711271

Clinical prediction guides

Lanfranconi S, Scola E, Meessen JMTA, Pallini R, Bertani GA, Al-Shahi Salman R, Dejana E, Latini R; Treat_CCM Investigators
Lancet Neurol 2023 Jan;22(1):35-44. Epub 2022 Nov 17 doi: 10.1016/S1474-4422(22)00409-4. PMID: 36403580
Hong T, Xiao X, Ren J, Cui B, Zong Y, Zou J, Kou Z, Jiang N, Meng G, Zeng G, Shan Y, Wu H, Chen Z, Liang J, Xiao X, Tang J, Wei Y, Ye M, Sun L, Li G, Hu P, Hui R, Zhang H, Wang Y
Brain 2021 Oct 22;144(9):2648-2658. doi: 10.1093/brain/awab117. PMID: 33729480
Gross BA, Du R
Expert Rev Neurother 2015;15(7):771-7. Epub 2015 Jun 22 doi: 10.1586/14737175.2015.1055323. PMID: 26098013
Petr O, Lanzino G
J Neurosurg Sci 2015 Sep;59(3):271-82. Epub 2015 May 6 PMID: 25943871
Kivelev J, Niemelä M, Hernesniemi J
J Clin Neurosci 2012 Apr;19(4):491-7. Epub 2012 Feb 9 doi: 10.1016/j.jocn.2011.08.015. PMID: 22325075

Recent systematic reviews

Harris L, Poorthuis MHF, Grover P, Kitchen N, Al-Shahi Salman R
Neurosurg Rev 2022 Feb;45(1):231-241. Epub 2021 Jun 30 doi: 10.1007/s10143-021-01591-5. PMID: 34191202
Merlino L, Del Prete F, Titi L, Piccioni MG
J Gynecol Obstet Hum Reprod 2021 Jan;50(1):101927. Epub 2020 Oct 6 doi: 10.1016/j.jogoh.2020.101927. PMID: 33035718
Akers A, Al-Shahi Salman R, A Awad I, 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
Neurosurgery 2017 May 1;80(5):665-680. doi: 10.1093/neuros/nyx091. PMID: 28387823Free PMC Article
Gross BA, Du R
J Neurosurg 2017 Apr;126(4):1079-1087. Epub 2016 May 20 doi: 10.3171/2016.3.JNS152419. PMID: 27203143
Poorthuis MH, Klijn CJ, Algra A, Rinkel GJ, Al-Shahi Salman R
J Neurol Neurosurg Psychiatry 2014 Dec;85(12):1319-23. Epub 2014 Mar 25 doi: 10.1136/jnnp-2013-307349. PMID: 24667206

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