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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
Gross BA, Du R
Expert Rev Neurother 2015;15(7):771-7. Epub 2015 Jun 22 doi: 10.1586/14737175.2015.1055323. PMID: 26098013

Recent clinical studies

Etiology

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
Wang K, Zhou HJ, Wang M
Stroke Vasc Neurol 2019 Jul;4(2):67-70. Epub 2019 Mar 2 doi: 10.1136/svn-2018-000195. PMID: 31338212Free PMC Article
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
Petr O, Lanzino G
J Neurosurg Sci 2015 Sep;59(3):271-82. Epub 2015 May 6 PMID: 25943871

Diagnosis

Shih YC, Chou CC, Peng SJ, Yu HY, Hsu SPC, Lin CF, Lee CC, Yang HC, Chen YC, Kwan SY, Chen C, Wang SJ, Lin CJ, Lirng JF, Shih YH, Yen DJ, Liu YT
Epilepsia 2022 Aug;63(8):2056-2067. Epub 2022 Jun 14 doi: 10.1111/epi.17309. PMID: 35593439
Su VL, Calderwood DA
Open Biol 2020 Nov;10(11):200263. Epub 2020 Nov 25 doi: 10.1098/rsob.200263. PMID: 33234067Free PMC Article
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

Scerrati A, Mantovani G, Travaglini F, Bradaschia L, De Bonis P, Farneti M, Cavallo MA, Dones F, Flacco ME, Auricchio AM, Benato A, Albanese A, Sturiale CL
Neurosurg Focus 2023 Oct;55(4):E15. doi: 10.3171/2023.7.FOCUS23355. PMID: 37778034
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
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
Nature 2017 May 18;545(7654):305-310. Epub 2017 May 10 doi: 10.1038/nature22075. PMID: 28489816Free PMC Article
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

Prognosis

Scerrati A, Mantovani G, Travaglini F, Bradaschia L, De Bonis P, Farneti M, Cavallo MA, Dones F, Flacco ME, Auricchio AM, Benato A, Albanese A, Sturiale CL
Neurosurg Focus 2023 Oct;55(4):E15. doi: 10.3171/2023.7.FOCUS23355. PMID: 37778034
Shih YC, Chou CC, Peng SJ, Yu HY, Hsu SPC, Lin CF, Lee CC, Yang HC, Chen YC, Kwan SY, Chen C, Wang SJ, Lin CJ, Lirng JF, Shih YH, Yen DJ, Liu YT
Epilepsia 2022 Aug;63(8):2056-2067. Epub 2022 Jun 14 doi: 10.1111/epi.17309. PMID: 35593439
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
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
Nature 2017 May 18;545(7654):305-310. Epub 2017 May 10 doi: 10.1038/nature22075. PMID: 28489816Free PMC Article

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
Shih YC, Chou CC, Peng SJ, Yu HY, Hsu SPC, Lin CF, Lee CC, Yang HC, Chen YC, Kwan SY, Chen C, Wang SJ, Lin CJ, Lirng JF, Shih YH, Yen DJ, Liu YT
Epilepsia 2022 Aug;63(8):2056-2067. Epub 2022 Jun 14 doi: 10.1111/epi.17309. PMID: 35593439
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

Recent systematic reviews

González-Gallardo E, Rauschenbach L, Santos AN, Riess C, Li Y, Tippelt S, Della Marina A, Dohna-Schwake C, Sure U, Dammann P
World Neurosurg 2023 Jun;174:30-41. Epub 2023 Mar 6 doi: 10.1016/j.wneu.2023.02.135. PMID: 36889633
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
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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