U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Cerebral cavernous malformation(CCM)

MedGen UID:
418825
Concept ID:
C2919945
Congenital Abnormality
Synonyms: CAVERNOUS ANGIOMA, FAMILIAL; CAVERNOUS ANGIOMATOUS MALFORMATIONS; Cavernous Hemangioma of Brain; CCM; CEREBRAL CAPILLARY MALFORMATIONS; Cerebral cavernous hemangioma (type); Cerebral cavernous malformations; Familial Cerebral Cavernous Malformation
SNOMED CT: Cavernous hemangioma of brain (444869007)
 
Gene (location): KRIT1 (7q21.2)
Related genes: CCM2, PDCD10, PIK3CA
 
HPO: HP:0033522
Monarch Initiative: MONDO:0000820
OMIM®: 116860
Orphanet: ORPHA164

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 descriptions

From OMIM
Cerebral cavernous angiomas are relatively rare vascular malformations that may involve any part of the central nervous system. Cerebral cavernous angiomas are to be distinguished from cerebral arteriovenous malformations (106070, 108010). CCMs are venous and not demonstrable by arteriography; hence they are referred to as angiographically silent. Capillary hemangiomas (602089) are classified as distinct from vascular malformations in that hemangiomas are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. Hemangiomas develop shortly after birth. In contrast, vascular malformations are present from birth, tend to grow with the individual, do not regress, and show normal rates of endothelial cell turnover (Mulliken and Young, 1988). Genetic Heterogeneity of CCM CCM2 (603284) is caused by germline mutation in the CCM2 gene (607929); CCM3 (603285) is caused by germline mutation in the PDCD10 gene (609118); and CCM4 (619538) is caused by somatic mutation in the PIK3CA gene (171834). Evidence suggests that a 2-hit mechanism involving biallelic germline and somatic mutations is responsible for CCM1 pathogenesis; see PATHOGENESIS and MOLECULAR GENETICS sections.  http://www.omim.org/entry/116860
From MedlinePlus Genetics
Approximately 25 percent of individuals with cerebral cavernous malformations never experience any related health problems. Other people with this condition may experience serious signs and symptoms such as headaches, seizures, paralysis, hearing or vision loss, and bleeding in the brain (cerebral hemorrhage). Severe brain hemorrhages can result in death. The location and number of cerebral cavernous malformations determine the severity of this disorder. These malformations can change in size and number over time.

There are two forms of the condition: familial and sporadic. The familial form is passed from parent to child, and affected individuals typically have multiple cerebral cavernous malformations. The sporadic form occurs in people with no family history of the disorder. These individuals typically have only one malformation.

Cerebral cavernous malformations are collections of small blood vessels (capillaries) in the brain that are enlarged and irregular in structure. These capillaries have abnormally thin walls, and they lack other support tissues, such as elastic fibers, which normally make them stretchy. As a result, the blood vessels are prone to leakage, which can cause the health problems related to this condition. Cavernous malformations can occur anywhere in the body, but usually produce serious signs and symptoms only when they occur in the brain and spinal cord (which are described as cerebral).  https://medlineplus.gov/genetics/condition/cerebral-cavernous-malformation

Clinical features

From HPO
Intracranial hemorrhage
MedGen UID:
101799
Concept ID:
C0151699
Pathologic Function
Hemorrhage occurring within the skull.
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%.
Hepatic vascular malformations
MedGen UID:
350099
Concept ID:
C1861790
Finding
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Cerebral calcification
MedGen UID:
124360
Concept ID:
C0270685
Finding
The presence of calcium deposition within the cerebrum.
Abnormality of the musculature
MedGen UID:
867380
Concept ID:
C4021745
Anatomical Abnormality
Abnormality originating in one or more muscles, i.e., of the set of muscles of body.
Abnormality of the skin
MedGen UID:
11449
Concept ID:
C0037268
Congenital Abnormality
An abnormality of the skin.
Retinal vascular malformation
MedGen UID:
350100
Concept ID:
C1861791
Finding

Conditions with this feature

Cerebral cavernous malformation 3
MedGen UID:
355121
Concept ID:
C1864040
Disease or Syndrome
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%.
Cerebral cavernous malformation 2
MedGen UID:
400438
Concept ID:
C1864041
Disease or Syndrome
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%.
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%.
Cerebral cavernous malformation 4
MedGen UID:
1794201
Concept ID:
C5561991
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%.
Intellectual developmental disorder, autosomal dominant 66
MedGen UID:
1812470
Concept ID:
C5677000
Mental or Behavioral Dysfunction
Autosomal dominant intellectual developmental disorder-66 (MRD66) is characterized by global developmental delay with mildly to moderately impaired intellectual development and mild speech delay. The phenotype and severity are highly variable. Some patients have behavioral problems or autism spectrum disorder, and about 50% have variable types of seizures. Additional features may include nonspecific dysmorphic facial features, tall or short stature, and mild skeletal anomalies (Rahimi et al., 2022).

Professional guidelines

PubMed

Hill CS, Borg A, Horsfall HL, Al-Mohammad A, Grover P, Kitchen N
Clin Neurol Neurosurg 2023 Feb;225:107576. Epub 2022 Dec 26 doi: 10.1016/j.clineuro.2022.107576. PMID: 36608471
Merello E, Pavanello M, Consales A, Mascelli S, Raso A, Accogli A, Cama A, Valeria C, De Marco P
J Mol Neurosci 2016 Oct;60(2):232-8. Epub 2016 Aug 25 doi: 10.1007/s12031-016-0806-8. PMID: 27561926
Poorthuis M, Samarasekera N, Kontoh K, Stuart I, Cope B, Kitchen N, Al-Shahi Salman R
Acta Neurochir (Wien) 2013 Apr;155(4):643-9. Epub 2013 Jan 31 doi: 10.1007/s00701-013-1621-4. PMID: 23371401

Suggested Reading

PubMed

Al-Shahi Salman R, Hall JM, Horne MA, Moultrie F, Josephson CB, Bhattacharya JJ, Counsell CE, Murray GD, Papanastassiou V, Ritchie V, Roberts RC, Sellar RJ, Warlow CP; Scottish Audit of Intracranial Vascular Malformations (SAIVMs) collaborators
Lancet Neurol 2012 Mar;11(3):217-24. Epub 2012 Jan 31 doi: 10.1016/S1474-4422(12)70004-2. PMID: 22297119Free PMC Article
Al-Shahi Salman R, Berg MJ, Morrison L, Awad IA; Angioma Alliance Scientific Advisory Board
Stroke 2008 Dec;39(12):3222-30. Epub 2008 Oct 30 doi: 10.1161/STROKEAHA.108.515544. PMID: 18974380

Recent clinical studies

Etiology

Schnitzler GR, Kang H, Fang S, Angom RS, Lee-Kim VS, Ma XR, Zhou R, Zeng T, Guo K, Taylor MS, Vellarikkal SK, Barry AE, Sias-Garcia O, Bloemendal A, Munson G, Guckelberger P, Nguyen TH, Bergman DT, Hinshaw S, Cheng N, Cleary B, Aragam K, Lander ES, Finucane HK, Mukhopadhyay D, Gupta RM, Engreitz JM
Nature 2024 Feb;626(8000):799-807. Epub 2024 Feb 7 doi: 10.1038/s41586-024-07022-x. PMID: 38326615Free PMC Article
Aras Y, Dolas I, Dolen D, Unal TC, Sahin D, Gulsever CI, Sabanci PA, Sencer A
Turk Neurosurg 2023;33(1):63-69. doi: 10.5137/1019-5149.JTN.36915-21.2. PMID: 36924006
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
Dammann P, Saban DV, Herten A, Chen B, Zhu Y, Santos A, Rauschenbach L, Wrede K, Jabbarli R, Schmidt B, Jöckel KH, Kleinschnitz C, Forsting M, Sure U
Eur J Neurol 2021 Jun;28(6):2000-2005. Epub 2021 Apr 3 doi: 10.1111/ene.14833. PMID: 33738912
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

Diagnosis

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
Eur J Neurol 2022 May;29(5):1427-1434. Epub 2022 Feb 3 doi: 10.1111/ene.15253. PMID: 35060255
Paddock M, Lanham S, Gill K, Sinha S, Connolly DJA
Pediatr Neurol 2021 Mar;116:74-83. Epub 2020 Nov 27 doi: 10.1016/j.pediatrneurol.2020.11.004. PMID: 33494000
Vieceli Dalla Sega F, Mastrocola R, Aquila G, Fortini F, Fornelli C, Zotta A, Cento AS, Perrelli A, Boda E, Pannuti A, Marchi S, Pinton P, Ferrari R, Rizzo P, Retta SF
Int J Mol Sci 2019 Oct 5;20(19) doi: 10.3390/ijms20194930. PMID: 31590384Free PMC Article
Retta SF, Glading AJ
Int J Biochem Cell Biol 2016 Dec;81(Pt B):254-270. Epub 2016 Sep 14 doi: 10.1016/j.biocel.2016.09.011. PMID: 27639680Free PMC Article
Poorthuis M, Samarasekera N, Kontoh K, Stuart I, Cope B, Kitchen N, Al-Shahi Salman R
Acta Neurochir (Wien) 2013 Apr;155(4):643-9. Epub 2013 Jan 31 doi: 10.1007/s00701-013-1621-4. PMID: 23371401

Therapy

Lazzaroni F, Meessen JMTA, Sun Y, Lanfranconi S, Scola E, D'Alessandris QG, Tassi L, Carriero MR, Castori M, Marino S, Blanda A, Nicolis EB, Novelli D, Calabrese R, Agnelli NM, Bottazzi B, Leone R, Mazzola S, Besana S, Catozzi C, Nezi L, Lampugnani MG, Malinverno M, Grdseloff N, Rödel CJ, Rezai Jahromi B, Bolli N, Passamonti F, Magnusson PU, Abdelilah-Seyfried S, Dejana E, Latini R
EBioMedicine 2024 Jan;99:104914. Epub 2023 Dec 18 doi: 10.1016/j.ebiom.2023.104914. PMID: 38113759Free PMC Article
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
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 May;50(5):1294-1301. doi: 10.1161/STROKEAHA.118.022314. PMID: 30909834Free PMC Article
Willie JT, Malcolm JG, Stern MA, Lowder LO, Neill SG, Cabaniss BT, Drane DL, Gross RE
Epilepsia 2019 Feb;60(2):220-232. Epub 2019 Jan 17 doi: 10.1111/epi.14634. PMID: 30653657Free PMC Article
Polster SP, Cao Y, Carroll T, Flemming K, Girard R, Hanley D, Hobson N, Kim H, Koenig J, Koskimäki J, Lane K, Majersik JJ, McBee N, Morrison L, Shenkar R, Stadnik A, Thompson RE, Zabramski J, Zeineddine HA, Awad IA
Neurosurgery 2019 Apr 1;84(4):954-964. doi: 10.1093/neuros/nyy108. PMID: 29660039Free PMC Article

Prognosis

Frias-Anaya E, Gallego-Gutierrez H, Gongol B, Weinsheimer S, Lai CC, Orecchioni M, Sriram A, Bui CM, Nelsen B, Hale P, Pham A, Shenkar R, DeBiasse D, Lightle R, Girard R, Li Y, Srinath A, Daneman R, Nudleman E, Sun H, Guma M, Dubrac A, Mesarwi OA, Ley K, Kim H, Awad IA, Ginsberg MH, Lopez-Ramirez MA
Arterioscler Thromb Vasc Biol 2024 Jun;44(6):1246-1264. Epub 2024 Apr 25 doi: 10.1161/ATVBAHA.123.320367. PMID: 38660801Free PMC Article
Lazzaroni F, Meessen JMTA, Sun Y, Lanfranconi S, Scola E, D'Alessandris QG, Tassi L, Carriero MR, Castori M, Marino S, Blanda A, Nicolis EB, Novelli D, Calabrese R, Agnelli NM, Bottazzi B, Leone R, Mazzola S, Besana S, Catozzi C, Nezi L, Lampugnani MG, Malinverno M, Grdseloff N, Rödel CJ, Rezai Jahromi B, Bolli N, Passamonti F, Magnusson PU, Abdelilah-Seyfried S, Dejana E, Latini R
EBioMedicine 2024 Jan;99:104914. Epub 2023 Dec 18 doi: 10.1016/j.ebiom.2023.104914. PMID: 38113759Free PMC Article
Perrelli A, Retta SF
Free Radic Biol Med 2021 Aug 20;172:403-417. Epub 2021 Jun 24 doi: 10.1016/j.freeradbiomed.2021.06.021. PMID: 34175437
Mikati AG, Tan H, Shenkar R, Li L, Zhang L, Guo X, Larsson HB, Shi C, Liu T, Wang Y, Shah A, Edelman RR, Christoforidis G, Awad I
Stroke 2014 Feb;45(2):598-601. Epub 2013 Dec 3 doi: 10.1161/STROKEAHA.113.003548. PMID: 24302484Free PMC Article
Harel L, Costa B, Fainzilber M
Dev Neurobiol 2010 Apr;70(5):298-303. doi: 10.1002/dneu.20769. PMID: 20186708

Clinical prediction guides

Frias-Anaya E, Gallego-Gutierrez H, Gongol B, Weinsheimer S, Lai CC, Orecchioni M, Sriram A, Bui CM, Nelsen B, Hale P, Pham A, Shenkar R, DeBiasse D, Lightle R, Girard R, Li Y, Srinath A, Daneman R, Nudleman E, Sun H, Guma M, Dubrac A, Mesarwi OA, Ley K, Kim H, Awad IA, Ginsberg MH, Lopez-Ramirez MA
Arterioscler Thromb Vasc Biol 2024 Jun;44(6):1246-1264. Epub 2024 Apr 25 doi: 10.1161/ATVBAHA.123.320367. PMID: 38660801Free PMC Article
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
Mikati AG, Tan H, Shenkar R, Li L, Zhang L, Guo X, Larsson HB, Shi C, Liu T, Wang Y, Shah A, Edelman RR, Christoforidis G, Awad I
Stroke 2014 Feb;45(2):598-601. Epub 2013 Dec 3 doi: 10.1161/STROKEAHA.113.003548. PMID: 24302484Free PMC Article
Harel L, Costa B, Fainzilber M
Dev Neurobiol 2010 Apr;70(5):298-303. doi: 10.1002/dneu.20769. PMID: 20186708
Mindea SA, Yang BP, Shenkar R, Bendok B, Batjer HH, Awad IA
Neurosurg Focus 2006 Jul 15;21(1):e1. doi: 10.3171/foc.2006.21.1.2. PMID: 16859247

Recent systematic reviews

Musmar B, Salim H, Abdelgadir J, Spellicy S, Adeeb N, Zomorodi A, Friedman A, Awad I, Jabbour PM, Hasan DM
J Am Heart Assoc 2024 Mar 19;13(6):e032910. Epub 2024 Mar 12 doi: 10.1161/JAHA.123.032910. PMID: 38471833Free PMC Article
Chen JS, Lamoureux AA, Shlobin NA, Elkaim LM, Wang A, Ibrahim GM, Obaid S, Harroud A, Guadagno E, Dimentberg E, Bouthillier A, Bernhardt BC, Nguyen DK, Fallah A, Weil AG
Epilepsia 2023 Aug;64(8):1957-1974. Epub 2023 Jun 8 doi: 10.1111/epi.17560. PMID: 36824029
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
Zuurbier SM, Hickman CR, Tolias CS, Rinkel LA, Leyrer R, Flemming KD, Bervini D, Lanzino G, Wityk RJ, Schneble HM, Sure U, Al-Shahi Salman R; Scottish Audit of Intracranial Vascular Malformations Steering Committee
Lancet Neurol 2019 Oct;18(10):935-941. Epub 2019 Aug 7 doi: 10.1016/S1474-4422(19)30231-5. PMID: 31401075Free PMC Article
Poorthuis M, Samarasekera N, Kontoh K, Stuart I, Cope B, Kitchen N, Al-Shahi Salman R
Acta Neurochir (Wien) 2013 Apr;155(4):643-9. Epub 2013 Jan 31 doi: 10.1007/s00701-013-1621-4. PMID: 23371401

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...