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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
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.

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.

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
Li DY, Whitehead KJ
Stroke 2010 Oct;41(10 Suppl):S92-4. doi: 10.1161/STROKEAHA.110.594929. PMID: 20876517Free PMC Article

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

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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
Kurihara N, Suzuki H, Kato Y, Rikimaru H, Sato A, Uenohara H
Jpn J Radiol 2020 Jul;38(7):613-621. Epub 2020 Mar 27 doi: 10.1007/s11604-020-00949-x. PMID: 32221793
Wei S, Li Y, Polster SP, Weber CR, Awad IA, Shen L
Int J Mol Sci 2020 Jan 20;21(2) doi: 10.3390/ijms21020675. PMID: 31968585Free PMC Article
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

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
Su VL, Calderwood DA
Open Biol 2020 Nov;10(11):200263. Epub 2020 Nov 25 doi: 10.1098/rsob.200263. PMID: 33234067Free PMC Article
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J Neuroophthalmol 2020 Jun;40(2):262-264. doi: 10.1097/WNO.0000000000000778. PMID: 30893269
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Therapy

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EBioMedicine 2024 Jan;99:104914. Epub 2023 Dec 18 doi: 10.1016/j.ebiom.2023.104914. PMID: 38113759Free PMC Article
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
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Lanfranconi S, Scola E, Meessen JMTA, Pallini R, Bertani GA, Al-Shahi Salman R, Dejana E, Latini R; Treat_CCM Investigators
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Prognosis

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Kuroedov D, Cunha B, Pamplona J, Castillo M, Ramalho J
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Fontanella MM, Agosti E, Zanin L, di Bergamo LT, Doglietto F
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Clinical prediction guides

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
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
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
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
Choquet H, Pawlikowska L, Lawton MT, Kim H
J Neurosurg Sci 2015 Sep;59(3):211-20. Epub 2015 Apr 22 PMID: 25900426Free PMC Article

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
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
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
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
Campbell PG, Jabbour P, Yadla S, Awad IA
Neurosurg Focus 2010 Sep;29(3):E6. doi: 10.3171/2010.5.FOCUS10120. PMID: 20809764Free PMC Article

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