Raras
Buscar doenças, sintomas, genes...
Malformação cavernosa cerebral familiar
ORPHA:221061CID-10 · Q28.3CID-11 · LA90.0YDOENÇA RARA

Malformação vascular evolutiva rara, caracterizada por capilares dilatados irregulares e agrupados que podem ser assintomáticos ou causar manifestações neurológicas variáveis, como convulsões, dores de cabeça inespecíficas, déficits neurológicos focais progressivos ou transitórios e/ou hemorragias cerebrais.

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Introdução

O que você precisa saber de cara

📋

Malformação vascular evolutiva rara, caracterizada por capilares dilatados irregulares e agrupados que podem ser assintomáticos ou causar manifestações neurológicas variáveis, como convulsões, dores de cabeça inespecíficas, déficits neurológicos focais progressivos ou transitórios e/ou hemorragias cerebrais.

Pesquisas ativas
4 ensaios
12 total registrados no ClinicalTrials.gov
Publicações científicas
99 artigos
Último publicado: 2026
Medicamentos
1 registrados
PROPRANOLOL

Tem tratamento?

1 medicamento registrado
Ver detalhes, fases e interações →
PROPRANOLOL

Escala de raridade

CLASSIFICAÇÃO ORPHANET · BRASIL 2024
1-5 / 10 000
Ultra-rara
<1/50k
Muito rara
1/20k
Rara
1/10k
Pouco freq.
1/5k
Incomum
1/2k
Prevalência
15.0
Worldwide
Início
All ages
🏥
SUS: Cobertura mínimaScore: 35%
Centros em: SP, PR, SC, RS, ES +10CID-10: Q28.3
🇧🇷Dados SUS / DATASUS
PROCEDIMENTOS SIGTAP (5)
0202010503
Cariótipo — bandas G, Q ou Rgenetic_test
0202010600
Pesquisa de microdeleções/microduplicações por FISHlab_test
0202010694
Sequenciamento completo do exoma (WES)rehabilitation
0202010260
Dosagem de alfa-fetoproteína
0301070040
Atendimento em reabilitação — doenças raras
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Entender a doença

Do básico ao detalhe, leia no seu ritmo

Preparando trilha educativa...

Sinais e sintomas

O que aparece no corpo e com que frequência cada sintoma acontece

Partes do corpo afetadas

🧠
Neurológico
8 sintomas
❤️
Coração
3 sintomas
💪
Músculos
2 sintomas
🫃
Digestivo
1 sintomas
👁️
Olhos
1 sintomas
🫘
Rins
1 sintomas

+ 15 sintomas em outras categorias

Características mais comuns

100%prev.
Malformação cavernosa cerebral
90%prev.
Hemorragia cerebral
Muito frequente (99-80%)
90%prev.
Convulsão
Muito frequente (99-80%)
90%prev.
Cefaleia
Muito frequente (99-80%)
55%prev.
Hemangioma
Frequente (79-30%)
55%prev.
Aumento da pressão intracraniana
Frequente (79-30%)
34sintomas
Muito frequente (4)
Frequente (10)
Ocasional (7)
Muito raro (4)
Sem dados (9)

Os sintomas variam de pessoa para pessoa. Abaixo estão as 34 características clínicas mais associadas, ordenadas por frequência.

Malformação cavernosa cerebralCerebral cavernous malformation
Muito frequente100%
Hemorragia cerebralCerebral hemorrhage
Muito frequente (99-80%)90%
ConvulsãoSeizure
Muito frequente (99-80%)90%
CefaleiaHeadache
Muito frequente (99-80%)90%
Hemangioma
Frequente (79-30%)55%

Linha do tempo da pesquisa

Publicações por ano — veja quando o interesse científico cresceu
Anos de pesquisa1desde 2026
Total histórico99PubMed
Últimos 10 anos103publicações
Pico202016 papers
Linha do tempo
2026Hoje · 2026🧪 2010Primeiro ensaio clínico📈 2020Ano de pico
Publicações por ano (últimos 10 anos)

Encontrou um erro ou informação desatualizada? Sugira uma correção →

Genética e causas

O que está alterado no DNA e como passa nas famílias

Genes associados

5 genes identificados com associação a esta condição. Padrão de herança: Autosomal dominant.

PIK3CAPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoformDisease-causing somatic mutation(s) inAltamente restrito
FUNÇÃO

Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396, PubMed:28676499). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1,

LOCALIZAÇÃO

VIAS BIOLÓGICAS (10)
Signaling by LTK in cancerNephrin family interactionsIRS-mediated signallingTie2 SignalingDAP12 signaling
EXPRESSÃO TECIDUAL(Ubíquo)
Artéria tibial
23.2 TPM
Linfócitos
22.4 TPM
Nervo tibial
21.4 TPM
Tecido adiposo
20.5 TPM
Fibroblastos
20.5 TPM
OUTRAS DOENÇAS (28)
seborrheic keratosismegalodactylyovarian cancerhepatocellular carcinoma
HGNC:8975UniProt:P42336
KRIT1Krev interaction trapped protein 1Disease-causing germline mutation(s) (loss of function) inTolerante
FUNÇÃO

Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits ERK1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establi

LOCALIZAÇÃO

Cytoplasm, cytoskeletonCell membraneCell junction

MECANISMO DE DOENÇA

Cerebral cavernous malformations 1

A form of cerebral cavernous malformations, a congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. CCM1 inheritance is autosomal dominant.

EXPRESSÃO TECIDUAL(Ubíquo)
Cervix Endocervix
28.4 TPM
Tireoide
28.1 TPM
Cervix Ectocervix
27.9 TPM
Ovário
27.3 TPM
Linfócitos
27.1 TPM
OUTRAS DOENÇAS (2)
cerebral cavernous malformation 1famililal cerebral cavernous malformations
HGNC:1573UniProt:O00522
PDCD10Programmed cell death protein 10Disease-causing germline mutation(s) inAltamente restrito
FUNÇÃO

Promotes cell proliferation. Modulates apoptotic pathways. Increases mitogen-activated protein kinase activity and STK26 activity (PubMed:27807006). Important for cell migration, and for normal structure and assembly of the Golgi complex (PubMed:27807006). Part of the striatin-interacting phosphatase and kinase (STRIPAK) complexes. STRIPAK complexes have critical roles in protein (de)phosphorylation and are regulators of multiple signaling pathways including Hippo, MAPK, nuclear receptor and cyt

LOCALIZAÇÃO

CytoplasmGolgi apparatus membraneCell membrane

MECANISMO DE DOENÇA

Cerebral cavernous malformations 3

A form of cerebral cavernous malformations, a congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. CCM3 inheritance is autosomal dominant.

EXPRESSÃO TECIDUAL(Ubíquo)
Linfócitos
60.6 TPM
Fibroblastos
33.6 TPM
Artéria tibial
33.1 TPM
Esôfago - Mucosa
32.8 TPM
Nervo tibial
31.3 TPM
OUTRAS DOENÇAS (2)
cerebral cavernous malformation 3famililal cerebral cavernous malformations
HGNC:8761UniProt:Q9BUL8
CCM2Cerebral cavernous malformations 2 proteinDisease-causing germline mutation(s) (loss of function) inTolerante
FUNÇÃO

Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3-dependent p38 activation induced by hyperosmotic shock (By similarity)

LOCALIZAÇÃO

Cytoplasm

MECANISMO DE DOENÇA

Cerebral cavernous malformations 2

A form of cerebral cavernous malformations, a congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. CCM2 inheritance is autosomal dominant.

OUTRAS DOENÇAS (2)
cerebral cavernous malformation 2famililal cerebral cavernous malformations
HGNC:21708UniProt:Q9BSQ5
MAP3K3Mitogen-activated protein kinase kinase kinase 3Disease-causing germline mutation(s) inAltamente restrito
FUNÇÃO

Component of a protein kinase signal transduction cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional regulators

LOCALIZAÇÃO

VIAS BIOLÓGICAS (1)
Interleukin-1 signaling
MECANISMO DE DOENÇA

Cerebral cavernous malformations 5

A form of cerebral cavernous malformations, a congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters.

VIAS REACTOME (1)
EXPRESSÃO TECIDUAL(Ubíquo)
Sangue
57.5 TPM
Nervo tibial
55.9 TPM
Baço
54.1 TPM
Artéria tibial
53.4 TPM
Útero
52.4 TPM
OUTRAS DOENÇAS (1)
cerebral cavernous malformations 5
HGNC:HGNC:6855UniProt:Q99759

Medicamentos e terapias

PROPRANOLOLPhase 1

Mecanismo: Beta-1 adrenergic receptor antagonist

Ver mais no OpenTargets

Variantes genéticas (ClinVar)

328 variantes patogênicas registradas no ClinVar.

🧬 MAP3K3: GRCh37/hg19 17q23.2-24.1(chr17:58773496-62757149)x3 ()
🧬 MAP3K3: NM_002401.5(MAP3K3):c.1323C>G (p.Ile441Met) ()
🧬 MAP3K3: GRCh37/hg19 17q23.1-24.2(chr17:57869604-67078443)x3 ()
🧬 MAP3K3: GRCh37/hg19 17q22-24.2(chr17:57357088-66306668) ()
🧬 MAP3K3: GRCh37/hg19 17p13.3-q25.3(chr17:526-81041938)x3 ()
Ver todas no ClinVar

Diagnóstico

Os sinais que médicos procuram e os exames que confirmam

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Tratamento e manejo

Remédios, cuidados de apoio e o que precisa acompanhar

Pipeline de tratamentos
Pipeline regulatório — de medicamentos já aprovados a drogas em pesquisa exploratória.
2Fase 23
1Fase 12
·Pré-clínico8
Medicamentos catalogadosEnsaios clínicos· 1 medicamento · 12 ensaios
Carregando informações de tratamento...

Onde tratar no SUS

Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)

🇧🇷 Atendimento SUS — Malformação cavernosa cerebral familiar

Centros de Referência SUS

24 centros habilitados pelo SUS para Malformação cavernosa cerebral familiar

Centros para Malformação cavernosa cerebral familiar

Detalhes dos centros

Hospital Universitário Prof. Edgard Santos (HUPES)

R. Dr. Augusto Viana, s/n - Canela, Salvador - BA, 40110-060 · CNES 0003808

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital Infantil Albert Sabin

R. Tertuliano Sales, 544 - Vila União, Fortaleza - CE, 60410-794 · CNES 2407876

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital de Apoio de Brasília (HAB)

AENW 3 Lote A Setor Noroeste - Plano Piloto, Brasília - DF, 70684-831 · CNES 0010456

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Estadual Infantil e Maternidade Alzir Bernardino Alves (HIABA)

Av. Min. Salgado Filho, 918 - Soteco, Vila Velha - ES, 29106-010 · CNES 6631207

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital das Clínicas da UFG

Rua 235 QD. 68 Lote Área, Nº 285, s/nº - Setor Leste Universitário, Goiânia - GO, 74605-050 · CNES 2338424

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital Universitário da UFJF

R. Catulo Breviglieri, Bairro - s/n - Santa Catarina, Juiz de Fora - MG, 36036-110 · CNES 2297442

Atenção Especializada

Rota
Anomalias Congênitas

Hospital das Clínicas da UFMG

Av. Prof. Alfredo Balena, 110 - Santa Efigênia, Belo Horizonte - MG, 30130-100 · CNES 2280167

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Julio Müller (HUJM)

R. Luis Philippe Pereira Leite, s/n - Alvorada, Cuiabá - MT, 78048-902 · CNES 2726092

Atenção Especializada

Rota
Anomalias Congênitas

Hospital Universitário João de Barros Barreto

R. dos Mundurucus, 4487 - Guamá, Belém - PA, 66073-000 · CNES 2337878

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Lauro Wanderley (HULW)

R. Tabeliao Estanislau Eloy, 585 - Castelo Branco, João Pessoa - PB, 58050-585 · CNES 0002470

Atenção Especializada

Rota
Anomalias Congênitas

Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)

R. dos Coelhos, 300 - Boa Vista, Recife - PE, 50070-902 · CNES 0000647

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Pequeno Príncipe

R. Des. Motta, 1070 - Água Verde, Curitiba - PR, 80250-060 · CNES 3143805

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital Universitário Regional de Maringá (HUM)

Av. Mandacaru, 1590 - Parque das Laranjeiras, Maringá - PR, 87083-240 · CNES 2216108

Atenção Especializada

Rota
Anomalias Congênitas

Hospital de Clínicas da UFPR

R. Gen. Carneiro, 181 - Alto da Glória, Curitiba - PR, 80060-900 · CNES 2364980

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Pedro Ernesto (HUPE-UERJ)

Blvd. 28 de Setembro, 77 - Vila Isabel, Rio de Janeiro - RJ, 20551-030 · CNES 2280221

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira (IFF/Fiocruz)

Av. Rui Barbosa, 716 - Flamengo, Rio de Janeiro - RJ, 22250-020 · CNES 2269988

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital São Lucas da PUCRS

Av. Ipiranga, 6690 - Jardim Botânico, Porto Alegre - RS, 90610-000 · CNES 2232928

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital de Clínicas de Porto Alegre (HCPA)

Rua Ramiro Barcelos, 2350 Bloco A - Av. Protásio Alves, 211 - Bloco B e C - Santa Cecília, Porto Alegre - RS, 90035-903 · CNES 2237601

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário da UFSC (HU-UFSC)

R. Profa. Maria Flora Pausewang - Trindade, Florianópolis - SC, 88036-800 · CNES 2560356

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital das Clínicas da FMUSP

R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo - SP, 05403-010 · CNES 2077485

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Base de São José do Rio Preto

Av. Brg. Faria Lima, 5544 - Vila Sao Jose, São José do Rio Preto - SP, 15090-000 · CNES 2079798

Atenção Especializada

Rota
Anomalias Congênitas

Hospital de Clínicas da UNICAMP

R. Vital Brasil, 251 - Cidade Universitária, Campinas - SP, 13083-888 · CNES 2748223

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas de Ribeirão Preto (HCRP-USP)

R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto - SP, 14015-010 · CNES 2082187

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

UNIFESP / Hospital São Paulo

R. Napoleão de Barros, 715 - Vila Clementino, São Paulo - SP, 04024-002 · CNES 2688689

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo
Sobre os centros SUS: Estes centros são habilitados pelo Ministério da Saúde como Serviços de Referência em Doenças Raras ou Serviços de Atenção Especializada. O atendimento é pelo SUS, com encaminhamento da rede de atenção básica.

Dados de DATASUS/CNES, SBGM, ABNeuro e Ministério da Saúde. Sempre confirme a disponibilidade diretamente com o estabelecimento.

Pesquisa ativa

Ensaios clínicos abertos e novidades científicas recentes

🟢 Recrutando agora

2 pesquisas recrutando participantes. Converse com seu médico sobre a possibilidade de participar.

Outros ensaios clínicos

12 ensaios clínicos encontrados, 4 ativos.

Distribuição por fase
Ver todos no ClinicalTrials.gov
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Publicações mais relevantes

Timeline de publicações
75 papers (10 anos)
#1

Obstructive hydrocephalus secondary to an anterior mesencephalic cavernous malformation with familial cerebral cavernous malformation syndrome: A case report.

Radiology case reports2026 Jun

Cerebral Cavernous malformations (CCM) are the second most common vascular malformation of the central nervous system accounting (CNS) for 5%-10% of vascular malformations in the CNS with a prevalence of 0.5%. Most CCM are supratentorial with fewer than 20% located in the brainstem, mostly in the pons but very rarely in the anterior mesencephalon. The optimal treatment strategy for anterior mesencephalic cerebral cavernous malformations (AMCCM) is still debatable. Up to 20% of CCM are familial with patients presenting with multiple CCM. We report the case of a 62 year-old female who presented with diplopia, gait disturbance and poor speech. No clinical improvement was noted after an initial treatment with steroids for a supposedly unidentified neuroinflammatory disease. When she later presented with impaired consciousness, aphasia, right abducens nerve palsy and left hemiparesia, an urgent brain MRI with gradient echo sequence revealed an obstructive hydrocephalus secondary to an anterior mesencephalic cerebral cavernous malformation with subacute hemorrhage (Zabramski type I) along with numerous CCM typical of familial cerebral cavernous malformation (FCCM) syndrome. The urgent insertion of a ventriculoperitoneal (VP) shunt allowed progressive recovery of a normal consciousness as well as a normal motor function in all 4 limbs, which enabled her to regain autonomous ambulation albeit with a broad-based gait. No CCM re-hemorrhage occurred after 9 months of follow-up. Obstructive hydrocephalus secondary to anterior mesencephalic cerebral cavernous malformations was treated with VP shunt without re-hemorrhage.

#2

Transient Dysphagia as a Presenting Symptom of Familial Cerebral Cavernous Malformation.

Cureus2026 Feb

Cerebral cavernous malformations (CCMs) are vascular lesions characterized by a collection of thin-walled capillaries with slow blood flow, which are often identified incidentally on MRI. CCMs are the most common cerebral vascular malformation after developmental venous anomalies. Familial CCM (FCCM) is a rare autosomal dominant disorder characterized by several lesions throughout the central nervous system. We report the case of a 47-year-old female patient who presented to the neurology clinic with a chief complaint of transient dysphagia. An MRI of the brain without contrast, including susceptibility-weighted imaging (SWI), demonstrated numerous punctate foci of susceptibility-related signal loss throughout the cerebral and cerebellar hemispheres. Genetic testing revealed a pathogenic KRIT1 mutation, confirming FCCM. The patient's dysphagia resolved within one month of the initial onset and, fortunately, has not returned. This case highlights an atypical presentation of FCCM and the importance of an extensive workup in patients with unexplained neurologic symptoms.

#3

Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.

Journal of neurochemistry2026 Jan

Familial cerebral cavernous malformations (FCCM) are a heritable neurovascular disorder defined by clusters of dilated, thin-walled capillaries in the brain and spinal cord. Although rare, FCCM offers a tractable model for understanding how genetic disruptions in endothelial junction biology, mechanotransduction, and kinase signaling drive vascular instability in the central nervous system. Pathogenic loss-of-function variants converge on signaling abnormalities that promote barrier dysfunction, iron deposition, inflammation, and progressive lesional growth. Clinically, FCCM may manifest with seizures, headaches, focal deficits, or intracerebral hemorrhage, yet many carriers remain asymptomatic owing to incomplete and age-dependent penetrance. Advances in neuroimaging have enhanced the detection of micro-lesions and iron accumulation, establishing these modalities as central biomarkers of disease expression. Complementing imaging, emerging circulating biomarkers, including inflammatory cytokines and plasma microRNAs associated with mutation status, may improve individualized risk stratification. This primer synthesizes current knowledge on FCCM pathophysiology, genetics, diagnostic strategies, and therapeutic perspectives. By integrating molecular mechanisms with clinical relevance, it outlines a framework for understanding FCCM as a disorder of perturbed endothelial signaling and neurovascular homeostasis, and highlights opportunities to advance precision medicine for this challenging condition.

#4

Natural history of familial cerebral cavernous malformations: the CCM_Italia cohort study.

Frontiers in neurology2025

Familial cerebral cavernous malformations (fCCMs) are a rare genetic autosomal dominant cerebrovascular disease characterized by multiple cerebral and spinal angiomas. The condition is caused by mutations in KRIT1 (CCM1), CCM2 (malcavernin), or PDCD10 (CCM3) and may lead to intracerebral hemorrhage (ICH) or non-hemorrhagic focal neurological deficits (FNDs), potentially leading to severe disability and even death. To date, little is known about disease progression, and tools to identify patients at higher risk are lacking. Pediatric and adult fCCM patients, whether symptomatic or asymptomatic, will be enrolled and followed annually over a 2-year period. Participants will undergo clinical assessments, blood sampling, and 3 T brain MRI scans at baseline, 12 months, and 24 months. The primary outcome is the new occurrence of symptomatic ICH or FNDs attributable to CCMs over 24 months. Patient characteristics will be assessed for the primary and secondary endpoints and illustrated using Kaplan-Meier curves and Cox proportional hazard regressions. This trial is registered with ClinicalTrials.gov, NCT06983132 and is currently recruiting participants. Despite increasing efforts in basic and clinical research and an improved understanding of the pathogenic mechanisms underlying fCCM, tools to predict disease progression, identify at-risk individuals, and pinpoint effective therapeutic targets are still lacking. This study aims to create the largest Italian cohort of fCCM patients, who will be monitored closely over time to collect data that may help identify risk factors and disease trajectories. The collection of standardized information on clinical and radiological evolution, along with results from circulating biomarkers, will help address the complexities of the disease and may suggest potential reliable markers of disease progression. ClinicalTrials.gov, identifier NCT06983132.

#5

Lifetime Risk of First Symptomatic ICH or Seizure in Familial Cerebral Cavernous Malformations: A Multicenter Patient Data Analysis.

Neurology2025 Aug 12

Familial cavernous malformations (FCMs) are vascular lesions that pose a lifelong risk of symptomatic hemorrhage (SH) and seizures, yet their natural history remains unclear. This study aims to determine the cumulative lifetime risk of a first SH and/or seizure and assess whether genetic variations influence these risks. This international, multicenter retrospective cohort study included data from 16 tertiary referral centers and 1 patient advocacy group. Eligible patients had confirmed or suspected FCM, available magnetic resonance imaging (MRI) data, documented baseline clinical features, and longitudinal follow-up (FU). Functional outcomes were assessed using the modified Rankin Scale (mRS) at last FU. Direct adjusted survival curves and mixed-effects Cox regression analyses were performed to estimate cumulative lifetime risk. The association between genetic variations and SH/seizure rates was evaluated, and mixed-effects logistic regression assessed the effect of SH/seizures on mRS outcomes. A total of 1,592 patients with FCM were included, with a mean age of 37.6 years (SD 17.1) and 55.7% female. The median FU was 42 years (IQR: 27-55), totaling 64,146 person-years. Of these, 869 (54.6%) had confirmed FCM, 775 (48.7%) experienced at least 1 hemorrhage, and 447 (28.1%) had at least 1 seizure. Genetic testing was performed in 47.7%, identifying CCM1 (31.0%), CCM2 (4.8%), and CCM3 (1.9%) variations. The lifetime risk of a first SH was ∼80%, with an event rate that remained constant beyond age 20. The lifetime risk of a first seizure was ∼45%. Patients with CCM3 variations exhibited a more aggressive hemorrhagic course than those with CCM1 (hazard ratio 1.799, 95% CI 1.008-3.208). SH and seizures were independently associated with worse mRS outcomes at last FU. The event rate of SH and seizures remained stable over time, leading to high cumulative lifetime risks. Patients with CCM3 variations exhibited a more aggressive disease course. Limitations include the non-population-based design, selection bias from tertiary centers, retrospective data collection, and variability in data extraction across centers. However, this study represents the largest international FCM cohort to date, improving the precision of risk estimates and providing valuable insights into disease progression.

Publicações recentes

Ver todas no PubMed

📚 EuropePMC49 artigos no totalmostrando 102

2026

Obstructive hydrocephalus secondary to an anterior mesencephalic cavernous malformation with familial cerebral cavernous malformation syndrome: A case report.

Radiology case reports
2026

Transient Dysphagia as a Presenting Symptom of Familial Cerebral Cavernous Malformation.

Cureus
2025

Natural history of familial cerebral cavernous malformations: the CCM_Italia cohort study.

Frontiers in neurology
2026

Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.

Journal of neurochemistry
2025

Late-onset familial cerebral cavernous malformation without a family history: a case description.

Quantitative imaging in medicine and surgery
2025

Familial cerebral cavernous malformations caused by a novel germline structural variant in the KRIT1 gene.

Neurogenetics
2025

Association of Quality of Life Domains and Clinical Symptoms in Patients With Familial Cerebral Cavernous Malformation.

Journal of the American Heart Association
2025

Familial Cerebral Cavernous Malformations : A Clinical Series and Literature Review.

Journal of Korean Neurosurgical Society
2025

Lifetime Risk of First Symptomatic ICH or Seizure in Familial Cerebral Cavernous Malformations: A Multicenter Patient Data Analysis.

Neurology
2025

Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants.

Human molecular genetics
2025

Comparative Analysis of the Health-Related Quality of Life Between Patients with Familial and Sporadic Forms of Cerebral Cavernous Malformation.

World neurosurgery
2025

Plasma biomarkers in patients with familial cavernous malformation and their first-degree relatives: a cross-sectional study.

Scientific reports
2025

Innovative Quantitative Analysis for Disease Progression Assessment in Familial Cerebral Cavernous Malformations.

IEEE transactions on bio-medical engineering
2025

Management of Maternal Genetic Conditions in Pregnancy, Part 1: Disorders of the Connective Tissue, Muscle, Vascular, and Skeletal Systems.

Obstetrical &amp; gynecological survey
2024

Clinical and radiologic distinctions between familial cavernous malformation syndrome and cerebral amyloid angiopathy.

Acta neurochirurgica
2024

Clinical features, hemorrhage risk and epilepsy outcomes of familial cerebral cavernous malformation: A 20-year observational pragmatic single-center study.

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
2025

Commentary on "Tobacco use increases lesion burden in familial cerebral cavernous malformation syndrome".

Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
2024

Teaching NeuroImage: Familial Cerebral Cavernous Malformation in PDCD10 Genotype.

Neurology
2024

Tobacco use increases lesion burden in familial cerebral cavernous malformation syndrome.

Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
2025

Prevalence, genetic and clinical characteristics in first-degree relatives of patients with familial cerebral cavernous malformations in China.

Stroke and vascular neurology
2024

Genotype-phenotype correlations in multiple lesions of familial cerebral cavernous malformations concerning phosphatidylinositol 3-kinase catalytic subunit alpha mutations.

Clinical and translational medicine
2024

Patient-reported outcome measures in patients with familial cerebral cavernous malformations: results from the Treat_CCM trial.

Frontiers in neurology
2024

Novel Development of a Large Cerebral Cavernous Malformation in an Adolescent With a History of Familial Cerebral Cavernous Malformation Syndrome.

Cureus
2024

Familial cerebral cavernous malformation presenting with cerebellopontine angle syndrome in a patient with autosomal dominant polycystic kidney disease.

Neurology perspectives
2024

Contralateral Interhemispheric Transfalcine Approach to the Basal Ganglia.

World neurosurgery
2024

Circulating biomarkers in familial cerebral cavernous malformation.

EBioMedicine
2023

Clinical characteristics of familial and sporadic pediatric cerebral cavernous malformations and outcomes.

Journal of neurosurgery. Pediatrics
2024

Towards a neurocognitive profile in familial cerebral cavernous malformations.

Acta neurologica Belgica
2023

A tangled web: Dual diagnosis of hereditary hemorrhagic telangiectasia and familial cerebral cavernous malformation.

Pediatric blood &amp; cancer
2023

Molecular genetic features and clinical manifestations in Chinese familial cerebral cavernous malformation: from a novel KRIT1/CCM1 mutation (c.1119dupT) to an overall view.

Frontiers in neuroscience
2023

Amplification of protease-activated receptors signaling in sporadic cerebral cavernous malformation endothelial cells.

Biochimica et biophysica acta. Molecular cell research
2023

A novel KRIT1/CCM1 mutation accompanied by a NOTCH3 mutation in a Chinese family with multiple cerebral cavernous malformations.

Neurogenetics
2023

Intracranial Hemorrhage Rate and Lesion Burden in Patients With Familial Cerebral Cavernous Malformation.

Journal of the American Heart Association
2023

Clinicoradiologic data of familial cerebral cavernous malformation with age-related disease burden.

Annals of clinical and translational neurology
2023

Magnetic susceptibility as a 1-year predictor of outcome in familial cerebral cavernous malformations: a pilot study.

European radiology
2023

Monogenic Causes in Familial Stroke Across Intracerebral Hemorrhage and Ischemic Stroke Subtypes Identified by Whole-Exome Sequencing.

Cellular and molecular neurobiology
2023

Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): a randomised, open-label, blinded-endpoint, phase 2 pilot trial.

The Lancet. Neurology
2023

Natural history of familial cerebral cavernous malformation syndrome in children: a multicenter cohort study.

Neuroradiology
2022

Identification of a novel LATS1 variant associated with familial cerebral cavernous malformations in a Chinese family.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
2022

Transcriptome Analysis Reveals Altered Expression of Genes Involved in Hypoxia, Inflammation and Immune Regulation in Pdcd10-Depleted Mouse Endothelial Cells.

Genes
2023

Circulating Plasma miRNA Homologs in Mice and Humans Reflect Familial Cerebral Cavernous Malformation Disease.

Translational stroke research
2022

Spinal involvement in pediatric familial cavernous malformation syndrome.

Neuroradiology
2022

A Chinese Family With Cerebral Cavernous Malformation Caused by a Frameshift Mutation of the CCM1 Gene: A Case Report and Review of the Literature.

Frontiers in neurology
2023

Primary Delayed Onset Craniosynostosis in a Child With ERF-Related Craniosynostosis Syndrome and Familial Cerebral Cavernous Malformation Syndrome.

The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association
2022

Medication intake and hemorrhage risk in patients with familial cerebral cavernous malformations.

Journal of neurosurgery
2022

De novo brain AVM following radiotherapy for cerebral cavernous malformation in a child: A 15-year clinical course.

The neuroradiology journal
2022

Multiple cerebral cavernous malformations: Clinical course of confirmed, assumed and non-familial disease.

European journal of neurology
2021

Familial Cerebral Cavernous Malformation Mimicking Cerebral Amyloid Angiopathy.

Neurology. Clinical practice
2024

A Midsummer Night's Gene: The familial Neurological Illness of Felix Mendelssohn.

Journal of medical biography
2021

Description of Two Families with New Mutations in Familial Cerebral Cavernous Malformations Genes.

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
2021

Fetal Familial Cerebral Cavernous Malformation With a Novel Heterozygous KRIT1 Variation.

Neurology
2021

Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation.

Molecular genetics &amp; genomic medicine
2021

Pilot investigation of circulating angiogenic and inflammatory biomarkers associated with vascular malformations.

Orphanet journal of rare diseases
2021

Seizure Incidence Rates in Children and Adults With Familial Cerebral Cavernous Malformations.

Neurology
2021

Feasibility and Morbidity of Magnetic Resonance Imaging-Guided Stereotactic Laser Ablation of Deep Cerebral Cavernous Malformations: A Report of 4 Cases.

Neurosurgery
2021

Asymptomatic Familial Multiple Cerebral Cavernous Malformation in a 73-Year-Old Woman.

Case reports in radiology
2021

Lingual Seizures Due to Familial Cerebral Cavernous Malformations.

Pediatric neurology
2021

Novel COL4A2 mutation causing familial malformations of cortical development.

European review for medical and pharmacological sciences
2020

A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family.

Frontiers in neuroscience
2020

Familial cerebral cavernous malformation presenting with epilepsy caused by mutation in the CCM2 gene: A case report.

Medicine
2020

First Report of Concomitant Pathogenic Mutations Within MGC4607/CCM2 and KRIT1/CCM1 in a Familial Cerebral Cavernous Malformation Patient.

World neurosurgery
2020

Genome-wide Genotyping of Cerebral Cavernous Malformation Type 1 Individuals to Identify Genetic Modifiers of Disease Severity.

Methods in molecular biology (Clifton, N.J.)
2020

Next Generation Sequencing (NGS) Strategies for Genetic Testing of Cerebral Cavernous Malformation (CCM) Disease.

Methods in molecular biology (Clifton, N.J.)
2020

High Prevalence of Spinal Cord Cavernous Malformations in the Familial Cerebral Cavernous Malformations Type 1 Cohort.

AJNR. American journal of neuroradiology
2020

Familial Cerebral Cavernous Malformation Syndrome with Concomitant Fourth Ventricular Ependymoma: True Association or Mere Coincidence?

Cancer genetics
2020

Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial.

Trials
2020

Concern regarding classification of c.703G>A/p.Gly235Arg as a novel missense variant in KRIT1 gene.

Human mutation
2020

Stereotactic laser interstitial thermal therapy for epilepsy associated with solitary and multiple cerebral cavernous malformations.

Neurosurgical focus
2020

A British family with familial cerebral cavernous malformation due to a rare mutation of the CCM2 gene.

Acta neurologica Belgica
2020

Novel CCM1 (KRIT1) Mutation Detection in Brazilian Familial Cerebral Cavernous Malformation: Different Genetic Variants in Inflammation, Oxidative Stress, and Drug Metabolism Genes Affect Disease Aggressiveness.

World neurosurgery
2020

Cutaneous findings of familial cerebral cavernous malformation syndrome due to the common Hispanic mutation.

American journal of medical genetics. Part A
2020

Vertebral Intraosseous Vascular Malformations in a Familial Cerebral Cavernous Malformation Population: Prevalence, Histologic Features, and Associations With CNS Disease.

AJR. American journal of roentgenology
2019

Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

Science translational medicine
2019

Cerebral cavernous malformation type 1 with retinal blood vessel tortuosity and KRIT1 gene mutation.

Ideggyogyaszati szemle
2019

"Radiologically Isolated" Spinal Cavernoma Associated with Familial Cerebral Cavernomatosis.

European neurology
2019

Molecular diagnostic workflow, clinical interpretation of sequence variants, and data repository procedures in 140 individuals with familial cerebral cavernous malformations.

Human mutation
2019

Familial Cerebral Cavernous Malformations.

Stroke
2020

Familial Cavernous Hemangioma.

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
2019

Two Novel CCM2 Heterozygous Mutations Associated with Cerebral Cavernous Malformation in a Chinese Family.

Journal of molecular neuroscience : MN
2019

Suboccipital Craniotomy for Resection of a Dorsal Medullary Cerebral Cavernous Malformation: 2-Dimensional Operative Video.

Operative neurosurgery (Hagerstown, Md.)
2018

A new heterozygous G duplicate in exon1 (c.100dupG) of gelsolin gene causes Finnish gelsolin amyloidosis in a Chinese family.

Brain and behavior
2019

A novel large deletion in CCM1 gene in a Tunisian family.

Revue neurologique
2018

Management of brothers with haemophilia A and familial cerebral cavernous malformations.

Haemophilia : the official journal of the World Federation of Hemophilia
2018

Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology
2018

First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing.

Neurogenetics
2018

A novel CCM1/KRIT1 heterozygous deletion mutation (c.1919delT) in a Chinese family with familial cerebral cavernous malformation.

Clinical neurology and neurosurgery
2017

Familial cerebral cavernous malformation: Report of a novel KRIT1 mutation in a Portuguese family.

Seizure
2017

Hereditary Multiple Cerebral Cavernous Malformations Associated with Wilson Disease and Multiple Lipomatosis.

World neurosurgery
2017

Automated algorithm for counting microbleeds in patients with familial cerebral cavernous malformations.

Neuroradiology
2017

Familial Cerebral Cavernous Malformations Are Associated with Adrenal Calcifications on CT Scans: An Imaging Biomarker for a Hereditary Cerebrovascular Condition.

Radiology
2017

A Novel CCM1/KRIT1 Heterozygous Nonsense Mutation (c.1864C>T) Associated with Familial Cerebral Cavernous Malformation: a Genetic Insight from an 8-Year Continuous Observational Study.

Journal of molecular neuroscience : MN
2017

Ascending Spinal Cord Infarction Secondary to Recurrent Spinal Cord Cavernous Malformation Hemorrhage.

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
2017

A Novel KRIT1/CCM1 Gene Insertion Mutation Associated with Cerebral Cavernous Malformations in a Chinese Family.

Journal of molecular neuroscience : MN
2017

Review of familial cerebral cavernous malformations and report of seven additional families.

American journal of medical genetics. Part A
2017

Genetically diagnosed Birt-Hogg-Dubé syndrome and familial cerebral cavernous malformations in the same individual: a case report.

Familial cancer
2016

A Novel CCM2 Gene Mutation Associated with Familial Cerebral Cavernous Malformation.

Frontiers in aging neuroscience
2017

Identification of a Novel Deletion Mutation (c.1780delG) and a Novel Splice-Site Mutation (c.1412-1G>A) in the CCM1/KRIT1 Gene Associated with Familial Cerebral Cavernous Malformation in the Chinese Population.

Journal of molecular neuroscience : MN
2016

Two cases of familial cerebral cavernous malformation caused by mutations in the CCM1 gene.

Korean journal of pediatrics
2016

Familial Multiple Cavernous Malformation Syndrome: MR Features in This Uncommon but Silent Threat.

Journal of the Belgian Society of Radiology
2016

Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1.

Free radical biology &amp; medicine
2015

Genetics of cerebral cavernous malformations: current status and future prospects.

Journal of neurosurgical sciences
2015

Increased number of white matter lesions in patients with familial cerebral cavernous malformations.

AJNR. American journal of neuroradiology

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Doenças relacionadas

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Referências e fontes

Bases de dados externas citadas neste artigo

Publicações científicas

Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.

  1. Obstructive hydrocephalus secondary to an anterior mesencephalic cavernous malformation with familial cerebral cavernous malformation syndrome: A case report.
    Radiology case reports· 2026· PMID 41868467mais citado
  2. Transient Dysphagia as a Presenting Symptom of Familial Cerebral Cavernous Malformation.
    Cureus· 2026· PMID 41804435mais citado
  3. Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.
    Journal of neurochemistry· 2026· PMID 41486746mais citado
  4. Natural history of familial cerebral cavernous malformations: the CCM_Italia cohort study.
    Frontiers in neurology· 2025· PMID 41561324mais citado
  5. Lifetime Risk of First Symptomatic ICH or Seizure in Familial Cerebral Cavernous Malformations: A Multicenter Patient Data Analysis.
    Neurology· 2025· PMID 40638881mais citado
  6. The effect of statins on the risk of bleeding in cerebral cavernous malformations: A systematic review and meta-analysis.
    Surg Neurol Int· 2026· PMID 41952755recente
  7. Late-onset familial cerebral cavernous malformation without a family history: a case description.
    Quant Imaging Med Surg· 2025· PMID 40893524recente

Bases de dados e fontes oficiais

Identificadores e referências canônicas usadas para montar este verbete.

  1. ORPHA:221061(Orphanet)
  2. MONDO:0031037(MONDO)
  3. GARD:13641(GARD (NIH))
  4. Variantes catalogadas(ClinVar)
  5. Busca completa no PubMed(PubMed)
  6. Q28020304(Wikidata)

Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.

Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar

Malformação cavernosa cerebral familiar
Compêndio · Raras BR

Malformação cavernosa cerebral familiar

ORPHA:221061 · MONDO:0031037
Prevalência
1-5 / 10 000
Herança
Autosomal dominant
CID-10
Q28.3 · Outras malformações dos vasos cerebrais
CID-11
Ensaios
4 ativos
Medicamentos
1 registrados
Início
All ages
Prevalência
15.0 (Worldwide)
MedGen
UMLS
C1864041
EuropePMC
Wikidata
Papers 10a
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