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The development of cerebral cavernous malformations (CCMs) is a well-recognized sequela of irradiation to the brain in pediatric tumors, particularly in medulloblastoma, glioma, and acute lymphoblastic leukaemia. So far, only one case of cerebral cavernoma after chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has been described. We describe a case of a patient with medulloblastoma aged 18 months at the time of oncological diagnosis who was treated with high-dose chemotherapy followed by HSCT and who developed CCM two years later. The patient was not treated for vascular malformation since he remained asymptomatic until now and is regularly followed with neuro-radiological check-ups. This represents the second case of acquired cavernoma developed in a patient who has not received radiation therapy. [ABSTRACT FROM AUTHOR]

The development of cerebral cavernous malformations (CCMs) is a well-recognized sequela of irradiation to the brain in pediatric tumors, particularly in medulloblastoma, glioma, and acute lymphoblastic leukaemia. So far, only one case of cerebral cavernoma after chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has been described. We describe a case of a patient with medulloblastoma aged 18 months at the time of oncological diagnosis who was treated with high-dose chemotherapy followed by HSCT and who developed CCM two years later. The patient was not treated for vascular malformation since he remained asymptomatic until now and is regularly followed with neuro-radiological check-ups. This represents the second case of acquired cavernoma developed in a patient who has not received radiation therapy.

BackgroundCerebral cavernous malformation (CCM) is a rare disease associated with a latent risk of intracranial hemorrhage. However, due to limited evidence, the safety of recommending intravenous tissue plasminogen activators for patients with acute stroke and CCM remains uncertain.MethodsOur study identified five patients with acute stroke and CCM treated between 2017 and 2023 across two hospitals. A comprehensive literature review was conducted, incorporating three similar case reports and two retrospective studies.ResultsAmong 30 patients reviewed, three exhibited symptomatic intracranial hemorrhage, two of whom were women. Additionally, three patients presented with calcification in their CCM, with two experiencing symptomatic intracranial hemorrhage.ConclusionThe observed incidence of symptomatic intracranial hemorrhage following intravenous tissue plasminogen activator administration appears to be elevated in patients with CCM. Therefore, before thrombolysis, a thorough evaluation of personalized risk–benefit ratios is crucial. Furthermore, conducting further research involving multiple centers and larger sample sizes is imperative to advance our understanding in this area, especially in identifying hemorrhage risk factors.

Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system and mainly characterized by enlarged capillary cavities without intervening brain parenchyma. Genetic studies have identified three diseasecausing genes (CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10) responsible for CCM. Here, we characterized a four-generation family diagnosed with CCM and identified a novel heterozygous mutation c.1159C>T, p.Q387X in KRIT1 gene by whole exome sequencing and Sanger sequencing. The Q387X mutation resulted in premature termination of KRIT1 protein, which was predicted to be deleterious by the ACMG/AMP 2015 guideline. Our results provide novel genetic evidence support that KRIT1 mutations cause CCM, and are helpful to the treatment and genetic diagnosis of CCM. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations are clusters of aberrant vessels that can lead to severe neurological complications. Pathogenic loss-of-function variants in the CCM1, CCM2, or CCM3 gene are associated with the autosomal dominant form of the disease. While interpretation of variants in protein-coding regions of the genes is relatively straightforward, functional analyses are often required to evaluate the impact of non-coding variants. Because of multiple alternatively spliced transcripts and different transcription start points, interpretation of variants in the 5′ untranslated and upstream regions of CCM1 is particularly challenging. Here, we identified a novel deletion of the non-coding exon 1 of CCM1 in a proband with multiple CCMs which was initially classified as a variant of unknown clinical significance. Using CRISPR/Cas9 genome editing in human iPSCs, we show that the deletion leads to loss of CCM1 protein and deregulation of KLF2, THBS1, NOS3, and HEY2 expression in iPSC-derived endothelial cells. Based on these results, the variant could be reclassified as likely pathogenic. Taken together, variants in regulatory regions need to be considered in genetic CCM analyses. Our study also demonstrates that modeling variants of unknown clinical significance in an iPSC-based system can help to come to a final diagnosis.

Cerebral cavernous malformations are slow-flow thrombi-containing vessels induced by two-step inactivation of the CCM1, CCM2 or CCM3 gene within endothelial cells. They predispose to intracerebral bleedings and focal neurological deficits. Our understanding of the cellular and molecular mechanisms that trigger endothelial dysfunction in cavernous malformations is still incomplete. To model both, hereditary and sporadic CCM disease, blood outgrowth endothelial cells (BOECs) with a heterozygous CCM1 germline mutation and immortalized wild-type human umbilical vein endothelial cells were subjected to CRISPR/Cas9-mediated CCM1 gene disruption. CCM1−/− BOECs demonstrated alterations in cell morphology, actin cytoskeleton dynamics, tube formation, and expression of the transcription factors KLF2 and KLF4. Furthermore, high VWF immunoreactivity was observed in CCM1−/− BOECs, in immortalized umbilical vein endothelial cells upon CRISPR/Cas9-induced inactivation of either CCM1, CCM2 or CCM3 as well as in CCM tissue samples of familial cases. Observer-independent high-content imaging revealed a striking reduction of perinuclear Weibel-Palade bodies in unstimulated CCM1−/− BOECs which was observed in CCM1+/− BOECs only after stimulation with PMA or histamine. Our results demonstrate that CRISPR/Cas9 genome editing is a powerful tool to model different aspects of CCM disease in vitro and that CCM1 inactivation induces high-level expression of VWF and redistribution of Weibel-Palade bodies within endothelial cells.

Cerebrovascular diseases are one of the leading causes of death worldwide, however, little progress has been made in preventing or treating these diseases to date. The transforming growth factor-β (TGF-β) signaling pathway plays crucial and highly complicated roles in cerebrovascular development and homeostasis, and dysregulated TGF-β signaling contributes to cerebrovascular diseases. In this review, we provide an updated overview of the functional role of TGF-β signaling in the cerebrovascular system under physiological and pathological conditions. We discuss the current understanding of TGF-β signaling in cerebral angiogenesis and the maintenance of brain vessel homeostasis. We also review the mechanisms by which disruption of TGF-β signaling triggers or promotes the progression of cerebrovascular diseases. Finally, we briefly discuss the potential of targeting TGF-β signaling to treat cerebrovascular diseases.

Cerebral cavernous malformations (CCMs) are the second most prevalent type of vascular malformation within the central nervous system. CCMs occur in two forms—sporadic and familial—the latter of which has an autosomal dominant mode of inheritance with incomplete penetrance and variable clinical expressivity. There are three genes considered to be associated with CCMs,—CCM1, which codes for KRIT1 protein; CCM2, which codes for MGC4607 protein; and CCM3, which codes for PDCD10 protein. To date, more than 74 gene mutations of CCM2 have been reported, and ~45% are deletion mutations. In this article, we disclose a novel CCM2 genetic variant (c.755delC, p.S252fs*40X) identified in a Chinese family to enrich the database of CCM2 genotypes.

Cerebral cavernous malformations (CCMs) are the second most prevalent type of vascular malformation within the central nervous system. CCMs occur in two forms—sporadic and familial—the latter of which has an autosomal dominant mode of inheritance with incomplete penetrance and variable clinical expressivity. There are three genes considered to be associated with CCMs,— CCM1 , which codes for KRIT1 protein; CCM2 , which codes for MGC4607 protein; and CCM3 , which codes for PDCD10 protein. To date, more than 74 gene mutations of CCM2 have been reported, and ~45% are deletion mutations. In this article, we disclose a novel CCM2 genetic variant (c.755delC, p.S252fs*40X) identified in a Chinese family to enrich the database of CCM2 genotypes. [ABSTRACT FROM AUTHOR]

Familial cerebral cavernous malformations (CCMs) are autosomal dominant disorders characterized by hemorrhagic strokes, recurrent headache, epilepsy, and focal neurological deficits. Genetic variants in KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3 genes contribute to CCMs. The clinical information of two Chinese families with CCMs was collected. MRI and video-electroencephalography were performed. Genetic variants of CCM1, CCM2, and CCM3 genes were investigated by exome sequencing. The patients were presented with recurrent epilepsy or headache. Susceptibility-weighted images of brains showed many dark dots, while video-electroencephalography revealed many spikes from multiple brain regions of patients. Exome sequencing revealed a novel CCM1 genetic variant (c.1599_1601TGAdel, p.Asp533del) and a novel CCM2 genetic variant (c.773delA, p.K258fsX34) in Family one and Family two, respectively; cosegregation existed in these two families. The two family members presented typical CCMs symptoms. These two novel genetic variants in CCM1 and CCM2 genes were the causation of CCM in the two Chinese families, and our data enriched the genetic variant spectrum of CCM genes.

Background: The best strategy to perform follow-up of patients with multiple cerebral cavernous malformations (mCCM) is unclear due to the unpredictable clinical course. Still, serial radiological follow-up is often performed. The objective of this work was to critically question whether active follow-up by serial imaging is justified and has an impact on clinical decision making.Methods: We included all consecutive patients with mCCM treated and followed at our Department between 2006 and 2016. Patient data were collected and analyzed retrospectively.Results: From a total number of 406 patients with CCM, n = 73 [18.0%; mean age at first diagnosis 45.2 years (±2.4 SE); n = 42 male (57.5 %)] were found to harbor multiple lesions (≤5 CCM in 58.9%; 6–25 in 21.9%; ≥ 25 in 19.2%). All of them were followed for a mean of 6.8 years (±0.85 SE). Conservative treatment was suggested in 43 patients over the complete follow-up period. Thirty patients underwent surgical extirpation of at least one CCM lesion. Forty-three surgical procedures were performed in total. During 500.5 follow-up years in total, routinely performed follow-up MRI in asymptomatic patients lead to an indication for surgery in only two occasions and even those two were questionable surgical indications.Conclusion: Routinely performed follow-up MRI in asymptomatic patients with mCCM is highly questionable as there is no evidence for therapeutic relevance.

Background: The best strategy to perform follow-up of patients with multiple cerebral cavernous malformations (mCCM) is unclear due to the unpredictable clinical course. Still, serial radiological follow-up is often performed. The objective of this work was to critically question whether active follow-up by serial imaging is justified and has an impact on clinical decision making. Methods: We included all consecutive patients with mCCM treated and followed at our Department between 2006 and 2016. Patient data were collected and analyzed retrospectively. Results: From a total number of 406 patients with CCM, n = 73 [18.0%; mean age at first diagnosis 45.2 years (±2.4 SE); n = 42 male (57.5 %)] were found to harbor multiple lesions (≤5 CCM in 58.9%; 6–25 in 21.9%; ≥ 25 in 19.2%). All of them were followed for a mean of 6.8 years (±0.85 SE). Conservative treatment was suggested in 43 patients over the complete follow-up period. Thirty patients underwent surgical extirpation of at least one CCM lesion. Forty-three surgical procedures were performed in total. During 500.5 follow-up years in total, routinely performed follow-up MRI in asymptomatic patients lead to an indication for surgery in only two occasions and even those two were questionable surgical indications. Conclusion: Routinely performed follow-up MRI in asymptomatic patients with mCCM is highly questionable as there is no evidence for therapeutic relevance. [ABSTRACT FROM AUTHOR]