Cavernous Hemangioma Research Articles

Cavernous Malformation From Cranial Nerves: A Systematic Review With a Novel Classification and Patient-Level Analysis.

Cavernous malformations (CMs) occurring in the cranial nerve (CN) are extremely rare, and there is currently no comprehensive review on CN CMs, leading to a lack of sufficient understanding of CN CMs. We aimed to systematically review all published CN CM cases; summarize the epidemiology, clinical manifestations, treatment, and prognosis of CN CMs; and identify factors influencing the prognosis of CN CMs. This systematic review identified all cases potentially diagnosed with CN CM through a systematic search of PubMed, SCOPUS, Web of Science, and Cochrane databases. This represents the most comprehensive systematic review to date. We classified CN CMs based on their anatomic origins. Patient characteristics, disease manifestations, treatment approaches, and prognosis were summarized descriptively. Further analysis was conducted to identify factors influencing the prognosis of CN CMs. The final analysis included 108 articles (127 individual patient cases). The optic nerve (49/128, 38.3%) is the most commonly affected nerve. Notably, CN CMs can be categorized into 3 types: Intraneural, Perineural, and Extraneural. Preoperative nerve function status and novel classification were associated with the prognosis of CN CMs (P = .001; P < .001). The postoperative neurological deterioration rate for the Intraneural type was 19/37 (51.4%); for the Extraneural type, it was 13/69 (18.8%); and for the Perineural type, it was 1/22 (4.5%) (P < .001). We reviewed all the published CN CMs to date, offering a comprehensive description of CN CMs for the first time and identifying prognostic factors. The classification of CN CMs proposed in this study could serve as guidance for the selection of intraoperative treatment regimens. The findings of this systematic review are expected to provide a foundation for clinical decision-making in this crucial rare disease and lay the groundwork for developing relevant clinical guidelines.

Commentary: Microsurgical Resection of a Left Temporal Stem Cavernous Malformation via Transsylvian Approach: 2-Dimensional Operative Video.

Commentary: Microsurgical Resection of a Left Temporal Stem Cavernous Malformation via Transsylvian Approach: 2-Dimensional Operative Video.

Single-cell and bulk RNA-seq unveils the immune infiltration landscape associated with cuproptosis in cerebral cavernous malformations

BackgroundCerebral cavernous malformations (CCMs) are vascular abnormalities associated with deregulated angiogenesis. Their pathogenesis and optimal treatment remain unclear. This study aims to investigate the molecular signatures of cuproptosis, a newly identified type of cell death, associated with CCMs development.MethodsBulk RNA sequencing (RNA-seq) from 15 CCM and 6 control samples were performed with consensus clustering and clustered to two subtypes based on expression levels of cuproptosis-related genes (CRGs). Differentially expressed genes and immune infiltration between subtypes were then identified. Machine learning algorithms including the least absolute shrinkage and selection operator and random forest were employed to screen for hub genes for CCMs associated with cuproptosis. Furthermore, Pathway enrichment and correlation analysis were used to explore the functions of hub genes and their association with immune phenotypes in CCMs. An external dataset was then employed for validation. Finally, employing the Cellchat algorithm on a single-cell RNA-seq dataset, we explored potential mechanisms underlying the participation of these hub genes in cell-cell communication in CCMs.ResultsOur study revealed two distinct CCM subtypes with differential pattern of CRG expression and immune infiltration. Three hub genes (BTBD10, PFDN4, and CEMIP) were identified and validated, which may significantly associate with CCM pathogenesis. These genes were found to be significantly upregulated in CCM endothelial cells (ECs) and were validated through immunofluorescence and western blot analysis. Single-cell RNA-seq analysis revealed the cellular co-expression patterns of these hub genes, particularly highlighting the high expression of BTBD10 and PFDN4 in ECs. Additionally, a significant co-localization was also observed between BTBD10 and the pivotal cuproptosis gene FDX1 in Mki67+ tip cells, indicating the crucial role of cuproptosis for angiogenesis in CCMs. The study also explored the cell-cell communication between subcluster of ECs expressing these hub genes and immune cells, particularly M2 macrophages, suggesting a role for these interactions in CCM pathogenesis.ConclusionThis study identifies molecular signatures linking cuproptosis to CCMs pathogenesis. Three hub genes—PFDN4, CEMIP, and BTBD10—may influence disease progression by modulating immunity. Further research is needed to understand their precise disease mechanisms and evaluate their potential as biomarkers or therapeutic targets for CCMs.

Clinical and Radiological Response Following Single-Session Gamma Knife Radiosurgery in Cavernous Sinus Hemangiomas

Abstract Purpose Cavernous sinus hemangiomas (CSH) represent 2 to 3% of lesions occupying the cavernous sinus. The optimal management strategy for CSH is not established, with microsurgical resection and radiosurgery employed alone or in combination. Therefore, we aimed to analyze the efficacy and safety of gamma knife radiosurgery (GKRS) for CSH in a cohort of primary and residual CSH. Methods A retrospective analysis of 33 patients (26 primary and 7 residual CSH) that underwent single-session GKRS between 2012 and 2021 for CSH was performed. Demographic, clinical, radiological, and follow-up data were acquired, and clinicoradiological response following GKRS was assessed. Results The mean age of the cohort was 43 ± 13.5 years (range, 10–77). There were 9 males (27.3%) and 24 females (72.7%). The median lesion volume was 6.9 cc, ranging from 1.46 to 19.06 cc. The mean dose administered to the tumor margin was 13.50 ± 1.5 Gy (range, 12 to 15 Gy). The median duration of clinical follow-up was 41 months, over which period the mean reduction in tumor volume was 87.6%. Complete response, defined as absence of tumor on follow-up imaging, occurred in 23 patients (69.7%). Twenty-three patients (69.7%) showed clinical improvement following GKRS. There were no radiation-induced complications. Conclusion CSH have a distinct radiological appearance and a predictable response to radiosurgery. When used primarily in radiologically diagnosed CSH and as adjunctive therapy supplementing a subtotal excision, GKRS produces a high rate of volume reduction with the improvement of neurological function and minimal cranial nerve morbidity. Therefore, GKRS presents a viable alternative to surgery without the morbidity associated with surgical resection.

Frequency of Hematologic and Nonhematologic Conditions in Pediatric Patients with Vascular Anomalies: A Pediatric Health Information System Database Study

Background: Vascular anomalies (VA) are a heterogeneous group of diseases which include vascular malformations and vascular tumors. In the pediatric population, there is a sparsity of data on the frequency of associated hematologic and nonhematologic conditions as well as overall outcomes for patients. Objectives: The objective of this study was to determine the rate of certain concurrent hematologic and nonhematologic conditions in patients with VA who underwent procedures and compare those to patients who did not undergo procedures. To examine the rates of intensive care unit admissions and discharge mortality in patients who had a vascular anomaly. Methods: This is a multicenter retrospective cohort study using data from the Pediatric Health Information System. The database was queried for children 0–18 years old with a diagnosis of a VA who had inpatient encounters between January 2016 and September 2021. Results: The most common hematologic conditions were thrombocytopenia, iron deficiency anemia, and venous thrombosis. The most common nonhematologic condition was electrolyte imbalances. Intensive care unit admissions were highest among patients with other congenital malformations of the peripheral vascular system, cerebral cavernous malformations, and sporadic arteriovenous malformations. Discharge mortality was highest in patients with lymphatic malformations and primary lymphedema. Conclusions: This is the largest database study of pediatric patients with VA and their concurrent medical conditions and outcomes to date. While our study could not prove associations, we hope that our results will serve as a foundation for more extensive research regarding the impact of these identified conditions and outcomes and contribute to improved management of patients with VA.

Cerebral cavernous malformations: to operate or not?

Cerebral cavernous malformations: to operate or not?

Role of artificial intelligence in ocular tumors: A systematic review.

e15070 Background: Integrating oncology and artificial intelligence (AI) shows significant potential in improving treatments and early detection of ocular tumors. This systematic review aims to strengthen existing evidence regarding the application of AI in diagnosing and treating ocular tumors. Methods: We systematically searched PubMed, Embase, Web of Science, Scopus, and Google Scholar until January 15, 2024. Inclusion criteria comprised original peer-reviewed human studies (retrospective or prospective) investigating AI approaches in patients with ocular tumors such as retinoblastoma, uveal melanoma, conjunctival melanoma, and choroidal melanoma. The quality of the literature was assessed using JBI checklists. The eligibility criteria involved assessing studies that explored the application of AI in ocular tumor detection, classification, and treatment planning. We employed a rigorous screening process, and subsequent data extraction focused on key characteristics, including tumor types, sample sizes, AI input data specifications, and study aims. Exclusion criteria encompassed studies not meeting the inclusion criteria, lacking relevant outcome measures, exhibiting insufficient methodological quality, or inadequate reporting. Results: The initial database search yielded 903 records, of which 37 studies (retrospective = 24 and prospective = 13) were included. Most studies selected the retinoblastoma (n = 12) and uveal melanoma (n = 14). Other studies utilized other types of ocular tumors, including ocular metastasis (n = 2), ocular surface squamous neoplasia (n = 2), and ocular lymphoma (n = 2). The conjunctival melanoma, choroidal melanoma, intraocular melanoma, cavernous hemangioma, and schwannoma patients were utilized once. The AI-based models were employed for the classification (n = 22), prognosis prediction (n = 6), lesion segmentation (n = 5), and predicting the gene expression (n = 4) tasks. The data types used Included magnetic resonance imaging (MRI), computed tomography (CT), whole-slide imaging (WSI), clinical data, and fundus images. A meta-analysis was precluded because of the significant heterogeneity observed across the included studies in terms of demographics, study design, interventions, and outcome measures. Conclusions: Although imaging and patient presentation have played a crucial role in ocular tumor diagnostics, AI presents promising results in prediction, prognosis, and disease management. Meanwhile, AI's primary role has been in classification, demonstrating significant success. Additionally, continued exploration of less-discussed eye tumors is essential for enhancing AI's predictive and therapeutic capabilities. The absence of reported evaluation criteria and low evaluation parameter rates in certain studies underscores the importance of standardized reporting practices for robust assessments in future ocular oncology research.

GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas

Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both invitro and invivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.

Stereotactic radiosurgery for haemorrhagic cerebral cavernous malformation: a multi-institutional, retrospective study

BackgroundCerebral cavernous malformations (CCMs) frequently manifest with haemorrhages. Stereotactic radiosurgery (SRS) has been employed for CCM not suitable for resection. Its effect on reducing haemorrhage risk is still controversial. The...

Surgical treatment of cavernous malformation-related epilepsy in children: case series, systematic review, and meta-analysis.

Cerebral cavernous malformations (CCMs) are cerebral vascular lesions that occasionally occur with seizures. We present a retrospective case series from IRCCS Gaslini Children's Hospital, a systematic review, and meta-analysis of the literature with the goal of elucidating the post-surgery seizure outcome in children with CCMs. a retrospective review of children with cavernous malformation related epilepsy who underwent surgery at Gaslini Children's Hospital from 2005 to 2022 was conducted. We also conducted a comprehensive search on PubMed/MEDLINE and Scopus databases from January 1989 to August 2022. Inclusion criteria were: presence of CCMs-related epilepsy, in under 18 years old subjects with a clear lesion site. Presence of post-surgery seizure outcome and follow-up ≥ 12 months. we identified 30 manuscripts and 223 patients with CCMs-related epilepsy, including 17 patients reported in our series. We identified 85.7% Engel class I subjects. The risk of expected neurological deficits was 3.7%; that of unexpected neurological deficits 2.8%. We found no statistically significant correlations between Engel class and the following factors: site of lesion, type of seizure, drug resistance, duration of disease, type of surgery, presence of multiple CCMs. However, we found some interesting trends: longer disease duration and drug resistance seem to be more frequent in subjects in Engel class II, III and IV; multiple cavernomas would not seem to influence seizure outcome. epilepsy surgery in children with CCMs is a safe and successful treatment option. Further studies are necessary to define the impact of clinical features on seizure prognosis.

Cryoprobe-Assisted Excision of Cavernous Hemangioma of the Orbit: A Clinical Case Report.

This case report details the management of orbital cavernous hemangioma in a middle-aged female. The treatment involved a medial orbitotomy combined with an innovative application of a cryoprobe. This approach underscores the benefits of open orbitotomy, particularly when combined with cryoextraction. This combination provides improved control over bleeding and results in a substantial reduction in surgical time, offering valuable insights in the context of the contemporary trend towards endoscopic surgeries.

Behavioral impairments are linked to neuroinflammation in mice with Cerebral Cavernous Malformation disease.

Cerebral Cavernous Malformations (CCMs) are neurovascular abnormalities in the central nervous system (CNS) caused by loss of function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3) genes. One of the most common symptoms in CCM patients is associated with motor disability, weakness, seizures, stress, and anxiety, and the extent of the symptom or symptoms may be due to the location of the lesion within the CNS or whether multiple lesions are present. Previous studies have primarily focused on understanding the pathology of CCM using animal models. However, more research has yet to explore the potential impact of CCM lesions on behavioral deficits in animal models, including effects on short-term and long-term memory, motor coordination, and function. We used the accelerating RotaRod test to assess motor and coordination deficits. We also used the open field test to assess locomotor activity and pathology-related behavior and Pavlovian fear conditioning to assess short-and long-term memory deficits. Our behavioral studies were complemented by proteomics, histology, immunofluorescence, and imaging techniques. We found that neuroinflammation is crucial in behavioral deficits in male and female mice with neurovascular CCM lesions (Slco1c1-iCreERT2; Pdcd10 fl/fl ; Pdcd10 BECKO ). Functional behavior tests in male and female Pdcd10 BECKO mice revealed that CCM lesions cause sudden motor coordination deficits associated with the manifestation of profound neuroinflammatory lesions. Our findings indicate that maturation of CCM lesions in Pdcd10 BECKO mice also experienced a significant change in short- and long-term memory compared to their littermate controls, Pdcd10 fl/fl mice. Proteomic experiments reveal that as CCM lesions mature, there is an increase in pathways associated with inflammation, coagulation, and angiogenesis, and a decrease in pathways associated with learning and plasticity. Therefore, our study shows that Pdcd10 BECKO mice display a wide range of behavioral deficits due to significant lesion formation in their central nervous system and that signaling pathways associated with neuroinflammation and learning impact behavioral outcomes. Our study found that CCM animal models exhibited behavioral impairments such as decreased motor coordination and amnesia. These impairments were associated with the maturation of CCM lesions that displayed a neuroinflammatory pattern.

Genetic Inactivation of the β1 adrenergic receptor prevents Cerebral Cavernous Malformations in zebrafish.

Propranolol reduces experimental murine cerebral cavernous malformations (CCMs) and prevents embryonic caudal venous plexus (CVP) lesions in zebrafish that follow mosaic inactivation of ccm2. Because morpholino silencing of the β1 adrenergic receptor (adrb1) prevents the embryonic CVP lesion, we proposed that adrb1 plays a role in CCM pathogenesis. Here we report that adrb1 -/- zebrafish exhibited 86% fewer CVP lesions and 87% reduction of CCM lesion volume relative to wild type brood mates at 2dpf and 8-10 weeks stage, respectively. Treatment with metoprolol, a β1 selective antagonist, yielded a similar reduction in CCM lesion volume. Adrb1 -/- zebrafish embryos exhibited reduced heart rate and contractility and reduced CVP blood flow. Similarly, slowing the heart and eliminating the blood flow in CVP by administration of 2,3-BDM suppressed the CVP lesion. In sum, our findings provide genetic and pharmacological evidence that the therapeutic effect of propranolol on CCM is achieved through β1 receptor antagonism.

Surgical management of cervical intramedullary cavernoma: case report and systematic review of the literature

BackgroundCavernous malformations can occur throughout the cerebral nervous system, most commonly located in the supratentorial compartment. The intramedullary location is rare and accounts for approximately 2.4% to 5% of all spinal vascular tumors. The cervical cord location and its clinical manifestations are underreported.MethodsThe authors report a case of spinal cord compression at the C5–C6 level by a cervical intramedullary cavernoma with a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and meta-analysis guidelines. Relevant studies (1980 to 2023) that reported patients with cervical intramedullary cavernoma were identified from PubMed databases.ResultsA total of 29 studies reporting 423 patients were included in this study with a mean age of 40.5 ± 6.3 years old. The overall male-to-female ratio was 1:2.5 with a median duration of follow-up of 46 months [18.5–63.9]. The type of resection as well as the patient’s outcome was also reported.ConclusionIntramedullary cavernous angiomas are rare. Early surgical total resection of the symptomatic lesions in adequate conditions is crucial for good outcomes.

Plasma water T2 detects age-stratified differences in cardiometabolic health among familial CCM patients with Hispanic CCM1 mutation.

Cerebral cavernous malformations (CCMs) are abnormal clusters of capillaries in the nervous system. This pilot study analyzed the cardiometabolic health status of individuals with familial CCMs caused by a rare mutation in the CCM1 gene (fCCM1). The aim was to compare plasma water T2 values from individuals with fCCM1 with values from metabolically unhealthy and healthy individuals with no known CCM mutations. This observational, cross-sectional study included 75 participants: 11 fCCM1 patients, 24 metabolically unhealthy and 40 metabolically healthy individuals. Plasma water T2, an early, global and practical marker of cardiometabolic health, was measured in the time domain using benchtop magnetic resonance relaxometry. The results were stratified by age (equal to or less than 45 vs. older than 45 years). Group means were compared using Welch's one-way ANOVA and post hoc Tukey-Kramer tests. Multivariable linear regression, with T2 as the outcome variable, was used to explore associations with age, gender, Hispanic ethnicity and fCCM1 status. In the younger age stratum, the fCCM1 group had a mean plasma water T2 value comparable to the metabolically healthy group (p = 0.6388), but higher than the unhealthy group (p < 0.0001). By contrast, in the older stratum, the mean plasma water T2 value for the fCCM1 group was comparable to the metabolically unhealthy group (p = 0.7819) and lower than the healthy group (p = 0.0005). Multivariable linear regression revealed that age and the interaction between age and fCCM1 status were significant predictors of T2, even after adjusting for gender and Hispanic ethnicity. Plasma water T2 shows potential as a biomarker for assessing the health status of individuals with fCCM1. Further research is needed to validate these preliminary observations and elucidate the association between CCMs and cardiometabolic health.

Improved differentiation of cavernous malformation and acute intraparenchymal hemorrhage on CT using an AI algorithm

This study aimed to evaluate the utility of an artificial intelligence (AI) algorithm in differentiating between cerebral cavernous malformation (CCM) and acute intraparenchymal hemorrhage (AIH) on brain computed tomography (CT). A retrospective, multireader, randomized study was conducted to validate the performance of an AI algorithm in differentiating AIH from CCM on brain CT. CT images of CM and AIH (< 3 cm) were identified from the database. Six blinded reviewers, including two neuroradiologists, two radiology residents, and two emergency department physicians, evaluated CT images from 288 patients (CCM, n = 173; AIH, n = 115) with and without AI assistance, comparing diagnostic performance. Brain CT interpretation with AI assistance resulted in significantly higher diagnostic accuracy than without (86.92% vs. 79.86%, p < 0.001). Radiology residents and emergency department physicians showed significantly improved accuracy of CT interpretation with AI assistance than without (84.21% vs. 75.35%, 80.73% vs. 72.57%; respectively, p < 0.05). Neuroradiologists showed a trend of higher accuracy with AI assistance in the interpretation but lacked statistical significance (95.83% vs. 91.67%, p = 0.56). The use of an AI algorithm can enhance the differentiation of AIH from CCM in brain CT interpretation, particularly for nonexperts in neuroradiology.

Mapping cell diversity in human sporadic cerebral cavernous malformations

BackgroundCerebral cavernous malformation (CCM) is a low-flow, bleeding-prone vascular disease that can cause cerebral hemorrhage, seizure and neurological deficits. Its inheritance mode includes sporadic or autosomal dominant inheritance with incomplete penetrance, namely sporadic CCM (SCCM) and familial CCM. SCCM is featured by single lesion and single affection in a family. Among CCM patients especially SCCM, the pathogenesis of the corresponding phenotypes and pathological features or candidate genes have not been fully elucidated yet. MethodsHere, we performed in-depth single-cell RNA sequencing (scRNA-Seq) and bulk assay for transposase-accessible chromatin sequencing (ATAC-Seq) in SCCM and control patients. Further validation was conducted for the gene of interest using qPCR and RNA in situ hybridization (RNA FISH) techniques to provide further atlas and evidence for SCCM generative process. ResultsWe identified six cell types in the SCCM and control vessels and found that the expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 were up-regulated in SCCM tissues. Among the six cell types, we found that compared with control conditions, PVT1 showed a rising peak which followed the pseudo-time axis in endothelial cell clusters of SCCM samples, while showed an increasing trend in smooth muscle cell clusters of SCCM samples. Further experiments indicated that, compared with the control vessels, PVT1 exhibited significantly elevated expression in SCCM samples. ConclusionIn SCCM conditions, We found that in the process of development from control to lesion conditions, PVT1 showed a rising peak in endothelial cells and showed an increasing trend in smooth muscle cells at the same time. Overall, there was a significantly elevated expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 in SCCM specimens compared to control samples.

Microsurgical Resection of a Left Temporal Stem Cavernous Malformation Through Transsylvian Approach: 2-Dimensional Operative Video.

Cavernous malformations (CMs) are rare, often oligosymptomatic vascular lesions. Common manifestations include seizures and focal neurological deficits. Depending on the symptoms, location, size, and risk factors of bleeding, such as the presence of a developmental venous anomaly, the injury can be highly morbid. Hence, one can consider surgical resection. Deep and eloquently located CMs, such as those located in the temporal trunk, can be quite challenging and require an exact operative technique.1-7 We present a 27-year-old patient with a history of headaches that began two years ago and significantly worsened in the last month, associated with visual blurring, scotomas, nausea, phonophobia, and photophobia as well as paresthesias in the hands and perioral region. Imaging investigation revealed a CM in the temporal stem (Zabramski classification II). Owing to the risk of rebleeding and the young age, surgical resection was performed using a transsylvian approach to preserve the temporal cortex. We describe the technique applied and demonstrate the necessary care manipulating the distal sylvian fissure and the superficial sylvian veins. We also detail the anatomy of the temporal stem and the benefit of the transsylvian approach to preserve the white matter fibers that compose the temporal stem. The patient consented to the procedure and to the publication of his/her image. This study was approved by the Ethics Committee of our institution. Performed CM resection using the transsylvian pterional craniotomy technique, and it proceeded without complications. The postoperative period was also uneventful. The postoperative imaging demonstrated total resection of the cavernoma.

Corrigendum to: Imaging Features and Misdiagnosis of Giant Cerebral Cavernous Malformations.

An error occurred in the Ethical Commiittie details of the manuscript titled "Imaging Features and Misdiagnosis of Giant Cerebral Cavernous Malformations", 2024; 20: e15734056273891 [1]. Original: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: This study was approved by the institutional review committee of First Affiliated Hospital of Sun Yat-sen University (ZF2022-216). Corrected: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The ethics approval was provied by the Biomedical Ethics Committee of Guangdong Provincial Hospital of Taditional Chinese Medicine and the written informed consent was exempted. The original article can be found online at https://www.eurekaselect.com/article/137176.

Loss of heterozygosity in CCM2 cDNA revealing a structural variant causing multiple cerebral cavernous malformations.

Loss-of-function variants in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations. However, genomic DNA sequencing combined with large rearrangement screening fails to detect a pathogenic variant in 5% of the patients. We report a family with two affected members harboring multiple CCM lesions, one with severe hemorrhages and one asymptomatic. No causative variant was detected using DNA sequencing of the three CCM genes, CNV detection analysis, and RNA sequencing. However, a loss of heterozygosity in CCM2 was observed on cDNA sequences in one of the two affected members, which strongly suggested that this locus might be involved. Whole genome sequencing (WGS) identified a balanced structural variant on chromosome 7 with a breakpoint interrupting the CCM2 gene, preventing normal mRNA synthesis. These data underline the importance of WGS in undiagnosed patients with typical multiple CCM.