Spinal Cavernous Malformations Research Articles

Surgical Outcomes of Symptomatic Intramedullary Spinal Cord Cavernous Malformations: Analysis of Consecutive Cases in a Single Center.

Intramedullary spinal cavernous malformations (ISCMs) are rare vascular lesions of the spinal cord with unclear natural history and controversy over treatment. This study aimed to report a series of symptomatic ISCMs underwent microsurgical management to illustrate the natural history, clinical presentation, and surgical outcomes and to evaluate factors associated with hemorrhage events and neurological prognosis. This single-center retrospective study included 29 consecutive patients with whose demographic, symptomology, imaging, neurological, and surgical data were collected. The risk for hemorrhage events and factors affecting surgical outcomes were retrospectively analyzed. There were 12 female (41.4%) and 17 male patients (58.6%), with an average age of 45.2 years (range, 17-69 years). The mean size of the lesion was 9.7 mm (range, 3-20 mm). Most patients had a bowel or/and bladder dysfunction symptom (n = 11, 37.9%), followed by sensory deficits (n = 5, 17.2%), gait disturbance (n = 5, 17.2%), pain (n = 4, 13.8%), and weakness (n = 4, 13.8%), most (n = 15, 51.7%) with a chronic onset. All patients received total resection without rehemorrhages after surgical resection in follow-up. Sixty-five point five percent patients (n = 19) improved, 13.8% (n = 4) remained stable, 20.7% (n = 6) got worsen. The overall annual hemorrhage risk was 2.1% per patient-year. A total of 27 hemorrhages occurred in the 18 patients, of which rehemorrhage rate increased to 50.0% (n = 9) with a previous history of hemorrhage. Patients with smaller lesion sizes were more likely to have hemorrhage or rehemorrhage events (p = 0.008). Recurrent hemorrhage of the lesions was a risk factor for neurological outcomes (p = 0.016). The risk of rehemorrhage was significantly increased in symptomatic ISCM patients with a previous history of hemorrhage. Rehemorrhage was a risk factor for neurological outcomes. Patients can benefit from microsurgical treatment to avoid rehemorrhage and further neurological deterioration.

Intramedullary spinal cavernous malformations with high ossification: a case report and review of the literature

BackgroundCavernous malformations of the spinal cord are a rare type of vascular malformation, comprising approximately 5 to 16% of all vascular lesions in the spinal cord. Depending on their origin position, these malformations can be distributed in different locations within the spinal canal. Although intramedullary cavernous malformations have been reported in the literature, they are exceedingly rare. Furthermore, highly calcified or ossified intramedullary cavernous spinal malformations are even rarer.Case presentationHere, we present a case report of a 28-year-old woman diagnosed with a thoracic intramedullary cavernous malformation. The patient had been experiencing progressive numbness in her distal limbs for a period of 2 months. During routine lung computed tomography screening for COVID-19, a hyperdense mass was noted in the patient’s spinal canal. Magnetic resonance imaging revealed a mulberry-shaped intramedullary mass at the T1-2 level. The patient underwent surgical treatment, during which the entire lesion was successfully removed, resulting in a gradual improvement of her symptoms. Histological examination confirmed the presence of cavernous malformations with calcification.ConclusionsIntramedullary cavernous malformations with calcification are rare and special type that should be treated surgically in the early stage without significant neurological impairment before rebleeding or enlargement of the lesion can occur.

Functional neurological outcome of spinal cavernous malformation surgery

PurposeSpinal cavernous malformations (SCM) present a risk for intramedullary hemorrhage (IMH), which can cause severe neurologic deficits. Patient selection and time of surgery have not been clearly defined.MethodsThis observational study included SCM patients who underwent surgery in our department between 2003 and 2021. Inclusion required baseline clinical factors, magnetic resonance imaging studies, and follow-up examination. Functional outcome was assessed using the Modified McCormick scale score.ResultsThirty-five patients met the inclusion criteria. The mean age was 44.7 ± 14.5 years, and 60% of the patients were male. In univariate analysis, the unfavorable outcome was significantly associated with multiple bleeding events (p = .031), ventral location of the SCM (p = .046), and incomplete resection (p = .028). The time between IMH and surgery correlated with postoperative outcomes (p = .004), and early surgery within 3 months from IMH was associated with favorable outcomes (p = .033). This association remained significant in multivariate logistic regression analysis (p = .041).ConclusionsRemoval of symptomatic SCM should be performed within 3 months after IMH when gross total resection is feasible. Patients with ventrally located lesions might be at increased risk for postoperative deficits.

Functional impact of multiple bleeding events in patients with conservatively treated spinal cavernous malformations.

The aim of this study was to investigate the functional outcome in spinal cavernous malformation (SCM) patients with single or multiple intramedullary hemorrhagic events. SCM patients who were conservatively treated between 2003 and 2021 and had complete clinical baseline characteristics, an MRI data set, at least one SCM-related intramedullary hemorrhage (IMH), and at least one follow-up examination were included in this study. Functional status was assessed using the modified McCormick Scale score at diagnosis, before and after each bleeding event, and at the last follow-up. A total of 45 patients were analyzed. Univariate analysis identified multiple bleeding events as the only statistically significant predictor for an unfavorable functional outcome at the last follow-up (OR 15.28, 95% CI 3.22-72.47; p < 0.001). Patients significantly deteriorated after the first hemorrhage (29.0%, p = 0.006) and even more so after the second hemorrhage (84.6%, p = 0.002). Multiple bleeding events were significantly associated with functional deterioration at the last follow-up (76.9%, p = 0.003). The time between the last IMH and the last follow-up did not influence this outcome. IMH due to SCM is linked to functional worsening. Such outcomes tend to improve after each hemorrhage, but the probability of full recovery declines with each bleeding event.

Prediction of outcomes for symptomatic spinal cavernous malformation surgery: a multicenter prospective clinical study.

Clinical outcome of spinal cavernous malformation (SCM) varies because of its unclear natural history, and reliable prognostic prediction model for SCM patients is limited. The aim of the present study was to investigate potential factors that predict one-year neurological status in postoperative patients with SCM. This was a multicenter prospective observational study in consecutive patients with SCMs. SCMs treated microsurgically between January 2015 and January 2021 were included. Outcome was defined as the American Spinal Injury Association Impairment Scale (AIS) grade at one year after operation. Multivariable analyses were used to construct the best predictive model for patient outcomes. We identified 268 eligible SCM patients. Neurological outcome had worsened from preoperative baseline in 51 patients (19.0%) at one year. In the multivariable logistic regression, the best predictive model for unfavorable outcome included symptom duration ≥ 26 months (95% CI 2.80-16.96, P < 0.001), size ≤ 5mm (95% CI 1.43-13.50, P = 0.010), complete intramedullary (95% CI 1.69-8.14, P = 0.001), subarachnoid hemorrhage (95% CI 2.92-12.57, P < 0.001), AIS B (95% CI 1.91-40.93, P = 0.005) and AIS C (95% CI 1.12-14.54, P = 0.033). Admission size of the lesion, morphology, symptom duration, AIS grade and the presence of subarachnoid hemorrhage were strong outcome predictors regarding prognostication of neurological outcome in postoperative patients with SCMs. A decision to surgically remove a symptomatic SCM should be justified by systematic analysis of all factors potentially affecting outcome.

Modifiable vascular risk factors in patients with cerebral and spinal cavernous malformations: a complete 10-year follow-up study.

The aim was to investigate the effect of modifiable vascular risk factors on the risk of first and recurrent bleeding for patients with a cavernous malformation (CM) of the central nervous system (CNS) over a 10-year period. A retrospective review of our CM institutional database was performed spanning from 2003 to 2021. The inclusion criteria were non-missing serial magnetic resonance imaging studies and clinical baseline metrics such as vascular risk factors. The exclusion criteria were patients who underwent surgical CM removal and patients with less than a decade of follow-up. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative risk (10 years) of hemorrhage. Eighty-nine patients with a CM of the CNS were included. Our results showed a non-significant increased risk of hemorrhage during 10 years of follow-up in patients using nicotine (hazard ratio 2.11, 95% confidence interval 0.86-5.21) and in patients with diabetes (hazard ratio 3.25, 95% confidence interval 0.71-14.81). For the presence of modifiable vascular risk factors at study baseline different cumulative 10-year risks of bleeding were observed: arterial hypertension 42.9% (18.8%-70.4%); diabetes 66.7% (12.5%-98.2%); hyperlipidemia 30% (8.1%-64.6%); active nicotine abuse 50% (24.1%-76%); and obesity 22.2% (4%-59.8%). Overall cumulative (10-year) hemorrhage risk was 30.3% (21.3%-41.1%). The probability of hemorrhage in untreated CNS CM patients increases progressively within a decade of follow-up. None of the modifiable vascular risk factors showed strong indication for an influence on hemorrhage risk, but our findings may suggest a more aggressive course in patients with active nicotine abuse or suffering from diabetes.

Surgical outcomes of spinal cavernous malformations: A retrospective study of 98 patients.

Spinal cord cavernous malformation (SCCM) is a rare vascular lesion, and the treatment strategy remains controversial at present. The goal of this retrospective study was to analyze the surgical outcomes of the SCCM and to find more appropriate treatment strategies for a better prognosis. A retrospective review of 98 patients with SCCM from 2009 to 2018 was conducted at the neurosurgical center of our hospital. Neurological function was assessed using the American Spinal Injury Association (ASIA) impairment scale. Clinical features were analyzed using the multivariable logistic regression. Ninety-eight patients with SCCM were included, of whom 36% were female and 64% male. The mean age was 41.6 years; and family history was reported in 8% of patients. Definite hemorrhage was found in 6%. Before surgery, the neurological status was Grade A in 2%, Grade B in 2%, Grade C in 12%, Grade D in 54%, and Grade E in 30% of the patients. 83% (81/98) patients had long-term follow-up, of whom, 42% had improved, 51% were stable and 7% had deteriorated. Patients with dorsal or superficial lesions showed better improvement than those with ventral or lateral deep lesions. Those with symptoms lasting less than three months had higher rates of improvement than those with symptoms lasting more than three months. However, there was no significant difference in prognosis between hemilaminectomy and laminectomy. These results suggest that surgical strategies should be preferred for severe symptomatic SCCMs if total resection can be achieved, thereby avoiding the risk of severe complications with subsequent lesion hemorrhage. Earlier (usually within 3 months of symptom duration) surgical resection generally may lead to a better prognosis. For ventral or lateral deep SCCMs, the surgical strategy should be considered more carefully.

Concomitant Thoracic Spinal Dural Arteriovenous Fistula and Spinal Cavernous Malformation

Both spinal dural arteriovenous fistula (SDAVF) and spinal cavernous malformation (SCM) are uncommon vascular malformations. To our knowledge, such a case of SDAVF concomitant with SCM has not been reported. We encountered a case of a 55-year-old man who had weakness and numbness in both lower extremities. Magnetic resonance imaging showed a round-shape lesion identified as a cavernous malformation in the middle segment of the thoracic spine, with spinal edema and obvious flow voids. Diagnostic angiography revealed an SDAVF fed by the right T7 radicular artery with venous drainage. The intramedullary venous hypertension due to fistula was suspected of inducing the formation of SCM. This case may provide new insight into the pathogenesis of SCM.

Surgical management of spinal cavernous malformations: extent of resection and outcome

Surgical management of spinal cavernous malformations: extent of resection and outcome

The Influence of Select Medications on Prospective Hemorrhage Risk in Patients with Spinal or Cerebral Cavernous Malformations

Effects of select medications on hemorrhage risk in patients with cerebral or spinal cavernous malformations (CMs) are unknown. From a single-institution prospective cohort of patients with CM (2015-2021), demographics, mode of clinical presentation, and radiographic data were collected. Follow-up was performed with electronic medical record review, in-person visits, and written surveys. Select medication use was ascertained from the time of CM diagnosis to a censor date of first prospective symptomatic hemorrhage, complete surgical excision of sporadic form CM, last follow-up, or death. Using Cox proportional hazards regression model, we assessed effects of antithrombotic agents, fish oil, selective serotonin reuptake inhibitors (SSRIs), vitamin E and D supplementation, statins, and beta blockers on prospective hemorrhage risk. The study included 364 patients with spinal or cerebral CM (58.0% female; 20.0% familial form; 42.3% presentation to medical attention owing to hemorrhage; 25.8% brainstem location). During a follow-up of 2018 patient-years, 103 prospective hemorrhages occurred. No studied medications increased the prospective CM hemorrhage risk. Antithrombotics, vitamin D supplementation, fish oil, and SSRI were associated with lower hemorrhage risk even after adjusting for age at diagnosis, hemorrhage at diagnosis, and brainstem location. Use of select medications with antithrombotic properties do not increase the risk of CM hemorrhage. Vitamin D supplementation, any antithrombotic agent, fish oil, and SSRI were associated with a lower prospective hemorrhage risk. Further studies should evaluate the mechanism of action and potential benefit of these select medications.

Magnetic Resonance Imaging of Multiple Cerebral and Spinal Cavernous Malformations of a Patient with Dementia and Tetraparesis

Cavernomas are rare cerebrovascular malformations that usually occur in sporadic forms with solitary lesions located most often in the hemispheric white matter, but also in the infratentorial or spinal region. Multiple lesions at different CNS levels are considered a hallmark for the familial form of the disease. The diagnostic modality of choice for cerebral cavernous malformations (CCMs) is magnetic resonance imaging (MRI). We present an intriguing case of a 65-year-old male admitted to our hospital with tetraparesis and cognitive impairment where highly sensitive MRI sequences identified many cerebral cavernous lesions at the supra-, infratentorial and cervical–thoracic spine levels, some of them with recent signs of bleeding in a patient with oral anticoagulant therapy due to atrial fibrillation. The mechanism of cognitive impairment in this patient is most probably the interruption of strategic white matter tracts, as it is known to happen in other subcortical vascular pathologies. MRI can be helpful not only in mapping the anatomical distribution of lesions, but also in weighing the risks and making decisions regarding whether or not to continue oral anticoagulant therapy.

407 Residual and Recurrent Spinal Cord Cavernous Malformations: Outcomes and Technical Notes for Optimal Resection

INTRODUCTION: Intramedullary spinal cord cavernous malformations (SCCMs) account for a small proportion (5%) of CMs overall and of spinal vascular malformations. However, they are well reported in the literature, with over 700 cases as of 2020. To date, the occurrence of recurrent or residual SCCMs has not been assessed or discussed, nor have the technical nuances of resection related to this issue. METHODS: An institutional database of vascular malformations was queried for all surgically managed cases of intramedullary cavernous malformations. Demographic, radiologic, intraoperative findings, and surgical outcomes data were obtained and retrospectively analyzed. A systematic review was performed using three databases (PubMed, Ovid MEDLINE, and Scopus) to analyze all cases of spinal cavernous malformations in the literature, to augment a prior review. RESULTS: 146 cases of SCCM surgeries were identified in the database, including 17 recurrent lesions. Recurrences occurred at various time points, from as few as 3 to 264 months following initial resection. At the postoperative exam, 10 patients had better outcome scores than preoperative scores, 1 of which was status post resection of a recurrent lesion. A total of 21 patients had worse outcome scores, 4 of which were status post resection of recurrent lesion. CONCLUSION: Intramedullary spinal cord cavernous malformations are rare findings but may cause significant symptoms. Resection of these lesions is technically challenging, akin to the resection of brainstem cavernous malformations. Care should be taken to avoid leaving residual lesion, as this can leave the patient vulnerable to future hemorrhagic events and neurological morbidity. Satisfactory results are still achievable even with secondary or tertiary resections.

Modifiable cardiovascular risk factors in patients with cerebral and spinal cavernous malformations: a complete ten-year follow-up study

Modifiable cardiovascular risk factors in patients with cerebral and spinal cavernous malformations: a complete ten-year follow-up study

Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies

The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause–effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it.

Treatment strategies and prognostic factors for spinal cavernous malformation: a single-center retrospective cohort study.

The authors aimed to identify factors that influence neurological function after treatment in order to facilitate clinician decision-making during treatment of spinal cavernous malformation (SCM) and about when and whether to perform surgical intervention. The authors performed a retrospective observational cohort study of patients with SCM who were treated at their institution between January 2004 and December 2019. Multiple logistic and Cox regression analyses were performed to determine the prognostic predictors of clinical outcome. Neurological status was assessed according to Frankel grade. A total of 112 patients met the inclusion criteria, and a minimum 24 months of follow-up was achieved by 73 surgically treated and 39 conservatively treated patients. The mean ± SD lesion size was 8.7 ± 5.2 mm. In the surgically treated group, preoperative lesion size ≤ 5 mm (OR 13.62, 95% CI 1.05-175.98, p = 0.045), complete intramedullary lesion (OR 7.48, 95% CI 1.39-40.15, p = 0.019), and subarachnoid hemorrhage (OR 6.26, 95% CI 1.13-34.85, p = 0.036) were independent predictors of worse outcome. In the conservative treatment group, lesion size ≥ 10 mm (HR 9.77, 95% CI 1.18-80.86, p = 0.034), ≥ 3 segments with hemosiderin deposition (HR 13.73, 95% CI 1.94-97.16, p = 0.009), and subarachnoid hemorrhage (HR 13.44, 95% CI 2.38-75.87, p = 0.003) were significant predictors of worse outcome. The annual hemorrhage rate of the conservatively treated patients was 4.3%. Subarachnoid hemorrhage, lesion size, morphology, extent of hemosiderin involvement, and motor dysfunction were independent risk factors of prognosis. In clinical practice, these parameters may help to identify patients at high risk for worse outcome. The treatment strategy for patients with SCM should be based on these risk factors and balanced with clinical symptoms.

Long-term surgical outcomes and prognostic factors of adult symptomatic spinal cord cavernous malformations

Cervical and thoracic or lumbar intramedullary spinal cavernous malformations (ISCMs) may behave differently. We conducted this retrospective study by using data from adult ISCMs to compare their natural histories and explore prognostic factors for improved clinical outcomes. Neurological functions were assessed by using the Modified McCormick Scale (MMCS) and Aminoff-Logue Disability Scale. A total of 111 study-eligible adult patients were included in this study. Patients with cervical ISCMs mostly demonstrated a shorter duration of symptoms (P = 0.026), an acute onset pattern with some recovery (P = 0.026), and a larger lesion size (P = 0.033) than their thoracic or lumbar counterparts. Thoracic or lumbar lesions had a higher proportion of motor symptoms (P = 0.001) and sphincter problems (P = 0.005), and they were usually associated with an aggressive clinical course (P = 0.001, OR = 9.491, 95% CI = 2.555–35.262) in multivariate analysis. There was no difference in age, sex distribution, hemorrhage risk between the cervical and thoracic-lumbar groups. A better preoperative neurological status (P = 0.034, OR = 2.768, 95% CI = 1.081–7.177) and improvement immediately after surgery (P < 0.001, OR = 8.756, 95% CI = 4.837–72.731) were identified as indicators for long-term improvement by multivariate analysis. Cervical lesions had a high proportion for long-term improvement, but it was not a predictor for improvement in multivariate analysis. ISCMs in the thoracic or lumbar location should be considered for surgical removal more aggressively than those in the cervical location. Surgical removal of symptomatic ISCMs can avoid further neurological deterioration and usually result in satisfactory long-term outcomes.

Influence of Pregnancy on Hemorrhage Risk in Women With Cerebral and Spinal Cavernous Malformations.

Pregnancy as a hemorrhage risk factor in women with cavernous malformations (CMs) is controversial. We describe prospective hemorrhage risk in women who become pregnant after an established CM diagnosis. Beginning in 2015, we recruited consecutive patients with radiologically confirmed CM of the brain or spinal cord to participate in a prospective registry. Participants underwent a baseline and annual medical record review, imaging review, and annual surveys to ascertain pregnancies, deliveries, and neurological complications. We collected prospective hemorrhage data on reproductive age women. We calculated prospective hemorrhage rates on childbearing age patients based on the number of hemorrhages occurring post-CM diagnosis during pregnancy and nonpregnancy, divided by the years of follow-up and censored at last follow-up, age 46, or surgery in sporadic-form CM. The hemorrhage rates were compared and the 95% CI presented with a P value of <0.05. Of 160 women, 90 presented with CM under the age of 46 (average age 31.6 years; 25.6% familial form; 46.7% with hemorrhage; 24.4% brain stem location). These 90 patients had 136 pregnancies before CM diagnosis; 36 pregnancies occurred at or after the diagnosis of CM. Four patients had a hemorrhage while pregnant or postpartum leading to the first CM diagnosis. During 402.6 years of follow-up while not pregnant, 42 hemorrhages occurred prospectively yielding a 10.4% per year (95% CI, 7.5-14.0) risk of hemorrhage while not pregnant. No hemorrhages occurred during 32 prospective pregnancies (26 live births including 1 twinset and 7 nonviable fetuses) after CM diagnosis during 26.9 years of pregnancy time yielding a rate of 0% per year (95% CI, 0-13.6). We found no statistical difference in the rates of hemorrhage during pregnant and nonpregnant time (P=0.09). No hemorrhage occurred during delivery. Our prospective data suggest that pregnancy does not increase the risk of hemorrhage in women with a known brain or spinal cord CM and that vaginal delivery is safe in appropriate candidates.

Safety of select headache medications in patients with cerebral and spinal cavernous malformations

Background: Patients with cerebral or spinal cavernous malformations (CM) and a primary headache disorder are often limited in medication options due to concern for bleeding risk. Methods: From a prospective cohort of CM patients (2015–2020), demographics, mode of clinical presentation, and radiographic data were collected. Follow up of patients was performed with electronic medical record review, in person visits and/or written surveys. Select medication use was ascertained from the time of the CM diagnosis to a censor date of first prospective symptomatic hemorrhage, complete surgical excision of sporadic form CM, or death. The influence of non-aspirin NSAID (NA-NSAID), triptan, or OnabotulinumtoxinA on prospective hemorrhage risk was assessed. Results: As of August 20, 2020, 329 patients with spinal or cerebral CM (58% female; 20.1% familial; 42.2% initial presentation due to hemorrhage; 27.4% brainstem) were included. During a follow-up of 1799.9 patient years, 92 prospective hemorrhages occurred. Use of NA-NSAIDs, triptans, and OnabotulinumtoxinA after the diagnosis of CM was unassociated with an increased risk of prospective hemorrhage. Conclusions: Use of triptans and NA-NSAIDs, does not precipitate CM hemorrhage. Similarly, we did not find that OnabotulinumtoxinA precipitated CM hemorrhage in a limited number of patients at doses &lt;200 units per session.

Intramedullary spinal cord cavernous malformations in the pediatric population.

Background: Intramedullary spinal cavernous malformations (ISCM) account for just 1% of all intramedullary pediatric spinal cord lesions. Pathologically, they are well-circumscribed vascular malformations that typically appear dark blue or reddish-brown, often coming to the spinal cord surface. With regard to the histopathology findings, ISCMs are comprised sinusoidal vascular spaces lined by a single layer of endothelial cells within a loose connective tissue stroma. As these lesions are often misdiagnosed in the pediatric population, appropriate treatment may be unduly delayed.Methods: The authors performed an extensive review of the published literature (PubMed) focusing on ISCM in the pediatric age group.Results: The search yielded 17 articles exclusively pertaining to ISCM affecting the pediatric population.Conclusion: Here, we reviewed the clinical, radiographic, surgical, and outcome data for the treatment of ISCM in the pediatric age groups. Notably, over 50% of pediatric patients with ISCM experienced an improvement in their neurological status after a mean postoperative follow-up duration of 4 years. Future meta-analyses are needed to highlight the potential presence of ISCM and, thereby, decrease the rate of misdiagnosis of these lesions in the pediatric population presenting with recurrent intramedullary spinal cord hemorrhages.

First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations

Autosomal dominant cerebral cavernous malformations (CCM) are leaky vascular lesions that can cause epileptic seizures and stroke-like symptoms. Germline mutations in either CCM1, CCM2 or CCM3 are found in the majority of patients with multiple CCMs or a positive family history. Recently, the first copy number neutral inversion in CCM2 has been identified by whole genome sequencing in an apparently mutation-negative CCM family. We here asked the question whether further structural genomic rearrangements can be detected within NGS gene panel data of unsolved CCM cases. Hybrid capture NGS data of eight index patients without a pathogenic single nucleotide, indel or copy number variant were analyzed using two bioinformatics pipelines. In a 58-year-old male with multiple CCMs in his brain and spinal cord, we identified a 294 kb insertion within the coding sequence of CCM2. Fine mapping of the breakpoints, molecular cytogenetic studies, and multiplex ligation-dependent probe amplification verified that the structural variation was an inverted unbalanced insertion that originated from 1p12-p11.2. As this rearrangement disrupts exon 6 of CCM2 on 7p13, it was classified as pathogenic. Our study demonstrates that efforts to detect structural variations in known disease genes increase the diagnostic sensitivity of genetic analyses for well-defined Mendelian disorders.