Arterial Malformations Research Articles

Head and Neck Paraganglioma in Pacak-Zhuang Syndrome.

Head and neck paragangliomas (HNPGLs) are typically slow-growing, hormonally inactive tumors of parasympathetic paraganglia. Inactivation of prolyl-hydroxylase domain-containing 2 protein causing indirect gain-of-function of hypoxia-inducible factor-2α (HIF-2α), encoded by EPAS1, was recently shown to cause carotid body hyperplasia. We previously described a syndrome with multiple sympathetic paragangliomas caused by direct gain-of-function variants in EPAS1 (Pacak-Zhuang syndrome, PZS) and developed a corresponding mouse model. We evaluated a cohort of patients with PZS (n = 9) for HNPGL by positron emission tomography, magnetic resonance imaging, and computed tomography and measured carotid body size compared to literature reference values. Three patients had imaging consistent with HNPGL, one of which warranted resection and was confirmed on histology. Three additional patients had carotid body enlargement (Z-score > 2.0), and three had carotid artery malformations. Using high resolution ex vivo imaging and histology, we found that nine of ten adult mutant mice had carotid body tumors and six of eight had a paraganglioma on the cranio-caval vein, the murine homologue of the superior vena cava; these were also found in four of five mutant mice at post-natal day 8. These tumors and the one resected from a patient were positive for tyrosine hydroxylase, synaptophysin, and chromogranin A. Brown fat in a resected patient tumor carried the EPAS1 pathogenic variant. These findings 1) suggest HNPGL as a feature of PZS and 2) show that these pathogenic variants are sufficient to cause the development of these tumors, which we believe represents a continuous spectrum of disease starting from hyperplasia.

Cinematic Rendering of Pure Arterial Malformations.

Cinematic Rendering of Pure Arterial Malformations.

Abstract 381: Pure Arterial Malformations: A Case Report and Review of the Literature

Abstract 381: Pure Arterial Malformations: A Case Report and Review of the Literature

Double umbilical artery converging into a single umbilical artery: A case report.

The normal structure and Doppler parameters of the umbilical cord are closely related to many diseases, including fetal infection, chromosomal abnormalities, hypoxia, and growth and development restrictions. We report a case of bilateral umbilical artery confluence resulting in the formation of a single umbilical artery in the free segment of the fetal umbilical cord, diagnosed at 24 weeks and 4 days gestation. The fetus was born prematurely after premature membrane rupture at 31 weeks and 3 days gestation. The Toxoplasma, Others, Rubellavirus, Cytomegalovirus, Herpesvirus test showed positive results for Toxoplasma gondii, rubella virus, and herpes simplex virus IgG antibodies. A 36-year-old woman had vaginal discharge for > 1 hour at 31 weeks + 3 days gestation and came to our obstetrics department for treatment. The pregnant woman sought treatment due to premature membrane rupture and vaginal discharge for > 1 hour. The vaginal discharge was caused by Escherichia coli. After cesarean section, the Toxoplasma, Others, Rubellavirus, Cytomegalovirus, Herpesvirus test revealed positive results for the following: T gondii, rubella virus, and herpes simplex virus IgG antibodies. The patient underwent 2 ultrasound examinations and was diagnosed with umbilical artery malformation (the free segment of the umbilical cord on the fetal side converged into a single umbilical artery), which may have been related to fetal infection. The patient received anti-inflammatory and fetal lung maturation treatment for 2 days before undergoing a cesarean section. The mother and newborn received anti-inflammatory, symptomatic, and supportive treatment and were discharged after 1 week of improvement. After 1 month, 6 months, and 1 year of follow-up after birth, the growth and development of the infant (height and weight) were significantly lower than those of her peers, and her responses to sound and light were slightly delayed. Umbilical artery malformation is extremely rare and may be related to intrauterine parasitic and viral infections. Ultrasound has the advantages of being noninvasive and cost-effective and can be used to dynamically observe umbilical artery structure. An abnormal change in umbilical artery structure found during ultrasound examination can indicate intrauterine infection risk, which provides clinical guidance for further examination of pregnant women, early diagnosis, timely targeted treatment, and fetal prognosis improvement.

Epidemiology of paediatric chronic heart failure in Germany-A population-based analysis.

Paediatric chronic heart failure (CHF) is associated with significant morbidity. The aim of this study was to describe paediatric CHF epidemiology in Germany. This is a retrospective cross-sectional analysis of anonymized healthcare claims data in the InGef database. This database includes longitudinal data from a representative sample of the German population of approximately 4.8 million insured members. We included individuals <18years from 2016 to 2021. CHF was defined by ≥2 diagnoses in different quarters of the year as inpatient or outpatient, using ICD-10-GM codes I50.- or P29.0. The number of eligible children in the database was 674462 in 2016 and 660692 in 2021. Prevalence of CHF per 100000 children was 20.6 [95% confidence interval (CI), 17.3-24.3] in 2016 and 19.4 (95% CI, 16.2 to 23.0) in 2021. Incidence per 100000 children was 9.6 (95% CI, 7.4 to 12.3) in 2016 and 7.6 (95% CI, 5.6 to 10.0) in 2021 for newly diagnosed CHF. All-cause hospitalizations occurred in 47.3% to 57.7% of children with CHF per year. Up to 6.3% of children with CHF were hospitalized, coded primarily for heart failure. Mortality of children with CHF was <5 death per year in the studied population. In 128 children with CHF in 2021, the most common ICD-coded comorbidities were congenital malformations of cardiac septa (57.8%), atrial septal defect (44.5%), congenital malformations of the great arteries (43.0%) and ventricular septal defect (32.0%). Coded treatment modalities for paediatric CHF in 2021 included angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers (18.8%), beta-blockers (17.2%), mineralocorticoid receptor antagonists (14.8%) and surgical procedures (13.3%). This representative cohort study reveals a relatively high incidence proportion. Approximately half of the children with CHF are hospitalized annually while mortality is low.

Role of Hysteroscopy in the Management of Uterine Vascular Malformations with a Focus on Enhanced Myometrial Vascularity - A Review of Diagnosis and Treatment with the Suggested Algorithm.

Postpregnancy bleeding is common after failed pregnancy, termination of pregnancy, and postnatally after both vaginal and cesarean delivery. Pelvic ultrasound (US) is usually the initial imaging modality of choice to ascertain the cause when the bleeding is heavy or prolonged. When used in combination with Doppler studies, US can help differentiate retained products of conception (RPOC) from rarer uterine vascular malformations (UVM), including true arterial vascular malformations and areas of enhanced endometrial vascularity (EMV), which may themselves be associated with any RPOC present. While the management of RPOC is well established and has evolved from an almost universal surgical approach to increasingly more medical or expectant alternatives, clinical decisions over the management of a concurrent UVM are less clear and treatment options need to be individualized depending on features of the lesion and the clinical situation with hysteroscopy featured as an important modality, especially when dealing with EMV's. In this review, we discuss the role of hysteroscopy in the treatment of enhanced myometrial vascularity with and without associated RPOC and propose a management algorithm.

Pure arterial malformation of the fetal PCA treated with flow diverter stent-case report and literature review.

Thirty-three-year-old female underwent diagnostic work-up for chronic headaches. Cerebral DSA on the right side showed fetal posterior cerebral artery (PCA) with unusually shaped arterial malformation on its proximal part. Malformation was formed by multiple convolutions and loops with no arteriovenous shunting. During endovascular procedure, flow diverter stent was placed in the right C6 segment. Patient was put on double antiaggregation therapy. Four weeks after procedure, patient was admitted to ER with signs of dyphasia. No recent ischemic lesions were detected on emergent magnetic resonance. Dyphasia resolved spontaneously. On follow-up magnetic resonance angiography 5 years after the procedure, main portion of malformation has diminished with slightly filling of posterior part supplied by right P1. Here, reported finding is consistent with previously described pure arterial malformation (PAM). Main intention of our treatment was to induce malformation remodeling with flow diverter placement. Two main risks arise when using flow diverters on fetal PCA region. Firstly, there is possibility of occluding fetal PCA alongside malformation. On the contrary, high flow through fetal PCA could hinder malformation thrombosis. Some case series reported high rate of fetal PCA occlusion without ischemic sequelae in the PCA teritory. Others consider flow diverters highly ineffective treatment for the fetal PCA aneurysms due to low rate of complete aneurysm occlusion. We presented first reported case in which flow diverter was used to treat PAM. Slow malformation thrombosis leaves enough time for collateral circulation to recruit and supply territory of the vessel affected by the malformation.

Successful percutaneous coronary intervention in a congenital single right coronary artery with acute myocardial infarction: A case report and literature review.

Single coronary artery (SCA) is a rare coronary artery malformation. SCA combined with atherosclerotic plaques can cause severe and widespread myocardial ischemia and infarction, leading to hemodynamic instability and even sudden death. A 48-year-old Chinese man was admitted for treatment of persistent chest tightness and panic for 5 hours. The patient was a lorry driver with high work intensity and mental stress, with body mass index of 33.78, history of smoking and alcohol consumption, but no history of hypertension and diabetes. Admission examination showed Troponin was 183.083 µg/L and CK-MB value was >300 µg/L. The patient was diagnosed with a congenital single right coronary artery (RCA) with acute myocardial infarction (AMI) by coronary angiography (CAG). Due to atherosclerotic plaques rupture, a complete occlusion of the proximal RCA with thrombolysis in myocardial infarction grade 0 of distal blood flow were found. The patient was treated with thrombus aspiration and thrombolytic therapy by percutaneous coronary intervention under the support of intra-aortic balloon pump. Postoperative the chest tightness and panic were relieved, and CAG revealed that the proximal thrombus of the RCA was reduced, and distal blood flow was restored to thrombolysis in myocardial infarction grade 3. After 2 weeks of intensive antithrombotic and lipid-regulating drug therapy, the patient was successfully discharged. Follow-up for 6 months, the patient was able to live and work normally without experiencing chest tightness and chest pain. Computed tomography angiography (CTA) confirmed a congenital single RCA with patent lumen and no severe stenosis. The congenital single RCA is very rare, and it is fatal in conjunction with acute coronary syndrome. Early detection and appropriate treatment is critical for AMI patient with single RCA. CAG is the gold standard for diagnosis of single RCA, and CTA is a necessary to describe the anatomical course of abnormal coronary arteries.

A Hybrid Approach for the Treatment of a Pure Arterial Malformation Located at an Accessory Middle Cerebral Artery. Cerebral Revascularization Followed by Endovascular Occlusion Using nBCA: Case Report

BACKGROUND AND IMPORTANCE: Pure arterial malformations (PAMs) are rare vascular lesions with unknown natural history. Described in 2013 and initially considered benign, recent evidence of ruptured cases and progressive angioarchitectural changes may support the need for interventional treatment for selected patients. We present the first case of an accessory middle cerebral artery PAM successfully treated using a hybrid approach, including microsurgical revascularization and endovascular occlusion using Glubran2/Lipiodol. CLINICAL PRESENTATION: A 58-year-old woman with a history of spontaneous basal ganglia hemorrhage 2 years before presented to our clinic with a dilated, multilobulated, and overlapping lesion located at a dominant left accessory middle cerebral artery, compatible with the diagnostic criteria of a PAM. The lesion was near the previous bleeding site, and since perforating and cortical vessels arose from its distal lobule, a safeguarding superficial temporal artery-MCA bypass was considered necessary before the successful endovascular embolization of the malformation using nBCA (Glubran2/Lipiodol). CONCLUSION: PAMs can be associated with intracranial bleeding; thus, active treatment is warranted for selected patients. A hybrid microsurgical-endovascular approach is feasible and can be considered the optimal treatment for specific complex anatomies.

Pure arterial malformation: Reports of two rare cases

Pure arterial malformation: Reports of two rare cases

OnyxTMGel or Coil versus Hydrogel as Embolic Agents in Endovascular Applications: Review of the Literature and Case Series.

This review focuses on the use of conventional gel or coil and "new" generation hydrogel used as an embolic agent in endovascular applications. In general, embolic agents have deep or multidistrict vascular penetration properties as they ensure complete occlusion of vessels by exploiting the patient's coagulation system, which recognises them as substances foreign to the body, thus triggering the coagulation cascade. This is why they are widely used in the treatment of endovascular corrections (EV repair), arteriovenous malformations (AVM), endoleaks (E), visceral aneurysms or pseudo-aneurysms, and embolisation of pre-surgical or post-surgical (iatrogenic) lesions. Conventional gels such as Onyx or coils are now commercially available, both of which are frequently used in endovascular interventional procedures, as they are minimally invasive and have numerous advantages over conventional open repair (OR) surgery. Recently, these agents have been modified and optimised to develop new embolic substances in the form of hydrogels based on alginate, chitosan, fibroin and other polymers to ensure embolisation through phase transition phenomena. The main aim of this work was to expand on the data already known in the literature concerning the application of these devices in the endovascular field, focusing on the advantages, disadvantages and safety profiles of conventional and innovative embolic agents and also through some clinical cases reported. The clinical case series concerns the correction and exclusion of endoleak type I or type II appeared after an endovascular procedure of exclusion of aneurysmal abdominal aortic (EVAR) with a coil (coil penumbra released by a LANTERN microcatheter), the exclusion of renal arterial malformation (MAV) with a coil (penumbra coil released by a LANTERN microcatheter) and the correction of endoleak through the application of Onyx 18 in the arteries where sealing by the endoprosthesis was not guaranteed.

Preventing Iatrogenic Injury to the Vertebral Artery in Cervical Spine Surgery: A Case Report.

Iatrogenic injury of the vertebral artery (VA) in the context of surgical approaches to the cervical spine has been cited as a relatively rare complication with varying degrees of severity ranging from minimal injury to acute stroke and can result in death. It is estimated that ~50% of cases of iatrogenic VA injury are preventable after postoperatively examining a patient's preoperative imaging. Despite the low incidence (<2%) of this complication, the potential associated morbidity demonstrates the importance of meticulous preoperative vascular consideration. This study aims to emphasize the importance of preoperative vascular screening during anterior cervical access planning visualized through a rare case of a VA aberration in a 47-year-old patient. This study is designed as a retrospective case report. A thorough chart review was performed for this subject including all prior medical records, imaging studies, imaging reports, operative notes, and communication records. The subject was found to have a history of patent foramen ovale (PFO) repair with a rare vertebral artery malformation described as a medial transposition of the vertebral artery out of the vertebral artery foramen between C3 and C4. Consideration of cervical anatomy, particularly the VA, is key to minimizing the risk of adverse surgical outcomes in both anterior and posterior approaches to the cervical spine. During the workup process, the patient's primary care providers, radiologists, and surgeons should be aware of the potential variations of the VA with particular attention given to the course of the VA on MR imaging. Level IV.

Clinical features of congenitally enlarged bony portion of Eustachian tube

Objective:To investigate the clinical features of patients with congenitally enlarged bony portions of the Eustachian tube（ET）. Methods:The medical history, physical examination, hearing test, temporal bone high resolution computed tomography（HRCT） of six patients（nine ears） with congenitally enlarged bony portion of the ET were retrospectively analyzed. Results:Four patients were men and two were women. The minimum, maximum, and average ages were 5, 21, and（14.7±6.4） years, respectively. Three malformations were bilateral and three were left-sided. Three ears had conductive hearing loss（average bone and air conduction thresholds were 13.7 dB and 71.3 dB）, three had mixed hearing loss（average bone and air conduction thresholds were 27.7 dB and 83.7 dB）, and one had extremely severe sensorineural hearing loss. The average maximum length and width of the enlarged bony ET on temporal bone HRCT were（22.61±2.94） mm and（6.50±2.33） mm, respectively. The enlargement was combined with an external auditory canal malformation in six ears, narrow tympanic cavity in six, tympanic antrum malformation in five, ossicular chain malformation in seven, cochlear malformation in six, helicotrema malformation in three, vestibule widening in two, semicircular canal malformation in three, vestibular window malformation in six, facial nerve abnormality in five, internal auditory meatus malformation in two, low middle cranial fossa in eight, and severe internal carotid artery malformation in one. Conclusion:Bony ET enlargement is a rare congenital middle ear malformation which could combined with other ear malformations. Patients can have no ET dysfunction but different patterns of hearing loss. The defect is usually found unintentionally during imaging, and the HRCT of temporal bone is significant.

Diagnosis of single umbilical artery and risk of foetal congenital malformations by prenatal ultrasound: a retrospective study

BackgroundSingle umbilical artery (SUA) is strongly associated with foetal structural abnormalities; however, the exact pattern of this association has not been described. We aimed to investigate the occurrence of malformations in singleton pregnancies with SUA in China and to study the association between the absent side of the umbilical artery and foetal malformations.MethodsThis was a retrospective study of singleton pregnancies for which routine first-trimester anatomical screening was performed at 11+ 0-13+ 6 gestational weeks and, if the pregnancy continued, a second-trimester scan was performed at 20+ 0-24+ 0 weeks. Data were extracted from records at the referral centre, the Obstetrics and Gynecology Hospital of Fudan University, between January 2011 and April 2019 (n = 47,894). Using logistic regression, the odds ratios (OR) with 95% confidence intervals (CIs) were calculated for malformations associated with SUA.ResultsThe incidence of SUA in our study was 2.0% (970/47,894). Of all foetuses with SUA, 387 (39.9%) had structural malformations. The malformation type varied, with cardiovascular complications being the most common. A robust association was observed between SUA and oesophageal stenosis or atresia (OR: 25.33), followed by cardiovascular (OR: 9.98–24.02), scoliosis (OR: 18.62), genitourinary (OR: 2.45–15.66), and brain malformations (OR: 4.73–9.12). The absence of the left umbilical artery (n = 445, 45.9%) was consistent with that of the right umbilical artery (n = 431, 44.4%). Furthermore, a significantly higher rate of an absent right than the left umbilical artery (p<0.01) was observed in SUA with foetal abnormalities than in SUA with no malformations.ConclusionsOverall, we observed a higher risk of various specific malformations in foetuses with SUA, and a strong association between SUA and oesophageal stenosis or atresia. The absence of the right umbilical artery was most common in foetuses with SUA and structural malformations. This study provides a reference for ultrasonographers in conducting foetal structural screening for pregnant women with SUA.

Variations in the Evaluation and Management of Vascular Rings: A Survey of American Clinicians.

Vascular rings are arterial malformations that lead to the compression of the trachea and/or esophagus. While "tight" rings often produce symptoms and require surgery, "loose" rings rarely produce symptoms. Given advances in fetal echocardiography, this diagnosis is now more often made prenatally. This poses a new conundrum in the management of asymptomatic patients, leading to practice variation and creating a target for clinical system improvement. Hence, we conducted this survey aiming to demonstrate the practice variation existing in current evaluation and management of these patients. An anonymous web-based survey was distributed to several listservs for pediatric cardiologists and pediatric cardiothoracic surgeons. Survey questions targeted respondent practice characteristics, testing obtained, and indications for testing or surgical referral. In total 61 responses were received, predominantly from pediatric cardiologists (95%) in the United States (97%). About 60% of clinicians reported frequently diagnosing patients with vascular rings by fetal echocardiogram, with only about 20% diagnosing them frequently on evaluation of symptoms. Computed tomography angiography and echocardiogram were the most common imaging modalities employed. Most clinicians obtained cross-sectional imaging at the time of diagnosis and referred to surgery once patients had at least occasional symptoms. Respondents demonstrated a low degree of agreement (Krippendorf's alpha 0.48). Few statistically significant patterns were identified between respondents based on their practice characteristics. This study identified significant variation between clinicians regarding the evaluation and management of vascular rings. Further research or expert opinions may help to standardize practice, saving costs and improving the quality of care for affected patients.

Facing PHACES Syndrome; Anesthesiologist’s Point of View

Introduction: PHACES syndrome is a neurocutaneous syndrome that consists of posterior fossa brain malformation, hemangiomas of the face, arterial cerebrovascular malformation, cardiovascular anomalies (Coarctation of the aorta), eye anomaly, and sternal defect or supraumbilical raphe. Most of these manifestations would interfere with anesthesia and hence need major considerations. Case Presentation: A 2.5-month-old female weighing 2100 gr was a candidate for laser therapy due to retinopathy of prematurity. She was diagnosed with PHACES syndrome. Her anesthesia was induced and maintained with sevoflurane. LMA #1 was used for airway management. No complications occurred during or after anesthesia, and she was discharged the next day. Conclusions: PHACES syndrome interacts with numerous anesthesia-related characteristics, such as airway management, cardiovascular disease, and CNS malformations. Based on the accompanying characteristics, perioperative care for these patients should be tailored.

Incidence and Management of Congenital Vascular Malformations – An Institutional Experience

Abstract Introduction: Congenital vascular malformations (CVMs) are malformed vessels developed due to arrested development at various stages of embryogenesis. Arterial venous malformations (VMs) are complex primitive networks of arterial and venous channels (a nidus) that bypass the normal capillary bed. The management of CVM remains challenging because of their unpredictable behavior, high recurrence rate, and need for multidisciplinary management. In this study, we report on the incidence and management of CVM in our institution and its outcome. Materials and Methods: This is a retrospective analysis of CVM patients who were admitted in our institute from January 2010 to June 2023. In this study, 321 patients who presented with CVM are considered. Once a CVM was diagnosed, all underwent angiographic confirmation as a roadmap for treatment. Embolization, sclerotherapy, and surgical procedures were instituted by the multidisciplinary team with periodic follow-up. Results: Out of the 321 patients analyzed, VM predominates with 202 cases (62.9%), out of which 105 (51.9%) were treated with sclerotherapy, 66 (28.21%) were treated with excision, 40 (19.8%) were managed conservatively. Among 108 arteriovenous malformation (33.64%), 33 (30.55%) patients were treated with excision followed by repair and flap cover/split skin graft, 32 (29.62%) were treated with glue Embolization, 7 (6.48%) were treated with embolization followed by excision, one patient presented with life-threatening bleeding was treated by emergency ECA ligation followed by elective excision, 21 (19.44%) were managed conservatively and 13 (12.03%) patients were not willing for surgery. Seven (2.1%) lymphovenous malformation and 4 (1.24%) lymphatic malformations patients were also treated. Conclusion: Diagnosis and management of CVMs by a multidisciplinary approach that integrates surgical therapy with embolization and sclerotherapy appear to improve the results and management.

Pathological tortuosity of intracranial arteries (pure arterial malformation) - diagnosis and management tactics

Tortuosity of intracranial arteries is rare and usually mistaken for arteriovenous malformations. In the world literature, the term «pure arterial malformations» is used to refer to this disease. To summarize the experience of the Burdenko Neurosurgery Center on diagnosis of intracranial artery tortuosity, management and treatment of these patients, as well as to review appropriate literature data. Tortuosity of intracranial arteries was detected in 11 patients (8 women and 3 men) aged 7-48 years who underwent outpatient or inpatient examination and treatment at the Burdenko Neurosurgery Center between 2009 and 2022. We analyzed angiographic, clinical and follow-up data of these patients, as well as appropriate literature data. According to angiography data, all patients had moderate dilatation, elongation and tortuosity of intracranial arteries without signs of arteriovenous shunting. The most common finding was tortuosity of several segments of internal carotid artery (5 cases). Lesion of PCA, PComA, MCA and ACA was less common. In 7 cases, the walls of the deformed vessels had calcified zones. In two cases, there were saccular aneurysms in the walls of the tortuous vessels. In one case, tortuosity was combined with kinking of the left subclavian artery, in another one - tortuosity of C1 segment of the right ICA. No patient had specific clinical manifestations. The follow-up period was 1-10 years in 7 patients. There were no changes in structure of tortuosity or appearance of new aneurysms. Tortuosity of intracranial arteries is an extremely rare disease with the highest incidence in young women. This abnormality has no specific clinical manifestations and does not require surgical or conservative treatment. Tortuosity of intracranial arteries should be differentiated from arterial dolichoectasia, fusiform aneurysms and AVMs.

Discovery and Characterization of Ephrin B2 and EphB4 Dysregulation and Novel Mutations in Cerebral Cavernous Malformations: In Vitro and Patient-Derived Evidence of Ephrin-Mediated Endothelial Cell Pathophysiology.

Intracranial vascular malformations manifest on a continuum ranging from predominantly arterial to predominantly venous in pathology. Cerebral cavernous malformations (CCMs) are capillary malformations that exist at the midpoint of this continuum. The axon guidance factor Ephrin B2 and its receptor EphB4 are critical regulators of vasculogenesis in the developing central nervous system. Ephrin B2/EphB4 dysregulation has been implicated in the pathogenesis of arterial-derived arteriovenous malformations and vein-based vein of Galen malformations. Increasing evidence supports the hypothesis that aberrant Ephrin B2/EphB4 signaling may contribute to developing vascular malformations, but their role in CCMs remains largely uncharacterized. Evidence of Ephrin dysregulation in CCMs would be important to establish a common link in the pathogenic spectrum of EphrinB2/Ephb4 dysregulation. By studying patient-derived primary CCM endothelial cells (CCMECs), we established that CCMECs are functionally distinct from healthy endothelial cell controls; CCMECs demonstrated altered patterns of migration, motility, and impaired tube formation. In addition to the altered phenotype, the CCMECs also displayed an increased ratio of EphrinB2/EphB4 compared to the healthy endothelial control cells. Furthermore, whole exome sequencing identified mutations in both EphrinB2 and EphB4 in the CCMECs. These findings identify functional alterations in the EphrinB2/EphB4 ratio as a feature linking pathophysiology across the spectrum of arterial, capillary, and venous structural malformations in the central nervous system while revealing a putative therapeutic target.

A new variant in the ZCCHC8 gene: diverse clinical phenotypes and expression in the lung.

Pulmonary fibrosis is a severe disease which can be familial. A genetic cause can only be found in ∼40% of families. Searching for shared novel genetic variants may aid the discovery of new genetic causes of disease. Whole-exome sequencing was performed in 152 unrelated patients with a suspected genetic cause of pulmonary fibrosis from the St Antonius interstitial lung disease biobank. Variants of interest were selected by filtering for novel, potentially deleterious variants that were present in at least three unrelated pulmonary fibrosis patients. The novel c.586G>A p.(E196K) variant in the ZCCHC8 gene was observed in three unrelated patients: two familial patients and one sporadic patient, who was later genealogically linked to one of the families. The variant was identified in nine additional relatives with pulmonary fibrosis and other telomere-related phenotypes, such as pulmonary arterial venous malformations, emphysema, myelodysplastic syndrome, acute myeloid leukaemia and dyskeratosis congenita. One family showed incomplete segregation, with absence of the variant in one pulmonary fibrosis patient who carried a PARN variant. The majority of ZCCHC8 variant carriers showed short telomeres in blood. ZCCHC8 protein was located in different lung cell types, including alveolar type 2 (AT2) pneumocytes, the culprit cells in pulmonary fibrosis. AT2 cells showed telomere shortening and increased DNA damage, which was comparable to patients with sporadic pulmonary fibrosis and those with pulmonary fibrosis carrying a telomere-related gene variant, respectively. The ZCCHC8 c.586G>A variant confirms the involvement of ZCCHC8 in pulmonary fibrosis and short-telomere syndromes and underlines the importance of including the ZCCHC8 gene in diagnostic gene panels for these diseases.