Capillary Malformation-arteriovenous Malformation Syndrome Research Articles

RASopathies for Radiologists.

RASopathies are a heterogeneous group of genetic syndromes caused by germline mutations in a group of genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include neurofibromatosis type 1, Legius syndrome, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, central conducting lymphatic anomaly, and capillary malformation-arteriovenous malformation syndrome. These disorders are grouped together as RASopathies based on our current understanding of the Ras/MAPK pathway. Abnormal activation of the Ras/MAPK pathway plays a major role in development of RASopathies. The individual disorders of RASopathies are rare, but collectively they are the most common genetic condition (one in 1000 newborns). Activation or dysregulation of the common Ras/MAPK pathway gives rise to overlapping clinical features of RASopathies, involving the cardiovascular, lymphatic, musculoskeletal, cutaneous, and central nervous systems. At the same time, there is much phenotypic variability in this group of disorders. Benign and malignant tumors are associated with certain disorders. Recently, many institutions have established multidisciplinary RASopathy clinics to address unique therapeutic challenges for patients with RASopathies. Medications developed for Ras/MAPK pathway-related cancer treatment may also control the clinical symptoms due to an abnormal Ras/MAPK pathway in RASopathies. Therefore, radiologists need to be aware of the concept of RASopathies to participate in multidisciplinary care. As with the clinical manifestations, imaging features of RASopathies are overlapping and at the same time diverse. As an introduction to the concept of RASopathies, the authors present major representative RASopathies, with emphasis on their imaging similarities and differences. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

SAM domain variants of EPHB4 associated with aberrant signaling are linked to lymphatic-related fetal hydrops and facial dysmorphology.

Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.

Prevalence and Predictors of Hereditary Hemorrhagic Telangiectasia and Capillary-Malformation Arteriovenous Malformation Syndrome Among Children with Neurovascular Malformations

To investigate the prevalence and predictors of hereditary hemorrhagic telangiectasia (HHT) and capillary-malformation arteriovenous malformation (CM-AVM) syndrome among children with no prior personal or family history of these diseases who presented with an arteriovenous shunt lesion. A retrospective chart review was completed on patients aged 0 through 21 years with AV shunt lesions evaluated at our Cerebrovascular Center. Diagnosis of definite or suspected HHT or CM-AVM was based on clinical features and genetic testing. Associations between final diagnosis and type and number of lesions, epistaxis, telangiectasias, CM, and pulmonary AVMs were assessed. Eighty-nine patients were included. Thirteen (14.6%) had definite HHT, 11 (12.4%) suspected HHT, and 4 (4.5%) definite CM-AVM. Having ≥ 2 episodes of epistaxis/year and ≥ 2 sites with telangiectasias were each associated with definite HHT (p<0.001). Having ≥ 2 CM was associated with definite CM-AVM (p<0.001). Pulmonary AVM was associated with increased odds of having definite HHT (OR=6.3, 95% CI: 1.2-33.4). Multiple lesions (OR=24.5, 95% CI: 4.5-134.8) and AVFs (OR=6.2, 95% CI: 1.9-20.3) each increased the likelihood of having definite HHT or CM-AVM. Genetic testing was positive in 31% of patients tested. We recommend that children with neurovascular shunt lesions be offered genetic testing and undergo further evaluation for HHT and CM-AVM. Awareness and early diagnosis of these conditions is a critical step towards improving long-term outcomes and preventing disease-associated complications.

Large saccular intracranial aneurysm in a child with RASA1-associated capillary malformation-arteriovenous malformation syndrome: illustrative case.

Large cerebral aneurysms are much less common in children than in adults. Thus, when present, these lesions require careful surgical evaluation and comprehensive genetic testing. RASA1-associated capillary malformation-arteriovenous malformation (RASA1-CM-AVM) syndrome is a rare disorder of angiogenic remodeling known to cause port-wine stains and arteriovenous fistulas but not previously associated with pediatric aneurysms. The authors report the case of a previously healthy 6-year-old boy who presented with seizure-like activity. Imaging demonstrated a lesion in the right ambient cistern with compression of the temporal lobe. Imaging characteristics were suggestive of a thrombosed aneurysm versus an epidermoid cyst. The patient underwent craniotomy, revealing a large saccular aneurysm, and clip ligation and excision were performed. Postoperative genetic analysis revealed a RASA1-CM-AVM syndrome. This is a rare case of a RASA1-associated pediatric cerebral aneurysm in the neurosurgical literature. This unique case highlights the need for maintaining a broad differential diagnosis as well as the utility of genetic testing for detecting underlying genetic syndromes in young children presenting with cerebral aneurysms.

Genotype–Phenotype and Genotype–Outcome Analysis of Capillary Malformation–Arteriovenous Malformation

Objective(s): Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a rare autosomal-dominant complex vascular disorder that can be associated with fast-flow vascular malformations (FFVMs). The purpose of this study is to explore the genotype–phenotype and genotype–outcome associations based on a large parallel sequencing of CM-AVM patients to improve the understanding of the development and risk factors for FFVM. Methods: A total of 117 patients with CM-AVMs were enrolled in this multicenter cohort study. All patients underwent detailed clinical phenotyping, including age, sex, capillary malformation (CM) size, with or without FFVM, and outcome (Schobinger stage). Next-generation sequencing was performed with peripheral blood and tissue samples. Genotype–phenotype, genotype–outcome, and phenotype–outcome analyses were performed. Results: Germline or mosaic RASA1 variants were the most common cause of CM-AVM, found in 61.5%, with EPHB4 variants in 32.5%. A total of 76.9% of patients had a dominant CM lesion larger than 5 cm. No obvious correlations between genotypes and phenotypes, including sex, age, location, and size of CMs, were found in this cohort. Comparing the patients with FFVMs with those without FFVMs, we found significant differences in age and the size of dominant CM lesions but not in genotype, sex, or location. Conclusion: CM-AVMs can be categorized as complex vascular malformations caused by different gene alterations in the RAS/RAF/MEK pathway. No obvious correlations between genotypes and phenotypes were identified. Critically, the occurrence and progression of FFVM is strongly determined by phenotypes, including age and the size of the dominant CM, rather than genotypes.

345 Structural Cardiac Defects and Vascular Anomalies in Vein of Galen Malformation Patients: A Multi-Institutional Cohort With Genetic Sequencing

INTRODUCTION: Vein of Galen malformations (VOGM) are rare, potentially lethal brain arteriovenous malformations (AVM). The roles of EPHB4, RASA1, and ACVRL1 have been described in VOGM pathogenesis, and previous studies have reported the co-occurrence of VOGM with cardiac and vascular disorders. METHODS: We queried our cross-institutional cohort of 129 VOGM patients with detailed genotypic and phenotypic data. Genetic samples from a subset of 114 VOGM probands, including 90 trios, underwent whole exome sequencing. RESULTS: We found that 9.3% of our patients had structural cardiac defects, as compared to 0.8-1.2% in the general population. Our cohort’s cardiac defects included 3.9% with patent ductus arteriosus, compared to 0.1% in the general population, and 1.6% with atrial septal defect, a congenital condition previously connected to VOGM. 22.5% of our patients had vascular abnormalities, including 16.3% with cutaneous vascular lesions and 4.7% with recurrent epistaxis. One patient presented with VOGM and moyamoya disease. Our whole exome sequencing found that patients with damaging RASA1 mutations presented with significantly more cutaneous vascular lesions relative to the rest of the VOGM cohort (60% vs 16%, p = 0.007) and patients with damaging ACVRL1 mutations had significantly higher rates of recurrent epistaxis (50% vs 5%, p = 0.002). CONCLUSIONS: RASA1 is associated with capillary malformation-arteriovenous malformation syndrome (CM-AVM), and ACVRL1 is associated with hereditary hemorrhagic telangiectasia (HHT); CM-AVM and HHT are neurovascular disorders in which the VOGM phenotype is frequently encountered. Our findings demonstrate the high incidence of cardiac defects and vascular abnormalities in VOGM patients and the value of clinical sequencing of VOGM patients with these co-occurring clinical features.

Dermatoscopic features differentiating among port wine stain, arteriovenous malformation, and capillary malformation-arteriovenous malformation syndrome: to detect potential fast-flow vascular malformations at an early stage

To the Editor: Arteriovenous malformations (AVMs), capillary malformation-arteriovenous malformations (CM-AVMs), and port wine stains (PWSs) are different vascular anomalies that can present with similar morphology but differ in genetics, pathogenesis, progression, treatment, and prognosis.1-3 Early AVMs and CM-AVMs may mimic PWS clinically, leading to misdiagnosis and inappropriate management. In this study, we sought to determine the dermatoscopic features of AVMs and CM-AVMs, compare them with those of PWSs (controls) in a blinded manner, and detect potential fast-flow vascular malformations (FFVMs) at an early stage.

The genetics of vascular birthmarks

One in 10 infants are born with a vascular birthmark each year. Some vascular birthmarks, such as infantile hemangiomas, are common, while vascular malformations, such as capillary, lymphatic, venous, and arteriovenous malformations, are less so. Diagnosing uncommon vascular birthmarks can be challenging, given the phenotypic heterogeneity and overlap among these lesions. Both sporadic and germline variants have been detected in various genes associated with vascular birthmarks. Identification of these genetic variants offers insight into both diagnosis and underlying molecular pathways and can be fundamental in the discovery of novel therapeutic approaches. The PIK3/AKT/mTOR and RAS/MEK/ERK signaling pathways, which mediate cell growth and angiogenesis, are activated secondary to genetic variations in vascular malformations. Somatic variants in TEK (TIE2) and PIK3CA cause venous malformations. Variants in PIK3CA also cause lymphatic malformations as well as a number of overgrowth syndromes associated with vascular anomalies. Variants in GNAQ and GNA11 have been identified in both so-called “congenital” hemangiomas and capillary malformations. RASA1 and EPHB4 variants are associated with capillary malformation-arteriovenous malformation syndrome. This review discusses the genetics of vascular birthmarks, including the various phenotypes, genetic variants, pathogenesis, associated syndromes, and new diagnostic techniques.

Capillary Malformation - Arteriovenous Malformation Type 2: Case Report and Review.

Capillary malformation - Arteriovenous malformation syndrome (CM-AVM) is a rare genodermatosis with cutaneous capillary malformations (CMs) and a risk of associated fast-flow malformations. A four-generation family with a novel heterozygous pathogenic variant in the EPHB4-gene (NM_004444.5 (EPHB4): c.2224G>C, p.(Ala742Pro)) is presented. Based on a review of literature we retrieved 127 CM-AVM2 patients with confirmed variants in EPHB4. Multiple CMs were present in 114 (89,76 %) patients and 12 (9,44 %) patients had a solitary CM. arteriovenous malformations/fistulas were present in 23 (18,1 %) patients and located within CNS in five (3,9 %) patients. Not all included papers included description of epistaxis. Telangiectasias were reported in 28 (22 %) patients and Bier spots described in 20 (15,7 %) patients. The clinical characteristics of CM-AVM2 are diverse and often discrete which makes it difficult to distinguish CM-AVM2 from HHT.

The RASopathies: Biology, genetics and therapeutic options.

The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and capillary malformation-arteriovenous malformation syndrome. Many of these genetic disorders share clinical features in common such as abnormal facies, short stature, varying degrees of cognitive impairment, cardiovascular abnormalities, skeletal abnormalities and a predisposition to develop benign and malignant neoplasms. Others are more dissimilar, even though their mutations are in the same gene that is mutated in a different RASopathy. Here, we describe the clinical features of each RASopathy and contrast them with the other RASopathies. We discuss the genetics of these disorders, including the causative mutations for each RASopathy, the impact that these mutations have on the function of an individual protein and how this dysregulates the Ras/MAPK signaling pathway. As several of these individual disorders are genetically heterogeneous, we also consider the different genes that can be mutated to produce disease with the same phenotype. We also discuss how our growing understanding of dysregulated Ras/MAPK signaling had led to the development of new therapeutic agents and what work will be critically important in the future to improve the lives of patients with RASopathies.

Capillary Malformation-Arteriovenous Malformation Syndrome Due to EPHB4 Gene Mutation: Clinical, Dermoscopic, Ecographic and Histopathological Features.

Capillary Malformation-Arteriovenous Malformation Syndrome Due to EPHB4 Gene Mutation: Clinical, Dermoscopic, Ecographic and Histopathological Features.

Abstract No. 598 Clinical manifestations of patients with novel mutations associated with hereditary hemorrhagic telangiectasia and related vascular anomalies

In this series, 4 patients with HHT were identified with novel GDF2 mutations. They were compared to an individual with capillary malformation-arteriovenous malformation syndrome (CM-AVM) secondary to a RASA1 mutation to highlight the clinical similarity between the two diseases. With IRB exemption, the electronic medical record was searched with the search term HHT, genetic mutation, pulmonary arteriovenous malformation. The eligibility criteria included only those patients with a novel mutation in the GDF2 and RASA1 locus. The initial search resulted in 776 total patients with a suspected diagnosis of HHT. 162 patients had genetic testing done. We derived 5 patients with HHT-like clinical presentations found to have a novel (GDF2, n = 4) or related (RASA1, n = 1) mutation. 5 patients were included with a mean age of 17 years (range, < 1–37) with 60% female. 4 patients had a mutation or deletion in the GDF2 gene, and 1 patient had a RASA1 mutation and was diagnosed with CM-AVM. See Table. All GDF2 patients reported childhood nosebleeds, but only 1/ 4 patients continue to experience epistaxis by adulthood. 2/4 patients reported self-limited nosebleeds that resolved by adulthood. Mucocutaneous telangiectasia was observed only in 1/4 patients and in an atypical location. Unlike classic HHT, AVM and telangiectasia were not observed in the pulmonary or the hepatic vasculatures of GDF2 patients. 1 patient with a missense GDF2 mutation was found to have a hepatic focal nodular hyperplasia. The patient with CM-AVM also did not exhibit pulmonary or hepatic vascular involvement. GDF2 mutations predominately affected the cerebrovasculature. 2/4 GDF2 mutated patients suffered from brain vascular malformation. A third patient presented for evaluation after her daughter was diagnosed with a brain AVM. A frontal AVM and macrocephaly were diagnosed in the CM-AVM patient.3 patients with GDF2 mutations and one with RASA1 mutation were found to have some form of cardiac abnormalities. Clinical manifestations of HHT secondary to GDF2 mutations presented differently and exhibit overlapping features as CM-AVM due to RASA1 mutation.Tabled 1SexAge (years)DiagnosisGeneNucleotide ChangeProtein ChangeMutation TypeSignificanceF3CM-AVMRASA1c.2131C >Tp.Arg711TerNonsensePathogenicF37HHTGDF2c.1063G >Cp.Glu355GlnMissenseUnknownM32HHTGDF2c.1207G >Ap.Val403IleMissenseUnknownF13HHTGDF25.10-Mb deletion of 10q11.22 to 10q11.2336 genes deletedDeletionLikely pathogenicM0HHTGDF25.5-Mb deletion of 10q11.22 to 10q11.23UndeterminedDeletionLikely pathogenic Open table in a new tab

RhoA activation-mediated vascular permeability in capillary malformation-arteriovenous malformation syndrome: a hypothesis

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a class of capillary anomalies that are associated with arteriovenous malformations and arteriovenous fistulas, which carry a risk of hemorrhages. There are no broadly effective pharmacological therapies currently available. Most CM-AVMs are associated with a loss of RASA1, resulting in constitutive activation of RAS signaling. However, protein interaction analysis revealed that RASA1 forms a complex with Rho GTPase-activating protein (RhoGAP), a negative regulator of RhoA signaling. Herein, we propose that loss of RASA1 function results in constitutive activation of RhoA signaling in endothelial cells, resulting in enhanced vascular permeability. Therefore, strategies aimed at curtailing RhoA activity should be tested as an adjunctive therapeutic approach in cell culture studies and animal models of RASA1 deficiency.

Capillary malformation-arteriovenous malformation syndrome: a multicentre study.

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a rare syndrome with characteristic skin lesions that are associated with fast-flow vascular malformations (FFVMs) in one-third of patients. Few case series have been described, and none in Spain. To identify the prevalence of dermatological parameters, FFVMs and associated features in a large series of patients with CM-AVM. We conducted an observational study of patients with CM-AVM syndrome diagnosed in 15 Spanish hospitals over 3years. The main clinical, radiological, genetic findings and associated diseases were analysed. In total, 64 patients were assessed. In 26.5% of cases, the diagnosis was incidental. In 75% of patients, there was one significantly larger macule, which we termed the 'herald patch'. FFVMs were detected in 34% of the patients, with 30% located on the skin, 7.8% in the brain and in 1.5% in the spine. There was a positive family history in 65% of the 64 patients. Genetic analysis was performed for RASA1 mutations in 57 patients, of whom 42 (73%) had a positive result. All 4 patients tested for EPHB4 mutations had a positive result. No tumour lesions were detected in the series, except for five infantile haemangiomas. Our data on clinical lesions, associated FFVM, family history and genetics are similar to those previously published in the literature. An extensive data analysis failed to demonstrate any statistically significant association between the presence of an FFVM and any clinical, familial or genetic parameter that could predict its onset, although a link between the presence of a herald patch on the midline face and the presence of a brain FFVM was observed. We did not detect any genotype-phenotype correlation.

Recurrent gastrointestinal bleeding arising from a jejunal arteriovenous malformation in a child with capillary malformation-arteriovenous malformation syndrome

Abstract Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is classically a RASA1 mutation with small CMs and either central nervous system or musculoskeletal AVMs. However, CM-AVM2 has recently been discovered, and is characterized by an EPHB4 mutation to the EPHB4-RAS-ERK pathway. The skin findings favor those of hereditary hemorrhagic telangiectasia with Bier spots and telangiectasias, and the presence of central nervous system and musculoskeletal AVMs mirror classic CM-AVM. To our knowledge, this is the first report of a visceral AVM in CM-AVM2 in the literature. The patient presented with recurrent gastrointestinal bleeds, and after an extensive workup culminating in diagnostic visceral angiography, was found to have a CM-AVM2 with a jejunal AVM.

Characterization of vascular stains associated with high flow

High-flow vascular stains (HFVS) arelesions that have the appearance of capillary malformations/port wine stains but are associated with increased arterial flow. To identify features of HFVS that differentiate them from typical "slow-flow" port wine stains. Retrospective multicenter cohort study of HFVS evaluated across 7 centers was conducted. HFVS were characterized by clinical features (warmth, thrill, rapid capillary refill), radiologic findings (fast flow), or mutations associated with capillary malformation-arteriovenous malformation syndrome. Investigators reviewed photographs. The study reviewed 70 patients with HFVS (47 multifocal and 23 solitary). Most were flat (77%), warm to the touch (60%), and red or pink-red in color (35%), with heterogeneous color saturation (73%) and well-defined borders (71%). Regional soft tissue swelling/overgrowth was common (47%). Head and neck location was most common (38%). Among 34 HFVS with photographic review over time, all demonstrated changes in appearance. Retrospective design, recall bias, lack of standardized time points or visual analog scale, and image variability. Heterogeneity of stain color saturation, warmth to touch, peripheral pallor, and overgrowth/soft tissue swelling help distinguish HFVS from port wine stains. Darkening of color and increased border demarcation may develop over time. These findings raise suspicion for HFVS and provide an indication to assess for extracutaneous involvement.

Histopathological hallmarks of cutaneous lesions of capillary malformation-arteriovenous malformation syndrome.

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a recently described syndrome with distinctive cutaneous lesions. Very little is known about the histopathology of these lesions. The purpose of the study was to evaluate the histopathological characteristics of the pink macules of the CM-AVM syndrome and to investigate if these pink macules could be classified as capillary malformations or arteriovenous malformations based on their histopathological features. We conducted a retrospective multicenter study involving eight hospitals in Spain. Fifteen biopsies from pink macules of the CM-AVM syndrome were analysed and compared with five biopsies of diverse capillary malformations and three stage I arteriovenous malformations. Pink macules' biopsies of the CM-AVM syndrome showed similar features including a high vascular density encompassing capillaries and numerous thick-walled arterioles mainly located in the superficial dermis, a predominance of elongated over round vessels, scarce or absent erythrocytes within the lumina and discrete perivascular inflammation. CMs were characterized by an increased number of capillary-type vessels mostly rounded and located in the upper dermis. AVMs were composed by highly increased numbers of vessels with a branching pattern involving the full thickness of the dermis, without erythrocytes within the lumina. Wilms tumour 1 protein was positive in the endothelial cells both in pink macules of the CM-AVM and in arteriovenous malformations. Pink macules of the CM-AVM syndrome seem to be different from capillary malformations. Our results suggest that histologically and immunohistochemically they are closer to incipient arteriovenous malformations than to capillary malformations. A deepened knowledge about the nature of these skin lesions will contribute to the better understanding of capillary malformation-arteriovenous malformation syndrome, and will open the possibility of new and more specific treatments in the future.

Role of colour-Doppler high-frequency ultrasonography in capillary malformation-arteriovenous malformation syndrome: a case series.

High-frequency ultrasonography (HFUS) represents a useful adjunct for dermatologists in the diagnosis of capillary malformation-arteriovenous malformation (CM-AVM) syndrome. We present a paediatric case series of 6 patients with confirmed RASA1 gene mutation in whom HFUS demonstrated AVM beneath cutaneous CM-like lesions greater than 1.5cm.

Identification of a novel frameshift mutation in the Rasa1 gene associated with capillary malformation-arteriovenous malformation syndrome: Case report

Identification of a novel frameshift mutation in the Rasa1 gene associated with capillary malformation-arteriovenous malformation syndrome: Case report

Exome Sequencing Defines the Molecular Pathogenesis of Vein of Galen Malformation

Abstract INTRODUCTION Vein of Galen malformations (VOGMs) are morbid arteriovenous malformations, with poorly described genetis. 1 Despite improvement in endovascular treatment, VOGM mortality remains high. 2 VOGM has been reported as a rare finding in Capillary Malformation-Arteriovenous Malformation Syndrome (RASA1; OMIM #605384) and Hereditary Hemorrhagic Telangiectasia (ENG, ACVRL1; OMIM #187300, #600376). 3-4 Our previous work has identified EPH receptor tyrosine kinase as also playing a role in VOGM pathogenesis. 5 Here, we report a larger cohort of probands and identify a new gene in the same pathway as EPHB4 as playing a role in VOGM. METHODS Germline DNA was isolated from 84 unrelated probands harboring radiographically confirmed VOGMs Both parents were available for 69/84 probands. Exome capture and paired-end WES was performed on DNA samples from participating individuals (n = 237). Data was bioinformatically analyzed to identify rare de-novo and transmitted mutations. Binomial analysis tested for exome-wide significance of mutational burden. RESULTS Only 3/75 patients harbored mutations in previously reported VOGM-associated genes (2.3%; RASA1 n = 2, 1.1%; ACVRL1 n = 1). Significant enrichment of rare damaging mutations was found for a member of the EPH receptor tyrosine kinase family (EPHB4, n = 5; 6.0%; P = 3.31 × 10–7, 36.62-fold enrichment). Entirely novel mutations in the integrin family were also identified (n = 2; 1.1%, P = 6.03 × 10–5, 179.6-fold enrichment). Both of these mutations are located in the c-terminal domain and disrupt a binding motif. Furthermore, this integrin protein mutation is involved in the same pathway as EPHB4, although whether or not they directly interact remains unknown. CONCLUSION This work represents an expansion upon the largest phenotyped, exome-sequenced VOGM cohort in the world. Having discovered a new gene in the same pathway as EPHB4 strongly implicates said pathway in VOMG development. We are currently pioneering tissue sampling from endovascular instruments used during treatment to explore potential somatic mutations. Our findings continue to uncover genetic determinants of VOGM pathogenesis, providing novel insight into vascular developmental biology.