Capillary Malformation-arteriovenous Malformation 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.

Spectrum of lymphatic anomalies in patients with RASA1-related CM-AVM.

Capillary malformation-arteriovenous malformation (CM-AVM) is characterized by multifocal fast-flow capillary malformations, sometimes with arteriovenous malformations/fistulas, skeletal/soft tissue overgrowth, telangiectasias, or Bier spots. Lymphatic abnormalities are infrequently reported. We describe seven patients with CM-AVM and lymphatic anomalies. Following IRB approval, we identified patients with CM-AVM and lymphatic anomalies seen at the Vascular Anomalies Center at Boston Children's Hospital from 2003 to 2023. We retrospectively reviewed records for clinical, genetic, laboratory, and imaging findings. We found seven patients with CM-AVM and lymphatic abnormalities. Five patients were diagnosed prenatally: four with pleural effusions (including one suspected chylothorax) and one with ascites. Pleural effusions resolved after neonatal drainage in three patients and fetal thoracentesis in the fourth; however, fluid rapidly reaccumulated in this fetus causing hydrops. Ascites resolved after neonatal paracentesis, recurred at 2 months, and spontaneously resolved at 5 years; magnetic resonance lymphangiography for recurrence at age 19 years suggested a central conducting lymphatic anomaly (CCLA), and at age 20 years a right spermatic cord/scrotal lymphatic malformation (LM) was detected. Chylous pericardial effusion presented in a sixth patient at 2 months and disappeared after pericardiocentesis. A seventh patient was diagnosed with a left lower extremity LM at 16 months. Six patients underwent genetic testing, and all had RASA1 mutation. RASA1 variant was novel in three patients (c.1495delinsCTACC, c.434_451delinsA, c.2648del), previously reported in two (c.2603+1G>A, c.475_476del), and unavailable in another. Median follow-up age was 5.8 years (4 months-20 years). CM-AVM may be associated with lymphatic anomalies, including pericardial/pleural effusions, ascites, CCLA, and LM.

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.

BG09 RASA1 exon deletion in a neonate with vascular malformations

Abstract A full-term infant was noted to have a large, macular, pale-pink vascular birthmark across the left side of the chest, extending to the upper arm. Three smaller pale-pink irregular birthmarks on the elbow, thigh and flank were noted, as was an enlarged left upper arm. He had an oxygen dependency shortly after birth for which he required admission to the neonatal unit. A detailed history revealed that his father, paternal grandmother and aunt had similar birthmarks. His paternal aunt had an episode of bleeding from a spinal arteriovenous malformation (AVM) in her teens, which had been investigated with genetic testing by Sanger sequencing, but this did not identify a variant in RASA1. Following involvement from the dermatology, neonatology, genetics and radiology teams, investigations were organized. Findings included a high-flow vascular malformation with arteriovenous shunting on magnetic resonance imaging (MRI) of the left arm, normal MRI head and spine, and normal cardiac anatomy. Genetic testing by next-generation sequencing detected a heterozygous exon 21–23 deletion in RASA1. A diagnosis of capillary malformation–AVM syndrome (CM–AVM) was confirmed. Results of genetic testing of the father are awaited. Referral to a tertiary centre for consideration of management of AVM is underway. CM–AVM is a rare autosomal dominant condition. Pathogenic variants in RASA1 result in a lack of functional p120-RasGAP protein, which leads to abnormalities in angiogenesis, although this pathway is not well understood (Wooderchak-Donahue W, Johnson P, McDonald J et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet 2018; 26:1521–36). Cutaneous vascular malformations, classically pink–red with a pale halo, are the most consistent cutaneous manifestation, but they may be subtle and can mimic other vascular birthmarks such as segmental infantile haemangioma, salmon patches or port wine stain. In our patient, pale halos were not apparent until 4 months of age. Identification is important as life-threatening complications from cutaneous vascular arteriovenous fistulas can occur (Wooderchak-Donahue et al.). This case highlights the importance of clarifying a family history, classifying vascular birthmarks and working with the multidisciplinary team. Genetic testing should be considered, even with previous negative analysis, as test sensitivity has improved and will now include analysis of EPHB4, which has also been associated with CM–AVM.

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.

Prenatal Clinical Findings in RASA1-Related Capillary Malformation-Arteriovenous Malformation Syndrome.

Pathogenic variants in RASA1 are typically associated with a clinical condition called "capillary malformation-arteriovenous malformation" (CM-AVM) syndrome, an autosomal dominant genetic disease characterized by a broad phenotypic variability, even within families. In CM-AVM syndrome, multifocal capillary and arteriovenous malformations are mainly localized in the central nervous system, spine and skin. Although CM-AVM syndrome has been widely described in the literature, only 21 cases with prenatal onset of clinical features have been reported thus far. Here, we report four pediatric cases of molecularly confirmed CM-AVM syndrome which manifested during the prenatal period. Polyhydramnios, non-immune hydrops fetalis and chylothorax are only a few possible aspects of this condition, but a correct interpretation of these prenatal signs is essential due to the possible fatal consequences of unrecognized encephalic and thoracoabdominal deep vascular malformations in newborns and in family members carrying the same RASA1 variant.

Capillary Malformation-Arteriovenous Malformation Type 2, A Report of 6 Cases and Main Differential Diagnosis

Objectives: Capillary malformation-arteriovenous malformation (CM-AVM) is a rare disorder characterized by multifocal CMs associated with AVMs. While the phenotype of CMAVM1 has been well established in the literature, there are limited published reports documenting the clinical features of CMAVM2. Our aim is to highlight this phenotype, and the distinctive features of CMAVM2 compared with CMAVM1 and hereditary hemorrhagic telangiectasia, as prompt recognition is crucial to screen for fast-flow vascular malformations, which, if left untreated, can sometimes be life-threatening. Methods: This is a retrospective review of cases seen at multiple tertiary care centers in the United States and Argentina. Results and Conclusions: We report 6 pediatric patients with CMAVM2 presenting with diffuse multifocal cutaneous CMs, telangiectases favoring the lips, perioral area and upper trunk, and Bier spots. Three patients had epistaxis. One patient had an extracranial AVM and 1 patient had Parkes Weber syndrome. EPHB4 pathogenic variants were identified in all patients. CMAVM2 remains an underrecognized condition. Genetic testing and imaging studies are recommended to guide management.

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.

Angiogenesis depends upon EPHB4-mediated export of collagen IV from vascular endothelial cells.

Capillary malformation-arteriovenous malformation (CM-AVM) is a blood vascular anomaly caused by inherited loss-of-function mutations in RASA1 or EPHB4 genes, which encode p120 Ras GTPase-activating protein (p120 RasGAP/RASA1) and Ephrin receptor B4 (EPHB4). However, whether RASA1 and EPHB4 function in the same molecular signaling pathway to regulate the blood vasculature is uncertain. Here, we show that induced endothelial cell–specific (EC-specific) disruption of Ephb4 in mice resulted in accumulation of collagen IV in the EC ER, leading to EC apoptotic death and defective developmental, neonatal, and pathological angiogenesis, as reported previously in induced EC-specific RASA1-deficient mice. Moreover, defects in angiogenic responses in EPHB4-deficient mice could be rescued by drugs that inhibit signaling through the Ras pathway and drugs that promote collagen IV export from the ER. However, EPHB4-mutant mice that expressed a form of EPHB4 that is unable to physically engage RASA1 but retains protein tyrosine kinase activity showed normal angiogenic responses. These findings provide strong evidence that RASA1 and EPHB4 function in the same signaling pathway to protect against the development of CM-AVM independent of physical interaction and have important implications for possible means of treatment of this disease.

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 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.

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.

RASopathies: Dermatologists' viewpoints.

Ras/mitogen-activated protein kinase pathway dysregulation results in a group of disorders, collectively termed as RASopathies. Neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome/loose anagen hair, Legius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome and capillary malformation-arteriovenous malformation are the well-recognized RASopathies. These are characterized by multi-organ tumours and hamartomas. Some other features in common are facial dysmorphism, skeletal abnormalities, congenital heart disease, neurocognitive abnormalities and risk of various solid-organ and haematological malignancies. Some of the RASopathies are heterogeneous, caused by several gene mutations resulting in variations in phenotypes and severity ranging from mild to fatal. Significant phenotypic overlaps among different disorders, often makes it difficult to pinpoint a clinical diagnosis. Specific cutaneous manifestations are present in some of the RASopathies and are often the earliest clinical signs/symptoms. Hence, dermatologists contribute significantly as primary care physicians by identifying disorder-specific cutaneous lesions. However, diagnostic work-up and management of these disorders are often multidisciplinary. Confirmation of diagnosis is possible only by genetic mapping in each case. Genetic counseling of the patients and the affected families is an important component of the management. The aim of this review is description of cutaneous manifestations of RASopathies in the background of multi-system involvement to enable dermatologists a comprehensive and logical approach to work up and diagnose such patients in the absence of facility for specific molecular testing.

Central nervous system screening in capillary malformation-arteriovenous malformation syndrome: An observational study

To the Editor: Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant disorder characterized by small, multifocal capillary malformations (CMs), sometimes skin telangiectasias, and increased risk of fast-flow vascular malformations, mostly arteriovenous malformations (AVMs) located in the central nervous system (CNS) and soft tissues.1,2 Pathogenic variants of RASA1 (CM-AVM type 1 [CM-AVM1]) and EPHB4 [CM-AVM2] are identified in about 50% and 25% of patients, respectively.

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.