MRC1 and LYVE1 expressing macrophages in vascular beds of GNAQ p.R183Q driven capillary malformations in Sturge Weber syndrome.

Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures, strokes, and glaucoma, and only symptomatic treatment is available. CM are comprised of enlarged vessels with endothelial cells (ECs) and disorganized mural cells. Our recent finding indicated that the R183Q mutation in ECs leads to heightened signaling through phospholipase Cß3 and protein kinase C, leading to increased angiopoietin-2 (ANGPT2). Furthermore, knockdown of ANGPT2, a crucial mediator of pro-angiogenic signaling, inflammation, and vascular remodeling, in EC-R183Q rescued the enlarged vessel phenotype in vivo. This prompted us to look closer at the microenvironment in CM-affected vascular beds. We analyzed multiple brain histological sections from patients with GNAQ-R183Q CM and found enlarged vessels devoid of mural cells along with increased macrophage-like cells co-expressing MRC1 (CD206, a mannose receptor), CD163 (a scavenger receptor and marker of the monocyte/macrophage lineage), CD68 (a pan macrophage marker), and LYVE1 (a lymphatic marker expressed by some macrophages). These macrophages were not found in non-SWS control brain sections. To investigate the mechanism of increased macrophages in the perivascular environment, we examined THP1 (monocytic/macrophage cell line) cell adhesion to EC-R183Q versus EC-WT under static and laminar flow conditions. First, we observed increased THP1 cell adhesion to EC-R183Q compared to EC-WT under static conditions. Next, using live cell imaging, we found THP1 cell adhesion to EC-R183Q was dramatically increased under laminar flow conditions and could be inhibited by anti-ICAM1. ICAM1, an endothelial cell adhesion molecule required for leukocyte adhesion, was strongly expressed in the endothelium in SWS brain histological sections, suggesting a mechanism for recruitment of macrophages. In conclusion, our findings demonstrate that macrophages are an important component of the perivascular environment in CM suggesting they may contribute to the CM formation and SWS disease progression.

Developmental expression of the Sturge-Weber syndrome-associated genetic mutation in Gnaq: a formal test of Happle's paradominant inheritance hypothesis.

Sturge-Weber Syndrome (SWS) is a sporadic (non-inherited) syndrome characterized by capillary vascular malformations in the facial skin, leptomeninges, or the choroid. A hallmark feature is the mosaic nature of the phenotype. SWS is caused by a somatic mosaic mutation in the GNAQ gene (p.R183Q), leading to activation of the G protein, Gαq. Decades ago, Rudolf Happle hypothesized SWS as an example of "paradominant inheritance", that is, a "lethal gene (mutation) surviving by mosaicism". He predicted that the "presence of the mutation in the zygote will lead to death of the embryo at an early stage of development". We have created a mouse model for SWS using gene targeting to conditionally express the GNAQ p.R183Q mutation. We have employed two different Cre-drivers to examine the phenotypic effects of expression of this mutation at different levels and stages of development. As predicted by Happle, global, ubiquitous expression of this mutation in the blastocyst stage results in 100% embryonic death. The majority of these developing embryos show vascular defects consistent with the human vascular phenotype. By contrast, global but mosaic expression of the mutation enables a fraction of the embryos to survive, but those that survive to birth and beyond do not exhibit obvious vascular defects. These data validate Happle's paradominant inheritance hypothesis for SWS and suggest the requirement of a tight temporal and developmental window of mutation expression for the generation of the vascular phenotype. Furthermore, these engineered murine alleles provide the template for the development of a mouse model of SWS that acquires the somatic mutation during embryonic development, but permits the embryo to progress to live birth and beyond, so that postnatal phenotypes can also be investigated. These mice could then also be employed in pre-clinical studies of novel therapies.

Update on the diagnosis and treatment of choroidal hemangioma.

Choroidal hemangioma (CH) is a benign vascular tumor dependent on the choroid. Two types of lesions are distinguished: circumscribed (CCH), the most frequent variant, and diffuse (DCH), normally associated with Sturge-Weber syndrome. HCC appears as an orange mass that can present asymptomatically, however, when it produces symptoms, the most frequent is decreased visual acuity due to neurosensory retinal detachment. Due to its benign nature, only those that produce symptoms should be eligible for treatment. Knowledge of this pathology and its correct differential diagnosis is very relevant to establish the appropriate diagnosis and treatment, avoiding unnecessary treatments. There is currently a wide variety of multimodal diagnostic imaging tests that allow us to identify and adequately monitor this tumor. In addition, in recent years, there has been a change in the paradigm of the treatment of these tumors thanks to the use of photodinamic therapy, which has led to a significant improvement in the visual prognosis of these patients. This has been due to the use of photodynamic therapy as the treatment of choice for HCC.

Updates on Sturge-Weber Syndrome.

Sturge-Weber syndrome (SWS) is a rare, noninherited neurovascular disorder characterized by abnormal vasculature in the brain, skin, and eye. Patients with SWS characteristically have facial capillary malformation, also known as port-wine birthmark, a leptomeningeal vascular malformation seen on contrast-enhanced magnetic resonance imaging images, abnormal blood vessels in the eye, and glaucoma. Patients with SWS have impaired perfusion to the brain and are at high risk of venous stroke and stroke-like episodes, seizures, and both motor and cognitive difficulties. While the activating R183Q GNAQ somatic mutation is the most common somatic mutation underlying SWS, recent research also implicates that GNA11 and GNB2 somatic mutations are related to SWS. Recent retrospective studies suggest the use of low-dose aspirin and vitamin D in treatment for SWS and prospective drug trials have supported the usefulness of cannabidiol and Sirolimus. Presymptomatic treatment with low-dose aspirin and antiepileptic drugs shows promising results in delaying seizure onset in some patients. This review focuses on the latest progress in the field of research for Sturge-Weber syndrome and highlights directions for future research.

Port-wine Birthmarks: Update on Diagnosis, Risk Assessment for Sturge-Weber Syndrome, and Management.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder that classically presents with a triad of vascular anomalies affecting the skin, eyes, and brain. Previously, the trigeminal nerve distribution of a port-wine birthmark (PWB) of the face was used to identify risk of SWS. However, recent evidence has demonstrated that PWBs are vascular, not neurologic, in embryologic origin, and facial PWBs at highest risk for the brain involvement of SWS involve the forehead location. Furthermore, a PWB involving the upper or lower eyelid carries a risk of glaucoma, which requires lifelong monitoring. The gold standard of treatment for PWB is the pulsed dye laser, which has many advantages when started as early as possible in infancy. In this review, we discuss the locations of facial PWBs at risk for neurologic and ophthalmologic complications, the differential diagnosis of facial vascular birthmarks, recommendations for patient referral(s) when needed, and the advantages of early laser therapy when desired for the PWB. We also provide additional resources for pediatricians to support patients and their families.

Computed tomography angiography-assisted embolization of arteriovenous malformation prior to dental extractions in a patient with Sturge-Weber syndrome.

Sturge-Weber syndrome is a developmental condition characterized by hamartomatous vascular proliferation involving the tissues of the brain and face. Hemangiomatous proliferations and arterial venous malformations are common intraoral alterations that may be fatal due to incontrollable bleeding when performing surgical procedures in the face. The goal of this case report is to present the management of a 21-year-old woman with Sturge-Weber syndrome in whom it was necessary to perform embolization guided by computed tomography angiography before multiple tooth extractions.

Study protocol: retrospectively mining multisite clinical data to presymptomatically predict seizure onset for individual patients with Sturge-Weber.

INTRODUCTION: Secondary analysis of hospital-hosted clinical data can save time and cost compared with prospective clinical trials for neuroimaging biomarker development. We present such a study for Sturge-Weber syndrome (SWS), a rare neurovascular disorder that affects 1 in 20 000-50 000 newborns. Children with SWS are at risk for developing neurocognitive deficit by school age. A critical period for early intervention is before 2 years of age, but early diagnostic and prognostic biomarkers are lacking. We aim to retrospectively mine clinical data for SWS at two national centres to develop presymptomatic biomarkers. METHODS AND ANALYSIS: We will retrospectively collect clinical, MRI and neurocognitive outcome data for patients with SWS who underwent brain MRI before 2 years of age at two national SWS care centres. Expert review of clinical records and MRI quality control will be used to refine the cohort. The merged multisite data will be used to develop algorithms for abnormality detection, lesion-symptom mapping to identify neural substrate and machine learning to predict individual outcomes (presence or absence of seizures) by 2 years of age. Presymptomatic treatment in 0-2 years and before seizure onset may delay or prevent the onset of seizures by 2 years of age, and thereby improve neurocognitive outcomes. The proposed work, if successful, will be one of the largest and most comprehensive multisite databases for the presymptomatic phase of this rare disease. ETHICS AND DISSEMINATION: This study involves human participants and was approved by Boston Children's Hospital Institutional Review Board: IRB-P00014482 and IRB-P00025916 Johns Hopkins School of Medicine Institutional Review Board: NA_00043846. Participants gave informed consent to participate in the study before taking part. The Institutional Review Boards at Kennedy Krieger Institute and Boston Children's Hospital approval have been obtained at each site to retrospectively study this data. Results will be disseminated by presentations, publication and sharing of algorithms generated.

Managing pregnancy in women with Sturge-Weber syndrome: case report and review of the literature.

Sturge-Weber syndrome (SWS) is a sporadic congenital neuro-cutaneous anomaly with capillary-venous malformation involving the brain, eye, and the ophthalmic division of the trigeminal nerve. In these cases, physiological changes in pregnancy, including hormonal and hemodynamic changes, may predispose to increased seizure frequency and even a life-threatening intracranial haemorrhage. There are only few case reports available about the management of women with pregnancy and SWS. We report two patients with SWS diagnosed in childhood and managed during pregnancy and reviewed the outcomes and complications during pregnancy in women with this disorder.

Consensus Statement for the Management and Treatment of Sturge-Weber Syndrome: Neurology, Neuroimaging, and Ophthalmology Recommendations.

BACKGROUND: Sturge-Weber syndrome (SWS) is a sporadic, neurocutaneous syndrome involving the skin, brain, and eyes. Because of the variability of the clinical manifestations and the lack of prospective studies, consensus recommendations for management and treatment of SWS have not been published. OBJECTIVE: This article consolidates the current literature with expert opinion to make recommendations to guide the neuroimaging evaluation and the management of the neurological and ophthalmologic features of SWS. METHODS: Thirteen national peer-recognized experts in neurology, radiology, and ophthalmology with experience treating patients with SWS were assembled. Key topics and questions were formulated for each group and included (1) risk stratification, (2) indications for referral, and (3) optimum treatment strategies. An extensive PubMed search was performed of English language articles published in 2008 to 2018, as well as recent studies identified by the expert panel. The panel made clinical practice recommendations. CONCLUSIONS: Children with a high-risk facial port-wine birthmark (PWB) should be referred to a pediatric neurologist and a pediatric ophthalmologist for baseline evaluation and periodic follow-up. In newborns and infants with a high-risk PWB and no history of seizures or neurological symptoms, routine screening for brain involvement is not recommended, but brain imaging can be performed in select cases. Routine follow-up neuroimaging is not recommended in children with SWS and stable neurocognitive symptoms. The treatment of ophthalmologic complications, such as glaucoma, differs based on the age and clinical presentation of the patient. These recommendations will help facilitate coordinated care for patients with SWS and may improve patient outcomes.

Overgrowth syndromes and new therapies.

Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial for establishing the correct diagnosis and optimizing outcomes for these patients. Unique management considerations include increased risk for thrombosis and in some cases, cancer. In recent years, research has demonstrated that these disorders are primarily caused by somatic mutations in growth pathways, particularly the PI3K-mTOR pathway. This improved understanding had led to promising new therapies for this group of patients.

Headache in children with Sturge-Weber syndrome - Prevalence, associations and impact.

BACKGROUND: Sturge-Weber syndrome (SWS) is a congenital neurovascular disorder characterised by capillary-venous malformations involving the skin, brain and eye. Patients experience headache, however little is known about its characteristics or associations. We aimed to estimate prevalence, associations and the impact of headache in children with SWS. MATERIALS AND METHODS: Case notes of all patients in a national tertiary paediatric SWS clinic were retrospectively reviewed. Patients were categorised into those with or without a history of headache, with an analysis performed of clinical stigmata of their disease and headache symptomology, associations and treatment. A multivariable logistic regression analysis was undertaken to elicit independent predictors of headache. RESULTS: 37% of patients with SWS (n = 84) reported headaches that were variably associated with seizures, a preceding blow to the head and a minority had migraine features. In those reporting headaches, headaches interfered with daily activities of a quarter of the children and 39% experienced headaches frequently (more than 1/month). Headache was associated with glaucoma and aspirin administration while children with monoplegia and hemiplegia were less likely to have headache. CONCLUSIONS: Headache is common in children with SWS, often without classical migraine features and affects daily activities. Awareness of headache and its associations in SWS may improve management of this complex population.

Embolization Techniques for Arteriovenous Malformations in Parkes-Weber Syndrome.

BACKGROUND: Multiple high-flow arteriovenous malformations (AVMs) are the hallmark of Parkes-Weber syndrome (PWS). Surgical resection has historically shown poor outcomes with PWS. The aim of this study was to assess the management of PWS in the current era. METHODS: A retrospective review was performed from 2004 to 2017 on all patients presenting to a single institution for the management of PWS. Presentation, techniques, complications, and outcomes were reviewed. RESULTS: Fourteen patients (50% male) with PWS were seen at our institution, and mean age was 19.9 years (range, 4.7-68.8). The lower extremity was affected in 12 (86%) and the upper extremity in 2 (14%) patients. All patients presented with pain and swelling in the affected limb. Seven (50%) patients presented with ulcers, of which 3 (43%) had extensive wounds. Five (36%) patients had echocardiographic evidence of high-output cardiac failure. All patients underwent angiography with the intention to treat. Three (21%) patients were found to have diffuse arteriovenous communication with no discrete AVM nidus and thus did not undergo intervention. The remaining 11 (79%) patients underwent transcatheter embolization of the AVM's arterial inflow. Six (55%) patients required multiple or staged inflow embolization procedures, with a mean of 3.3 (range, 1-10) interventions. Thirty-two arterial embolization procedures were performed in total. n-Butyl-2-cyanoacrylate (nBCA) adhesive was used in 22 (69%), microspheres in 8 (25%), and a combination of coils and nBCA adhesive in 2 (6%) cases. Technical angiographic success was seen in all patients. Six (55%) patients also had interventions to treat the venous component of the malformation, either concomitantly or during a separate procedure. This included radiofrequency ablation in 1 (17%), coil embolization in 1 (17%), sodium tetradecyl sulfate (STS) sclerotherapy in 2 (33%), and a combination of STS, coil embolization, and vein stripping in 2 (33%) patients. Ten (91%) patients experienced a partial response and 1 (9%) patient experienced no response to treatment. No patients had a complete response, as expected with the diffuse nature of this disease. There were no periprocedural complications. Two of 3 patients with complex wounds required major amputations for gangrene, including one above-knee and one below-knee amputation at 128 months and 66 months after the index procedure, respectively. CONCLUSIONS: AVMs in PWS can be successfully treated by a transcatheter approach. Multiple interventions are usually required. Patients with extensive wounds remain at risk for loss of limb.

[Segmental overgrowth syndromes and therapeutic strategies]. / Les syndromes de surcroissance segmentaire et les stratégies thérapeutiques.

Overgrowth syndromes are a large group of rare disorders characterized by generalized or segmental excessive growth. Segmental overgrowth syndromes are mainly due to genetic anomalies appearing during the embryogenesis and leading to mosaicism. The numbers of patients with segmental overgrowth with an identified molecular defect has dramatically increased following the recent advances in molecular genetic using next-generation sequencing approaches. This review discusses various syndromes and pathways involved in segmental overgrowth syndromes and presents actual and future therapeutic strategies.

TITLE: Les syndromes de surcroissance segmentaire et les stratégies thérapeutiques. ABSTRACT: Les syndromes de surcroissance sont un groupe de pathologies caractérisées par une croissance excessive généralisée ou segmentaire. Les syndromes de surcroissance segmentaires sont principalement dus à des anomalies génétiques apparaissant durant l'embryogenèse et aboutissant à un mosaïcisme. Le nombre de patients atteints d'un syndrome de surcroissance avec une mutation identifiée a fortement augmenté grâce à des avancées récentes en génétique moléculaire, en utilisant le séquençage de nouvelle génération (NGS). Cette revue détaille les différents syndromes de surcroissance segmentaire ainsi que les voies moléculaires impliquées et les options thérapeutiques envisageables.

Síndrome Sturge-Weber. Revisión de la literatura a propósito de un caso / Sturge-Weber syndrome. Literature review about a case / Síndrome de Sturge-Weber. Revisão de literatura sobre um caso

RESUMEN Introducción: Entre las hamartoblastosis se reconoce el síndrome de Sturge-Weber (SSW), cuyo diagnóstico es inusual y complejo su tratamiento. Objetivo: Socializar la experiencia en la atención a un paciente pediátrico con síndrome de Sturge-Weber en el Hospital Pediátrico Docente "General Pedro Agustín Pérez" de Guantánamo. Método: Se presentó un paciente preescolar, sin antecedentes familiares de interés. Al mes de nacido fue operado de glaucoma congénito. Durante el primer año de vida presentó retardo del desarrollo psicomotor y movimientos involuntarios considerados convulsiones tónico-clónicas. Se revisó la literatura para transmitir a la comunidad médica, de modo particular, a estudiantes de medicina y médicos generales, información para lograr un diagnóstico y un seguimiento adecuado de esta afección. Resultados: Según las manifestaciones clínicas, examen físico mediante el método clínico y los resultados de los exámenes complementarios, se planteó el diagnóstico de síndrome neurocutáneo, de modo particular un SSW. Se aplicó tratamiento con diazepam y al persistir la crisis, fenitoína. La primera clasificación de los síndromes neurocutáneos la realizó Jan Van der Hoeve, que acuñó el término facomatosis. Es un trastorno neurológico congénito, no hereditario aunque hay descrito casos familiares, poco común pero frecuente respecto a otros síndromes neurocutáneos. Se estima una incidencia de 5 x 100,000 nacidos vivos. Afecta a todos los grupos étnicos y ambos sexos. Conclusiones: No siempre hay relación entre la gravedad de las manifestaciones cutáneas, neurológicas y oculares del SSW con las alteraciones cerebrales. Es importante el examen físico para establecer el diagnóstico oportuno y evitar futuras secuelas y complicaciones.

ABSTRACT Introduction: Sturge-Weber syndrome (SSW) is recognized among hamartoblastosis, whose diagnosis is unusual and complex treatment. Objective: To socialize the experience in the care of a pediatric patient with Sturge-Weber syndrome at the "General Pedro Agustín Pérez" Pediatric Teaching Hospital in Guantanamo. Method: A preschool patient was presented, with no family history of interest. One month after birth, he underwent congenital glaucoma surgery. During the first year of life he presented retardation of psychomotor development and involuntary movements considered tonic-clonic seizures. Literature was reviewed to transmit to the medical community, in particular, to medical students and general practitioners, information to achieve a diagnosis and adequate follow-up of this condition. Results: According to the clinical manifestations, physical examination by means of the clinical method and the results of the complementary examinations, the diagnosis of neurocutaneous syndrome was proposed, in particular a SSW. Treatment with diazepam was applied and when the crisis persisted, phenytoin. The first classification of neurocutaneous syndromes was carried out by Jan Van der Hoeve, who coined the term phacomatosis. It is a congenital neurological disorder, not inherited although there have been family cases described, uncommon but frequent compared to other neurocutaneous syndromes. An incidence of 5 x 100,000 live births is estimated. It affects all ethnic groups and both sexes. Conclusions: There is not always a relationship between the severity of cutaneous, neurological and ocular manifestations of SSW with brain disorders. The physical examination is important to establish the timely diagnosis and avoid future sequelae and complications.

RESUMO Introdução: A síndrome de Sturge-Weber (SSW) é reconhecida entre as hamartoblastose, cujo diagnóstico é tratamento incomum e complexo. Objetivo: Socializar a experiência no atendimento de um paciente pediátrico com síndrome de Sturge-Weber no Hospital Pediátrico "General Pedro Agustín Pérez" em Guantánamo. Método: Foi apresentado um paciente pré-escolar, sem histórico familiar de interesse. Um mês após o nascimento, ele foi submetido a uma cirurgia de glaucoma congênito. Durante o primeiro ano de vida, apresentou retardo no desenvolvimento psicomotor e movimentos involuntários considerados convulsões tônico-clônicas. A literatura foi revisada para transmitir à comunidade médica, em particular aos estudantes de medicina e clínicos gerais, informações para obter um diagnóstico e acompanhamento adequado dessa condição. Resultados: De acordo com as manifestações clínicas, o exame físico por meio do método clínico e os resultados dos exames complementares, foi proposto o diagnóstico de síndrome neurocutânea, em particular um SSW. O tratamento com diazepam foi aplicado e, quando a crise persistiu, fenitoína. A primeira classificação das síndromes neurocutâneas foi realizada por Jan Van der Hoeve, que cunhou o termo facomatose. É um distúrbio neurológico congênito, não herdado, embora haja casos familiares descritos, incomum, mas frequente em comparação com outras síndromes neurocutâneas. É estimada uma incidência de 5 x 100.000 nascidos vivos. Afeta todos os grupos étnicos e ambos os sexos. Conclusões: Nem sempre existe relação entre a gravidade das manifestações cutâneas, neurológicas e oculares da SSW com distúrbios cerebrais. O exame físico é importante para estabelecer o diagnóstico oportuno e evitar futuras sequelas e complicações.

Neurological Complications of Sturge-Weber Syndrome: Current Status and Unmet Needs.

OBJECTIVE: We aimed to identify the current status and major unmet needs in the management of neurological complications in Sturge-Weber syndrome. METHODS: An expert panel consisting of neurologists convened during the Sturge-Weber Foundation Clinical Care Network conference in September 2018. Literature regarding current treatment strategies for neurological complications was reviewed. RESULTS: Although strong evidence-based standards are lacking, the implementation of consensus-based standards of care and outcome measures to be shared across all Sturge-Weber Foundation Clinical Care Network Centers are needed. Each patient with Sturge-Weber syndrome should have an individualized seizure action plan. There is a need to determine the appropriate abortive and preventive treatment of migraine headaches in Sturge-Weber syndrome. Likewise, a better understanding and better diagnostic modalities and treatments are needed for stroke-like episodes. As behavioral problems are common, the appropriate screening tools for mental illnesses and the timing for screening should be established. Brain magnetic resonance imaging (MRI) preferably done after age one year is the primary imaging modality of choice to establish the diagnosis, although advances in MRI techniques can improve presymptomatic diagnosis to identify patients eligible for preventive drug trials. CONCLUSION: We identified the unmet needs in the management of neurological complications in Sturge-Weber syndrome. We define a minimum standard brain MRI protocol to be used by Sturge-Weber syndrome centers. Future multicenter clinical trials on specific treatments of Sturge-Weber syndrome-associated neurological complications are needed. An improved national clinical database is critically needed to understand its natural course, and for retrospective and prospective measures of treatment efficacy.

The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation.

Port wine stain (PWS) is a congenital vascular malformation involving human skin. Approximately 15-20% of children a facial PWS involving the ophthalmic (V1) trigeminal dermatome are at risk for Sturge Weber syndrome (SWS), a neurocutaneous disorder with vascular malformations in the cerebral cortex on the same side of the facial PWS lesions. Recently, evidence has surfaced that advanced our understanding of the pathogenesis of PWS/SWS, including discoveries of somatic genetic mutations (GNAQ, PI3K), MAPK and PI3K aberrant activations, and molecular phenotypes of PWS endothelial cells. In this review, we summarize current knowledge on the etiology and pathology of PWS/SWS based on evidence that the activation of MAPK and/or PI3K contributes to the malformations, as well as potential futuristic treatment approaches targeting these aberrantly dysregulated signaling pathways. Current data support that: (1) PWS is a multifactorial malformation involving the entire physiological structure of human skin; (2) PWS should be pathoanatomically re-defined as "a malformation resulting from differentiation-impaired endothelial cells with a progressive dilatation of immature venule-like vasculatures"; (3) dysregulation of vascular MAPK and/or PI3K signaling during human embryonic development plays a part in the pathogenesis and progression of PWS/SWS; and (4) sporadic low frequency somatic mutations, such as GNAQ, PI3K, work as team players but not as a lone wolf, contributing to the development of vascular phenotypes. We also address many crucial questions yet to be answered in the future research investigations.

A somatic missense mutation in GNAQ causes capillary malformation.

PURPOSE OF REVIEW: Capillary malformations, the most common type of vascular malformation, are caused by a somatic mosaic mutation in GNAQ, which encodes the Gαq subunit of heterotrimeric G-proteins. How the single amino acid change - predicted to activate Gαq - causes capillary malformations is not known but recent advances are helping to unravel the mechanisms. RECENT FINDINGS: The GNAQ R183Q mutation is present not only in endothelial cells isolated from skin and brain capillary malformations but also in brain tissue underlying the capillary malformation, raising questions about the origin of capillary malformation-causing cells. Insights from computational analyses shed light on the mechanisms of constitutive activation and new basic science shows Gαq plays roles in sensing shear stress and in regulating cerebral blood flow. SUMMARY: Several studies confirm the GNAQ R183Q mutation in 90% of nonsyndromic and Sturge-Weber syndrome (SWS) capillary malformations. The mutation is enriched in endothelial cells and blood vessels isolated from skin, brain, and choroidal capillary malformations, but whether the mutation resides in other cell types must be determined. Further, the mechanisms by which the R183Q mutation alters microvascular architecture and blood flow must be uncovered to develop new treatment strategies for SWS in particular, a devastating disease for which there is no cure.

[Sturge-Weber syndrome in children. Clinical features, diagnosis and approaches to therapy on the example of three clinical cases]. / Sindrom Shturge-Vebera u detei. Osobennosti kliniki, diagnostiki i podkhodov k terapii paroksizmal'nykh sostoianii na primere trekh klinicheskikh nabliudenii.

Sturge-Weber syndrome belongs to the group of phacomotoses and is characterized by a combined lesion of the skin, eyes, nervous system and internal organs. The clinical course of Sturge-Weber syndrome is quite diverse. Of particular interest in the practice of pediatric neurology and neurosurgery is the fact that 72-90% of patients present with epilepsy. Of particular difficulty is the differential diagnosis of epileptic seizures and stroke-like episodes. The article presents clinical cases of patients with Sturge-Weber syndrome of various ages with epileptic seizures and transient ischemic attacks.

Pathophysiology and management of glaucoma associated with phakomatoses.

The phakomatoses, encephalotrigeminal angiomatosis (ETA; Sturge-Weber Syndrome), neurofibromatosis type 1 (NF1 or von Recklinghausen disease), Von Hippel-Lindau (VHL) disease, tuberous sclerosis (TSC), oculodermal melanocytosis (ODM), and phakomatosis pigmentovascularis are a group of neurocutaneous disorders that have characteristic systemic and ocular manifestations. Through many different mechanisms, they may cause glaucomatous damage of the optic nerve and subsequent vision loss varying from mild to severe. Glaucoma commonly affects patients with ETA (43-72%), orbito-facial NF1 (23-50%), and ODM (10%). Rarely, it may present as neovascular glaucoma in VHL and TSC. In ETA, glaucoma typically occurs ipsilateral to the port-wine stain, which is caused by a mutation in the GNAQ gene. Specifically, mechanical malformation of the anterior chamber angle and elevated episcleral venous pressure has been implicated as causes of glaucoma in ETA. In NF1, which is caused by a mutation in the NF1 tumor suppressor gene, glaucoma commonly occurs ipsilateral to lid plexiform neurofibromas. Histological studies of eyes with NF1 have revealed direct anterior chamber infiltration by neurofibromas, secondary angle closure, fibrovascularization, and developmental angle abnormalities as mechanisms of glaucoma. Lastly, phakomatosis pigmentovascularis is a rare combination of ODM and port-wine stain. Affected patients are at very high risk of developing glaucoma. Despite the many different mechanisms of glaucomatous damage, management follows similar principles as that for congenital glaucoma and primary open angle glaucoma. First-line therapy is topical intraocular pressure-lowering eye drops. Surgical management, including goniotomy, trabeculotomy, trabeculectomy, and tube shunt placement may be required for more severe cases.

A Multidisciplinary Consensus for Clinical Care and Research Needs for Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber syndrome is a neurocutaneous disorder associated with port-wine birthmark, leptomeningeal capillary malformations, and glaucoma. It is associated with an unpredictable clinical course. Because of its rarity and complexity, many physicians are unaware of the disease and its complications. A major focus moving ahead will be to turn knowledge gaps and unmet needs into new research directions. METHODS: On October 1-3, 2017, the Sturge-Weber Foundation assembled clinicians from the Clinical Care Network with patients from the Patient Engagement Network of the Sturge-Weber Foundation to identify our current state of knowledge, knowledge gaps, and unmet needs. RESULTS: One clear unmet need is a need for consensus guidelines on care and surveillance. It was strongly recommended that patients be followed by multidisciplinary clinical teams with life-long follow-up for children and adults to monitor disease progression in the skin, eye, and brain. Standardized neuroimaging modalities at specified time points are needed together with a stronger clinicopathologic understanding. Uniform tissue banking and clinical data acquisition strategies are needed with cross-center, longitudinal studies that will set the stage for new clinical trials. A better understanding of the pathogenic roles of cerebral calcifications and stroke-like symptoms is a clear unmet need with potentially devastating consequences. CONCLUSIONS: Biomarkers capable of predicting disease progression will be needed to advance new therapeutic strategies. Importantly, how to deal with the emotional and psychological effects of Sturge-Weber syndrome and its impact on quality of life is a clear unmet need.