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BackgroundPort-Wine Birthmarks (PWB) are congenital capillary malformations requiring multiple treatments. Optical coherence tomography (OCT), a noninvasive imaging technique, characterizes vessels in cutaneous vascular lesions, including PWBs.ObjectiveTo assess variability in blood vessel characteristics within and between individual PWBs.MethodsOCT was used to measure blood vessel density (%) and modal vessel diameter (micrometers) at increments of 0.05 mm from the skin surface to a depth of 0.50 mm at several adjacent spots of single PWBs in this cross-sectional study. Average ratios of vessel density and diameter in affected to control skin were obtained for each PWB by averaging data for all spots within a lesion. Statistical analysis was performed with a linear mixed effects model using SPSS software (IBM Corporation).ResultsThere was great variability in vessel density and diameter within and between PWBs. Depths where average ratios of vessel density were consistently greater in affected to control skin were shallow, between 0.15 mm and 0.2 mm deep from the skin surface.LimitationsSmall sample size and device's inability to measure diameters smaller than 20 micrometers.ConclusionThere is variability in vessel density and diameter within and between PWBs. Individualized treatment planning guided by OCT mapping should be studied further.

Capillary malformations (CM) are congenital vascular irregularities of capillary and venous blood vessels that appear in the skin, leptomeninges of the brain, and the choroid of the eye in the disorder known as Sturge Weber Syndrome (SWS). More common are non-syndromic CM found only in the skin, without brain or ocular involvement. A somatic activating mutation in GNAQ (p.R183Q) is found in ~ 90% of syndromic and non-syndromic CM specimens and is present in CD31pos endothelial cells isolated from brain and skin CM specimens. Endothelial expression of the GNAQ p.R183Q variant is sufficient to form CM-like vessels in mice. Given the distinct features and functions of blood vessels in the brain versus the skin, we examined the features of CM vessels in both tissues to gain insights into the pathogenesis of CM. Herein, we present morphologic characteristics of CM observed in specimens from brain and skin. The GNAQ p.R183Q variant allelic frequency in each specimen was determined by droplet digital PCR. Sections were stained for endothelial cells, tight junctions, mural cells, and macrophages to assess the endothelium as well as perivascular constituents. CM blood vessels in brain and skin were enlarged, exhibited fibrin leakage and reduced zona occludin-1 and claudin-5, and were surrounded by MRC1pos/LYVE1pos macrophages. In contrast, the CMs from brain and skin differ in endothelial sprouting activity and localization of mural cells. These characteristics might be helpful in the development of targeted and/or tissue specific therapies to prevent or reverse non-syndromic and syndromic CM. [ABSTRACT FROM AUTHOR]

RASopathies encompass a diverse set of disorders affecting genes that encode proteins within the RAS‐MAPK pathway. RASA1 mutations are the cause of an autosomal dominant disorder called capillary malformation‐arteriovenous malformation type 1 (CM‐AVM1). Unlike other RASopathies, facial dysmorphism has not been described in these patients. We phenotypically delineated a large family of individuals with multifocal fast‐flow capillary malformations, severe lymphatic anomalies of perinatal onset, and dysmorphic features not previously described. Sequencing studies were performed on probands and related family members, confirming the segregation of dysmorphic features in affected members of a novel heterozygous variant in RASA1 (NM_002890.3:c.2366G>A, p.(Arg789Gln)). In this work, we broaden the phenotypic spectrum of CM‐AVM type 1 and propose a new RASA1 variant as likely pathogenic. [ABSTRACT FROM AUTHOR]

Vascular anomalies can be broadly classified as vascular tumors or vascular malformations, depending on the degree of endothelial involvement. These lesions can be subtle and challenging to diagnose in individuals with darker skin tones, which can lead to a delay in treatment. Improving diagnostic accuracy of these lesions may prevent progression and potential adverse outcomes when left untreated. Here, we present a review of common vascular anomalies with a focus on diagnostic considerations in individuals with skin of color. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) is a minimally invasive therapy that was gradually established as a first-line treatment for vascular abnormalities. Its action depends on the appropriate wavelength of light and photosensitizer to produce toxic oxygen species and cause cell death. Objective: Several new clinical improvements and trends in PDT have been described in recent years. The aim of this review is to provide an overview of the current data from clinical trials. Methods: In this review, we introduce and generalize the wavelength, duration, dose, strength, and photosensitizer of PDT for the treatment of vascular abnormalities, such as circumscribed choroidal hemangiomas (CCH), choroidal neovascularization (CNV) and capillary malformation (CM). Results: The systematic review findings indicate that the application of PDT is a safe effective method to treat CCH, CNV and CM. However, PDT also has early onset side effects and late onset side effects. Conclusions: Based on the discussion of the effectiveness of PDT, we conclude that PDT has great potential for clinical use, although PDT has possible side effects. [ABSTRACT FROM AUTHOR]

Approximately 10% of people with hereditary hemorrhagic telangiectasia (HHT) have brain vascular malformations (VMs). Few reports describe de novo brain VM formation. International HHT Guidelines recommend initial brain VM screening upon HHT diagnosis in children but do not address rescreening. We aimed to confirm whether brain VMs can form de novo in patients with HHT. The Brain Vascular Malformation Consortium HHT project is a 17-center longitudinal study enrolling patients since 2010. We analyzed the database for de novo VMs defined as those detected (1) on follow-up neuroimaging in a patient without previous brain VMs or (2) in a location distinct from previously identified brain VMs and reported those in whom a de novo VM could be confirmed on central neuroimaging review. Of 1909 patients enrolled, 409 (21%) had brain VMs. Seven patients were recorded as having de novo brain VMs, and imaging was available for central review in four. We confirmed that three (0.7% of individuals with brain VMs) had de novo brain VMs (two capillary malformations, one brain arteriovenous malformation) with intervals of six, nine, and 13 years from initial imaging. Two with de novo brain VMs were <18 years. The fourth patient, a child, did not have a de novo brain VM but had a radiologically confirmed increase in size of an existing brain arteriovenous malformation. Brain VMs can, albeit rarely, form de novo in patients with HHT. Given the potential risk of hemorrhage from brain VMs, regular rescreening in patients with HHT may be warranted. [ABSTRACT FROM AUTHOR]

Abstract 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 Cβ3 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.

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 Cβ3 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. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Cutaneous capillary malformations (CMs) describe a group of vascular birthmarks with heterogeneous presentations. CMs may present as an isolated finding or with other associations, including glaucoma and leptomeningeal angiomatosis (i.e., Sturge-Weber syndrome) or pigmentary birthmarks (i.e., phakomatosis pigmentovascularis). The use of targeted genetic sequencing has revealed that postzygotic somatic variations in GNAQ and GNA11 at codon 183 are associated with CMs. We report five patients with early-onset hypertension and discuss possible pathogenesis of hypertension. METHODS: Twenty-nine patients with CMs, confirmed GNAQ/11 postzygotic variants, and documented past medical history were identified from a multi-institutional vascular anomalies study. Early-onset hypertension was defined as hypertension before the age of 55 years. Clinical data were reviewed for evidence of hypertension, such as documentation of diagnosis or elevated blood pressure measurements. RESULTS: Five of the 29 patients identified as having GNAQ/11 postzygotic variants had documented early-onset hypertension. Three individuals harbored a GNAQ p.R183Q variant, and two individuals harbored a GNA11 p.R183C variant. All individuals had extensive cutaneous CMs involving the trunk and covering 9%-56% of their body surface area. The median age of hypertension diagnosis was 15 years (range 11-24 years), with three individuals having renal abnormalities on imaging. CONCLUSIONS: Early-onset hypertension is associated with extensive CMs harboring somatic variations in GNAQ/11. Here, we expand on the GNAQ/11 phenotype and hypothesize potential mechanisms driving hypertension. We recommend serial blood pressure measurements in patients with extensive CMs on the trunk and extremities to screen for early-onset hypertension.

Sánchez-Espino LF, Ivars M, Antoñanzas J, Baselga E. Appl Clin Genet. 2023;16:63–81. It has come to our attention that there is an error in the paper title on page 63, the title “Sturge-Weber Syndrome: A Review of Pathophysiology, Genetics, Clinical Features, and Current Management Approache” should read “Sturge-Weber Syndrome: A Review of Pathophysiology, Genetics, Clinical Features, and Current Management Approach”.

Port wine birthmarks (PWB) are capillary vascular malformations within the papillary and reticular dermis, most commonly occurring on the head and neck and may darken and thicken with age. Pulsed dye laser (PDL) is the gold standard of treatment for PWB as it selectively targets involved vessels. Sirolimus is a macrolide antibiotic that selectively inhibits mammalian target of rapamycin, thereby suppressing the angiogenesis pathways that can be activated by PDL. Sirolimus and PDL may be used together to treat PWB. We present a case series describing three cases of delayed ulceration and systemic sirolimus absorption following combination therapy, highlighting a potential complication and patient safety concern. [ABSTRACT FROM AUTHOR]

The coexistence of kaposiform hemangioendothelioma (KHE) and capillary malformation (CM) is quite rare, and few relevant studies can be found to confirm whether this phenomenon is accidental. We diagnosed and treated two such patients, revealing interesting phenomena associated with the development of vascular diseases.These cases offer the possibility that the coexistence of KHE and CM is not accidental and open up a new field of research related to pediatric vascular tumors and vascular malformations. Personalization and precision are required in the diagnosis and treatment of such patients, and the present findings provide a reliable theoretical and practical basis for further research on the pathogenesis and therapy of patients with multiple vascular diseases.

Port-wine birthmarks (PWBs) are caused by somatic, mosaic mutations in the G protein guanine nucleotide binding protein alpha subunit q (GNAQ) and are characterized by the formation of dilated, dysfunctional blood vessels in the dermis, eyes, and/or brain. Cutaneous PWBs can be treated by current dermatologic therapy, like laser intervention, to lighten the lesions and diminish nodules that occur in the lesion. Involvement of the eyes and/or brain can result in serious complications and this variation is termed Sturge-Weber syndrome (SWS). Some of the biggest hurdles preventing development of new therapeutics are unanswered questions regarding disease biology and lack of models for drug screening. In this review, we discuss the current understanding of GNAQ signaling, the standard of care for patients, overlap with other GNAQ-associated or phenotypically similar diseases, as well as deficiencies in current in vivo and in vitro vascular malformation models.

BackgroundPort wine birthmarks (PWBs) are congenital capillary malformations. Vessel characteristics, such as diameter and depth, may impact presentation and outcomes. They can be imaged using dynamic optical coherence tomography, a high-resolution, noninvasive imaging method.PurposeWe conducted a cross-sectional observational study to measure in vivo vascular characteristics as a function of PWB color.MethodsPatients undergoing treatment for PWB were recruited from 3 sites. PWBs were classified by color. Dynamic optical coherence tomography images with calculations were obtained.ResultsOne hundred eight patients were enrolled. Mean age correlated with PWB color, with birthmarks being lighter in younger patients and darker in older patients (P

A 6‐year‐old boy with multiple capillary malformations of the port‐wine birthmark (PWB) type on the right leg since birth presented with a varicose vein and segmental overgrowth of the affected leg. Genetic testing on affected skin confirmed the presence of a somatic novel pathogenic HRAS 30 bp in‐frame duplication/insertion in the switch II domain. This case illustrates the phenotypic overlap of different genotypes and shows that somatic HRAS pathogenic variants, especially in‐frame duplications/insertions, must be added to the list of the underlying causes in capillary malformations. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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). Conclusion: CM‐AVM may be associated with lymphatic anomalies, including pericardial/pleural effusions, ascites, CCLA, and LM. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cutis marmorata telangiectatica congenita (CMTC) is a capillary malformation characterized by congenital, reticulated, well‐demarcated dark blue, red‐purple, or violaceous macules or plaques, with a coarse fixed livedo pattern. Nearly always, contiguous areas of skin atrophy and/or ulceration are present. CMTC is usually localized but may rarely be generalized. Such generalized cases may be a feature of Adams‐Oliver syndrome (AOS). The nosologic confusion surrounding the term CMTC and uncertainty about the risk of associated abnormalities hinders the appropriate workup of patients and prognostic counseling for families. We hypothesized that the risk of associated anomalies in children with localized CMTC is very low. Methods: We performed a literature review and retrospective review of patients with CMTC to propose a more precise clinical definition and ascertain the risk of associated anomalies. Results: We included 78 patients determined to have a diagnosis of CMTC based on consensus. The majority of patients had localized CMTC. Most patients with generalized CMTC met the criteria for the diagnosis of AOS. The associations found in patients with localized CMTC were mostly dermatological, with atrophy, ulcerations, or erosions present in 71%. Extracutaneous findings were present in 34.4% of patients and consisted mainly of extremity asymmetry (24.5%) that improved over time. Conclusion: Our study showed a very low frequency of extracutaneous anomalies among patients with localized CTMC, ipsilateral limb discrepancy being the most common. We did not find a strong association with any other visceral anomalies that would justify routine evaluation in patients with localized CMTC. [ABSTRACT FROM AUTHOR]

Luis Fernando Sánchez-Espino,1 Marta Ivars,1 Javier Antoñanzas,2 Eulalia Baselga1 1Pediatric Dermatology Department, Barcelona Children’s Hospital Sant Joan de Dèu, Barcelona, Cataluña, Spain; 2Dermatology Department, Clínica Universidad de Navarra, Pamplona, Navarra, SpainCorrespondence: Eulalia Baselga, Department of Dermatology, Hospital Sant Joan de Deu, Passeig de Sant Joan de Déu, 2, Esplugues de Llobregat, Barcelona, 08950, Spain, Tel +34-686-68-9669, Email eulalia.baselga@sjd.esAbstract: Sturge-Weber syndrome (SWS) is a congenital, sporadic, and rare neurocutaneous disorder, characterized by the presence of a facial port-wine birthmark (PWB), glaucoma, and neurological manifestations including leptomeningeal angiomatosis and seizures. It is caused by a postzygotic, somatic, gain-of-function variant of the GNAQ gene, and more recently, the GNA11 gene in association with distinctive clinical features. Neuroimaging can help identify and stratify patients at risk for significant complications allowing closer follow-up; although no presymptomatic treatment has been demonstrated to be effective to date, these patients could benefit from early treatment and/or supportive interventions. Choroid plexus (CP) thickness measurements in brain magnetic resonance imaging (MRI) have a high sensitivity and specificity for early and incipient changes in SWS. In contrast, the absence of pathologic findings makes it possible to rule out associated neurological involvement and leads to periodical observation, with new imaging studies only in cases of new clinical signs/symptoms. Periodic ophthalmological examination is also recommended every 3 months during the first year and yearly afterwards to monitor for glaucoma and choroidal hemangiomas. Treatment for SWS depends on the extent and areas that are affected. These include laser surgery for PWB, anticonvulsants in the case of brain involvement, with either seizures or abnormal EEG, and medical treatment or surgery for glaucoma. Sirolimus has been used in a limited number of patients and appears to be a safe and potentially effective treatment for cutaneous and extra-cutaneous features, however controlled clinical studies have not been carried out. Better knowledge of GNAQ/GNA11 molecular pathways will help to develop future targeted treatments.Keywords: Sturge-Weber-syndrome, port-wine stain, capillary malformation, targeted therapies, GNAQ/GNA11, sirolimus

Port-wine stains (PWS) are frequently refractory to laser treatments. The aim of this study is to evaluate the role of treatment interval time. From 1990, 216 patients underwent Pulsed Dye Laser sessions. The laser sessions were scheduled at a minimum interval of 4 weeks to a maximum of 48 weeks. Clinical outcomes were assessed 8 weeks after the last laser session. Better results were obtained with 8 weeks interval time between therapy session, and high efficacies were also found for intervals of 4, 6 and 10 weeks. For greater interval instead, the effectiveness is significantly lower. [ABSTRACT FROM AUTHOR]

Capillary malformations are slow‐flow vascular malformations that affect the microcirculation including capillaries and post capillary venules and can be associated with growth differences. Specifically, the association of capillary malformations with undergrowth is a vastly understudied vascular syndrome with few reports of genetic causes including PIK3CA, GNAQ, and GNA11. Recently, a somatic pathogenic variant in AKT3 was identified in one child with a cutaneous vascular syndrome similar to cutis marmorata telangiectatica congenita, undergrowth, and no neurodevelopmental features. Here, we present a male patient with a capillary malformation and undergrowth due to a somatic pathogenic variant in AKT3 to confirm this association. It is essential to consider that mosaic pathogenic variants in AKT3 can cause a wide spectrum of disease. There is a need for future studies focusing on capillary malformations with undergrowth to understand the underlying mechanism. [ABSTRACT FROM AUTHOR]

Sturge–Weber Syndrome (SWS) is a rare vascular malformation disorder characterized by abnormal blood vessels in the brain, skin, and eye. SWS is most commonly caused by a somatic mosaic GNAQ‐p.Arg183Gln variant. In this series, 12 patients presented for clinical evaluation of SWS but were noted to have atypical features, and therefore germline and/or somatic genetic testing was performed. Atypical features included extensive capillary malformation on the body as well as the face, frontal bossing, macrocephaly, telangiectasia, overgrowth of extremities, absence of neurologic signs and symptoms, and family history of vascular malformations. Five patients had a somatic GNAQ or GNA11 pathogenic variant, one patient had a somatic mosaic likely‐pathogenic variant in PIK3CA, and another one had a somatic mosaic deletion that disrupted PTPRD. The other five patients had germline variants in RASA1, EPHB4, or KIT. Our findings suggest that patients presenting for SWS evaluation who have atypical clinical characteristics may have pathogenic germline or somatic variants in genes other than GNAQ or GNA11. Broad germline and somatic genetic testing in these patients with atypical findings may have implications for medical care, prognosis, and trial eligibility. [ABSTRACT FROM AUTHOR]

Capillary malformations (MCs), also referred to as port-wine stains (PWSs), or port-wine birthmarks (PWBs) represent one of the most common congenital vascular birthmarks. They consist of ectatic postcapillary venules within the papillary and superficial reticular dermis. The pathogenesis is due to a somatic activating mutation in guanine nucleotide–binding protein G(q) subunit alpha which mosaically occurs in endothelial cells (ECs) during embryogenesis. As a true congenital vascular malformation, PWSs are always present at birth, appearing as a flat pink to red macula mostly arising in the head and neck unilaterally. Although lightening during the first few months of life is possible, these lesions generally stay stable or thicken and darken over time. Consequent functional impairment, tissue thickening, development of blebs, and psychological burden may be relevant, so early laser therapy should often be considered to deter progression. What we present here is a unique cohort of 10 children presented to the Vascular Birthmarks Foundation (VBF) in Latham, NY, between 2016 and 2021, who were followed over time for cutaneous vascular anomalies present at birth. The clinical features were strongly suggestive of PWSs. However, all 10 of these children showed a significant spontaneous regression of the lesions during the observational period. In four cases, there was complete resolution. According to the international literature, capillary malformations persist throughout life and typically grow and darken if early laser treatment is not initiated. Such spontaneous improvement is extremely rare after the first 6 months of life. In the present case series, we photographically documented this previously unreported circumstance. Level of evidence: Level V, risk/prognostic study. [ABSTRACT FROM AUTHOR]

Resumen: El síndrome Capillary vascular malformation of the lower lip, Lymphatic malformations of the head and neck, Asymmetry and Partial/generalized Overgrowth (CLAPO) es una entidad recientemente descrita, con muy pocos casos publicados en la literatura, y sin tratamiento estandarizado. El objetivo de nuestro estudio fue evaluar la eficacia y seguridad del láser de colorante pulsado (PDL) en los pacientes con este síndrome. Tratamos a siete pacientes con dos a cuatro sesiones de PDL a longitud de onda de 595 nm. La terapia láser fue realizada utilizando un tamaño de spot de 7 a 10 mm, una duración del pulso de 0,5 a 1,5 ms, y una fluencia de 6 a 8 J/cm2. Se realizaron fotografías clínicas antes del tratamiento y tres semanas tras el procedimiento. La supresión del eritema fue > 75% en cuatro pacientes. La púrpura transitoria estuvo presente en todos los pacientes durante alrededor de dos semanas, presentando un paciente con hipopigmentación postinflamatoria. A modo de conclusión consideramos que el PDL parece ser un tratamiento seguro y efectivo para las malformaciones capilares propias del síndrome CLAPO. Se logró una notable reducción del eritema en todos los pacientes, con baja incidencia de efectos secundarios. Abstract: CLAPO syndrome (Capillary vascular malformation of the lower lip, Lymphatic malformations of the head and neck, Asymmetry and Partial/generalized Overgrowth) is a recently described entity, with very few published cases in the literature, and no standardized treatment. The objective of our study was to assess the efficacy and safety of PDL in patients with this syndrome. Seven patients were treated with two to four sessions of PDL at 595-nm wavelength. Laser therapy was performed using a spot size of 7 to 10 mm, a pulse duration of 0,5 to 1,5 ms and a fluence from 6 to 8 J/cm2. Clinical photographs were taken before treatment and 3 weeks after procedure. Clearance of the erythema was > 75% in 4 patients. Transient purpura was present in all patients for about 2 weeks and 1 patient presented post inflammatory hypopigmentation. In conclusion we consider that PDL seems to be a safe and effective treatment for capillary malformations of the CLAPO syndrome. A marked reduction in erythema was achieved in all patients with a low incidence of side effects.

CLAPO (Capillary Malformation of the Lower Lip, Lymphatic Malformation of the Face and Neck, Asymmetry and Partial/generalized Overgrowth) syndrome is a complex capillary, lymphatic, and venous malformation associated with partial or generalized overgrowth. Infantile hemangioma is the most frequent infantile vascular tumor. When the capillary malformation of CLAPO syndrome is its only manifestation, it can simulate an infantile hemangioma, especially the so-called abortive hemangioma, which does not grow in the first months: hence the need for a differential diagnosis between the two vascular lesions. [ABSTRACT FROM AUTHOR]

Port-wine birthmarks (PWBs) are caused by somatic, mosaic mutations in the G protein guanine nucleotide binding protein alpha subunit q (GNAQ) and are characterized by the formation of dilated, dysfunctional blood vessels in the dermis, eyes, and/or brain. Cutaneous PWBs can be treated by current dermatologic therapy, like laser intervention, to lighten the lesions and diminish nodules that occur in the lesion. Involvement of the eyes and/or brain can result in serious complications and this variation is termed Sturge-Weber syndrome (SWS). Some of the biggest hurdles preventing development of new therapeutics are unanswered questions regarding disease biology and lack of models for drug screening. In this review, we discuss the current understanding of GNAQ signaling, the standard of care for patients, overlap with other GNAQ-associated or phenotypically similar diseases, as well as deficiencies in current in vivo and in vitro vascular malformation models. [ABSTRACT FROM AUTHOR]

Vascular anomalies arising in the mandible comprise under 1% of all intraosseous tumors originating from the mandible, and their occurrence is extremely rare. Few pediatric cases of mandibular capillary vascular malformations have been reported. We report two pediatric intraosseous capillary mandibular malformations with a similar clinical course. A 15-year-old boy and 10-year-old girl each developed a painless, rapidly growing mandibular swelling. Imaging and tissue biopsy did not establish a definitive diagnosis. As the destruction of the mandible progressed, mandibular resection and reconstruction were performed, and capillary malformation was diagnosed on the grounds of tissue examination. There has been no postoperative recurrence, and good function and appearance have been maintained. Mandibular vascular malformations require prompt, appropriate diagnosis and treatment because bone destruction progresses as the lesions grow. Although the surgical treatment of pediatric vascular malformations involves various problems peculiar to the growth phase, it is important to consider resection, including reconstruction, so that the postoperative function and appearance are not impaired. Level of evidence: Level V, therapeutic study. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Not only germline but also postzygotic mutations in the RASA1 or EPHB4 genes can lead to capillary malformation-arteriovenous malformation (CM-AVM) syndrome. As it is not always possible to clinically distinguish between constitutional variants and postzygotic mosaicism, a sufficiently high sequencing depth must be used in genetic diagnostics to detect both., Abstract: Capillary malformation-arteriovenous malformation (CM-AVM) syndrome, with or without Parkes Weber syndrome, is a rare autosomal dominant disease caused by pathogenic RASA1 or EPHB4 variants. Up to 80% of CM-AVM cases have an affected parent. Gene panel sequencing was performed for a 4-year-old girl with multiple CMs, two capillary stains on the left leg, and associated overgrowth of the second toe. We also reviewed published cases with mosaic RASA1 and EPHB4 mutations. A mosaic RASA1 loss-of-function mutation was detected with a variant allele frequency (VAF) of 20% in the blood and oral epithelial cells of the index patient. The literature review illustrates that the severity of the clinical phenotype does not correlate with the VAF. We also identified a germline nonsense variant in the patient's TEK gene. However, inactivating TEK variants do not cause a vascular phenotype but can confer an increased risk for primary congenital glaucoma with variable expressivity. The case presented here illustrates that the choice of the sequencing depth of a diagnostic next-generation sequencing test for CM-AVM patients should always take mosaicism into account and that a good knowledge of the sequenced genes and associated disease mechanisms is necessary for adequate genetic counseling., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations of the skin. This disorder has been described as two distinct entities: CM-AVM1 and CM-AVM2. The diagnosis of these disorders has been associated with pathogenic variants in the RASA1 gene for RASA1-CM-AVM, formerly known as CM-AVM1, and, more recently, the EPHB4 genes for EPHB4-CM-AVM, formerly known as CM-AVM2. Affected patients with either type may also have arteriovenous malformations and fistulas, which can cause life-threatening bleeding, congestive heart failure, or neurologic consequences such as stroke. These syndromes are typically either sporadic or inherited in an autosomal dominant manner with variable expressivity. We report a case series of a father and three daughters who have clinically diagnosed EPHB4-CM-AVM syndrome who were found to have a variant of uncertain significance (VUS) in EPHB4 that has only been reported once prior., (© 2024 Wiley Periodicals LLC.)

Background: Port-wine stain (PWS) has been classified not as the hyperplasia of cells, but rather, as an expansion of malformed vessels. However, previous studies have reported upregulated expression of proangiogenic factors in PWS. Several studies have indicated that the pathology exhibits proliferation of numerous endothelial cells in hypertrophic/nodular PWS. This study aimed to determine the expression of vascular epithelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), angiopoietin-2 (ANG-2), and basic fibroblast growth factor (bFGF) in hypertrophic PWS. Methods: Immunohistochemistry was used to analyze skin samples from 33 patients with hypertrophic PWS. Expression levels of VEGF, MMP-9, ANG-2, and bFGF in hypertrophic PWS were determined by multiplying the intensity by the percentage of immunoreactive cells. Immunoreactivity scores were classified as follows: negative (0), low (1), moderate (2, 3, and 4), or high (6). Results: Based on pathological characteristics, hypertrophic PWS was divided into vascular malformation and pyogenic granuloma (PG) types. VEGF, MMP-9, ANG-2, and bFGF were significantly activated in the blood vessels of PG-type PWS samples compared with their counterparts in blood vessels of vascular malformation-type PWS samples and controls. PG-type hypertrophic PWS, which exhibited proliferation of endothelial cells, showed the strongest activation. Conclusion: The exuberant proliferation of endothelial cells in PG-type hypertrophic PWS may be associated with the regulation of proangiogenic factors during development. These proangiogenic factors that function in the angiogenesis and proliferation of endothelial cells may play an important role in the pathogenesis and progression of PWS. Furthermore, these factors may be dynamic and behave differently in various types of hypertrophic PWS.

Nevus flammeus is the most common benign congenital capillary malformation, often known as a port-wine stain. Sturge–Weber syndrome (SWS) is a congenital, sporadic, nonfamilial disease characterized by intracranial and ophthalmic vascular anomalies and nevus flammeus. It usually manifests as developmental delay, learning problems, paralysis, seizures, glaucoma and attention deficit, and hyperactivity disorder. A 29-year-old male patient presented with a reddish patch over the face since birth. He was found to have hemihypertrophy of face, hemiparesis of right limbs, and low intelligence quotient. On ophthalmic examination, the patient was found to have glaucoma and only perception of light in the left eye. Computed tomography brain showed atrophy of the left cerebral hemisphere and calcifications in the left frontal, parietal and occipital regions. With these findings, he was diagnosed as SWS type I. A multidisciplinary approach was followed for patient evaluation and management. This case also highlights the irreversible sequelae of this rare phacomatosis.

Meyerson phenomenon, also known as “halo-eczema,” has been widely described over melanocytic and non-melanocytic lesions. However, its appearance over vascular anomalies is rarely observed and could lead to diagnostic errors. A case study of five patients aged between four months and two years is reported. These patients developed unique erythematous and pruritic scaly patches, being diagnosed and treated as fungal infections. Due to the lack of response to the treatment, they were referred to the pediatric dermatology practice, where the diagnosis of Meyerson phenomenon over capillary malformations was made. Topical treatment with corticosteroids led to improvement in all cases. Although Meyerson phenomenon developing over vascular anomalies is a rare condition, it is important for pediatricians and dermatologists to assess it as a part of the differential diagnosis when treating a patient with skin lesions. Recognizing this phenomenon will prevent diagnostic and therapeutic errors.

Facial capillary malformations (CMs) become hypertrophic and nodular overtime and pose great therapeutic challenge. Here, we describe safe and effective use of tumescent‐assisted sclerotherapy (TAS) in conjunction with yellow vascular laser (577 nm) for the treatment of HFCMs. Three patients underwent TAS were included in the case series, and complete resolution in nodularity was achieved in all patients with TAS, with no major complications such as skin necrosis, distal embolisation, blindness and neurological adverse events such as stroke or TIA occurred in any patients. [ABSTRACT FROM AUTHOR]

Background: Vascular-targeted photodynamic therapy (PDT) is an effective alternative treatment choice for port-wine stains (PWSs). The histological characteristics of PWSs after PDT treatment have not yet been reported. Objective: To investigate the morphological features of PWSs treated by PDT and define the histopathological characteristics of PWS that achieve clinical cure. Methods: Thirteen patients with facial PWSs, who presented with complete regressive PWS lesions after a mean of 4.38 (standard deviation = 4.907) sessions of PDT. Post-treatment biopsy samples were obtained from each patient. The number of blood vessels, vascular diameter, and depth were measured and compared in all samples of PDT-regressive sites, PDT-resistant sites, and normal skin. Results: Within the 7-year follow-up after PDT, there was no recurrence in the regression area of PDT. In the PDT-regressive sites, within 800 lm of the dermal--epidermal junction, the dilated vessels were occluded and remained fissure-like after PDT. Conclusions: When the vascular lesions within 800 lm of the dermal--epidermal junction were closed after PDT, a stable clinical cure (no recurrence) was achieved. [ABSTRACT FROM AUTHOR]

Morphea and facial capillary malformations (port‐wine stains) are distinct conditions that can affect the pediatric population. Early localized morphea mimicking a capillary malformation is an uncommon clinical presentation. We present two new cases of girls, aged 2 and 3 years, who presented with erythematous patches, initially diagnosed as capillary malformations, which were later diagnosed as morphea. We also performed a literature review, yielding 12 additional cases that underscore that the unusual presentation of morphea may delay correct diagnosis. Although early management of morphea reduces long‐term sequelae, it is important to delay laser treatment for selected acquired vascular malformations, until the diagnosis of morphea is excluded. [ABSTRACT FROM AUTHOR]

Vascular anomalies are classified as vascular tumors or vascular malformations according to their cellular features and biological behavior. Detailed history and clinical assessment allow for the proper clinical diagnosis of most vascular anomalies and guide the choice of imaging to evaluate them. This article discusses the general information needed from a clinical history and physical exam to formulate a diagnosis of vascular anomaly. Then, the authors review the clinical findings from the most common vascular tumors and vascular malformations. [ABSTRACT FROM AUTHOR]

The pulsed dye laser (PDL) is the standard treatment for port-wine stains (PWS). Maximal improvement occurs after multiple treatment sessions; however, the optimal treatment interval has yet to be determined. The aim of this study was to review whether there is an association between PDL treatment interval and outcome of PWS. Six databases were searched by three reviewers for publications investigating treatment of PWS with PDL. The 75% improvement rates (75IR) were extracted for quantitative analysis. Meta-regression was used to investigate the association between treatment intervals and 75IR. The systematic review included 1 RCT and 33 cohort studies (7 prospective cohorts and 26 retrospective cohorts), with a total of 3777 patients. The pooled 75IR was 37% (95% CI 29–45%; I2 = 95%). Light Fitzpatrick skin type (p = 0.04), facial anatomic location (p = 0.01), and young age (p = 0.008) were associated with 75IR. In an unadjusted (p = 0.42) and multivariable adjusted (p = 0.98) meta-regression, no association was found between time interval between treatments and 75IR. These results persisted in a sensitivity analysis of studies with a mean patient age of ≤ 1. The majority of included studies were heterogeneous and retrospective. Based on cohort studies of low-to-moderate quality, time intervals between PDL treatments are not associated with PWS outcome. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) is a minimally invasive therapy that was gradually established as a first-line treatment for vascular abnormalities. Its action depends on the appropriate wavelength of light and photosensitizer to produce toxic oxygen species and cause cell death. Objective: Several new clinical improvements and trends in PDT have been described in recent years. The aim of this review is to provide an overview of the current data from clinical trials. Methods: In this review, we introduce and generalize the wavelength, duration, dose, strength, and photosensitizer of PDT for the treatment of vascular abnormalities, such as circumscribed choroidal hemangiomas (CCH), choroidal neovascularization (CNV) and capillary malformation (CM). Results: The systematic review findings indicate that the application of PDT is a safe effective method to treat CCH, CNV and CM. However, PDT also has early onset side effects and late onset side effects. Conclusions: Based on the discussion of the effectiveness of PDT, we conclude that PDT has great potential for clinical use, although PDT has possible side effects.

Hemangiomas are benign vascular tumours of the head and neck. Lobular capillary hemangioma (LCH) is a common, acquired proliferative reaction in vascular tissue. It has female predilection, and peak incidence occurs in adolescents and young adults. Histopathologically, it is characterised by nodular proliferation of capillary-sized vessels lined by endothelial cells with plump nuclei. The capillary lumen shows the presence of numerous erythrocytes. To distinguish this lesion from other vascular lesions, a precise diagnosis is required. The majority of oral hemangiomas will regress without any treatment. If these tumours continue into adulthood, it may lead to difficulty in speech and swallowing. This case report presents an atypical manifestation of LCH of the buccal mucosa in a 51-year-old male patient., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kalmegh et al.)