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Common capillary malformations are red vascular skin lesions, most commonly associated with somatic activating GNAQ or GNA11 mutations. We focused on capillary malformations lacking such a mutation to identify previously unreported genetic causes. We used targeted next-generation sequencing on 82 lesions. Bioinformatic analysis allowed the identification of 9 somatic pathogenic variants in PIK3R1 and PIK3CA, encoding for the regulatory and catalytic subunits of phosphoinositide 3-kinase, respectively. Recharacterization of these lesions unraveled a common phenotype: a pale capillary malformation associated with visible dilated veins. Primary endothelial cells from 2 PIK3R1-mutated lesions were isolated, and PI3k-Akt-mTOR and RAS-RAF-MAPK signaling were assessed by western blot. This unveiled an abnormal increase in Akt phosphorylation, effectively reduced by PI3K pathway inhibitors, such as mTOR, Akt, and PIK3CA inhibitors. The effects of mutant PIK3R1 were further studied using zebrafish embryos. Endothelium-specific expression of PIK3R1 mutants resulted in abnormal development of the posterior capillary-venous plexus. In summary, capillary malformation associated with visible dilated veins emerges as a clinical entity associated with somatic pathogenic variants in PIK3R1 or PIK3CA (nonhotspot). Our findings suggest that the activated Akt signaling can be effectively reversed by PI3K pathway inhibitors. In addition, the proposed zebrafish model holds promise as a valuable tool for future drug screening aimed at developing patient-tailored treatments., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this study, we present two young patients with a CM-like phenotype associated with cerebral anomalies and severe epilepsy. Pathogenic variants in PIK3CA and PIK3R1, as well as GNAQ and GNA11, were absent in affected cutaneous tissue biopsies. Instead, we identified two somatic pathogenic variants in the AKT3 gene. Subsequent analysis of the DNA obtained from surgically resected brain tissue of one of the two patients confirmed the presence of the AKT3 variant. Focal cortical dysplasia was also detected in this patient. Genetic analysis thus facilitated workup to reach a precise diagnosis for these patients, associating the vascular anomaly with the neurological symptoms. This study underscores the importance of searching for additional signs and symptoms to guide the diagnostic workup, especially in cases with atypical vascular malformations. In addition, it strongly emphasizes the significance of genotype-phenotype correlation studies in guiding clinicians' informed decision-making regarding patient care., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%-2% of newborns. Patients with a CM localized on the forehead have an increased risk of developing a neurocutaneous disorder called encephalotrigeminal angiomatosis or Sturge-Weber syndrome (SWS), with complications including seizure, developmental delay, glaucoma, and vision loss. In 2013, a groundbreaking study revealed causative activating somatic mutations in the gene (GNAQ) encoding guanine nucleotide-binding protein Q subunit α (Gαq) in CM and SWS patient tissues. In this Review, we discuss the disease phenotype, the causative GNAQ mutations, and their cellular origin. We also present the endothelial Gαq-related signaling pathways, the current animal models to study CM and its complications, and future options for therapeutic treatment. Further work remains to fully elucidate the cellular and molecular mechanisms underlying the formation and maintenance of the abnormal vessels.

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., (© 2024. The Author(s).)

Introduction:  Parkes Weber's syndrome (PWS) is a rare genetic disorder characterized by overgrowth and vascular malformations, primarily affecting the extremities. While PWS is known to be associated with arteriovenous and capillary malformations, the potential involvement of lymphatic malformations (LMs) has not been previously reported. The objective of this study is to investigate the presence of lymphatic anomalies in PWS patients and their role in the development of limb asymmetry., Materials and Methods:  This is a retrospective study of patients diagnosed with PWS in a Vascular Anomalies Center from 1994 to 2020. Clinical data were obtained from medical records including diagnostic imaging, lymphoscintigraphy, and genetic testing. The Institutional Review Board and Ethics Committee have approved this study., Results:  A total of 16 patients aged 18 interquartile range 14.7 years diagnosed with PWS were included (50% female). Six of the 16 patients with PWS had clinical and imaging data suggestive of LM (37.5%) and 3 of them had genetic variants in RASA1 (2/3) or KRAS (1/3). Limb asymmetry was greater in patients with isolated PWS (2.6 ± 0.8 cm) than in the PWS-lymphatic anomalies population (2 ± 0.7 cm), although not significant ( p  = 0.247). One in 6 patients with PWS-LM required amputation (16.6%) versus 1 in 10 in isolated PWS (10%)., Conclusion:  Lymphatic anomalies may be present in a significant number of patients with PWS and could have a role in limb asymmetry and outcomes. It is paramount to investigate their existence and distinguish them from true overgrowth., Competing Interests: None declared., (Thieme. All rights reserved.)

While basal cell carcinoma is the most common type of skin cancer in humans, its subepidermal presentation is extremely rare. The risk factors for basal cell carcinoma development are well-known, but it remains unclear in which setting the tumor restricts itself to the dermal compartment. We present the fifth known case of subepidermal basal cell carcinoma. However, this particular presentation is unique due to arising beneath a capillary malformation. The patient had previously undergone multiple laser treatments which yielded no success. Initially, the vascular malformation was removed and sent for histopathological diagnosis. After the discovery of basal cell carcinoma, wide surgical resection was performed. The patient had no recurrence up to the last follow-up at 18 months postoperatively. This case demonstrates a new presentation of a very rare condition, but also highlights the importance of histopathological examination and the need for future research on any possible association between laser therapy and carcinogenesis.

Infantile hemangiomas (IHs) are the most common pediatric vascular tumors, although their genetic etiology is largely unknown. Congenital capillary malformations (CMs) are associated with known somatic pathogenic variants, including GNAQ, GNA11, PIK3CA, and PIK3R1. Co-occurrence of a facial CM such as port wine stain and IH is not associated with any recognized vascular anomaly syndromes and rarely reported in the literature. We describe a case of a 5-week-old female patient with a large facial CM and extensive IHs of the lower lip, airway, and orbit who presented with airway compromise and responded to propranolol therapy., (© 2023 Wiley Periodicals LLC.)

Background: Patients with capillary malformations (CMs) may undergo medical tattooing (MT) as an alternative to laser therapy. But little is known about treatment results and impact from the patients' perspective., Objectives: In this cross-sectional digital survey study, we evaluated the patient-reported outcomes of MT for CMs., Methods: MT practices were identified via the Dutch Association of Skin Therapists and Google. These practices invited all their CM patients who had undergone MT between January 2011 and September 2021 to participate. Baseline and treatment characteristics, tattooing effectiveness, patient satisfaction with treatment outcomes, and complications were evaluated using a custom-made online survey. Quality of life was assessed with the Dermatology Life Quality Index (DLQI) questionnaire. Factors associated with treatment effectiveness and patient satisfaction were identified via bivariate analysis and ordinal logistic regression analysis., Results: Most of the 89 respondents were female (69%). Almost all CMs were located on the face (90%) and mainly (dark) red (74%). Nearly all patients had undergone laser therapy (91%). Median number of tattooing sessions was 5 (IQR: 4.0-8.0). Thirty-seven percent of the patients perceived >75% color reduction. Younger patients were more likely to obtain lower treatment effectiveness (OR 0.44, 95% CI: 0.20-0.97). Most patients (83%) were satisfied with treatment results. Patients with lighter (OR 0.30, 95% CI: 0.13-0.72), non-facial (OR 0.15, 95% CI: 0.03-0.89), and hypertrophic CMs (OR 0.30, 95% CI: 0.11-0.82) were less likely to be satisfied with treatment outcomes. Patients with lighter skin types were more satisfied (OR 2.89, 95% CI: 1.23-6.80). Complications included transient pain (23%), bleeding (3.4%), hypertrophic scarring (1.1%), hypopigmentation (1.1%), and a halo around the tattoo (1.1%)., Conclusion: MT seems a valid alternative treatment in addition to laser therapy for CMs, with mild complications. Most patients are (very) satisfied with treatment results, while color reduction is incomplete. Hence, it seems appropriate to decide together with patients whether or not to use MT as primary treatment or secondary to laser therapy., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Competing Interests: Conflicts of interest None disclosed.

Capillary malformations (CMs) are the most common vascular anomalies, composed of enlarged capillaries and venules with thickened perivascular cell coverage in skin and mucous membranes. These congenital anomalies represent an error in vascular development during embryogenesis. Most of the CMs occur without any syndromic findings; the association between CMs systemic anomalies in some patients, however, makes the recognition of additional syndrome features critical. Some genetic disorders discussed, which feature CMs, include Sturge-Weber syndrome, diffuse CMs with overgrowth, Klippel-Trenaunay syndrome, CLOVES syndrome, among others. This article can aid clinicians in better identifying CMs and associated syndromes and provide consistent terminology to facilitate interdisciplinary management., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A female neonate was born with asymmetric lower limbs, the right leg appearing enlarged, with thickened, reddish-purple skin and ectasic superficial reticulum (figure 1A,B). Limb pulses were present and symmetrical. The girl's family history and prenatal scans were unremarkable. Laboratory findings were within the normal range, except for a mild thrombocytopenia (90 000/μL), which spontaneously resolved during the next few days. A leg X-ray and the Doppler analysis ruled out the presence of calcifications and venous varices, respectively. Ultrasound showed significant skin thickening, with marked dermal hypertrophy and hyperechogenicity. Magnetic resonance showed circumferential thickening of the derma, with mild hypertrophy of some perforating vessels (figure 2). A biopsy of the right thigh showed capillary malformations on histology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Conflict of interest The authors have no potential conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Capillary malformations - arteriovenous malformation, hereditary hemorrhagic telangiectasia and Sturge-Weber syndrome - are rare diseases in which cutaneous capillary malformations (CM) may be associated with cerebral vascular malformations. The clinical presentation of each disease is described with focus on how to distinguish them in the clinic and differential diagnoses are listed. This review finds that upon thorough and careful examination of patients, cutaneous CM might be a diagnostic hallmark for underlying disease and therefore a significant clinical observation.

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., (© 2022 The Authors. Australasian Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Australasian College of Dermatologists.)

Objectives: Design and validate a novel handheld device for the autonomous diagnosis of pediatric vascular anomalies using a convolutional neural network (CNN)., Study Design: Retrospective, cross-sectional study of medical images. Computer aided design and 3D printed manufacturing., Methods: We obtained a series of head and neck vascular anomaly images in pediatric patients from the database maintained in a large multidisciplinary vascular anomalies clinic. The database was supplemented with additional images from the internet. Four diagnostic classes were recognized in the dataset - infantile hemangioma, capillary malformation, venous malformation, and arterio-venous malformation. Our group designed and implemented a convolutional neural network to recognize the four classes of vascular anomalies as well as a fifth class consisting of none of the vascular anomalies. The system was based on the Inception-Resnet neural network using transfer learning. For deployment, we designed and built a compact, handheld device including a central processing unit, display subsystems, and control electronics. The device focuses upon and autonomously classifies pediatric vascular lesions., Results: The multiclass system distinguished the diagnostic categories with an overall accuracy of 84%. The inclusion of lesion metadata improved overall accuracy to 94%. Sensitivity ranged from 88% (venous malformation) to 100% (arterio-venous malformation and capillary malformation)., Conclusions: An easily deployed handheld device to autonomously diagnose pediatric skin lesions is feasible. Large training datasets and novel neural network architectures will be required for successful implementation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mixed vascular naevus (MVN) is characterized by the co-occurrence of telangiectatic capillary malformation and naevus anaemicus, which can appear as a pure cutaneous phenotype or be combined with systemic manifestations such as brain malformations, neurological abnormalities and musculoskeletal disorders. Recently, GNA11 and GNAQ somatic mutations have been reported in some patients with isolated and syndromic MVN. We report three children with MVN syndrome with generalized cutaneous manifestations and a number of systemic associations not reported to date, including ophthalmological anomalies, musculoskeletal abnormalities such as Sprengel deformity and posterior vertebral fusion anomalies, and septal heart defects. We also confirm a somatic mutation of GNA11 in both telangiectatic naevus and naevus anaemicus in two of our patients and discuss a possible common pathogenic mechanism underlying the different manifestations of the syndrome. Currently, there are no guidelines for the evaluation of patients with MVN syndrome, but according to the different known aspects of the disease, a complete clinical examination should be made, and complementary laboratory and imaging tests should be considered., (© 2021 British Association of Dermatologists.)

In the dermatologic medical literature, there is an underrepresentation of conditions in individuals of color. Due to the lack of representation, it may be harder for clinicians to recognize certain diagnoses in patients with darker skin phototypes leading to misdiagnosis and affecting overall patient management, outcomes, and satisfaction. Here, we present four Black or Indigenous People of Color who were initially referred for hyperpigmentation, hemihyperplasia, or café au lait spots and found to have syndromic capillary malformations., (© 2021 Wiley Periodicals LLC.)

We present a 12-year-old girl with multiple geographic capillary malformations in a segmental distribution over the left trunk and arm that were present at birth and evolved over years with ulceration, atrophy, and subsequent scarring. Our case is clinically consistent with the recently described entity "multifocal capillary malformation with segmental distribution and central atrophy." To our knowledge, our patient is the oldest reported to date., (© 2021 Wiley Periodicals LLC.)

Objectives: For selection of high-risk systemic lupus erythematosus (SLE) patients it is necessary to obtain indicators of disease severity that predict disease damage. As in systemic sclerosis, nailfold capillary abnormalities could be such a biomarker in SLE. The primary objective of this cross-sectional study is to describe capillary abnormalities in childhood-onset SLE (cSLE) cohort (onset < 18 years) and compare them with matched healthy controls. The secondary objective is to correlate the observed capillary abnormalities with demographical variables in both cohorts and with disease-specific variables in cSLE patients., Methods: Healthy controls were matched for ethnic background, age and gender. Videocapillaroscopy was performed in eight fingers with 2-4 images per finger. Quantitative and qualitative assessments of nailfold capillaroscopy images were performed according to the definitions of the EULAR study group on microcirculation in Rheumatic Diseases., Results: Both groups (n = 41 cSLE-patients and n = 41 healthy controls) were comparable for ethnic background (p = 0.317). Counted per mm, cSLE-patients showed significantly more 'giants' (p = 0.032), 'abnormal capillary shapes' (p = 0.003), 'large capillary hemorrhages' (p < 0.001) and 'pericapillary extravasations' (p < 0.001). Combined 'abnormal capillary shapes and pericapillary extravasations' (in the same finger) were detected in 78% (32/41 patients). By qualitative analysis, 'microangiopathy' was detected in 68.3% (28/41) and a 'scleroderma pattern' in 17.1% (7/41) of the cSLE-patients (without scleroderma symptoms). The difference of percentage positive anti-RNP antibodies in the group with or without a scleroderma pattern was not significant (p = 0.089). The number of 'abnormal capillary shapes per mm' was significantly correlated with treatment-naivety. The number of 'large pathological hemorrhages per mm' was significantly correlated with SLEDAI score and presence of nephritis. Compared to healthy controls, 'pericapillary extravasations' were found in significantly higher numbers per mm (p < 0.001) as well as in percentage of patients (p < 0.001)., Conclusions: Our observations confirm that giants, abnormal capillary morphology and capillary hemorrhages are also observed in cSLE, as was already known for adults with SLE. Number of capillary hemorrhages in cSLE was significantly correlated with disease activity. A high frequency and total amount of "pericapillary extravasations" was observed in cSLE patients, possibly revealing a new subtype of capillary hemorrhage that might reflect endothelial damage in these pediatric patients.

Background: Individuals with Sturge-Weber syndrome (SWS) often expereince intractable epilepsy and cognitive decline. We hypothesized that the extent of the leptomeningeal capillary malformation (LCM) may correlate with the severity of neurological impairment due to SWS. We tested the hypothesis in a cross-sectional study of seizure severity and electroencephalographic (EEG) findings and a retrospective cohort study for surgical indications related to the extent of the LCM., Methods: We enrolled 112 patients and classified them according to LCM distribution: (1) bilateral, (2) hemispheric, (3) multilobar, and (4) single lobe. Age at seizure onset, seizure semiology and frequency, and EEG findings were compared. Surgical indications were evaluated for each group by Fisher exact test, and predictors for surgery were evaluated by univariate and multivariate analyses. Therapeutic efficacy was evaluated by the SWS-Neurological Score (SWS-NS)., Results: The bilateral and hemispheric groups had early seizure onset (4.0 months old and 3.0 months old), frequent seizures (88.9% and 80.6% had more than one per month), focal-to-bilateral tonic-clonic seizures (88.9% and 74.2%), and status epilepticus (100% and 87.1%). The groups' EEG findings did not differ substantially. Surgical indications were present in 77.8% of the bilateral, 88.1% of the hemispheric, and 46.8% of the multilobar groups. Seizure more than once per month was a predictor of surgical treatment. Seizure subscore improved postoperatively in the hemispheric and multilobar groups. Even after surgical treatment, the bilateral and hemispheric groups exhibited higher SWS-NSs than members of the other groups., Conclusion: Our study demonstrated a strong association between extensive LCM and epilepsy severity. Surgical intervention improved seizure outcome in patients with SWS with large LCMs., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: 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., Aim: To identify the prevalence of dermatological parameters, FFVMs and associated features in a large series of patients with CM-AVM., Methods: We conducted an observational study of patients with CM-AVM syndrome diagnosed in 15 Spanish hospitals over 3 years. The main clinical, radiological, genetic findings and associated diseases were analysed., Results: 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., Conclusions: 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., (© 2020 British Association of Dermatologists.)

Background: Pulsed dye lasers (PDLs) are well-established for treatment of capillary malformations but are unable to penetrate the depth needed to treat deeper vascular lesions. A combined approach using a deeper penetrating wavelength with a "superficial" wavelength could more comprehensively treat vascular malformations than PDL alone., Objective: To evaluate the safety and efficacy of the long-pulsed 1064-nm neodymium:yttrium-aluminum-garnet (LP 1064-nm Nd:YAG) in conjunction with the 532-nm potassium titanyl phosphate (532-nm KTP) laser wavelengths for treatment of capillary venous and venous malformations., Methods: In this retrospective single-center study, we queried patient records who underwent treatment with the 532-nm KTP and LP 1064-nm Nd:YAG laser wavelengths. A blinded panel of 3 physicians evaluated improvement in lesion color, elevation, texture, and overall architecture on a four-point scale: 0% to 25%; 26% to 50%, 51% to 75%, and 76% to 100%., Results: Our cohort consisted of 23 cases. Sixteen cases had sufficient information for clinical assessment. Treatment number and parameters varied depending on lesion, skin type, and end point. Clinical assessment of treatment effectiveness revealed average scores of 51% to 75% improvement for color, elevation, texture, and overall architecture., Conclusion: This study illustrates that 2 wavelengths, 532-nm KTP to target superficial components and LP 1064-nm Nd:YAG for deeper components, can safely and effectively treat both capillary venous and venous malformations.

Vascular anomalies are developmental defects of the vasculature and encompass a variety of disorders. The identification of genes mutated in the different malformations provides insight into the etiopathogenic mechanisms and the specific roles the associated proteins play in vascular development and maintenance. A few familial forms of vascular anomalies exist, but most cases occur sporadically. It is becoming evident that somatic mosaicism plays a major role in the formation of vascular lesions. The use of Next Generating Sequencing for high throughput and "deep" screening of both blood and lesional DNA and RNA has been instrumental in detecting such low frequency somatic changes. The number of novel causative mutations identified for many vascular anomalies has soared within a 10-year period. The discovery of such genes aided in unraveling a holistic overview of the pathogenic mechanisms, by which in vitro and in vivo models could be generated, and opening the doors to development of more effective treatments that do not address just symptoms. Moreover, as many mutations and the implicated signaling pathways are shared with cancers, current oncological therapies could potentially be repurposed for the treatment of vascular anomalies., (Copyright © 2020. Published by Elsevier Inc.)

The head and neck are the most common site of involvement for vascular tumors and malformations, with more than half of all vascular anomalies seen in this region. Lesions in this location can cause significant disfigurement and can be associated with airway obstruction, impairment in vision or hearing, swallowing disorders and hemorrhage. Accurate diagnosis is critical in determining treatment, and interdisciplinary care is essential for optimal management. We review clinical and imaging features that are key to establishing the correct diagnosis, and review treatment modalities, with emphasis on interventional and surgical procedures., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

Capillary lymphatic venous malformations (CLVM) are complex vascular anomalies characterized by aberrant and enlarged lymphatic and blood vessels. CLVM appear during fetal development and enlarge after birth, causing life-long complications such as coagulopathy, pulmonary embolism, chronic pain, and disfigurement. Treatment includes surgical debulking, amputation, and recurrent sclerotherapy. Somatic, mosaic mutations in the 110-kD catalytic α-subunit of phosphoinositide-3-kinase (PIK3CA) gene have been previously identified in affected tissues from CLVM patients; however, the cell population harboring the mutation is still unknown. In this study, we hypothesized that endothelial cells (EC) carry the PIK3CA mutations and play a major role in the cellular origin of CLVM. We isolated EC from the lesions of seven patients with CLVM and identified PIK3CA hotspot mutations. The CLVM EC exhibited constitutive phosphorylation of the PI3K effector AKT as well as hyperproliferation and increased resistance to cell death compared to normal EC. Inhibitors of PIK3CA (BYL719) and AKT (ARQ092) attenuated the proliferation of CLVM EC in a dose-dependent manner. A xenograft model of CLVM was developed by injecting patient-derived EC into the flanks of immunocompromised mice. CLVM EC formed lesions with enlarged lymphatic and vascular channels, recapitulating the patient histology. EC subpopulations were further obtained by both immunomagnetic separation into lymphatic EC (LEC) and vascular EC (VEC) and generation of clonal populations. By sequencing these subpopulations, we determined that both LEC and VEC from the same patient express the PIK3CA mutation, exhibit increased AKT activation and can form lymphatic or vascular lesions in mouse.

Diffuse capillary malformation with overgrowth (DCMO) is a clinical diagnosis describing patients with multiple, extensive capillary malformations (CMs) associated with overgrowth and foot anomalies. The purpose of the study was to identify somatic variants in DCMO. Skin containing CM and overgrown subcutaneous adipose tissue was collected from patients with DCMO. Exons from 447 cancer-related genes were sequenced using OncoPanel. Variant-specific droplet digital PCR (ddPCR) independently confirmed the variants and determined variant allele frequencies (VAF). One subject contained a somatic PIK3CA p.G106V variant. A second patient had a PIK3CA p.D350G variant. VAF was 27% to 29% in skin and 16% to 28% in subcutaneous adipose. Variants were enriched in endothelial cells (VAF 50%-51%) compared to nonendothelial cells (1%-8%). DCMO is associated with somatic PIK3CA variants and should be considered on the PIK3CA-related overgrowth spectrum (PROS). Variants are present in both skin and subcutaneous adipose and are enriched in endothelial cells., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Bleomycin sclerotherapy is ineffective for treating capillary malformations (CMs) because bleomycin cannot adequately be injected into the small-diameter capillary lumina. Electrosclerotherapy (EST) might be a new treatment modality for CMs, as it combines bleomycin sclerotherapy and "electroporation"-an electric field applied to the tissue. Electroporation disrupts the transmembrane potential, facilitating bleomycin transportation across the vessel wall, hypothetically leading to targeted drug delivery and increased effectiveness of bleomycin in CMs., Objective: To explore the efficacy, safety, and feasibility of EST for CMs in a randomized within-patient controlled pilot study., Materials and Methods: Fifteen regions of interest (ROI) within the hypertrophic CMs of 5 patients were randomly allocated to EST, bleomycin injection, or no treatment. Outcome was assessed after 7 weeks by the patient and a blinded outcome assessor using the patient-observer scar assessment score (POSAS), global assessment of change (GAC), colorimetry, and laser speckle contrast imaging., Results: Color and hypertrophy of all ROIs treated with EST significantly improved, based on the POSAS (medians patient -11; observer -13), GAC, and colorimetry (ΔE 3.4-16.5) scores., Conclusion: This pilot study demonstrates the first proof of concept for electrosclerotherapy as a new treatment modality for CMs. Further research is warranted.

Introduction:  Capillary malformations (CMs) can be sporadic or syndromic, in association with other underlying venous malformation (VM) or lymphatic malformation (LM). The objective of this study is to describe the clinical patterns in the neonate that allow us to differentiate sporadic CMs from those associated with other vascular malformations., Materials and Methods:  A case-control study was performed in neonates with CM located in the trunk, followed at our institution between 2008 and 2018. The patients were divided into two groups: group A (cases: CM associated with VM or LM) and group B (controls: sporadic CM without associated malformations). Demographic and clinical variables collected in the clinical history were evaluated (color, location, multifocality, bilaterality, position regarding the vascular axis, and involvement of the midline)., Results:  Thirty-eight patients were included (18 cases and 20 controls) without differences in gender and age. In group A, the totality of patients presented CM with uniform color and lateral location ( p  < 0.001). In this group, bilateral and multifocal involvements were lower than in group B, without significant differences between both groups. The distribution of CMs in group A was always parallel to the vascular axis and the midline was always respected, without observing these characteristics in the group B ( p  < 0.001)., Conclusion:  The presence of a CM in the trunk of a neonate with uniform color, lateral location, parallel position to the vascular axis, and absence of involvement of the midline should make us suspect other underlying vascular malformations, which should be studied with complementary tests., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)