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We report two cases with localized vascular malformations clinically resembling the "dominant lesion" seen in capillary malformation-arteriovenous malformation (CM-AVM) syndrome, however, lacking germline RASA1 variants but presenting double somatic RASA1 variants in affected tissue. Both patients presented with localized and superficial high-flow vascular malformations were treated with surgery and laser therapy and showed partial resolution. The study underscores the rarity of somatic RASA1 variants, contributes to understanding the "second-hit" pathophysiology in vascular lesions, and emphasizes the significance of clinical distinctions and genotyping for accurate diagnoses, offering implications for diagnosis, prognosis, and genetic counseling., (© 2024 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

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.)

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., (© 2024 Wiley Periodicals LLC.)

Capillary malformations (CM) (port-wine stains) are congenital skin lesions that are characterized by dilated capillaries and postcapillary venules. CMs are caused by altered functioning of the vascular endothelium. Somatic genetic mutations have predominantly been identified in the endothelial cells of CMs, providing an opportunity for the development of targeted therapies. However, there is currently limited in-depth mechanistic insight into the pathophysiology and a lack of preclinical research approaches. In a monocenter exploratory study of 17 adult patients with CMs, we found somatic sequence variants in the GNAQ (p.R183Q, p.R183G, or p.Q209R) or GNA11 (p.R183C) genes. We applied an endothelial-selective cell isolation protocol to culture primary endothelial cells from skin biopsies from these patients. We successfully expanded patient-derived cells in culture in 3 of the 17 cases while maintaining endothelial specificity as demonstrated by vascular endothelial-cadherin immunostainings. In addition, we tested the angiogenic capacity of endothelial cells from a patient with a GNAQ (p.R183G) sequence substitution. These proof-of-principle results reveal that primary cells isolated from CMs may represent a functional research model to investigate the role of endothelial somatic mutations in the etiology of CMs, but improved isolation and culture methodologies are urgently needed to advance the field., (Copyright © 2023 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).)

Capillary malformation-arteriovenous malformation is a rare autosomal dominant disorder associated with EPHB4 loss-of-function mutations. We report the unique presentation of a 6-year-old girl with multiple capillary malformations in a unilateral segmental distribution affecting the right hemiface, right upper chest, and right arm associated with overgrowth. Targeted next-generation sequencing on a tissue sample revealed a novel heterozygotic variant in the EPHB4 gene (NM_004444.5 (EPHB4): c.715T>A, p.[Cys239Ser]). This case highlights a distinct presentation of CM-AVM type 2 and showcases a new variant in EPHB4 not previously reported in the literature., (© 2023 Wiley Periodicals LLC.)

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.)

A man in his 60s with hyperamylasemia underwent contrast-enhanced computed tomography, which revealed masses in his pelvic cavity on the right side and in the left axilla. Hence, a detailed examination was performed. Upon performing Sonazoid ® (perfluorobutane) contrast-enhanced ultrasound, it was discovered that the right-sided pelvic cavity mass exhibited centripetal contrast-enhancement right from the early stage. Subsequently, the contrast material disappeared from the center and was washed out in the postvascular phase. The mass was suspected to be caused by vascular malformations. The right-sided pelvic cavity mass was excised, and upon histopathological examination, it was detected to be composed of capillary malformations. Thus, it was found that Sonazoid ® contrast-enhanced ultrasound examination could aid in diagnosing retroperitoneal masses.

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: 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., (© 2023 Wiley Periodicals LLC.)

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., (© 2023 The Authors. American Journal of Medical Genetics Part A published by 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.

Sturge-Weber syndrome (SWS) is a sporadic, congenital, neuro-cutaneous disorder characterized by a mosaic, capillary malformation. SWS and non-syndromic capillary malformations are both caused by a somatic activating mutation in GNAQ encoding the G protein subunit alpha-q protein. The missense mutation R183Q is the sole GNAQ mutation identified thus far in 90% of SWS-associated or isolated capillary malformations. In this study, we sequenced skin biopsies of capillary malformations from 9 patients. We identified the R183Q mutation in nearly all samples, but one sample exhibited a Q209R mutation. This new mutation occurs at the same residue as the constitutively-activating Q209L mutation, commonly seen in tumors. However, Q209R is a rare variant in this gene. To compare the effect of the Q209R mutation on downstream signaling, we performed reporter assays with a GNAQ-responsive reporter co-transfected with either GNAQ WT, R183Q, Q209L, Q209R, or C9X (representing a null allele). Q209L showed the highest reporter activation, with R183Q and Q209R showing significantly lower activation. To determine whether these mutations had similar or different downstream consequences we performed RNA-seq analysis in microvascular endothelial cells (HMEC-1) electroporated with the same GNAQ variants. The R183 and Q209 missense variants caused extensive dysregulation of a broad range of transcripts compared to the WT or null allele, confirming that these are all activating mutations. However, the missense variants exhibited very few differentially expressed genes (DEGs) when compared to each other. These data suggest that these activating GNAQ mutations differ in magnitude of activation but have similar downstream effects., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

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.)

A 23-day-old boy with prenatal diagnosis of basilar artery aneurysm presented with multiple congenital red patches consistent with capillary malformations. Genetic testing confirmed the presence of a heterozygous pathogenic variant of the RASA1 gene, confirming the diagnosis of capillary malformation-arteriovenous malformation (CM-AVM) syndrome. This case illustrates an atypical presentation of the RASA1 associated CM-AVM syndrome, with the intracranial vascular malformation diagnosis preceding the identification of the skin lesions. Arterial aneurysms have been associated with CM-AVM syndrome in rare instances but to our knowledge this is the first reported case of an aneurysm of the basilar artery., (© 2022 Wiley Periodicals LLC.)

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.

Objectives: This study aimed to quantify nailfold capillary (NFC) abnormalities in anti-melanoma differentiation-associated gene 5 (MDA5) -positive DM patients and to evaluate the association with clinical parameters, including serum biomarkers. In addition, we aimed to clarify the period leading to remission of NFC abnormalities during immunosuppressive treatment in patients with DM., Methods: A prospective observational study was conducted including patients (n = 10) who first visited Hiroshima University Hospital and were diagnosed with DM or clinically amyopathic DM with anti-MDA5 antibodies. We compared the NFC abnormalities detected by nailfold-video capillaroscopy (NVC), physical findings, blood tests, respiratory function tests, and vascular-related growth factors measured using a LEGENDplexTM Multi-Analyte Flow Assay Kit., Results: NFC abnormalities improved in all patients from 2 to 17 weeks after the initiation of immunosuppressive treatment. The NVC scores were inversely correlated with anti-MDA5 antibody titres at baseline. NVC scores and forced vital capacity were positively correlated. Baseline values of M-CSF and stem cell factor were correlated with anti-MDA-5 titres., Conclusion: Our study suggested that NVC scores and disease activity were inversely correlated before treatment. Vascular-related growth factors, such as M-CSF and stem cell factor, may be associated with the disease mechanism in patients with anti-MDA5 antibody-positive DM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.)

Cutis marmorata telangiectatica congenita (CMTC) is characterized by coarse-meshed capillary malformations arranged in asymmetrically distributed patches. The disorder may be associated with hyper- or hypoplastic limbs, syndactyly, cleft palate, and glaucoma. Because the disease usually occurs sporadically, the concept of a lethal mutation surviving by mosaicism was proposed about 30 years ago. Here we describe three children with CMTC due to a postzygotic GNA11 mutation c547C > T (p.Arg183Cys), documented in saliva (patient 1) or lesional cutaneous tissue (patients 2 and 3). All three individuals had widespread and asymmetric CMTC which was present from birth and became fainter during the first years of life. Variably associated anomalies included glaucoma, choroidal capillary malformation, and body asymmetry. In previous case reports, postzygotic GNA11 mutations were documented in two cases of phacomatosis cesiomarmorata, being characterized by CMTC coexisting with segmental dermal melanocytosis. Moreover, postzygotic GNA11 mutations were noted in two CMTC patients described under the incorrect diagnosis of "nevus vascularis mixtus". Hence, the present cases convincingly support the concept that CMTC can be caused by mosaic GNA11 mutations and thus belongs to the GNA11-Related Capillary Nevus (GNARCAN) spectrum. In two other bona fide cases of CMTC, however, we were unable to find a mutation in GNA11, which may be explained either by our inability to detect a very low percentage of mutant cells or by genetic heterogeneity of the phenotype., (Copyright © 2022. Published by Elsevier Masson SAS.)

The megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth disorder caused by mosaic gain-of-function variants in PIK3CA It is characterized by megalencephaly or hemimegalencephaly, vascular malformations, somatic overgrowth, among other features. Epilepsy is commonly associated with MCAP, and a subset of individuals have cortical malformations requiring resective epilepsy surgery. Like other mosaic disorders, establishing a molecular diagnosis is largely achieved by screening lesional tissues (such as brain or skin), with a low diagnostic yield from peripheral tissues (such as blood). Therefore, in individuals with MCAP in whom lesional tissues are scarce or unavailable or those ineligible for epilepsy surgery, establishing a molecular diagnosis can be challenging. Here we report on the utility of cerebrospinal fluid (CSF)-derived cfDNA for the molecular diagnosis of an individual with MCAP syndrome harboring a mosaic PIK3CA variant (c.3139C > T, p.His1047Tyr). The proband presented with asymmetric megalencephaly without significant dysgyria. He did not have refractory epilepsy and was therefore not a candidate for epilepsy surgery. However, he developed diffuse large B-cell lymphoma (DLBCL) in late childhood, with four CSF samples obtained via lumbar puncture for cancer staging during which one sample was collected for cfDNA extraction and sequencing. PIK3CA variant allele fractions in CSF cell-free DNA (cfDNA), skin fibroblasts, and peripheral blood were 3.08%, 37.31%, and 2.04%, respectively. This report illustrates the utility of CSF-derived cfDNA in MCAP syndrome. Minimally invasive-based molecular diagnostic approaches utilizing cfDNA not only facilitate accurate genetic diagnosis but also have important therapeutic implications for individuals with refractory epilepsy as repurposed PI3K-AKT-MTOR pathway-inhibitors become more widely available., (© 2022 Chen et al.; Published by Cold Spring Harbor Laboratory Press.)

Capillary malformation-arteriovenous malformation syndrome is a rare genodermatosis with cutaneous capillary malformations and a risk of associated fast-flow malformations. We describe here a four-generation family with a novel heterozygous pathogenic variant in the EPHB4 gene (NM_004444.5 (EPHB4): c.2224G>C, p.(Ala742Pro)). A review of the literature retrieved 127 patients with capillary malformation-arteriovenous malformation syndrome and confirmed variants in EPHB4. Multiple capillary malformations were present in 114 (89.76%) patients, and 12 (9.44%) patients had a solitary capillary malformation. Arteriovenous malformations/fistulas were present in 23 (18.1%) patients, and were located within the central nervous system in 5 (3.9%) patients. Not all papers included description of epistaxis. Telangiectasias were reported in 28 (22%) patients, and Bier spots were described in 20 (15.7%) patients. The clinical characteristics of capillary malformation-arteriovenous malformation syndrome are diverse and often discrete, which can make it difficult to distinguish capillary malformation-arteriovenous malformation syndrome from hereditary haemorrhagic telangiectasia.

Objective: Time to diagnosis of autoimmune disease in pediatric populations can take years but nailfold capillaroscopy (NFC) may identify early signs of autoimmune disease. The aim of this study is to assess the association between nailfold capillary abnormalities and autoimmune disease in children., Methods: A systematic search of PubMed, EMBASE, and Scopus was performed to identify all studies published before March 17, 2021. Observational studies reporting NFC outcomes in children with autoimmune disease and healthy controls (HC) were eligible for inclusion. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effects meta-analytical model., Results: Nine of 3665 studies reporting on 641 patients (398 subjects, 243 controls) were included. Pediatric patients with autoimmune disease were 9.88 (95% CI 3.16-30.87, I 2  = 80.1%) times more likely to have abnormal nailfold capillaries than HC. Of the capillaroscopic features, dilated capillaries (OR 27.90, 95% CI 2.17-349.05, I 2  = 59.9%) were the most likely abnormality observed on NFC. This was followed by the likelihood of reduced capillary density (<7 capillaries/mm) (OR 19.91, 95% CI 3.79-105.52, I 2  = 0%), giant capillaries (OR 12.87, 95% CI 2.38-69.45, I 2  = 0%), hemorrhages (OR 13.89, 95% CI 5.34-36.16, I 2  = 0%), and avascularity (OR 10.38, 95% CI 2.20-49.04, I 2  = 0%)., Conclusions: Children with autoimmune disease are significantly more likely to have nailfold capillary abnormalities. NFC may be useful in identifying early signs of underlying rheumatic disease and potentially decrease the time to diagnosis for this patient population., (© 2022 Wiley Periodicals LLC.)

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is an autosomal dominant condition characterized by multifocal, noncontiguous pink patches on the skin that often have a surrounding pale halo. In some cases, an association with a fast flow, arteriovenous malformation (AVM) can be identified. Here, we describe a case report of a 16-year-old woman with CM-AVM syndrome and significant cardiac compromise successfully treated with trametinib, a mitogen-activated protein kinase (MEK) inhibitor., (© 2022 Wiley Periodicals LLC.)