Capillary malformations.

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.

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

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

Macrocheilia as an Atypical Clinical Presentation of Capillary Malformation-Arteriovenous Malformation Type 2.

This case report describes a 53-year-old man with multiple erythematous macules and papules diffusely distributed on the frontal area, cheeks, eyelids, nose, and supralabial skin.

Lymphatic Malformations in Parkes Weber's Syndrome: Retrospective Review of 16 Cases in a Vascular Anomalies Center.

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.

Delayed ulceration following combination pulse dye laser and topical sirolimus treatment for port wine birthmarks: A case series.

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.

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

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.

Patient-Reported Outcomes of Medical Tattooing for Capillary Malformations.

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.

A case of large airway and orbital hemangiomas with facial capillary malformation.

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.

Mosaic pathogenic variants in AKT3 cause capillary malformation and undergrowth.

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.

Genetic testing in the evaluation of individuals with clinical diagnosis of atypical Sturge-Weber syndrome.

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.

Capillary Malformations.

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.

Further clinical delineation of microcephaly-capillary malformation syndrome.

Microcephaly-Capillary Malformation syndrome (MIC-CAP) is a rare genetic disorder reported in 18 individuals to date. The clinical features typically include microcephaly, multiple cutaneous capillary malformations, seizures, neurologic impairment, and global developmental delay. Currently, there is little published information about the natural history and long-term outcomes for individuals with MIC-CAP. In this report, we provide follow up on two previously published patients and describe four new patients. The included patients highlight increased variability in the clinical spectrum and provide novel information regarding medical complications and recurrent variants.