The growth and expansion of meningeal lymphatic networks are affected in craniosynostosis

Skull malformations are associated with vascular anomalies that can impair fluid balance in the central nervous system. We previously reported that humans with craniosynostosis and mutations in TWIST1 have dural venous sinus malformations. It is still unknown whether meningeal lymphatic networks, which are patterned alongside the venous sinuses, are also affected. We now show that the growth and expansion of meningeal lymphatics are perturbed in Twist1 craniosynostosis models. Changes to the local meningeal environment, including hypoplastic dura and venous malformations, affect the ability of lymphatic networks to sprout and remodel. Dorsal networks along the transverse sinus are hypoplastic with reduced branching. By contrast, basal networks closer to the skull base are more variably affected, showing exuberant growth in some animals suggesting they are compensating for vessel loss in dorsal networks. Injecting a molecular tracer into cerebrospinal fluid reveals significantly less drainage to the deep cervical lymph nodes, indicative of impaired lymphatic function. Collectively, our results show that meningeal lymphatic networks are affected in craniosynostosis, suggesting the clearance of beta-amyloid and waste from the central nervous system may be impeded.

The experimental rationale for new bleomycin-polidocanol mini-foam administration in the treatment of children with head and neck venous malformations

Relevance. Venous malformation (VM) is an abnormal development of the collecting blood vessels based on the vascular wall formation disorder, which occurs during the peripheral vascular network differentiation. According to various sources, VM prevalence ranges from 1 to 2 in 10 000 newborns. Head and neck VMs significantly reduce patients’ quality of life, causing severe functional and aesthetic impairments. Sclerotherapy is an effective treatment method for children with venous malformations. In recent years, bleomycin has been the most commonly used sclerosant. It is a glycopeptide antibiotic synthesized by Streptomyces verticillus and belongs to cytostatic medications. They successfully use it for venous malformations sclerotherapy, also in children. Purpose – the study aimed to improve the sclerotherapy method by combining the advantages of foam sclerotherapy and bleomycin.Materials and methods. 48 samples of rats’ external femoral veins were morphologically examined. We divided the rats into 2 groups depending on the administrated agent: the first group – 3% polidocanol (lauromacrogol 400), the second group – bleomycin-polidocanol mini-foam composition. The histological assessment identified the changes in the vein endothelium, necrosis of tissue structures, cell dystrophy characteristics.Results. The first group, which used the bleomycin-polidocanol mini-foam composition, demonstrated more pronounced irreversible changes in the venous vessel endothelium compared to the second group.Conclusions. The experimental study revealed that the proposed method of VM sclerotherapy using new bleomycin-polidocanol mini-foam composition is more effective than the polidocanol foam sclerotherapy. The new method is highly effective, minimally invasive, safe and can be considered an independent treatment method in children with head and neck VM.

Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K–RAS–MAPK pathway (Padia et al., Laryngoscope Investig Otolaryngol 4: 170–173 [2019]). Activating pathogenic variants in the gene PIK3CA, which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., Pediatr Dev Pathol 16: 51 [2013]; Luks et al., J Pediatr 166: 1048–1054.e1–5 [2015]; Al-Olabi et al., J Clin Invest 128: 1496–1508 [2018]). These vascular malformations are part of the PIK3CA-related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic PIK3CA pathogenic variants (Keppler-Noreuil et al., Am J Med Genet A 167A: 287–295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet–Dechaume–Blanc syndrome, and Wyburn–Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., Interv Neuroradiol 7: 5–17 [2001]; Krings et al., Neuroimaging Clin N Am 17: 245–258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., Am J Neuroradiol 39: 2103–2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene PIK3CA. We propose that CVMS be recognized as part of the PIK3CA-related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.

Microfoam sclerotherapy of superficial venous malformations of the upper limbs

Venous malformations are the most common type of angiodysplasia, which cause both physiological and emotional discomfort to patients. Arteriovenous malformations occur most often in the upper and lower limbs at the ratio of 20.9% and 46.4%, respectively. On top of that, 70% of cases of superficial arteriovenous malformations are found in women. In this article, the authors present a clinical example of the effectiveness of microfoam sclerotherapy and show a long-term outcome in a patient with superficial venous malformations of her hands, which are accompanied with such symptoms as as pain and bleeding. As a sclerosing agent, a 1–3% sodium tetradecyl sulphate solution was used, followed by compression using class 2 garments (RAL standard) such as an arm sleeve and gloves. The interval between procedures was 4 to 6 weeks. After several sessions, the superficial venous malformations of the upper limb decreased in the size and volume, and the patient presented less complaints. A 5-year follow-up showed no growth of malformations and re-bleeding complications. Microfoam sclerotherapy of superficial venous malformations in the upper limbs (hands) has good long-term outcomes and allows patients to avoid traumatic surgery. Given this comparability of the surgical and minimally invasive techniques, the use of the latter option, in particular, the foam sclerotherapy technique, makes economic and financial sense.

The effects of surgical treatment and sclerotherapy for intramuscular venous malformations: a comparative clinical study

Background Venous malformations (VMs) are the most common type of vascular malformations. Intramuscular venous malformations (IMVMs) are lesions involving the muscles, excluding intramuscular hemangiomas. The purpose of this study was to compare clinical outcomes between patients with IMVMs who were treated with sclerotherapy and those who were treated with surgical excision.Methods Of 492 patients with VMs treated between July 2011 and August 2020 at a single medical center for vascular anomalies, 63 patients diagnosed with IMVM were retrospectively reviewed. Pain, movement limitations, swelling, and quality of life (QOL) were evaluated subjectively, while radiological outcomes were assessed by qualified radiologists at the center. Complication rates were also evaluated, and radiological and clinical examinations were used to determine which treatment group (sclerotherapy or surgical excision) exhibited greater improvement.Results Although there were no significant differences in pain (P=0.471), swelling (P=0.322), or the occurrence of complications (P=0.206) between the two treatment groups, the surgical treatment group exhibited significantly better outcomes with regard to movement limitations (P=0.010), QOL (P=0.013), and radiological outcomes (P=0.017). Moreover, both duplex ultrasonography and magnetic resonance imaging showed greater improvements in clinical outcomes in the surgical excision group than in the sclerotherapy group.Conclusions Although several studies have examined IMVM treatment methods, no clear guidelines for treatment selection have been developed. Based on the results of this study, surgical excision is strongly encouraged for the treatment of IMVMs.

Intraoral Venous Malformation-A Case report

The vascular anomalies consist of vascular tumours and vascular malformations. One among these are the venous malformations which constitute about 40% of all vascular malformations. Usually, the venous malformations present as localized lesions in the form of swellings/nodules with phleboliths, are diagnosed by ultrasonography, CT and MRI. Summary: This is a report of a rare longstanding case of wide spread venous malformations of oral cavity and facial area with phleboliths.

Identification of ACTA2 as a Key Contributor to Venous Malformation

Objectives: Proteomics and high connotation functional gene screening (HCS) were used to screen key functional genes that play important roles in the pathogenesis of venous malformation. Furthermore, this study was conducted to analyze and explore their possible functions, establish a gene mutation zebrafish model, and perform a preliminary study to explore their possible pathogenic mechanisms in venous malformation.Methods: Pathological and normal tissues from patients with disseminated venous malformation were selected for Tandem Mass Tag (TMT) proteomics analysis to identify proteins that were differentially expressed. Based on bioinformatics analysis, 20 proteins with significant differential expression were selected for HCS to find key driver genes and characterize the expression of these genes in patients with venous malformations. In vitro experiments were then performed using human microvascular endothelial cells (HMEC-1). A gene mutant zebrafish model was also constructed for in vivo experiments to explore gene functions and pathogenic mechanisms.Results: The TMT results showed a total of 71 proteins that were differentially expressed as required, with five of them upregulated and 66 downregulated. Based on bioinformatics and proteomics results, five highly expressed genes and 15 poorly expressed genes were selected for functional screening by RNAi technology. HCS screening identified ACTA2 as the driver gene. Quantitative polymerase chain reaction (qPCR) and western blot were used to detect the expression of ACTA2 in the pathological tissues of patients with venous malformations and in control tissues, and the experimental results showed a significantly lower expression of ACTA2 in venous malformation tissues (P < 0.05). Cell assays on the human microvascular endothelial cells (HMEC-1) model showed that cell proliferation, migration, invasion, and angiogenic ability were all significantly increased in the ACTA2 over-expression group (P < 0.05), and that overexpression of ACTA2 could improve the inhibitory effect on vascular endothelial cell proliferation. We constructed an ACTA2-knockdown zebrafish model and found that the knockdown of ACTA2 resulted in defective vascular development, disruption of vascular integrity, and malformation of micro vein development in zebrafish. Further qPCR assays revealed that the knockdown of ACTA2 inhibited the Dll4/notch1 signaling pathway, Ephrin-B2 signaling pathway, and vascular integrity-related molecules and activated the Hedgehog signaling pathway.Conclusion: This study revealed that ACTA2 deficiency is an important factor in the pathogenesis of venous malformation, resulting in the disruption of vascular integrity and malformed vascular development. ACTA2 can be used as a potential biomarker for the treatment and prognosis of venous malformations.