GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.

Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.

The importance of patient-specific resources for families dealing with prenatal rare diseases.

Rare diseases (RDs) are defined as diseases that affect a low number of the population. Prenatal diagnoses of RDs can add a lot of unique stress for parents. For example, parents who have prenatal diagnoses experience not only grief of expectation, but are forced to become patient advocates with incomplete information as their child is not yet born, and in many cases parents experience a lot of uncertainty. This typically involves seeking support groups and finding pre- and postnatal specialists all which come with mental and financial cost. Here we discuss the importance of targeted patient resources for parents to help alleviate some of their stress. Patient advocacy organizations can be incredibly useful for parents to navigate the complex healthcare system and help mitigate feelings of isolation, especially when parents can talk to others in a similar situation. We collaborated with a patient organization to create a prenatal parent support guide to address how parental needs such as mental well-being and practicing self-care can be met. We hope that resources such as these can help empower those with a pregnancy affected with a RD diagnosis.

How we use angiopoietin-2 in the diagnosis and management of vascular anomalies.

The diagnosis of vascular anomalies remains challenging due to significant clinical heterogeneity and uncertain etiology. Evaluation using biopsy and/or genetic testing for somatic variants is invasive, expensive, and prone to sampling error. There is great need for noninvasive and easily measured blood laboratory biomarkers that can aid not only in diagnosis, but also management of treatments for vascular anomalies. Angiopoietin-2, a circulating blood angiogenic factor, is highly elevated in patients with kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and kaposiform lymphangiomatosis. Here, we describe our clinical experience using serum angiopoietin-2 as a biomarker for diagnosis and monitoring response to treatment.

NRASQ61R mutation drives elevated angiopoietin-2 expression in human endothelial cells and a genetic mouse model.

BACKGROUND: Angiopoietin-2 (Ang-2) is increased in the blood of patients with kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE). While the genetic causes of KHE are not clear, a somatic activating NRASQ61R mutation has been found in the lesions of KLA patients. PROCEDURE: Our study tested the hypothesis that the NRASQ61R mutation drives elevated Ang-2 expression in endothelial cells. Ang-2 was measured in human endothelial progenitor cells (EPC) expressing NRASQ61R and a genetic mouse model with endothelial targeted NRASQ61R. To determine the signaling pathways driving Ang-2, NRASQ61R EPC were treated with signaling pathway inhibitors. RESULTS: Ang-2 levels were increased in EPC expressing NRASQ61R compared to NRASWT by Western blot analysis of cell lysates and ELISA of the cell culture media. Ang-2 levels were elevated in the blood of NRASQ61R mutant mice. NRASQ61R mutant mice also had reduced platelet counts and splenomegaly with hypervascular lesions, like some KLA patients. mTOR inhibitor rapamycin attenuated Ang-2 expression by NRASQ61R EPC. However, MEK1/2 inhibitor trametinib was more effective blocking increases in Ang-2. CONCLUSIONS: Our studies show that the NRASQ61R mutation in endothelial cells induces Ang-2 expression in vitro and in vivo. In cultured human endothelial cells, NRASQ61R drives elevated Ang-2 through MAP kinase and mTOR-dependent signaling pathways.

Optical coherence tomography-measured blood vessel characteristics of port-wine birthmarks by depth: A cross-sectional study.

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

Immunohistochemical Expression of Lymphatic Endothelial Markers in Blue Rubber Bleb Nevus Syndrome.

INTRODUCTION: Blue rubber bleb nevus syndrome (BRBNS) is an uncommon vascular anomaly characterized by multifocal cutaneous, visceral, and other soft tissue or solid organ venous malformations. We observed that BRBNS lesions express immunohistochemical markers of lymphatic differentiation. METHODS: BRBNS histopathologic specimens assessed at our institution during the past 27 years were reviewed. Slides from 19 BRBNS lesions were selected from 14 patients (9 cutaneous, 9 gastrointestinal, and 1 hepatic). We recorded the involved anatomical compartments and presence/absence of thrombi or vascular smooth muscle. Immunohistochemical endothelial expression of PROX1 (nuclear) and D2-40 (membranous/cytoplasmic) was evaluated semi-quantitatively. RESULTS: Endothelial PROX1 immunopositivity was noted in all specimens; the majority (89.5%) demonstrated staining in more than 10% of cells. D2-40 immunopositivity was present in one-third (33%) of cutaneous lesions and only 1 gastrointestinal lesion. CONCLUSION: Endothelial cells in BRBNS almost always express 1 or more immunohistochemical markers of lymphatic differentiation.

Patient characteristics and disease spectrum in a German vascular anomalies center.

BACKGROUND: Vascular malformations are rare diseases that should be treated in dedicated vascular anomaly centers (VAC). There is only a small amount of data on the diagnostic and therapeutic handling of these patients, before they are referred to a VAC. PURPOSE: To demonstrate the disease-specific patient characteristics in a German VAC, which are required to determine diagnostic and therapeutic steps. MATERIAL AND METHODS: In a retrospective study, all patients who were treated in the VAC from April 2014 until August 2021 were identified. In total, 593 patients were included in this study. RESULTS: Almost all patients had previously consulted a physician (591/593, 99.7%). A mean of two different physicians had been consulted (range 0-10). Patients with more complex, syndromal vascular malformations had significantly more previous appointments (P = 0.0018). In only 44% (261/593) of patients, the referral diagnosis was made correctly. Most patients had been previously treated for their vascular anomaly: pharmacotherapy (n = 130; 21.9%), compression garments (n = 141; 23.8%), surgical resection (n = 80; 17.3%) and sclerotherapy (n = 68; 11.5%). Fifty-two patients who had been falsely diagnosed had also received therapy prior to their referral to the VAC (8.8%). Most patients received an ultrasound examination in the VAC (n = 464; 78.2%). Most frequently, compression therapy was prescribed (n = 256; 43.2%), followed by sclerotherapy (n = 175, 29.5%) and pharmacotherapy (n = 55; 9.3%). CONCLUSION: Patients suffering from vascular anomalies often go through a complicated scheduling with numerous outpatient appointments and have a high risk of misdiagnosis and mistreatment prolonging the medical condition. Therefore, patients with vascular anomalies should be treated in a dedicated vascular anomaly center.

Frequency of the prominent transverse nasal root vein in children.

BACKGROUND: The presence of a vascular, blue linear discoloration on the nasal root of infants and young children is a frequent incidental feature, rarely reported in the medical literature. It is related to the trajectory of the transverse nasal root vein (TNRV). OBJECTIVE: To study the frequency and clinical characteristics of the vascular discoloration of the nasal root in children. METHODS: A prospective study was performed to address the presence or absence of vascular discoloration of the nasal root in all children under 6 years of age attending a pediatric dermatology clinic from November 2022 to November 2023. Data on age and skin phototype (Fitzpatrick classification I-VI) were also collected. RESULTS: Of 701 patients examined, 345 (49.2%) presented with a vascular discoloration of the nasal root. This was present in 97 of 193 (50.3%), 127 of 261 (48.7%), and 121 of 247 (49.0%) patients for the age groups 0-1, 1-3, and 3-6 years, respectively. The presence of vascular discoloration of the nasal root was more frequent in patients with lighter Fitzpatrick skin phototypes: 49 of 69 (71.0%) phototype II, 157 of 290 (54.1%) phototype III, and 137 of 337 (40.7%) phototype IV. CONCLUSIONS: A vascular discoloration of the nasal root is a frequent skin feature in infants and children, persisting at least until the age of 6. It does not constitute any medical problem aside from cosmetic concern and parents can be reassured of its benign nature. We propose the medical term "prominent TNRV" to describe this condition.

Sirolimus experience in adult patients with vascular malformations.

AIM: Sirolimus, a mammalian target of rapamycin inhibitor, inhibits cell growth and proliferation by controlling ribosome biogenesis and protein synthesis in vascular anomalies and cancers. However, most sirolimus studies on vascular anomalies were conducted in the pediatric population, with limited data in adults. In this study, we assessed the effectiveness and safety of sirolimus in adult patients with vascular malformation, a subtype of vascular anomaly. METHODS: We conducted a retrospective analysis of adult vascular malformation patients aged over 16, treated at Hacettepe University Cancer Institute from January 2013 to September 2022. Patient demographics and clinical characteristics were recorded. The primary outcome was the efficacy of sirolimus evaluated by response and disease control rates. The disease control rate was defined as the cumulative percentage of complete or partial responses, along with stable disease. The secondary endpoint was toxicity and safety. RESULTS: 38 patients with a median age of 21 (IQR: 18-33) were recruited. Prior to sirolimus treatment, 57.9% of patients had undergone other therapeutic interventions, predominantly sclerotherapy and surgery. The median follow-up time during sirolimus treatment was 18.5 (IQR: 11.3-74.5) months. The disease control rate was 92.1% (35/38). Head-neck localization was associated with better response rates (p = .001). Sirolimus was generally well tolerated and grade 1 or 2 oral mucositis (n = 4) and skin rash (n = 3) were the most common side effects. CONCLUSION: In this study, we found sirolimus was efficacious and well tolerated in adult patients with vascular malformation.

Enlargement of the hepatic artery is present in dogs with a congenital extrahepatic portosystemic shunt and is independent of shunt insertion into the systemic circulation.

The accurate diagnosis of portovascular anomalies has been facilitated by improvements in diagnostic imaging technology. In humans, hepatic arterial blood flow changes in response to the reduction in portal blood flow. The hepatic arterial buffer response characterizes an intrinsic regulatory mechanism in response to reduced portal venous blood flow, which results in hepatic arterial enlargement. At the authors' institution, enlargement of the hepatic artery has been anecdotally observed in a population of dogs with extrahepatic portosystemic shunting, consistent with previous literature that documents variability in hepatic arterial size. In this retrospective, blinded, analytical study, a hepatic artery:aorta (Ha:Ao) ratio was assessed on CT studies from 112 dogs, with (n = 43) and without (n = 69) an extrahepatic congenital portosystemic shunt in order to compare the hepatic artery size independent of body weight between the two populations. A significant increase in the Ha:Ao ratio was documented in dogs with an extrahepatic portosystemic shunt (EHPSS) compared with those dogs with no EHPSS independent of the location of shunt insertion into the systemic circulation (P < .001). Three cases had repeat CT after surgery, and all had Ha:Ao ratio reductions following treatment. The authors propose that this may be an additional imaging feature observed in dogs with an EHPSS.

Fibroadipose vascular anomaly: a clinicopathological study of 75 cases.

AIMS: Fibroadipose vascular anomaly (FAVA) is a complex vascular malformation that is likely to be under-recognised. In this study we aimed to report the pathological features and somatic PIK3CA mutations associated with the most common clinicopathological features. METHODS AND RESULTS: Cases were identified by reviewing the lesions resected from patients with FAVA registered at our Haemangioma Surgery Centre and unusual intramuscular vascular anomalies in our pathology database. There were 23 males and 52 females, who ranged in age from 1 to 51 years. Most cases occurred in the lower extremities (n = 62). The majority of the lesions were intramuscular, with a few disrupting the overlying fascia and involving subcutaneous fat (19 of 75), and a minority of the cases had cutaneous vascular stains (13 of 75). Histopathologically, the lesion was composed of anomalous vascular components that were intertwined with mature adipocytic and dense fibrous tissues and vascular components with: (a) clusters of thin-walled channels, some with blood-filled nodules and others with thin walls resembling pulmonary alveoli; (b) numerous small vessels (arteries, veins and indeterminate channels) - proliferative small blood vessels were often mixed with adipose tissue; (c) larger abnormal venous channels usually irregularly and sometimes excessively muscularised; (d) lymphoid aggregates or lymphoplasmacytic aggregates were usually observed; and (e) lymphatic malformations were sometimes seen as minor elements. All patients had their lessons subjected to PCR, and 53 patients had somatic PIK3CA mutations (53 of 75). CONCLUSIONS: FAVA is a slow-flow vascular malformation with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for targeted therapy.

Communication with parents and young adult patients affected by complex vascular malformations.

BACKGROUND: Vascular malformations (VMs) are rare disorders that can cause pain, coagulopathy, disfigurement, asymmetric growth, and disability. Families affected by complex VMs experience misdiagnosis, limited trustworthy information, delayed or inappropriate treatments, and persistent uncertainty. However, more research is needed to understand the communication experiences of these families during clinical encounters. PROCEDURE: We performed semi-structured interviews with 34 parents of children with VMs (18% men; 82% women; mean age = 41 years) and 25 young adults with VMs (8% men; 88% women; 4% nonbinary; mean age = 29) living in the United States, recruited through four patient advocacy groups. We performed thematic analysis to assess communication experiences, using a previously developed functional model of communication in pediatric oncology as an a priori framework. RESULTS: We identified evidence of eight communication functions previously identified in pediatric oncology: building relationships, exchanging information, enabling self-management, managing uncertainty, responding to emotions, making decisions, providing validation, and supporting hope. Uncertainty was pervasive through participants' experiences and seemed to influence the fulfillment of communication functions. Fewer participants seemed to highlight the role of clinicians in responding to emotions or supporting hope, compared to other communication functions. CONCLUSION: Interviews with parents and young adult patients with VMs provided evidence for eight functions of communication. While exchanging information and building relationships were described by nearly every respondent, supporting hope and responding to emotions were mentioned less frequently. Future studies should develop patient-reported communication measures to quantify the fulfillment of these functions and to identify areas of communication in need of intervention.

Radiomics-based machine learning approach in differentiating fibro-adipose vascular anomaly from venous malformation.

BACKGROUND: As a complex vascular malformation, fibro-adipose vascular anomaly was first proposed in 2014. Its overlap with other vascular malformations regarding imaging and clinical features often leads to misdiagnosis and improper management. OBJECTIVE: To construct a radiomics-based machine learning model to help radiologists differentiate fibro-adipose vascular anomaly from common venous malformations. MATERIALS AND METHODS: We retrospectively analyzed 178 children, adolescents and young adults with vascular malformations (41 fibro-adipose vascular anomaly and 137 common vascular malformation cases) who underwent MRI before surgery between May 2012 to January 2021. We extracted radiomics features from T1-weighted images and fat-saturated (FS) T2-weighted images and further selected features through least absolute shrinkage and selection operator (LASSO) and Boruta methods. We established eight weighted logistic regression classification models based on various combinations of feature-selection strategies (LASSO or Boruta) and sequence types (single- or multi-sequence). Finally, we evaluated the performance of each model by the mean area under the receiver operating characteristics curve (ROC-AUC), sensitivity and specificity in 10 runs of repeated k-fold (k = 10) cross-validation. RESULTS: Two multi-sequence models based on axial FS T2-W, coronal FS T2-W and axial T1-W images showed promising performance. The LASSO-based multi-sequence model achieved an AUC of 97%±3.8, a sensitivity of 94%±12.4 and a specificity of 89%±9.0. The Boruta-based multi-sequence model achieved an AUC of 97%±3.7, a sensitivity of 95%±10.5 and a specificity of 87%±9.0. CONCLUSION: The radiomics-based machine learning model can provide a promising tool to help distinguish fibro-adipose vascular anomaly from common venous malformations.

Sirolimus treatment for paediatric head and neck lymphatic malformations: a systematic review.

PURPOSE: This PRISMA-compliant systematic review aimed to assess risks and benefits of sirolimus treatment for paediatric lymphatic malformations by focusing not only on treatment efficacy but also on possible treatment-related adverse events, and treatment combinations with other techniques. METHODS: Search criteria were applied to MEDLINE, Embase, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov databases and included all studies published up to March 2022 reporting paediatric lymphatic malformations treated with sirolimus. We selected all original studies that included treatment outcomes. After the removal of duplicates, selection of abstracts and full-text articles, and quality assessment, we reviewed eligible articles for patient demographics, lymphatic malformation type, size or stage, site, clinical response rates, sirolimus administration route and dose, related adverse events, follow-up time, and concurrent treatments. RESULTS: Among 153 unique citations, 19 studies were considered eligible, with reported treatment data for 97 paediatric patients. Most studies (n = 9) were case reports. Clinical response was described for 89 patients, in whom 94 mild-to-moderate adverse events were reported. The most frequently administered treatment regimen was oral sirolimus 0.8 mg/m2 twice a day, with the aim of achieving a blood concentration of 10-15 ng/mL. CONCLUSION: Despite promising results for sirolimus treatment in lymphatic malformation, the efficacy and safety profile of remains unclear due to the lack of high-quality studies. Systematic reporting of known side effects, especially in younger children, should assist clinicians in minimising treatment-associated risks. At the same time, we advocate for prospective multicentre studies with minimum reporting standards to facilitate improved candidate selection.

A Case of Vascular Malformation in the Buccal Fat Pad.

Vascular anomalies are categorized as vascular tumors or vascular malformations (VMs) based on the system of classification (updated in 2018) established by the International Society for the Study of Vascular Anomalies. In the orofacial region, such anomalies are most likely to occur in the lips or tongue, and only rarely in the buccal fat pad. This report describes a case of a VM in the buccal fat pad. A 47-year-old woman was referred to our hospital with a mass lesion in her left cheek. On palpation, an elastic, hard, painless, and mobile mass was found anterior to the left masseter muscle. Computed tomography, magnetic resonance imaging, and ultrasonography revealed a mass in the left buccal fat pad. The lesion was identified as a benign tumor and surgical excision performed under general anesthesia. Histopathological examination revealed that the lesion was composed of a large number of vascular structures of various sizes covered with endothelial cells. Based on the clinical and histopathological findings, a diagnosis of a venous VM was made. One year has passed since the operation and no recurrence has been observed. Long-term follow-up is planned.

Aberrant right subclavian artery: case report and literature review.

The aberrant right subclavian artery, also known as the arteria lusoria, is the most common aortic arch anomaly, occurring in 0.5 to 1% of the population. There is a higher prevalence in women and it is usually associated with other anatomical variations, such as the non-recurrent laryngeal nerve, present in 86.7% of cases. In the majority of cases, the aberrant right subclavian artery causes no symptoms. We describe this anomaly in an 82-year-old, hypertensive, and asymptomatic patient who had undergone a thoracoabdominal angiography to investigate a chronic DeBakey type III aortic dissection with dilation of the descending aorta. The aberrant right subclavian artery followed a retroesophageal course and was associated with a Kommerell diverticulum. In view of its rarity, we conducted an integrative bibliographic review of literature from the last 6 years indexed on the Medline, UpToDate, Lilacs, Scielo, and Portal Capes databases and discuss the most frequent anatomical changes, symptomatology, and therapeutic management adopted.

NRASQ61R mutation in human endothelial cells causes vascular malformations.

Somatic mutations in NRAS drive the pathogenesis of melanoma and other cancers but their role in vascular anomalies and specifically human endothelial cells is unclear. The goals of this study were to determine whether the somatic-activating NRASQ61R mutation in human endothelial cells induces abnormal angiogenesis and to develop in vitro and in vivo models to identify disease-causing pathways and test inhibitors. Here, we used mutant NRASQ61R and wild-type NRAS (NRASWT) expressing human endothelial cells in in vitro and in vivo angiogenesis models. These studies demonstrated that expression of NRASQ61R in human endothelial cells caused a shift to an abnormal spindle-shaped morphology, increased proliferation, and migration. NRASQ61R endothelial cells had increased phosphorylation of ERK compared to NRASWT cells indicating hyperactivation of MAPK/ERK pathways. NRASQ61R mutant endothelial cells generated abnormal enlarged vascular channels in a 3D fibrin gel model and in vivo, in xenografts in nude mice. These studies demonstrate that NRASQ61R can drive abnormal angiogenesis in human endothelial cells. Treatment with MAP kinase inhibitor U0126 prevented the change to a spindle-shaped morphology in NRASQ61R endothelial cells, whereas mTOR inhibitor rapamycin did not.

Bloom where you are planted: Hemangioma or malignancy?

Vascular anomalies comprise a spectrum of disorders characterized by the abnormal development or growth of blood and lymphatic vessels. These growths have unique features and diverse behaviors, mandating a multidisciplinary approach in their evaluation, diagnosis, and management. Here we describe the case of a male toddler presenting with an abdominal mass, originally treated as a metastatic retroperitoneal tumor, but subsequently felt to represent a vascular anomaly.

How we established a multidisciplinary program for vascular anomalies.

The care of patients with vascular anomalies is quickly becoming a complex field requiring high-quality, coordinated multidisciplinary care. In this article, we review the history of multidisciplinary care in this field, discuss the benefits of this model of care, and outline some of the essential components and structure of a successful vascular anomalies team. We provide an overview of two example programs and a roadmap for other centers to develop their own multidisciplinary vascular anomalies teams.

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data.

Extensive venous malformations involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. But patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Available pharmacological treatments (e.g., sirolimus) are not universally effective. Novel therapies are urgently needed for patients with treatment-resistant venous malformations. We report three patients with TIE-2 receptor mutations treated with alpelisib for 6 months (daily dosing: 50 mg for children weighing <50 kg and 100 mg for those >50 kg). Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy dramatically improved. Drug exposure was highly variable, suggesting that alpelisib dosing should be individualized to patient's characteristics and guided by therapeutic drug monitoring.