Capillary Venous Malformations Research Articles

Targeted therapy for capillary-venous malformations

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations’ occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

Targeted Diode Laser Therapy for Oral and Perioral Capillary-Venous Malformation in Pediatric Patients: A Prospective Study.

This study describes the management protocol for capillary-venous malformations in pediatric patients and reports the epidemiology of diagnosed and treated cases at the Unit of Odontostomatology of the Aldo Moro University of Bari from 2014 to 2022. The authors classified the intraoral and perioral capillary-venous malformations by superficial diameter (<1 cm, 1-3 cm, >3 cm) and ultrasonographical depth extension (≤5 mm, >5 mm). All patients underwent pulsed-mode diode laser transmucosal photocoagulation (8-12 W/cm2); those with malformations that were wide (>3 cm) and deep (>5 mm) received intralesional photocoagulation, too (13 W/cm2). The children received general anesthesia based on their compliance and lesions' extension. The follow-up lasted six months. A total of 22 females and 14 males (age range 4-18 years) presented 63 capillary-venous malformations. Five patients with Sturge-Weber syndrome, seven with hereditary hemorrhagic telangiectasia, and five with angiomatosis showed multiple malformations. The authors found no intraoperative or postoperative complications. Seventeen patients with lesions >1 cm and >5 mm deep required multiple laser sessions to heal. The results of the current study support diode laser photocoagulation as the gold standard for the treatment of intraoral and perioral capillary-venous malformations in pediatric patients.

Management of “Large” Vascular Malformation: An Institutional Review

Background: Large vascular malformations (VM) are complex lesions anatomically, functionally or both. The criteria to define “Large” vascular malformations were unclear. This study aims to retrospectively identify Large VM based on clinical features and discussed about the method we adopted in management. Methods: This is retrospective study of analyzing all patients of vascular malformations treated by us since 2003. The criteria to categorize large vascular malformations were outlined after analyzing the anatomical area of involvement, functional disturbances by these lesions, operability of the lesions, morbidity associated with resection, and the requirement of reconstruction. All cases were managed by a multi-disciplinary team. Various methods utilized to control the bleeding varied from simple wound packing to cardiopulmonary bypass (CPB) assistance. The resection was either curative or palliative. Complete excision in the form of radical resection was carried out in all possible cases intended with curative aim. Vascularized tissue transfer was done to reduce the morbidity following surgical resection. Results: Out of 268 patients, 26 patients fulfilled the criteria for large vascular malformations. The predominant site of involvement is head and neck. 80% had more than one indication for surgery. Majority of the cases 54% were arterio-venous malformations (AVM) followed by 31% of capillary venous malformations (CVM). The commonest indication for surgery is bleeding in 73% followed by cosmetic disfigurement in 61.5%. Compressive wound packing with delayed wound closure and preoperative embolization were the commonly employed methods for bleeding control. CPB assisted resection was carried out in 5 cases. On analysing the recurrence, 7.7% had in complete excision, 36% in incomplete excision and 12% in cases of vascularized tissue transfer. Conclusion: The clinical criteria outlined in our study will be useful in identifying “Large” vascular malformations. Compression wound packing with delayed closure plays a major role in bleeding control immediately after resection. CPB assistance for aiding resection can be considered in selected cases. Complete resection in the form of radical excision will reduce the recurrence. Palliative resection provides symptom free disease when complete resection is not viable. The tissue transfer for the wound cover controls the residual disease in cases of incomplete resection.

Rehabilitation Management of A Child with Atypical Case of Sturge Weber Syndrome

Sturge-Weber syndrome (SWS) is a capillary-venous malformation affecting the brain, the eye, and the adjacent trigeminal dermatomes of the skin or a facial port wine stain or nevus. Type 3 SWS is a form of disease that comes without the physical facial angioma that made the disease undiagnosed and untreated optimally. We report a case of a 6-year-old girl with history of seizures without fever since she was 13 months old. The seizure was repeated couple times within a month and a year afterwards, but relatively controlled with routine oral medications, with last seizure attack was when she was 4 years 8 months old. Unluckily, by the age of 6 and 3 months old, she was brought to the emergency department due to sudden focal seizure and weakness on her right extemities. The enhanced MSCT angio and brain MRI examination revealed the abnormality of the cerebral angiography, and raised the diagnostic of Sturge-Weber syndrome. After several medical treatment and rehabilitation programs, her gross motor ability and balance was getting much improved with some dysfunction on fine motor ability on her right hands and little difficulties on her basic speech. There was also some disturbance of her cognitive skill since she seemed to have a slower memory recall and speed processing after the latest seizure attack.

A review of the natural history of Sturge-Weber syndrome through adulthood.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder caused by a somatic mutation in the GNAQ gene, leading to capillary venous malformations with neurological, ocular, and cutaneous abnormalities. Descriptions of adult and elderly patients with SWS are scarce compared to those of neonates or children. We reviewed clinical, neuro-radiological and electroencephalographical findings of adult patients diagnosed with SWS, treated in our tertiary center for rare epilepsies. Ten adult patients were identified with a median age of 48years at inclusion. All patients had seizures, with features of temporal lobe involvement for five patients. One patient presented typical drug-resistant mesial temporal seizures with ipsilateral hippocampal sclerosis and leptomeningeal enhancement, and was treated surgically. Other patients presented typical neurological and brain imaging features found in SWS. One patient without visible leptomeningeal angioma or brain calcifications presented neurological symptoms (tonic-clonic generalized seizures) for the first time at the age of 56. Two of the oldest patients in our cohort with supratentorial leptomeningeal angioma displayed contralateral cerebellar atrophy, consistent with crossed cerebellar diaschisis. Over 70years of follow-up data were available for one patient whose epilepsy started at the age of 6months, offering a vast overview of the course of SWS, in particular the onset of dementia and contralateral micro-bleeds in relation to the leptomeningeal angioma. The long follow-up of our cohort allows for a description of the course of SWS and a characterization of uncommon neurological features in adult and elderly patients.

Abstract #1180419: A rare case of Central Hypogonadism and Growth Hormone Deficiency in a patient with Sturge-Weber Syndrome

Sturge-Weber Syndrome (SWS) is a rare non-hereditary disorder characterized by capillary-venous malformations affecting brain and eyes leading to complications such as epilepsy, hemiparesis, intellectual disabilities, glaucoma and visual field defects. SWS may also lead to neuroendocrine disorders and cases of growth hormone deficiency as well as central hypothyroidism have been reported. One study found an 18 fold increase in GH deficiency in this population. This report describes a rare case of a patient with SWS who was found to have growth hormone deficiency and central hypogonadism without evidence of structural pituitary abnormality.

Teaching NeuroImage: Sturge-Weber Syndrome in an Adult.

We report a 19-year-old right-handed man with a history of Sturge-Weber syndrome (SWS) based on port-wine stain involving the first division of the trigeminal nerve in the right hemiface (Figure 1) and leptomeningeal capillary-venous malformations associated with calcification involving the ipsilateral occipital lobe (Figures 2, E–G) and resultant refractory epilepsy. He was referred to our center for a presurgical epilepsy evaluation. Video-EEG data showed electroclinical and electrographic seizures arising from the right frontotemporal region and right posterior quadrant, respectively. In addition, there were frequent right temporal interictal discharges. He also had evidence of right hippocampal sclerosis (Figures 2, C and D), suspected to be the result of longstanding refractory epilepsy (i.e., dual pathology). SWS is a neurocutaneous disorder characterized by ipsilesional facial and leptomeningeal capillary-venous malformations with regional atrophy, gyral calcification, focal leptomeningeal enhancement, and bony changes (Figures 2, A, B, E–H).1,2

Sturge–Weber syndrome and glaucoma

Sturge–Weber syndrome (SWS) is a neurocutaneous syndrome characterized by capillary venous malformations in the skin, eye, and brain with the occurrence of angiomas of the face, choroid, and leptomeninges. The characteristics signs include facial port-wine birth mark, glaucoma, choroidal hemangioma with brain malformations, and cognitive abnormalities. In this article, we have documented the case report of a 24-year-old male with SWS presenting with glaucoma.

Sturge Weber Syndrome With Posterior Fossa Involvement : A Rare Case

Sturge-Weber syndrome (SWS) is a rare congenital vascular disorder characterized by facial capillary malformation, associated capillary-venous malformations affecting the brain and eye along with calcification in the occipital or frontoparietal region. Occipital and posterior parietal lobes are the common site of involvement in SWS. Posterior fossa involvement is a rare finding with very few number of reported cases. Contrast enhanced MRI is considered as the gold standard for the diagnosis of SWS demonstrating the enhancement of pial angioma

Novel Murine Models of Cerebral Cavernous Malformations.

Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D3, and a combination of the three drugs, failed to substantially reduce CCM formation when treatment was administered for 5weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage.

Headache in children with Sturge-Weber syndrome - Prevalence, associations and impact.

Sturge-Weber syndrome (SWS) is a congenital neurovascular disorder characterised by capillary-venous malformations involving the skin, brain and eye. Patients experience headache, however little is known about its characteristics or associations. We aimed to estimate prevalence, associations and the impact of headache in children with SWS. Case notes of all patients in a national tertiary paediatric SWS clinic were retrospectively reviewed. Patients were categorised into those with or without a history of headache, with an analysis performed of clinical stigmata of their disease and headache symptomology, associations and treatment. A multivariable logistic regression analysis was undertaken to elicit independent predictors of headache. 37% of patients with SWS (n=84) reported headaches that were variably associated with seizures, a preceding blow to the head and a minority had migraine features. In those reporting headaches, headaches interfered with daily activities of a quarter of the children and 39% experienced headaches frequently (more than 1/month). Headache was associated with glaucoma and aspirin administration while children with monoplegia and hemiplegia were less likely to have headache. Headache is common in children with SWS, often without classical migraine features and affects daily activities. Awareness of headache and its associations in SWS may improve management of this complex population.

Vertebral Intraosseous Vascular Malformations in a Familial Cerebral Cavernous Malformation Population: Prevalence, Histologic Features, and Associations With CNS Disease.

OBJECTIVE. The purpose of this study was to investigate whether MRI-typical and MRI-atypical intraosseous vascular malformations are associated with familial cerebral cavernous malformation (FCCM). MATERIALS AND METHODS. In a retrospective matched case-control study, two radiologists reviewed the spinal imaging, both CT and MRI, of 22 patients with FCCM seen between 2006 and 2017 and of age- and sex-matched control subjects for MRI-typical and MRI-atypical intraosseous vascular malformations. Quantitative analysis of lesions identified included vertebral level, size, and number of lesions. Pathologic samples from two lesions were analyzed for histologic and immunohistochemical features. Whether the presence of typical, atypical, and total intraosseous vascular malformations differed between patients and control subjects was tested. For patients with complete spinal imaging, whether intraosseous vascular malformations were associated with age, sex, brain lesion count, and spinal lesion count was also tested. RESULTS. MRI-atypical intraosseous vertebral malformations were more commonly present in patients with FCCM (p = 0.003). Sixteen lesions were found in nine patients and none in the control group. The numbers of MRI-typical intraosseous vascular malformations were similar between patients and control subjects (p = 0.480). Age was associated with typical intraosseous vascular malformations (p = 0.027), though not with atypical malformations. MRI-atypical malformations were larger (mean diameter double) than MRI-typical malformations (p = 0.023). Histologic analysis of two lesions from different patients with pathologic collapse revealed the same histologic features consistent with combined capillary-venous malformations. CONCLUSION. Vertebral capillary-venous malformations (MRI-atypical intraosseous vascular malformations) are common in patients with FCCM and may have a more aggressive clinical course than MRI-typical malformations.

Sturge-Weber Syndrome: A Boy with Port-wine Stain and Seizure

Neurocutaneous disorders are a heterogeneous group of genetic disorders that include Sturge-Weber syndrome (SWS), which is characterized by congenital capillary-venous malformation manifesting as port-wine stain, leptomeningeal angiomatosis and ocular angiomas. Diagnosis is made when at least two of these three areas are involved. Abnormal vessels lead to stasis and congestion resulting in decreased regional perfusion and eventually cause hypoxic brain injury with neuronal loss and gliosis. Seizures are common neurological manifestation in SWS patients and many patients have intractable seizures, eventually leading to motor deficits or developmental and cognitive delays. Here we report a case of a 16-year-old boy who presented with typical port-wine stain and seizure disorder since childhood. Neuroimaging revealed evidence of cerebral vascular malformation ipsilateral to the cutaneous lesion. Seizure was controlled with antiepileptic drugs. Early diagnosis and prompt treatment may reduce the incidence of neurologic sequelae. Proper counselling is necessary to improve compliance.

Clinical experience using neodymium-doped yttrium aluminum garnet laser in cutaneous vascular malformations among Indian patients

Introduction: Cutaneous vascular anomalies are relatively common in clinical practice with varied clinical features and deformity. Various treatment modalities are used to manage this condition. Aims and Objectives: In this study, our aims were to evaluate the outcome of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser in this type of vascular malformations. Materials and Methods: This was a prospective study conducted in the Department of Plastic Surgery in our institute from January 2014 to December 2015 among the patients having cutaneous vascular malformations. Results: There were total 34 patients; 20 patients were females and 14 were males. Sixteen were adults (>18 years) and 11 patients were below 1 year of age. Among different types of lesions, 23 (67.7%) were vascular malformations and 11 (32.3%) were hemangiomas. Most of the lesions (58.7%) showed positive effect of laser treatment as it becomes flat. All (100%) hemangiomas, i.e., infantile hemangioma and pyogenic granuloma become flat. However, 41.3% lesions showed no significant change in height. Among them, 58.3% were venous malformations, 25% capillary malformations, and 16.7% capillary venous malformations. Skin color was not changed in color among 58.9% cases. About 58.9% cases showed no skin texture changes (atrophic/hypertrophic). Excellent-to-fair outcome was observed among 64.8% cases. Conclusion: Nd:YAG laser therapy on cutaneous hemangiomas and vascular malformations is a good therapeutic option among Indian patients.

Physical and Family History Variables Associated With Neurological and Cognitive Development in Sturge-Weber Syndrome

BackgroundSturge-Weber syndrome (SWS) is caused by a somatic mutation in GNAQ leading to capillary venous malformations in the brain presenting with various neurological, ophthalmic, and cognitive symptoms of variable severity. This clinical variability makes accurate prognosis difficult. We hypothesized that the greater extent of physical factors (extent of skin, eye, and brain involvement), presence of possible genetic factors (gender and family history), and age of seizure onset may be associated with greater symptom severity and need for surgery in patients with SWS. MethodsThe questionnaire was collected from 277 participants (age: two months to 66 years) with SWS brain involvement at seven US sites. ResultsBilateral brain involvement was associated with both learning disorder and intellectual disability, whereas port-wine birthmark extent was associated with epilepsy and an increased likelihood of glaucoma surgery. Subjects with family history of vascular birthmarks were also more likely to report symptomatic strokes, and family history of seizures was associated with earlier seizure onset. Learning disorder, intellectual disability, strokelike episodes, symptomatic stroke, hemiparesis, visual field deficit, and brain surgery were all significantly associated with earlier onset of seizures. ConclusionThe extent of brain and skin involvement in SWS, as well as the age of seizure onset, affect prognosis. Other genetic factors, particularly variants involved in vascular development and epilepsy, may also contribute to neurological prognosis, and further study is needed.

Efficacy and Safety of a Novel Method of Insulated Intralesional Radiofrequency Ablation for Deep Dermal and Subcutaneous Lesions: A 3-Year Institutional Experience.

Although insulated intralesional radiofrequency ablation (IL-RFA) is being increasingly used in other specialties, not much information on its safety and efficacy in dermatology is available. To describe our experience with insulated IL-RFA for various dermatological conditions. This is a retrospective review of the patients who underwent IL-RFA in the past 3 years. Our technique involved creating a small window in the proximal end of plastic sheath of an intravenous cannula using a surgical blade, and then touching the RF probe to the cannula through the window to deliver the electric current. Information regarding diagnosis, number of sessions, adverse effects, and follow-up was recorded. Clinical improvement was assessed on a visual analog scale by the patient and 2 independent observers. Data on 19 patients with lymphangioma circumscriptum (n = 9), venous or capillary-venous malformation (n = 4), angiolymphoid hyperplasia with eosinophilia (n = 3), arteriovenous malformation, hidradenitis suppurativa, and hypertrophic scar (n = 1 each) was available. The mean number of IL-RFA sessions was 2.26 ± 1.61. The mean patient and physician global assessment scores were 7.6 ± 2.22 and 7.3 ± 2.42, respectively. Adverse effects were seen in 9 (47.4%) patients. All patients, except 1, had sustained improvement in the mean follow-up period of 11.4 ± 11.6 months. Insulated IL-RFA seems to be safe and effective in selectively targeting deep-seated cutaneous lesions.

Klippel-Trenaunay-Weber syndrome as a cause of chronic thromboembolic pulmonary hypertension

A 52-year-old man was referred to an adult cardiovascular genetic clinic for lifelong venous tortuosity of the left leg. His medical history included recurrent deep venous thromboses of the left...

Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations.

Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

Giant popliteal vein aneurysm in Parkes-Weber syndrome

Parkes-Weber syndrome (PWS) is a congenital vascular anomaly that is characterized by limb overgrowth, macro arterio-venous fistula, and capillary-venous malformation. 1 ISSVA Classification of Vascular Anomalies [Internet] International Society for the Study of Vascular Anomalies. www.issva.orgDate: 2014 Date accessed: December 22, 2015 Google Scholar Clinical manifestations of PWS include limb hypertrophy, cutaneous ulceration, and congestive heart failure secondary to the high-flow fistula. 2 Straface G. Biscetti F. Ghirlanda G. Flex A. Images in vascular medicine. Parkes Weber syndrome: bone involvement visualized by computed tomography angiography. Vasc Med. 2009; 14: 91-92 Crossref PubMed Scopus (7) Google Scholar

Abstract 129: Overexpression of P110alpha Induces Vascular Malformation in Mouse Tail, Feet and Ears

Phosphoinositide-3 kinases (PI3Ks) are a family of signal transduction enzymes involved in critical cellular functions such as cell growth, proliferation, differentiation, motility and survival. Class IA PI3K is composed of a heterodimer between a P110 catalytic subunit and a p85 regulatory subunit. Upregulation of P110alpha protein significantly propagates second messenger response accelerating Akt signaling. To augment Akt activity in macrophages, we generated mice with conditional myeloid lineage-specific (LysM-Cre) overexpression of P110alpha (M-P110α+). Peritoneal macrophages isolated from these mice expressed an additional band slightly different in size than P110alpha protein and had markedly increased phosphorylation of Akt. These mice also exhibited dramatic changes in blood cells including lower levels of white blood cells, B-cells and an increase in neutrophils; whereas the levels of T-cells and monocytes were not different compared to wild-type mice. Because of the defects of B-cell development, M-P110α+ mice had also splenomegaly with decreased levels of follicles. Unexpectedly, M-P110α+ mice at age of 3-4 weeks spontaneously developed a striking phenotype with massive enlargements of small vessels forming malformations in the extremities including tail, feet and ears. These vascular malformations grew very rapidly, and, at age 5-7 months, M-P110α+ mice developed severe hemorrhages from lesions on the tail and feet. The malformations appeared to be mainly venous by Doppler color ultrasonography, and histologically they represented overgrowth of venous and capillary cells that expressed endothelial markers including CD31/PECAM-1, von Willibrand factor and panendothelial cell antigen, MECA-32. These endothelial cells exhibited high levels of proliferation detected by Ki67 staining. In addition, the malformations were surrounded by high numbers of macrophages. In conclusion, M-P110α+ mice develop spontaneous capillary-venous malformations that represent a novel model of the human PIK3CA-related overgrowth spectrum. This mouse model provides a unique opportunity to develop novel therapeutic strategies to prevent capillary and venous malformations.