Search

Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.

Objective Complicated lymphatic anomalies (CLAs) are chronic, progressive, and debilitating conditions that share clinical features, yet key elements for optimal evaluation and management have not been established. We aimed to formulate expert opinion consensus-based guidelines for comprehensive evaluation of CLAs. Study design Patient support groups dedicated to CLAs organized an international conference for vascular anomaly experts from 16 specialties to address the objective. Participants received a set of questions before the meeting and reviewed the literature. Data extracted from international lymphatic anomaly registries were presented and the group separated for panel discussions during the conference. The recommendations achieving consensus within the panel were presented to the entire audience. Open debate occurred until majority approval was achieved. Results The expert group was composed of 52 physicians who defined the clinical elements required to evaluate and diagnose a CLA. The radiology panel established the preferred anatomical and functional imaging methods for diagnosis and the elements required to be described during interpretation. Two medical panels compiled the metabolic and hematologic tests at diagnosis and also recommended functional studies. The surgical group recommended precautions for biopsy and the pathology panel provided biopsy specimen processing guidelines. Conclusions Patients with CLAs require a comprehensive and targeted diagnostic plan for appropriate management, prevention of complications, and conservation of resources. As this population is managed by diverse medical and surgical specialties, we offer an expert multidisciplinary consensus-based opinion on the current literature and on data extracted from international lymphatic anomaly registries.

This chapter, on peripheral malformations, provides an overview of vascular anomalies encountered in the practice of interventional radiology (IR), with a brief discussion of vascular tumors followed by vascular malformations. These include low-flow lesions, lymphatic malformations (LMs) and venous malformations (VMs); high-flow lesions, arteriovenous malformations (AVMs) and arteriovenous fistula (AVF); and Klippel-Trenaunay syndrome (KTS), the combined vascular lesion syndrome of the lower extremity. The natural history, signs and symptoms, clinical appearance, imaging appearance, and treatment of these lesions will be discussed, and illustrative photographs and radiologic studies of typical cases are provided. In recent years, much has been learned about the genetic basis of vascular malformations, which are caused by somatic mutations in a number of angiogenic proteins. Pharmacological treatment, based on these molecular findings, is available for some lesions. Extensive discussion on the biological basis for vascular anomalies is beyond the scope of this chapter.

IMPORTANCE: Patients with somatic overgrowth commonly require surgical intervention to preserve function and improve cosmesis. To our knowledge no observation of scarring outcomes in this population has been published to date. OBJECTIVE: To observe the frequency of abnormal scarring in patients with somatic overgrowth and sequencing-verified mutations in the PIK3CA gene. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study evaluated scarring outcomes in patients with PIK3CA-related overgrowth. Samples of affected tissue were sequenced between July 2015 and October 2016. Medical records from multiple large academic tertiary care centers were reviewed for surgical history and scar descriptions, and clinical photographs were assessed by 2 surgeons (J.N.J. and D.M.K.) to confirm abnormal scarring. Analysis of medical records and photographs was performed between April 2017 and June 2017 by a multidisciplinary team from dermatology, plastic surgery, orthopedic surgery, radiology, and genetics departments. All patients considered for the study were diagnosed with somatic overgrowth and previously had affected tissue sent for next-generation sequencing. Those with pathogenic PIK3CA variants and 1 or more prior surgical procedures were reviewed. MAIN OUTCOMES AND MEASURES: Presence of excessive scarring in patients with PIK3CA overgrowth. RESULTS: A total of 57 patients with segmental overgrowth syndromes were sequenced. Of the 57 patients, 25 (44%) had pathogenic or likely pathogenic variants in PIK3CA. Of those with pathogenic PIK3CA variants, 6 (24%) had past surgical procedures, all with preoperative and postoperative photographs. Of 6 patients with PIK3CA-related overgrowth and a history of 1 or more surgical procedure, 4 (67%) developed excessive scarring. The cohort with abnormal scarring comprised 3 females and 1 male, with a median age of 8.5 years. All abnormal scarring occurred in affected overgrowth tissue. Three of the 4 patients developed the excessive scarring after debulking procedures for overgrowth and/or vascular malformations of the upper or lower extremity. CONCLUSIONS AND RELEVANCE: Excessive scarring occurred frequently in patients with PIK3CA-related overgrowth syndromes. The risk of abnormal scarring should therefore be discussed preoperatively. Given the activating nature of these PIK3CA variants, we suggest that the excessive scarring may be owing in part to up-regulation of the PI3K-Akt-mTOR pathway. Additional studies are needed to assess scarring outcomes in patients with other types of overgrowth.

Background Central conducting lymphatic anomalies (CCLA) may cause chylous leaks and protein-losing enteropathy (PLE) owing to dysfunction of the central lymphatic channels. Most of the treatment strategies for these conditions are palliative and provide transient improvement. Methods We treated 14 patients with intractable chylous leak and/or PLE using a novel technique of lymphaticovenous bypass of the terminal portion of the thoracic duct. Chylous leaks occurred in multiple different anatomic sites. All patients had CCLA and failure of thoracic duct emptying demonstrated by preoperative intranodal lymphangiography. Results Five patients had complete resolution of symptoms, and two patients had partial improvement. There were no major complications. Of 5 patients with PLE, only one improved after lymphaticovenous bypass. Repeat traditional lymphangiography was performed in 4 patients who did not improve, demonstrating patency of the bypass in all cases with persistent sluggish drainage. One patient had repeat MR lymphangiography that did not show the thoracic duct well. Conclusions Bypass of the terminal thoracic duct is a novel procedure that offers improvement and a chance of cure for some patients with devastating manifestations of CCLA who lack other effective therapeutic options. Level of evidence IV.

Introduction Extensive cervicofacial venous malformations (VM) pose significant challenges to a patient's quality of life (altered breathing, dysphagia, dysarthria). Treatment options include: 1) Surgical debulking; 2) Sclerotherapy; 3) laser therapy; or 4) Combined modalities. Recent studies have demonstrated the importance of multimodality and multidisciplinary management of these patients. However, no studies have described combined single anesthetic laser and sclerotherapy treatment. We sought to demonstrate the safety and efficacy of combined Nd:YAG laser and sclerotherapy under the same anesthetic administration. Methods Retrospective review of 8 patients (Age 6 mo −74 yrs, x 31) with extensive cervicofacial VM with significant airway involvement. Patients were treated with combined suspension laryngoscopy with Nd:YAG laser of airway VM followed by image guided direct puncture sclerotherapy using bleomycin in the airway VM and sodium tetradecyl sulfate (STS) foam in the cervicofacial VM during the same anesthetic encounter. Results All 8 patients had extensive cervicofacial VMs that were symptomatic with snoring or orthopnea. Four of the patients had previously been treated at outside institutions with residual disease or significant complications. All patients remained intubated post procedure (Avg. 1.07 days) and tolerated extubation without re-intubation or any major complications. The average length of hospital stay was 3.2 days, of which 1.9 days were spent in the ICU. Patients reported symptomatic improvement or had decreased VM disease on MRI follow up. Conclusion Combined Nd:YAG laser therapy and sclerotherapy allows treatment of both superficial and deep components of VMs in a safe and efficient manner. In addition, suspension laryngoscopy provides improved visualization and access for the interventional radiologist in difficult to reach areas for sclerotherapy.

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant vascular disorder that is associated with inherited inactivating mutations of the RASA1 gene in the majority of cases. Characteristically, patients exhibit one or more focal cutaneous CM that may occur alone or together with AVM, arteriovenous fistulas or lymphatic vessel abnormalities. The focal nature and varying presentation of lesions has led to the hypothesis that somatic “second hit” inactivating mutations of RASA1 are necessary for disease development. In this study, we examined CM from four different CM-AVM patients for the presence of somatically acquired RASA1 mutations. All four patients were shown to possess inactivating heterozygous germline RASA1 mutations. In one of the patients, a somatic inactivating RASA1 mutation (c.1534C > T, p.Arg512*) was additionally identified in CM lesion tissue. The somatic RASA1 mutation was detected within endothelial cells specifically and was in trans with the germline RASA1 mutation. Together with the germline RASA1 mutation (c.2125C > T, p.Arg709*) in the same patient, the endothelial cell somatic RASA1 mutation likely contributed to lesion development. These studies provide the first clear evidence of the second hit model of CM-AVM pathogenesis.

This article describes three hereditary conditions known to be associated with arteriovenous malformation (AVM), along with their clinical and imaging features and angiographic angioarchitecture. Hereditary hemorrhagic telangiectasia, capillary malformation–AVM (CM–AVM), and PTEN tumor hamartoma syndrome are conditions with autosomal dominant inheritance, caused by mutations in different molecular pathways, which frequently present with symptomatic AVMs. Imaging biomarkers, including sites of predilection, angioarchitecture, and tissue overgrowth patterns, are helpful in identifying these patients and selecting appropriate treatment.

The role of angiogenesis in the pathogenesis and progression of vascular malformations is not fully understood. It is clear that vascular malformations develop because of defective angiogenesis or vasculogenesis caused by somatic or germline mutations in the proteins that regulate this process. Once formed, both normal angiogenesis involved in growth and reproduction, and pathological angiogenesis, often a reaction to intervention or injury, have roles in progression and symptomatology.

Endovascular treatment, or sclerotherapy, is the primary treatment for most symptomatic venous malformations [VM]. Different techniques and agents are used, but most patients benefit with decrease swelling and pain and improved appearance. Because of the progressive nature of VM, sclerotherapy is usually not curative. The aim of treatment should be to improve symptoms without risking major morbidity.

While drug treatment has been used to treat infantile hemangiomas for decades, targeted treatment for vascular malformations is relatively new, based largely on better understanding of the molecular regulatory pathways that control angiogenesis (Blatt et al., Pharmacol Ther 139(3):327–333, 2013; Margolin et al., Semin Plast Surg 28(2):79–86, 2014). In a small number of cases, drugs that inhibit various aspects of angiogenesis have been used for arteriovenous malformation (AVM). Mammalian target of rapamycin (MTOR) inhibitors are used in patients with severely symptomatic venous and lymphatic malformations as well as patients with symptomatic hamartomas in phosphatase and tensin homolog (PTEN) tumor hamartoma syndrome (Iacobas et al., Pediatr Blood Cancer 57(2):321–323, 2011).

Venous malformation [VM] presents with a wide spectrum of involvement, ranging from focal cyst-like, blood-filled lesions with minimal communication with the conducting veins to diffuse lesions involving all of the venous structures in multiple planes of an involved anatomic area. The genetic basis is fairly well understood. Clinical problems include pain, deformity, bleeding, and consumption coagulopathy. VMs are hyperintense on T2-weighted MRI sequences.

The diagnosis and management of vascular anomalies of the extremities can be challenging as these disorders are uncommon and may clinically overlap. The aim of this paper is to describe the clinical, radiologic, and histopathologic features of fibro-adipose vascular anomaly (FAVA), a previously unrecognized disorder of the limb.The clinical, imaging, operative, and histopathologic data from patients with a unique intramuscular lesion of the extremities comprising dense fibrofatty tissue and slow-flow vascular malformations were retrospectively reviewed.Sixteen patients diagnosed with FAVA of the extremity (3 male and 13 female individuals) met the clinical, radiologic, and histopathologic inclusion criteria. The age at presentation ranged from the time of birth to 28 years. The locations of the lesions were: calf (n=10), forearm/wrist (n=3), and thigh (n=3). Fourteen patients presented with severe pain. Seven of the patients with calf lesions had limited ankle dorsiflexion. On imaging, the complex intramuscular lesions replaced muscle fibers with fibrofatty overgrowth and phlebectasia (dilation of the veins). The extrafascial component comprised fatty overgrowth, phlebectasia, and an occasional lymphatic malformation. The histopathologic features comprised dense fibrous tissue, fat, and lymphoplasmacytic aggregates within atrophied skeletal muscle. Adipose tissue also infiltrated skeletal muscle at the periphery of the lesion. There were large, irregular, and sometimes excessively muscularized venous channels and smaller, clustered channels. Other findings include organizing thrombi, a lymphatic component, and dense fibrous tissue-encircled nerves.The constellation of clinical, radiologic, and histopathologic features constitutes a distinct entity comprising fibrofatty infiltration of muscle, unusual phlebectasia with pain, and contracture of the affected extremity. The clinical and radiologic findings permit the diagnosis of FAVA with major therapeutic implications.Level III.

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n=100), common CM(s) (port-wine stain; n=100), Sturge-Weber syndrome (n=37), or isolated AVM(s) (n=24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the second-hit hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up. (C) 2013 Wiley Periodicals, Inc.

Symptomatic slow-flow vascular malformations include venous malformations and lymphatic malformations, as well as combined anomalies. Endovascular therapy, consisting mainly of intralesional sclerosant injection, is now accepted as the primary treatment for most of these lesions. Magnetic resonance imaging and ultrasonography supplement physical examination for diagnosis and assessment of the extent of malformation. Endovascular treatment is usually carried out under general anesthesia. Sclerosants for venous malformations include ethanol, 3% sodium tetradecyl sulfate, and bleomycin. Lymphatic malformations can be injected with doxycycline, bleomycin, OK-432, or other sclerosants. Complications of sclerotherapy include tissue necrosis, peripheral nerve injury, hemoglobinuria, deep vein thrombosis, and pulmonary embolism. Although most vascular malformations are not cured, the majority of patients benefit from endovascular treatment.

The clinical implications of venous cerebrovascular maldevelopment remain poorly understood. We report on the association of cerebrofacial venous anomalies (including sinus pericranii), ocular abnormalities and mild developmental delay in two children. In addition, one child had a seizure disorder. Complex cerebrofacial slow-flow vascular anomalies may herald an underlying developmental aberration affecting the cerebrofacial and orbital regions.

Purpose To assess the safety and efficacy of percutaneous image-guided sclerotherapy with doxycycline as primary treatment of intraabdominal lymphatic malformations (LMs). Materials and Methods Retrospective review was performed of all cases of abdominal, mesenteric, or retroperitoneal LMs referred to a single center that were subsequently treated with image-guided percutaneous sclerotherapy. Results Ten patients were included, of whom six were male. The mean age was 13 years (range, 2–28 y). Preprocedural cross-sectional imaging demonstrated a macrocystic malformation in nine patients and a mixed macrocystic/microcystic malformation in one. The malformation was accessed under sonographic guidance, followed by injection of opacified sclerosant agent under fluoroscopic guidance. A drainage catheter was placed in eight cases, in which sclerotherapy was repeated through the catheter for another 1 day (n = 2) or 2 days (n = 6). Doxycycline was reconstituted at 10 mg/mL, with a mean per-session dose of 608 mg (range, 80–1,000 mg) and a mean total dose of 1,230 mg (range, 80–3,000 mg). Peritoneal spill was identified in one case, but the patient remained asymptomatic. No other complications were encountered. Follow-up imaging was available in eight patients: complete resolution was seen in seven, with partial resolution in one. There was no recurrence of clinical symptoms in the follow-up period. Conclusions Initial results indicate that percutaneous image-guided sclerotherapy of macrocystic intraabdominal LMs with doxycycline is a safe and effective procedure.

Objective CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis and spinal abnormalities) is a rare, complex overgrowth syndrome with serious morbidity. In this communication we studied the presence of central and thoracic phlebectasia in patients with CLOVES syndrome and its clinical implications. Methods We conducted a comprehensive search of our databases at Children's Hospital Boston over the last 10 years (1999–2008) for patients with CLOVES syndrome and central and thoracic phlebectasia. Medical records, clinical photographs, and imaging studies of varying modalities were reviewed. Results Review of the clinical data and imaging studies of 12 patients with CLOVES syndrome documented the presence of central and thoracic phlebectasia in 11 patients. Two patients had serious perioperative pulmonary embolism, and 1 died. Conclusions Central and thoracic phlebectasia in patients with CLOVES syndrome is common and increases the risk of pulmonary embolism. Aggressive prophylactic measures should be considered before major interventions.

Cystic fibrosis (CF) is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. There may be intermittent pulmonary exacerbations or acute worsening of infection and obstruction, which require more intensive therapies. Hemoptysis and pneumothorax are complications commonly reported in patients with cystic fibrosis.This document presents the CF Foundation's Pulmonary Therapies Committee recommendations for the treatment of hemoptysis and pneumothorax.The committee recognized that insufficient data exist to develop evidence-based recommendations and so used the Delphi technique to formalize an expert panel's consensus process and develop explicit care recommendations.The expert panel completed the survey twice, allowing refinement of recommendations. Numeric responses to the questions were summarized and applied to a priori definitions to determine levels of consensus. Recommendations were then developed to practical treatment questions based upon the median scores and the degree of consensus.These recommendations for the management of the patient with CF with hemoptysis and pneumothorax are designed for general use in most individuals but should be adapted to meet specific needs as determined by the individuals, their families, and their health care providers. It is hoped that the guidelines provided in this manuscript will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis.

Purpose We report thrombosis of portal and mesenteric veins in patients with a pattern of rectal venous malformations (VMs) and ectatic major mesenteric veins. Methods Eight patients having rectal VMs with either ectatic mesenteric veins and/or evidence of portomesenteric venous thrombosis (PVT), evaluated from 1995-2009, were reviewed. Results Portomesenteric venous thrombosis was evident in 5 patients at presentation. Three had patent ectatic mesenteric veins, 2 with demonstrated reversal of flow, and 2 of whom went on to thrombosis during observation. Six patients developed portal hypertension. Five remain on long-term anticoagulation. After recognizing this pattern, one patient underwent preemptive proximal ligation of the inferior mesenteric vein (IMV) to enhance antegrade portal vein flow and prevent propagation or embolization of venous thrombus from the IMV to the portal vein. Conclusion Rectal VMs should be evaluated for associated ectatic mesenteric veins. The ectatic vein siphons flow from the portal vein down to the rectal VM, leading to stagnation of blood in the portal vein and resultant thrombosis. Primary thrombosis in the stagnant rectal VM and/or mesenteric vein can also predispose to embolization up into the portal vein. This pattern of rectal VM and ectatic mesenteric vein should be considered a risk factor for devastating PVT.

BACKGROUND AND PURPOSE: CM-AVM is a recently recognized autosomal dominant disorder associated with mutations in RASA1. Arteriovenous lesions have been reported in the brain, limbs, and the face in 18.5% of patients. We report a novel association between RASA1 mutations and spinal arteriovenous anomalies. MATERIALS AND METHODS: In a collaborative study, 5 index patients (2 females, 3 males) with spinal AVMs or AVFs and cutaneous multifocal capillary lesions were investigated for the RASA1 gene mutation. RESULTS: All 5 patients were found to have RASA1 mutation (2 de novo, 3 familial), and all had multifocal capillary malformations at birth. Neurologic deficits developed at ages ranging from infancy to early adulthood. All spinal anomalies (2 AVMs at the conus, 1 AVM at the lumbosacral junction, and 1 cervical and 1 cervicothoracic AVF) were complex, extensive, and fast-flow lesions. All patients required treatment based on the clinical and/or radiologic appearance of the lesions. CONCLUSIONS: To our knowledge, an association of RASA1 mutation and spinal AVM/AVF has not been described. MR imaging screening of patients with characteristic CMs and neurologic symptoms presenting at a young age may be useful in detecting the presence of fast-flow intracranial or intraspinal arteriovenous anomalies before potentially significant neurologic insult has occurred.

BACKGROUND AND PURPOSE: The neuroradiology and neurosurgery literature is replete with references to “hemangioma” involving the central nervous system (CNS). However, the number of cases of true infantile hemangiomas in the CNS reported to date is 15. Our purpose was to delineate the definition of infantile hemangiomas, determine their prevalence in the neuraxis, and describe their imaging characteristics and associations in this location. MATERIALS AND METHODS: We reviewed our Vascular Anomalies Center data base from 1999 through May 2008 to assess the prevalence of intracranial or intraspinal involvement within the total cohort of infantile hemangiomas. Fifteen patients were identified with infantile hemangiomas that involved the neuraxis. Two board-certified neuroradiologists reviewed the available imaging of these 15 patients, and a board-certified pathologist reviewed the available histopathology. Clinical records of all 15 patients were reviewed to identify the type of treatment and the treatment response. RESULTS: Of the 1454 patients listed with infantile hemangioma, 15 (∼1.0%) had involvement of the CNS. Eight patients had intracranial infantile hemangioma, 6 had intraspinal hemangioma, and 1 had both. In most instances, there was continuous extension into the neuraxis from an extracranial or extraspinal lesion. There were no cases of a CNS hemangioma without an accompanying extra-CNS tumor. Two patients had findings consistent with posterior fossa anomalies, cervicofacial hemangioma, arterial anomalies, cardiac defects, ocular abnormalities, and associated sternal or ventral defect. Of note, there were no brain or spinal parenchymal signal-intensity abnormalities, and there was no evidence of parenchymal invasion. CONCLUSIONS: CNS involvement by infantile hemangiomas is an unusual occurrence, which, when recognized, can help optimize patient management.

Background: Mutations in the PTEN gene cause two disorders that predispose to cancer, Bannayan–Riley–Ruvalcaba and Cowden syndromes. Some patients with a PTEN mutation have only macrocephaly and autism, but they may still be at risk for neoplasms. Vascular anomalies occur in patients with a PTEN mutation, but they have not been systematically studied or precisely defined. Method: We analysed the clinical and radiological features of the vascular anomalies in 26 patients with PTEN mutations who were either seen or had their medical records reviewed at Children’s Hospital Boston. Results: All 23 patients who had their head circumference measured were macrocephalic, and all 13 male patients who were fully examined had penile freckling. Vascular anomalies were found in 14/26 (54%) of patients: 8/14 (57%) had multiple lesions and 11/13 (85%) who had cross-sectional imaging had intramuscular vascular lesions. Radiographic studies showed that 12/14 (86%) were fast-flow vascular anomalies, and angiography typically showed focal segmental dilatation of draining veins. Excessive ectopic fat in the vascular anomalies was present in 11/12 (92%) of patients on CT or MRI. Intracranial developmental venous anomalies (DVAs) were found in 8/9 (89%) of patients who had brain MRI with contrast. Conclusions: Vascular anomalies in patients with a PTEN mutation are typically multifocal intramuscular combinations of fast-flow channels and ectopic fat. Cerebral DVAs are very common. PTEN mutational analysis should be considered for all macrocephalic patients with fast-flow vascular anomalies or multiple intracranial DVAs.

Hepatic hemangiomas, though histologically benign, may be associated with significant morbidity and mortality in afflicted infants. The literature presents much confusion regarding the natural history and treatment options for hepatic hemangiomas. Clinical manifestations range from asymptomatic self-limiting lesions to congestive heart failure associated with high-volume vascular shunting to fulminant hepatic failure with hypothyroidism, abdominal compartment syndrome, and death. There has been little rationale to choose among observation, corticosteroid, other pharmacologic agents, arterial embolization, hepatic artery ligation, resection, or liver transplantation for any given patient.We analyzed several recent retrospective radiologic analyses and pathologic studies to determine whether hepatic hemangiomas could be categorized, allowing prediction of their natural history and rational choice of therapies based upon their clinical presentation and radiographic appearance.We propose that hepatic hemangiomas do not represent a single entity but, rather, 3 principle categories of lesions: focal, multifocal, and diffuse. Because these 2 categories represent different anatomical and physiologic variants, so, too, may they respond differently to previously anecdotally applied treatment regimens. With input from international multidisciplinary authorities on hemangiomas, we developed and proposed a clinical practice algorithm for the evaluation and management of hepatic hemangiomas. Toward that end, we propose a plan to institute a web-based international hepatic hemangioma registry. Participants in the registry could obtain no-cost centralized review of imaging studies (and histology if available) and guidance regarding the management algorithm from an established multidisciplinary team. In exchange, the registry will facilitate the acquisition of systematic clinical and imaging information.Longitudinal observation of response to more directed treatment protocols may contribute greatly to the understanding of these potentially fatal tumors.

Hemangiomas are high-flow tumors and thus are amenable to arterial embolization. However, due to the invasive nature of arterial embolization in infants, transcatheter therapy is usually reserved for patients with life-threatening symptoms who are failing appropriate medical treatment. Indications for embolization include high-output cardiac failure, bleeding, severe coagulopathy in kaposiform hemangioendothelioma, and control of vascularity prior to resection. Embolization of rapidly involuting congenital hemangiomas typically results in rapid improvement in cardiac volume overload. Improvement is sustained because the tumor usually involutes rapidly. Infantile hemangiomas respond initially to embolization, but response is less dramatic than with RICH, and symptoms usually recur with ongoing tumor proliferation. Infants with kaposiform hemangioendothelioma also respond with rapid increase in platelet counts, but the level drops again a few weeks later.

Vascular anomalies represent a spectrum of disorders from a simple “birthmark” to life- threatening entities. Incorrect nomenclature and misdiagnoses are commonly experienced by patients with these anomalies. Accurate diagnosis is crucial for appropriate evaluation and management, often requiring multidisciplinary specialists. Classification schemes provide a consistent terminology and serve as a guide for pathologists, clinicians, and researchers. One of the goals of the International Society for the Study of Vascular Anomalies (ISSVA) is to achieve a uniform classification. The last classification (1997) stratified vascular lesions into vascular malformations and proliferative vascular lesions (tumors). However, additional disease entities have since been identified that are complex and less easily classified by generic headings, such as capillary malformation, venous malformation, lymphatic malformation, etc. We hereby present the updated official ISSVA classification of vascular anomalies. The general biological scheme of the classification is retained. The section on tumors has been expanded and lists the main recognized vascular tumors, classified as benign, locally aggressive or borderline, and malignant. A list of well-defined diseases is included under each generic heading in the “Simple Vascular Malformations” section. A short definition is added for eponyms. Two new sections were created: one dealing with the malformations of individually named vessels (previously referred to as “truncular” malformations); the second groups lesions of uncertain or debated nature (tumor versus malformation). The known genetic defects underlying vascular anomalies are included in an appendix. This classification is meant to be a framework, acknowledging that it will require modification as new scientific information becomes available.

Summary Background: Pediatric patients who undergo diagnostic radiological imaging studies routinely require moderate or deep sedation to a Ramsay Sedation Score (RSS) of 4 or 5, respectively. The correlation between moderate and deep RSS and bispectral index (BIS) in children has never been validated. This study was designed to determine whether the BIS values correlate with RSS of children sedated for diagnostic imaging studies. Methods: After Institutional Review Board approval, data were prospectively collected on all children receiving pentobarbital alone for computed tomography or magnetic resonance imaging. On arrival in the recovery room, any child assigned a Ramsay score of 4 or 5 was subsequently monitored with the BIS. Receiver-operating characteristic (ROC) analysis was used to evaluate the discriminative ability of BIS in differentiating depth of anesthesia. Results: A total of 86 children over 1 year of age were enrolled. Children with Ramsay 4 (moderate) and Ramsay 5 (deep) sedation scores showed no significant difference in age or pentobarbital dose (mg·kg−1). BIS values followed a normal Gaussian-shaped distribution for both Ramsay scores. There was no significant difference in mean BIS values between the Ramsay groups (P = 0.64). There was a wide variation in BIS values (range of 31–90), which demonstrates that the BIS monitor does not correlate with the clinically assigned RSS depth of anesthesia in children. The ROC curve for BIS is equivalent to a line of nondiscrimination. Conclusion: BIS has limited ability to distinguish between moderate and deep Ramsay sedation levels in children who receive pentobarbital sedation for diagnostic imaging studies.

The extracellular dynamics after intravascular sclerotherapy with an injectable, fibroblast-based engineered construct is unknown.Rabbits underwent ethanol sclerotherapy of a jugular vein segment. Control animals (n = 40) underwent no further treatment or an acellular collagen hydrogel was injected. Experimental animals (n = 20) received a tissue-engineered construct. After 1, 2, 4, and 20 to 24 weeks, segments were evaluated for collagen, glycosaminoglycan (GAG), matrix metalloproteinase (MMP) 2 and 9, and tissue inhibitors of MMP (TIMPs) 1 and 2 and scored on a scale of 0 to 3. Groups and time points were compared using nonparametric statistical analysis.Collagen content was higher in animals that received fibroblasts (P.05). Glycosaminoglycan analysis showed a higher grade only at 1 week (P.05). Collagen and GAG deposition were prominent at weeks 1 through 4, and decreased over time. Both MMP-2 and MMP-9 and TIMP-1 and TIMP-2 grade decreased with time (P.01) in all groups, with no differences between groups.Enhancement of intravascular sclerotherapy by tissue engineering stems, at least in part, from increased local deposition of collagen and GAG. MMP and TIMPs may play a role in recanalization after experimental sclerotherapy. Tissue engineering may be a valuable adjunct for the treatment of vascular malformations.

Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital disorder. We describe an 8-year-old boy with CMTC who presented with symptomatic claudication and diminished distal pulses. Imaging showed severe stenosis of the right common iliac artery, and the child underwent uncomplicated ilio-iliac bypass using prosthetic graft. This is the first report of a patient with CMTC and major vessel stenosis, successfully treated with a prosthetic graft bypass.

Objective. Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on the urine of patients with vascular anomalies (tumors and malformations), relatively common and occasionally life-threatening disorders for which few therapies exist. We sought to determine whether these angiogenesis modulators are present in the urine and whether their expression is associated with the extent and clinical course of the vascular lesion. Methods. A total of 217 patients with vascular anomalies and 74 age-matched control subjects participated. Urinary MMP expression was determined by substrate gel electrophoresis. Urinary bFGF and VEGF levels were measured by enzyme-linked immunosorbent assay. Each patient was assigned to 1 of 2 categories (tumor or malformation) and 1 of 9 specific groups. Extent of the vascular lesion and activity were scored by a blinded clinician. Results. Urinary high molecular weight (hMW) MMPs and bFGF were significantly increased in patients with vascular tumors (53%) and vascular malformations (41%), compared with control subjects (22%). These percentages increased as a function of extent of the lesion and disease activity. hMW MMPs were increased in 4 groups: infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation. No significant differences among the groups were detected for low molecular weight MMPs or VEGF. Conclusions. Expression patterns of hMW MMPs and bFGF in the urine of patients with tumors and malformations are consistent with their different clinical behavior. These data represent the first evidence that MMPs are elevated in the urine of children with vascular anomalies. These data also suggest that the increased expression of urinary MMPs parallels the extent and activity of vascular anomalies in children. In addition to tumors, vascular malformations are angiogenesis dependent, suggesting that progression of a vascular malformation might be suppressed by angiogenic inhibitors, which would target bFGF and MMPs.

Background/Purpose Treatment of vascular malformations with sclerotherapy is often complicated by reexpansion secondary to endothelial recanalization. This study examined the use of an autologous fibroblast construct to enhance intraluminal scar formation after sclerotherapy. Methods New Zealand rabbits (n = 15) underwent ethanol sclerotherapy of a segment of the facial vein. After intraluminal saline flush, animals were equally divided into 3 groups. In group I, no further manipulations were performed. In groups II and III, collagen hydrogel was injected into the sclerosed vein, respectively, without and seeded with autologous green fluorescent protein–labeled fibroblasts. One week postoperatively, the vein segments were examined for patency and resected for histology. Results The sclerosed vein segments remained occluded in all animals. Histological examination of luminal thrombi demonstrated numerous viable fibroblasts in group III, whereas there were none in the control specimens from groups I and II. The presence of the injected autologous green fluorescent protein–labeled fibroblasts within thrombi of group III was confirmed by immunohistochemistry. Conclusions An injectable tissue-engineered construct enhances sclerotherapy of the jugular vein in a leporine model by reliably delivering fibroblasts that populate the resultant thrombus. Further analysis of this novel therapeutic concept as a means to augment permanent scar formation and reduce luminal recanalization is warranted.

Birthmarks are common and commonly ignored by patients and primary care doctors. Yet they sometimes represent significant vascular anomalies that require diagnosis and treatment. We summarize when and how to work up a variety of vascular anomalies.

To compare the effectiveness and safety of oral pentobarbital and oral chloral hydrate for sedation in infants younger than 1 year during magnetic resonance (MR) imaging and computed tomography (CT).A computerized database was used to collect information about all cases in which sedation was used. Outcomes of all infants who received oral pentobarbital or oral chloral hydrate for sedation between 1997 and 2002 were reviewed. Two study groups were compared for sedation and discharge times by using Student t test and for adverse events by using Fisher exact test and multiple logistic regression analysis.Infants (n = 1,316) received an oral medication for sedation. Mean doses were 50 mg/kg chloral hydrate and 4 mg/kg pentobarbital. Student t test demonstrated no difference in mean time to sedation and in time to discharge between groups. Overall adverse event rate during sedation was lower with pentobarbital (0.5%) than with chloral hydrate (2.7%) (P.001). There were fewer episodes of oxygen desaturation with pentobarbital (0.2%) than with chloral hydrate (1.6%) (P.01). Both medications were equally effective in providing successful sedation.Although oral pentobarbital and oral chloral hydrate are equally effective, the incidence of adverse events with pentobarbital was significantly reduced.

Varicocele is a very common condition. Although some patients may have pain, it is usually asymptomatic. Treatment of adolescent and pediatric patients is based on the desire to prevent testicular dysfunction and infertility that may be irreversible in adulthood. Venous embolization of the spermatic vein is an effective and minimally invasive method to occlude the varicocele and is known to improve testicular size and function. Embolization can be optimized by use of sclerosant, such as sodium tetradecyl sulfate (STS) foam or ethanol to permanently occlude the internal spermatic vein. About 10 to 15% of patients have recurrent varicocele after embolization. This is usually due to collateral vessels, such as from the right spermatic vein or the splanchnic veins. Embolizing as low as possible, while preventing pampiniform phlebitis by externally compressing the external inguinal ring, and empiric bilateral embolization appear to have the best outcome for preventing recanalization. Complications of varicocele embolization are uncommon. They include pampiniform phlebitis and venous thromboembolism into the renal vein or pulmonary artery.

The purpose of this study was to compare the safety and efficacy of oral cherry-flavored pentobarbital sodium (Nembutal) and oral chloral hydrate to sedate infants undergoing radiologic imaging.We prospectively recorded data for all infants sedated with oral cherry-flavored pentobarbital sodium and oral chloral hydrate for imaging examinations between January 1997 and August 1999. The parameters recorded were each patient's age, weight, and American Society of Anesthesiologists classification; the time required to sedate; the total length of sedation time; the time required to discharge from the recovery room; and adverse events. The two-sample Student's t test and Fisher's exact test were used for statistical analysis.Oral pentobarbital sodium was administered to 317 infants. These infants had a mean age +/- SD of 6.9 +/- 3.1 months and a mean weight of 7.8 +/- 4.8 kg; they received a median dose of 4 mg/kg of body weight. Oral chloral hydrate was administered to 358 infants. These infants had a mean age of 5.9 +/- 3.3 months and a mean weight of 7.3 +/- 4.9 kg; they received a median dose of 50 mg/kg of body weight. The mean time required to sedate was 19 +/- 14 min for infants receiving oral pentobarbital sodium and 16 +/- 11 min for infants receiving oral chloral hydrate (p = 0.02); the mean time required to discharge was 100 +/- 35 min for infants in the oral pentobarbital sodium group and 103 +/- 36 min for infants in the oral chloral hydrate group (p = 0.31); the mean length of sedation was 81 +/- 34 min for the oral pentobarbital sodium group and 86 +/- 36 min for the oral chloral hydrate group (p = 0.07); and median American Society of Anesthesiologists classification for both groups was P1. Oral pentobarbital sodium was inadequate for sedation in one patient (0.3%) and chloral hydrate was inadequate for sedation in another (0.3%) (p = 1.00). Adverse events were recorded for five patients (1.6%) in the oral pentobarbital sodium group and for six patients (1.7%) in the chloral hydrate group (p = 0.99).Oral pentobarbital sodium is as safe and efficacious as oral chloral hydrate for sedating infants.

The goal of sclerotherapy is to obliterate abnormal channels by damaging the endothelium, thereby resulting in subsequent inflammation and fibrosis. Venous malformations (VMs) are caused by abnormal development of the vein wall, with thinning and asymmetric disruption of the smooth muscle layer of the vein in association with endothelial cell abnormalities. This results in progressive, often asymmetric, dilation of the affected channels. Associated absence or insufficiency of valves in the conducting veins contributes to swelling. Affected channels become progressively enlarged, and the resulting stagnation of blood causes thrombosis, swelling, and pain. Most VMs undergo a continuous cycle of spontaneous thrombosis and thrombolysis. Calcification of thrombi results in formation of phleboliths. Symptoms and signs include blue or purple cutaneous lesions, swelling with dependency or effort, pain, deformity, and consumption coagulopathy. Pulmonary embolism can occur, especially when the conducting venous channels are malformed.

Aim. To describe the imaging findings (MR imaging and angiography) of high-flow vascular anomalies of the tongue, hemangiomas and arteriovenous malformations (AVMs), with emphasis on the discrepant imaging findings in lingual AVMs. Materials and methods. Retrospective review of clinical records, histologic reports and imaging studies of five consecutive patients with high-flow lingual vascular anomalies. Results. One patient had hemangioma (aged 1 month) and four patients had AVMs (aged 15 months, 6, 24, and 33 years). Diagnosis was made on the basis of histology in four lesions and was based on typical clinical history in one lesion. MR imaging and angiographic findings of the hemangioma were typical, but similar findings of focal hyperintense mass on T2-weighted images and angiographic stain were seen in three AVMs (patients aged 15 months, 6 and 33 years). On angiography, there was no nidus or direct arteriovenous (AV) shunting in one AVM (patient aged 15 months). The fourth AVM had typical MR imaging and angiographic findings. Conclusion. The imaging findings in lingual AVMs can be atypical or inconclusive and can mimic hemangiomas, especially in the young patient. Since treatment depends on accurate diagnosis, biopsy may be necessary for lesions with inconclusive imaging findings.

Rapidly involuting congenital hemangioma (RICH) is a recently recognized entity in which the vascular tumor is fully developed at birth and undergoes rapid involution. Angiographic findings in two infants with congenital hemangioma are reported and compared with a more common postnatal infantile hemangioma and a congenital infantile fibrosarcoma. Congenital hemangiomas differed from infantile hemangiomas angiographically by inhomogeneous parenchymal staining, large and irregular feeding arteries in disorganized patterns, arterial aneurysms, direct arteriovenous shunts, and intravascular thrombi. Both infants had clinical evidence of a high-output cardiac failure and intralesional bleeding. This congenital high-flow vascular tumor is difficult to distinguish angiographically from arteriovenous malformation and congenital infantile fibrosarcoma.

Background/Purpose: Vascular anomalies are diagnosed prenatally with increasing frequency. The authors reviewed a group of children treated at their center who had an abnormal prenatal diagnosis to determine (1) fetal age at which the vascular anomaly was detected, (2) general diagnostic accuracy, and (3) impact on ante- and postnatal care. Their findings are compared with reported cases and series. The authors clarify appropriate terminology and underscore the need for interdisciplinary participation of specialists in the field of vascular anomalies. Methods: Patients referred during prenatal life and children with a history of abnormal antenatal findings seen at our vascular anomalies center during a 1-year period (September 1999 through August 2000) were included in this study. The fetal age at diagnosis, pre- and postnatal diagnoses, antenatal course, and neonatal outcome were obtained from the parents, through chart reviews, and through telephone interviews with the treating obstetricians. Results: Twenty-nine patients with vascular anomalies were identified: 17 had a correct prenatal diagnosis, and 12 had an incorrect diagnosis, an overall diagnostic accuracy of 59%. Capillary-lymphatic-venous malformations (CLVM) most often were correctly diagnosed (67%), followed by lymphatic malformation (LM, 62%) and hemangioma (59%). In the infants who received correct diagnoses in utero, there were no fetal deaths and there was no neonatal morbidity. Maternal steroids were administered for a fetus with an intrahepatic hemangioma and deteriorating cardiac function, with subsequent stabilization and successful delivery of a healthy neonate. Among infants with incorrect diagnoses, there was 1 postnatal death, 1 case of erroneous gender assignment, 1 case of unnecessary fetal surgical intervention, 1 unnecessary neonatal laparotomy, and 1 delay in diagnosis of a malignancy. Cesarean section was done for 65% of correctly diagnosed cases, (including 2 ex utero intrapartum [Exit] procedures) and for 33% of incorrectly diagnosed cases. Most diagnoses were made during the mid- to late second trimester and third trimester; only 4 cases (14%) were detected before 20 weeks. Conclusions: In this series, accurate diagnosis optimized antenatal care by providing an opportunity for planning deliveries, for pharmacologic fetal intervention in 1 case, and for appropriate parental counselling. Inaccurate diagnosis was associated with significantly increased morbidity and mortality. Finally, the intrauterine diagnosis of LM should be distinguished from posterior nuchal translucency, an obstetric term applied to fetal lymphatic abnormalities detected in the first and second trimesters that do not manifest as postnatal LM.

Bannayan-Riley-Ruvacalba syndrome (BRRS) belongs to the PTEN hamartoma tumor syndromes and is characterized by a high risk of malignancy in early adulthood added to local destructive effects of hamartomas in childhood. There is no standard treatment for this condition and patients are usually offered symptomatic surgical relief. Rapamycin has been reported to be effective in the management of other conditions associated with PTEN mutation. We report here a case of BRRS in a 6-year-old male with progressive loss of function of left hand and forearm associated with pain. He was treated with oral rapamycin and regained pain-free full mobility.