Delphi Consensus on Diagnostic Criteria for LUMBAR Syndrome.

OBJECTIVE: To develop consensus on diagnostic criteria for LUMBAR syndrome, the association of segmental infantile hemangiomas that affect the Lower body with Urogenital anomalies, Ulceration, spinal cord Malformations, Bony defects, Anorectal malformations, Arterial anomalies and/or Renal anomalies. STUDY DESIGN: These diagnostic criteria were developed by an expert multidisciplinary and multi-institutional team based on analysis of peer-reviewed data, followed by electronic-Delphi consensus of a panel of 61 international pediatric specialists. RESULTS: After 2 Delphi rounds, a 92% or higher level of agreement was reached for each Delphi statement. 98% of panelists agreed with the diagnostic criteria, and 100% agreed the criteria would be useful in clinical practice. The diagnosis of LUMBAR requires the presence of a segmental, or patterned, infantile hemangioma of the lumbosacral, sacrococcygeal, or pelvic cutaneous regions plus one additional criterion of the urogenital, spinal, bony, anorectal, arterial, or renal organ systems. CONCLUSIONS: These diagnostic criteria will enhance clinical care by improving screening, detection, and overall awareness of this poorly understood neurocutaneous disorder. The criteria can be utilized by a wide variety of pediatric subspecialists. In addition, formal criteria will improve phenotypic uniformity among LUMBAR syndrome cohorts and a patient registry, allowing investigators to assess clinical features, long-term outcomes, and results of genetic sequencing in a standardized manner. Finally, these criteria will serve as a starting point for prospective studies to establish formal screening and management guidelines.

Practice Variations in Managing Infantile Hemangiomas.

Infantile hemangioma (IH) is the most common benign tumor of infancy. For children with IH who require treatment, propranolol and other beta blockers have been shown to be safe and effective. Although consensus guidelines for managing IH have been published, anecdotal experience suggests that there remain variations in management. This study was performed to document these variations amongst providers and to identify areas for future research. We conducted an Internet-based survey of clinicians who treat patients with IH. Hypothetical cases and management scenarios were presented. Twenty-nine respondents participated in the survey. Most respondents use generic propranolol in infants with growing IH of the head and neck, with a goal dose of 2 mg/kg/d, until ~1 year of age. A variety of management strategies were documented including which patients should be treated, optimal dose and duration of therapy, how patients should be monitored, which patients should get additional workup, how propranolol should best be discontinued, and how often to see patients in follow-up. This study demonstrates wide practice variations in managing patients with IH. Further research is indicated to address these variations and develop additional/updated evidence-based guidelines.

Vascular Anomalies Care in the United States: A Cross-Sectional National Survey.

OBJECTIVE: To characterize the current distribution, composition, and practice patterns of multidisciplinary vascular anomalies (VAs) teams in the US. STUDY DESIGN: This is a cross-sectional survey of children's hospitals in the US offering VAs care. We approached 142 children's hospitals that provided care for VAs via email. The survey evaluated VA clinic location, medical staffing, research participation, and treatments offered. The survey was administered between October 2021 and July 2022. RESULTS: Participants from 95 eligible hospitals responded to the survey (response rate = 67%). Large areas of the Midwest and Northwest US had no available multidisciplinary VA teams or clinics. Most respondents worked at academic centers (89%), with 66% at a freestanding children's hospital, and 56% reported having a multidisciplinary clinic. Most common physician participants in clinic included hematology-oncology (91%), interventional radiology (87%), dermatology (85%), plastic surgery (81%), and otolaryngology (74%). Only 38% of programs included medical geneticists. Smaller hospitals had fewer medical and ancillary staff and offered fewer therapeutic options. Research was available at most larger institutions (69%) but less commonly at smaller hospitals (34%). CONCLUSIONS: Major portions of the US lack multidisciplinary VA care. Furthermore, VA programs vary in composition and geneticists are absent from the majority of programs. These findings should inform efforts to address disparate access and develop standards of care for multidisciplinary VA care in the US.

No Association of Sirolimus with Wound Complications in Children With Vascular Anomalies.

INTRODUCTION: Sirolimus has demonstrated effectiveness as a treatment option for several types of vascular anomalies; however, it has a potential side effect of delayed surgical wound healing. The purpose of this study was to evaluate the association of sirolimus with postoperative complications in the pediatric vascular anomaly population. METHODS: A retrospective cohort study was performed for children with a vascular anomaly who underwent excision or debulking of the anomaly from 2015 to 2020. Patient demographics, vascular anomaly characteristics, operative variables, sirolimus dosing information, and perioperative outcomes were collected. Univariate analysis was performed to compare outcomes based on the administration of sirolimus. RESULTS: Forty-seven patients with vascular anomalies underwent 57 surgical procedures (36 without perioperative sirolimus, 21 with perioperative sirolimus). The median age at the time of surgery was seven years (IQR 1.7-14.0). The most common anomalies were lymphatic and venolymphatic malformations. Of the patients administered perioperative sirolimus, the median preoperative and postoperative sirolimus levels were comparable (preoperative 6.9 ng/mL (IQR 4.9-10.1), postoperative 6.5 ng/mL (IQR 4.7-9.4)). The rate of postoperative complications (sirolimus 19%, without sirolimus 11%; p = 0.45) and wound complications (sirolimus 14%, without sirolimus 6%; p = 0.26) were comparable between the cohorts. CONCLUSION: Our results suggest sirolimus may not significantly increase perioperative complication rates in pediatric patients undergoing resection of their vascular anomaly. LEVEL OF EVIDENCE: Level III.

Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: Impact on symptomatology, quality of life, and radiographic response.

BACKGROUND: Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel-Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large-scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM. PROCEDURE: A combined prospective and retrospective cohort of pediatric and young adult patients with CLVM treated with sirolimus was evaluated for disease response, including symptom improvement, quality of life (QOL), and radiologic response. Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Twenty-nine patients with CLVM, including KTS and CLOVES, were included. Ninety-three percent of patients reported improved QOL, and 86% had improvement in at least one symptom. Most significantly, improvement was noted in 100% of patients with bleeding and 89% with thrombotic complications with corresponding decreases in mean D-dimer (p = .008) and increases in mean fibrinogen (p = .016). No patients had progressive disease on sirolimus. Most common side effects included neutropenia, lymphopenia, infection, and aphthous ulcers/stomatitis. No toxicities were life-threatening, and none required long-term discontinuation of sirolimus. CONCLUSION: Sirolimus appears to be effective at reducing complications and improving QOL in patients with CLVM and associated syndromes. In this patient cohort, sirolimus was well tolerated and resulted in few treatment-related toxicities.

Germline genetic mutations in pediatric cerebrovascular anomalies: a multidisciplinary approach to screening, testing, and management.

OBJECTIVE: Genetic alterations are increasingly recognized as etiologic factors linked to the pathogenesis and development of cerebrovascular anomalies. Their identification allows for advanced screening and targeted therapeutic approaches. The authors aimed to describe the role of a collaborative approach to care and genetic testing in pediatric patients with neurovascular anomalies, with the objectives of identifying what genetic testing recommendations were made, the yield of genetic testing, and the implications for familial screening and management at present and in the future. METHODS: The authors performed a descriptive retrospective cohort study examining pediatric patients genetically screened through the Pediatric Neurovascular Program of a single treatment center. Patients 18 years of age and younger with neurovascular anomalies, diagnosed radiographically or histopathologically, were evaluated for germline genetic testing. Patient demographic data and germline genetic testing and recommendation, clinical, treatment, and outcome data were collected and analyzed. RESULTS: Sixty patients were included; 29 (47.5%) were female. The mean age at consultation was 11.0 ± 4.9 years. Diagnoses included cerebral arteriovenous malformations (AVMs) (n = 23), cerebral cavernous malformations (n = 19), non-neurofibromatosis/non-sickle cell moyamoya (n = 8), diffuse cerebral proliferative angiopathy, and megalencephaly-capillary malformation. Of the 56 patients recommended to have genetic testing, 40 completed it. Genetic alterations were found in 13 (23%) patients. Four patients with AVMs had RASA1, GDF2, and ACVRL1 mutations. Four patients with cavernous malformations had Krit1 mutations. One with moyamoya disease had an RNF213 mutation. Three patients with megalencephaly-capillary malformation had PIK3CA mutations, and 1 patient with a cavernous sinus lesion had an MED12 mutation. The majority of AVM patients were treated surgically. Patients with diffuse cerebral proliferative angiopathy were treated medically with sirolimus. At-risk relatives of 3 patients positive for genetic anomalies had also been tested. CONCLUSIONS: This study demonstrates a role for exploring genetic alterations in the identification and treatment of pediatric neurovascular disease pathogenesis. Germline genetic mutations were found in almost one-quarter of the patients screened in this study, results that helped to identify medically targeted treatment modalities for some pediatric neurovascular patients. Insight into the genetic etiology of vascular anomalies may provide broader clinical implications for risk assessment, family screening, follow-up surveillance, and medical management.

Multidisciplinary management of a neonate with kaposiform hemangioendothelioma with extensive cranial fossa destruction.

Kaposiform hemangioendothelioma is a rare, benign, locally destructive vascular tumor. Kasabach-Merritt phenomenon, a consumptive coagulopathy, is a life-threatening complication associated with kaposiform hemangioendothelioma. We describe a case of kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon in a neonate born with a large facial mass with deep extension toward the cranium and airway. The mass was not identified prenatally. The patient was a 37-week gestation age female neonate born via spontaneous vaginal delivery and noted to have a large left-sided facial mass that was not noted on the most recent prenatal ultrasound at 22 weeks gestation age. At birth, the patient was in respiratory distress and required continuous positive airway pressure support. Imaging revealed a large highly vascularized soft tissue mass adjacent to the airway with intracranial extension and bony destruction. Fine needle aspiration confirmed kaposiform hemangioendothelioma. On day of life 6, the patient was noted to have thrombocytopenia, elevated d-dimer, anemia, and hypofibrinogenemia, consistent with Kasabach-Merritt phenomenon, which resolved at day of life 12. Given the location and extent of the mass, medical therapy with single agent oral sirolimus was chosen over surgery. At 13-month follow-up, the infant is well on sirolimus therapy, and the mass has decreased in size, both clinically and on imaging. This case highlights the importance of prompt diagnosis and management of kaposiform hemangioendothelioma with extensive craniofacial and bony involvement with Kasabach-Merritt phenomenon with single oral therapy of sirolimus. Fibrinogen concentrate may be considered in the Kasabach-Merritt phenomenon refractory to cryoprecipitate.

Vascular Anomaly Syndromes in the ISSVA Classification System: Imaging Findings and Role of Interventional Radiology in Management.

Vascular anomalies encompass a spectrum of tumors and malformations that can cause significant morbidity and mortality in children and adults. Use of the International Society for the Study of Vascular Anomalies (ISSVA) classification system is strongly recommended for consistency. Vascular anomalies can occur in isolation or in association with clinical syndromes that involve complex multifocal lesions affecting different organ systems. Thus, it is critical to be familiar with the differences and similarities among vascular anomalies to guide selection of the appropriate imaging studies and possible interventions. Syndromes associated with simple vascular malformations include hereditary hemorrhagic telangiectasia, blue rubber bleb nevus syndrome, Gorham-Stout disease, and primary lymphedema. Syndromes categorized as vascular malformations associated with other anomalies include Klippel-Trenaunay-Weber syndrome, Parkes Weber syndrome, Servelle-Martorell syndrome, Maffucci syndrome, macrocephaly-capillary malformation, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis, skeletal, and spinal anomalies) syndrome, Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome, and CLAPO (capillary malformations of the lower lip, lymphatic malformations of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome. With PHACES (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects and/or coarctation of the aorta, eye abnormalities, and sternal clefting or supraumbilical raphe) syndrome, infantile hemangiomas associated with other lesions occur. Diagnostic and interventional radiologists have important roles in diagnosing these conditions and administering image-guided therapies-embolization and sclerotherapy, and different ablation procedures in particular. The key imaging features of vascular anomaly syndromes based on the 2018 ISSVA classification system and the role of interventional radiology in the management of these syndromes are reviewed. Online supplemental material is available for this article. ©RSNA, 2022.

Institutional Management of Abdominal Lymphatic Malformations: Evolution of Treatment Over a Decade.

INTRODUCTION: Abdominal lymphatic malformations (LM) have been historically managed with surgical resection; however, sclerotherapy and sirolimus have emerged as effective therapies. The purpose of our study is to evaluate our institutional change in management and outcomes for abdominal LM over the past decade. METHODS: A retrospective cohort study was performed for all children with an abdominal LM managed at our multidisciplinary Vascular Anomalies Center from 2011 to 2020. Patient demographics, symptoms, treatment, treatment response, and complications were analyzed with descriptive statistics. RESULTS: Twenty-nine patients with abdominal LM were identified with a median age at treatment of 6 y (interquartile range 3-14). A majority of lesions were identified as macrocystic (n = 18, 62%). The most common intervention was surgery alone (n = 14, 48%) followed by sirolimus alone (n = 4, 14%), and sclerotherapy + sirolimus (n = 4, 14%). Five patients were observed due to lack of symptoms at presentation. Prior to 2017, 91% (10/11) of LM were treated with surgery alone. Following 2017, only 31% (4/13) were treated with surgery alone. Sixty-seven percent (16/24) of treated patients had >95% reduction in LM maximum diameter. A majority of patients (23/24) who received treatment had improvement or resolution of symptoms at median 9-mo follow-up. Only three patients had post-treatment complications, including a drain site infection, small bowel obstruction, and an aspiration event. Complications only occurred after sclerotherapy sessions. CONCLUSIONS: Over the study period, our institution has transitioned to initial management of symptomatic abdominal LM with sclerotherapy and/or sirolimus with almost all treated patients having excellent or satisfactory treatment response. Post-treatment complications were rare.

How we approach the diagnosis and management of complex lymphatic anomalies.

Complex lymphatic anomalies (CLA) are congenital diseases of the lymphatic circulation system that are associated with significant morbidity and early mortality. While guidelines for the comprehensive evaluation of the CLA were recently published, the diagnostic approach and medical management are not standardized. This article presents the clinical features of four CLA: Gorham-Stout disease, generalized lymphatic anomaly, kaposiform lymphangiomatosis, and central collecting lymphatic anomaly. We also offer three cases from the authors' practice and our views on diagnostic testing and disease management including supportive care, medical therapies, and other interventions.

Treatment Outcomes of Manual Lymphatic Drainage in Pediatric Lymphedema.

BACKGROUND: Pediatric lymphedema can result in irreversible, debilitating limb swelling, tissue fibrosis, skin ulcers, infection, and impaired limb function in children at an early age. Manual lymphatic drainage (MLD) is a noninvasive technique, which is a part of intensive decongestive therapy to reroute lymphatic flow to healthy channels used to manage lymphedema. Outcomes of this treatment option in children have not been studied. We evaluated the effect of decongestive therapy involving MLD in pediatric patients with complex lymphatic anomalies by measuring treatment progress and functional outcomes via changes in limb circumference, limb functionality, dexterity, skin quality, and pain. METHODS: A single-institution retrospective study on a cohort of 8 pediatric patients with lymphatic anomalies who completed a course of MLD was conducted from 2015 to 2017 to investigate the role MLD plays in their lymphedema reduction. Pain scores were measured on a scale of 0-10, with 0 being no pain and 10 being the worst pain imaginable. The functional performance was measured by the Canadian Occupational Performance Measurement questionnaire. RESULTS: Among all patients, there were 4 cases affecting the upper extremities, 4 affecting the lower extremities, and 3 affecting the truncal region. Five of 8 patients demonstrated a reduction in lymphedema with an average girth reduction of 8.2% in the lower extremities, 3.0% in the upper extremities, and 7.4% in the truncal regions. In unilateral cases, the difference in limb circumference between the affected and normal extremity decreased by an average of 25.6%. Four patients completed the Canadian Occupational Performance Measurement questionnaire with an average improvement of 30% in daily task performance. Three patients reported complete resolution of pain. CONCLUSIONS: MLD can be used as a reliable noninvasive method for decongestion and analgesia to delay the onset of lymphedema-associated fibrosis and long-term disability in children with complex lymphatic malformations.

Sirolimus efficacy in the treatment of critically ill infants with congenital primary chylous effusions.

BACKGROUND: Chylothorax can be a presenting symptom of complex lymphatic anomaly in children and is associated with significant respiratory morbidity. Historically, the traditional pharmacological treatment has been octreotide. There are several treatments that have been utilized in the past few years including sirolimus; however, data regarding their efficacy and outcomes is limited. Furthermore, sirolimus has proven efficacy in complex vascular malformations, and hence, its utility/efficacy in infantile primary chylous effusions warrants further investigation. METHODS: In this retrospective study at Texas Children's Hospital, data were extracted for all infants with chylothorax who were treated with sirolimus between 2009 and 2020. Details regarding underlying diagnosis, comorbidities, and number of days from sirolimus initiation to resolution of effusion were collected. RESULTS: Initially a total of 12 infants were identified. Among them, seven patients had complete data and were included in the study. Reasons for chylous effusions include presumed complex lymphatic anomaly, generalized lymphatic anomaly, and complex congenital lymphatic anomaly. The mean duration of sirolimus treatment needed for chest tube removal was 16 days, with a median of 19 days and range of 7-22 days. No patients had progression of effusions while on sirolimus. CONCLUSION: With close monitoring, sirolimus appears to be an effective therapy for pediatric lymphatic effusions even in critically ill infants. The study also demonstrates shorter duration of chest tube requirement after initiation of sirolimus compared to previous studies. Larger multi-institutional studies are needed to further support our findings.

Clinical variability in multifocal lymphangioendotheliomatosis with thrombocytopenia: a review of the literature.

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a recently recognized disorder characterized by vascular lesions marked by distinct endothelial proliferation. Lesions affect multiple tissues, and MLT can be associated with refractory thrombocytopenia resulting in life-threatening bleeding. Diagnosing MLT may be challenging given its rarity and phenotypic variability. There is no consensus on the optimal management or treatment duration. We report a 4-month-old male who presented with multiple vascular malformations involving the gastrointestinal tract, lung, bones, choroid plexus, and spleen, with minimal cutaneous involvement and no thrombocytopenia. Wedge resection of a pulmonary nodule was strongly positive for lymphatic vessel endothelial hyaluronan receptor 1 favoring MLT despite the lack of thrombocytopenia. The patient's clinical symptoms and vascular lesions improved on sirolimus therapy. We review the literature to highlight the clinical variability of MLT and discuss the diagnostic and therapeutic options for MLT.

Vascular tumors.

Vascular tumors are a rare subset of vascular anomalies. These are classified based on their malignant potential or local destruction potential. Classification has been historically difficult and treatment recommendations are based on case series. The purpose of this chapter is to review the presentation, pathologic and imaging characteristics. Treatment recommendations are summarized based on the current literature. Congenital and infantile hemangiomas are covered separately in a separate chapter in this issue.

Renal Lymphangiectasia in a Pediatric Patient.

Renal lymphatic abnormalities are rare, and the understanding of pathophysiology involving renal lymphatics is limited. Symptoms can include hypertension, hematuria, proteinuria, chyluria, and abdominal and lumbar pain. Imaging techniques specific to the renal lymphatics have not been clarified. We review the intrahospital imaging evaluation/workup and clinical course of a 6-year-old male who presented to our institution with a large perirenal cyst. His presentation presented a diagnostic and management challenge. The cyst was determined to be lymphatic in origin and required multiple interventional radiology and surgical procedures for management.

Segmental congenital hemangiomas: Three cases of a rare entity.

Congenital hemangiomas (CHs) are unusual and diverse tumors distinguished from infantile hemangiomas by being largely developed at birth and glucose transporter (GLUT1)-negative. We describe three infants who presented in utero or at birth with segmentally distributed vascular tumors that were GLUT1-negative, had histology compatible with congenital hemangioma, and exhibited spontaneous clinical involution. One of the three patients had high-output cardiac failure and was found to have a mutation in GNAQ (c.626A>c, p.Gln209Pro); another had high-output cardiac failure, heterotaxy, and transient hematologic abnormalities and was found to have a mutation in GNA11 (c.626_627delinsCC, p.Gln209Pro). In addition to describing a novel segmental pattern of congenital hemangioma variant with genetic correlations, these cases illustrate the utility of targeted genetic testing to elucidate the exact mutation and thus classification of vascular tumors.

Impact of vascular anomalies on the PTEN phenotype in children and young adults.

Germline PTEN (phosphatase and tensin homolog) mutations lead to inappropriate cell survival and growth, and a predisposition to multiple cancers. Some patients also have vascular anomalies (VAs), and it is unclear whether these patients have different phenotypes or oncologic risks. We conducted a two-institution retrospective cohort study to better understand the phenotypes of children and young adults with PTEN mutations, and to compare individuals with VA to those without. Almost half of the patients had thyroid tumors and nearly one quarter developed gastrointestinal tumors before 30 years of age. The presence of VA was positively associated with bulky overgrowth but did not appear to modify oncologic risk.

Multidisciplinary guidelines for initial evaluation of complicated lymphatic anomalies-expert opinion consensus.

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.

First case of neutropenia and thrombocytopenia in the setting of cerebral cavernous malformation 3.

Cerebral cavernous malformation 3 (CCM3) is a vascular malformation disorder causing brain slow-flow vascular parenchymal lesions. These lesions are the result of variants in the Programmed Cell Death Protein 10 (PDCD10) gene, located on 3q26.1. We report an 8-month-old patient who was presented with seizures and intracranial abscesses and was found to have a variant of PDCD10 on whole exome sequencing, representing, to our knowledge, the youngest case of CCM3 described in the literature. Her clinical course was complicated by the development of neutropenia, requiring granulocyte colony-stimulating factor, and thrombocytopenia, requiring intermittent platelet transfusions, with later development of B acute lymphoblastic leukemia 2 years after initial presentation. This case represents the first description in the literature of hematologic complications in the setting of CCM3. We hypothesize that these hematological manifestations are the result of alterations in the actin and microtubule cytoskeleton, affecting the process of hematopoiesis in a similar fashion to the documented effect of the PDCD10 variant on neuronal migration.