Current Practice: Rationale for Screening Children with Hereditary Hemorrhagic Telangiectasia for Brain Vascular Malformations.

BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular dysplasia characterized by mucocutaneous telangiectasias, recurrent epistaxis, and organ vascular malformations including in the brain, which occur in about 10% of patients. These brain vascular malformations include high-flow AVMs and AVFs as well as low-flow capillary malformations. High-flow lesions can rupture, causing neurologic morbidity and mortality. STATE OF PRACTICE: International guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia recommend screening children for brain vascular malformations with contrast enhanced MR imaging at hereditary hemorrhagic telangiectasia diagnosis. Screening has not been uniformly adopted by some practitioners who contend that screening is not justified. Arguments against screening include application of short-term data from the adult A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) trial of unruptured sporadic brain AVMs to children with hereditary hemorrhagic telangiectasia as well as concerns about administration of sedation or IV contrast and causing patients or families increased anxiety. ANALYSIS: In this article, a multidisciplinary group of experts on hereditary hemorrhagic telangiectasia reviewed data that support screening guidelines and counter arguments against screening. Children with hereditary hemorrhagic telangiectasia have a preponderance of high-flow lesions including AVFs, which have the highest rupture risk. The rupture risk among children is estimated at about 0.7% per lesion per year and is additive across lesions and during a lifetime. ARUBA, an adult clinical trial of expectant medical management versus treatment of unruptured brain AVMs, favored medical management at 5 years but is not applicable to pediatric patients with hereditary hemorrhagic telangiectasia given the life expectancy of a child. Additionally, interventional, radiosurgical, and surgical techniques have improved with time. Experienced neurovascular experts can prospectively determine the best treatment for each child on the basis of local resources. The "watch and wait" approach to imaging means that children with brain vascular malformations will not be identified until a potentially life-threatening and deficit-producing intracerebral hemorrhage occurs. This expert group does not deem this to be an acceptable trade-off.

Capillary malformations.

Capillary malformation (CM), or port wine birthmark, is a cutaneous congenital vascular anomaly that occurs in 0.1%-2% of newborns. Patients with a CM localized on the forehead have an increased risk of developing a neurocutaneous disorder called encephalotrigeminal angiomatosis or Sturge-Weber syndrome (SWS), with complications including seizure, developmental delay, glaucoma, and vision loss. In 2013, a groundbreaking study revealed causative activating somatic mutations in the gene (GNAQ) encoding guanine nucleotide-binding protein Q subunit α (Gαq) in CM and SWS patient tissues. In this Review, we discuss the disease phenotype, the causative GNAQ mutations, and their cellular origin. We also present the endothelial Gαq-related signaling pathways, the current animal models to study CM and its complications, and future options for therapeutic treatment. Further work remains to fully elucidate the cellular and molecular mechanisms underlying the formation and maintenance of the abnormal vessels.

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.

Barriers to Genetic Testing in Vascular Malformations.

Importance: Vascular malformations (VMs) are rare disorders of vasculogenesis associated with substantial morbidity. Improved understanding of their genetic basis is increasingly guiding management, but logistical barriers to obtaining genetic testing in patients with VM may constrain treatment options. Objectives: To examine the institutional mechanisms for and obstacles to obtaining genetic testing for VM. Design, Setting, and Participants: This survey study invited members of the Pediatric Hematology-Oncology Vascular Anomalies Interest Group, representing 81 vascular anomaly centers (VACs) serving individuals up to 18 years of age, to complete an electronic survey. Respondents were mostly pediatric hematologists-oncologists (PHOs) but included geneticists, genetic counselors, clinic administrators, and nurse practitioners. Responses that were received between March 1 and September 30, 2022, were analyzed with descriptive methods. Requirements for genetic testing by several genetics laboratories were also reviewed. Results were stratified by size of the VAC. Main Outcomes and Measures: Vascular anomaly center and associated clinician characteristics and practice patterns for ordering and obtaining insurance approval for genetic testing for VMs were collected. Results: Responses were received from 55 of 81 clinicians, for a response rate of 67.9%. Most respondents were PHOs (50 [90.9%]). Most respondents (32 of 55 respondents [58.2%]) replied that they order genetic testing on 5 to 50 patients per year and reported a genetic testing volume increase of 2- to 10-fold over the past 3 years (38 of 53 respondents [71.7%]). Most testing was ordered by PHOs (35 of 53 respondents [66.0%]), followed by geneticists (28 [52.8%]) and genetic counselors (24 [45.3%]). In-house clinical testing was more common at large and medium-sized VACs. Small VACs were more likely to use oncology-based platforms, which potentially miss low-frequency allelic variants in VM. Logistics and barriers varied by size of the VAC. Obtaining prior authorization was the duty shared among PHOs, nurses, and administrative staff, but the burden of insurance denials and appeals were on PHOs (35 of 53 respondents [66.0%]). Lack of administrative support; unclear institutional, insurance, and laboratory requirements; and lack of clinician education were barriers to genetic testing at VACs of all sizes. The effort to obtain genetic testing for patients with VM, compared with patients with cancer, was perceived as excessive, despite genetic testing being considered standard of care for this population. Conclusions and Relevance: Results of this survey study showed the barriers to genetic testing for VM across VACs, described differences between VACs based on size, and proposed multiple interventions to support clinicians ordering genetic testing for VM. The results and recommendations should have broader application to clinicians caring for patients for whom molecular diagnosis is important to medical management.

Kaposiform lymphangiomatosis: Diagnosis, pathogenesis, and treatment.

Kaposiform lymphangiomatosis (KLA) is a life-threatening rare disease that can cause substantial morbidity, mortality, and social burdens for patients and their families. Diagnosis often occurs long after initial symptoms, and there are few centers in the world with the expertise to diagnose and care for patients with the disease. KLA is a lymphatic anomaly and significant advancements have been made in understanding its pathogenesis and etiology since its first description in 2014. This review provides multidisciplinary, comprehensive, and state-of-the-art information on KLA patient presentation, diagnostic imaging, pathology, organ involvement, genetics, and pathogenesis. Finally, we describe current therapeutic approaches, important areas for research, and challenges faced by patients and their families. Further insights into the pathogenesis of KLA may advance our understanding of other vascular anomalies given that similar signaling pathways may be involved.

Genetic testing in the evaluation of individuals with clinical diagnosis of atypical Sturge-Weber syndrome.

Sturge-Weber Syndrome (SWS) is a rare vascular malformation disorder characterized by abnormal blood vessels in the brain, skin, and eye. SWS is most commonly caused by a somatic mosaic GNAQ-p.Arg183Gln variant. In this series, 12 patients presented for clinical evaluation of SWS but were noted to have atypical features, and therefore germline and/or somatic genetic testing was performed. Atypical features included extensive capillary malformation on the body as well as the face, frontal bossing, macrocephaly, telangiectasia, overgrowth of extremities, absence of neurologic signs and symptoms, and family history of vascular malformations. Five patients had a somatic GNAQ or GNA11 pathogenic variant, one patient had a somatic mosaic likely-pathogenic variant in PIK3CA, and another one had a somatic mosaic deletion that disrupted PTPRD. The other five patients had germline variants in RASA1, EPHB4, or KIT. Our findings suggest that patients presenting for SWS evaluation who have atypical clinical characteristics may have pathogenic germline or somatic variants in genes other than GNAQ or GNA11. Broad germline and somatic genetic testing in these patients with atypical findings may have implications for medical care, prognosis, and trial eligibility.

How we approach genetics in the diagnosis and management of vascular anomalies.

Vascular anomalies are a heterogeneous group of disorders that are currently classified based on their clinical and histological characteristics. Over the past decade, there have been significant advances in molecular genetics that have led to identification of genetic alterations associated with vascular tumors, vascular malformations, and syndromes. Here, we describe known genetic alterations in vascular anomalies, discuss when and how to test, and examine how identification of causative genetic mutations provides for better management of these disorders through improved understanding of their pathogenesis and increasing use of targeted therapeutic agents in order to achieve better outcomes for our patients.

A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations.

BACKGROUND: PIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA-related disorders. MAIN BODY: PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations, and PIK3CA-related nonvascular lesions. Somatic activating mutations (predominantly in hotspots in the helical and kinase domains of PIK3CA, but also in other domains), lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth. Diagnosis is complicated by the variability and overlap in phenotypes associated with PIK3CA-related disorders and should be performed by clinicians with the required expertise along with coordinated care from a multidisciplinary team. Although tissue mosaicism presents challenges for confirmation of PIK3CA mutations, next-generation sequencing and tissue selection have improved detection. Clinical improvement, radiological response, and patient-reported outcomes are typically used to assess treatment response in clinical studies of patients with PIK3CA-related disorders, but objective assessment of treatment response is difficult using imaging (due to the heterogeneous nature of these disorders, superimposed upon patient growth and development). Despite their limitations, patient-reported outcome tools may be best suited to gauge patient improvement. New therapeutic options are needed to provide an alternative or supplement to standard approaches such as surgery and sclerotherapy. Currently, there are no systemic agents that have regulatory approval for these disorders, but the mTOR inhibitor sirolimus has been used for several years in clinical trials and off label to address symptoms. There are also other agents under investigation for PIK3CA-related disorders that act as inhibitors to target different components of the PI3K signaling pathway including AKT (miransertib) and PI3K alpha (alpelisib). CONCLUSION: Management of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.

Multicenter Research Data of Epilepsy Management in Patients With Sturge-Weber Syndrome.

BACKGROUND: Epilepsy in typical Sturge-Weber syndrome (SWS) is common, and many questions remain regarding the treatment outcomes. We analyzed a large multicenter database with focus on neurological drug treatment in different demographic and SWS characteristic groups. METHODS: A total of 268 patients with brain involvement and a history of seizures were selected from a research data registry generated from a multicenter cross-sectional questionnaire. We examined associations between medication use and binary variables such as sex, ethnicity, and brain, skin, and eye involvement laterality. We analyzed group differences in mean number of antiseizure medications and age at diagnosis, enrollment, and seizure onset and examined differences in median SWS neurological scores in groups of interest. RESULTS: The most frequently used medications were levetiracetam (48.1%), low-dose aspirin (44.8%), oxcarbazepine (39.9%), and phenobarbital (14.9%). Lamotrigine was more frequently used in adults than in children (P = 0.001). History of neurosurgery was associated with no current antiseizure medication use (P = 0.001), whereas bilateral brain involvement and family history of seizures were associated with using a higher number of antiseizure medications (P = 0.002, P = 0.027, respectively). Subjects with bilateral brain involvement and early seizure onset were associated with using a higher number of antiseizure medications (P = 0.002) and phenobarbital use (0.003). CONCLUSIONS: Levetiracetam, low-dose aspirin, and oxcarbazepine were the most frequently used medications. More severely affected patients were frequently on a greater number of antiseizure medications. Surgery for epilepsy was associated with the ability to discontinue antiseizure medication. Longitudinal studies are needed to further investigate medication use in patients with SWS.

Sirolimus Treatment in Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome. METHODS: Ten patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit. RESULTS: Sirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus. CONCLUSIONS: Sirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.

Overgrowth syndromes and new therapies.

Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial for establishing the correct diagnosis and optimizing outcomes for these patients. Unique management considerations include increased risk for thrombosis and in some cases, cancer. In recent years, research has demonstrated that these disorders are primarily caused by somatic mutations in growth pathways, particularly the PI3K-mTOR pathway. This improved understanding had led to promising new therapies for this group of patients.

Retrospective study of hematologic complications in patients with slow-flow vascular malformations undergoing sclerotherapy.

BACKGROUND: Slow-flow vascular malformations (SFVM) are associated with localized intravascular coagulopathy (LIC), which is characterized by elevated D-dimer and, when severe, hypofibrinogenemia. LIC results in intralesional clotting and hemorrhage and increases risk for significant thrombotic and bleeding complications. Sclerotherapy has been a suggested potential trigger for LIC worsening to disseminated intravascular coagulopathy. Hematologic complications of sclerotherapy in SFVM, along with low-molecular-weight heparin (LMWH) used to prevent worsening LIC, are largely unstudied. PROCEDURE: Medical records of patients with SFVM and LIC who underwent sclerotherapy at Cincinnati Children's Hospital Medical Center from July 2008 to December 2016 were reviewed for periprocedural hematologic complications. LMWH dose, frequency, and course length were evaluated. RESULTS: Fifty-nine patients with SFVM and LIC underwent 281 sclerotherapy procedures, of which 86% were in children. Eighty-five percent of patients received periprocedural LMWH, although at various doses and course lengths. No thrombotic complications occurred in children. One adult on LMWH developed pulmonary emboli after sclerotherapy. No major bleeding complications occurred postoperatively. In four patients, fibrinogen dropped below 100 mg/dL post-sclerotherapy, requiring cryoprecipitate. One patient required packed red blood cell (RBC) transfusion for sclerotherapy-induced hemolysis. No intraoperative bleeding or thrombotic events occurred. CONCLUSION: LMWH use, at subtherapeutic dosing, was common in this patient population and did not appear to increase risk of significant bleeding before, during, or after sclerotherapy. In children with SFVM, bleeding and thrombotic complications after sclerotherapy appear rare. Although safe, prospective studies are needed to evaluate the efficacy of LMWH to prevent worsening coagulopathy with procedures.

Sirolimus for the treatment of juvenile nasopharyngeal angiofibroma.

Juvenile nasopharyngeal angiofibroma (JNA) is a pathologically benign yet locally aggressive and destructive tumor that develops in the choana and nasopharynx. Historical treatment of JNA has included embolization, surgical resection, and radiation. Here, we describe three patients who received therapy with the mTOR inhibitor sirolimus with improvement in clinical symptoms, imaging, and overall well-being.

Single-stage embolization with n-butyl cyanoacrylate and surgical resection of venous malformations.

PURPOSE: Sclerotherapy or surgical resection is options for symptomatic venous malformations (VM). Sclerotherapy may require repetitive intervention and resection is often avoided due to operative morbidity. The purpose of this study was to report use of single-stage n-butyl cyanoacrylate glue embolization and surgical resection of focal VM. METHODS: A review of patients with focal VM who underwent glue embolization followed by resection at a single tertiary care vascular malformations center was performed. All embolizations were performed with ultrasound and fluoroscopy under the same anesthetic as resection. Patient characteristics and outcomes were evaluated. RESULTS: Fifteen procedures were performed in 12 patients with a total of 20 VM addressed, as several patients had multiple VM. Mean age was 16 ± 9 years. Malformation locations included scalp, hip, gluteal, labial, toe, finger, face, lip, chest, and foot and size ranged from 1.0 to 10.5 cm. Median (range) of prior sclerotherapy treatments was 3 (0-5) and three patients previously underwent surgical resection. Median blood loss was zero (0-10) mL. Surgical complications occurred after five procedures (33%) including superficial wound dehiscence and cellulitis. No complications required readmission or reoperation. At a median follow up of 195 (103-266) days, no patients have required additional treatment. CONCLUSION: Glue embolization and resection of focal VM of variable size and location appears to have durable results and low surgical morbidity. This single-stage procedure, often performed as an outpatient, may be utilized as upfront treatment for symptomatic malformations or for VM refractory to other treatments.

Profound Iron Deficiency Anemia and Irreversible Dilated Cardiomyopathy in a Child.

Iron deficiency anemia has been associated with a secondary and potentially reversible cardiomyopathy. The pathophysiologic paradigm has been that the hematologic disease begets cardiac dysfunction. There may be, however, a point at which myocardial injury is irreversible in susceptible individuals. We present the case of a 4-year-old, developmentally normal, child who presented with iron deficiency anemia and a dilated cardiomyopathy with congestive heart failure. Despite appropriate correction of the anemia, the patient developed decompensated heart failure requiring milrinone therapy and eventual heart transplantation. This report will alert clinicians to the potential for irreversible adverse cardiac remodeling and the importance of close pediatric cardiology consultation and serial assessment in order to implement appropriate heart failure therapy.

Quality of Life in Children With Sturge-Weber Syndrome.

AIM: We assessed the utilization of the National Institutes of Health Quality of Life in Neurological Disorders (Neuro-QoL) in pediatric patients with Sturge-Weber syndrome, a rare neurovascular disorder which frequently results in seizures, brain atrophy, calcification, and a range of neurological impairments. METHODS: Subjects were seen clinically and consented for research. All 22 patients filled out the Pediatric Neuro-QoL. The Neuro-QoL subscores were converted to T-scores to compare with the referenced control population. Twenty-one participants also filled out the Brain Vascular Malformation Consortium Database Questionnaire containing data pertaining to Sturge-Weber syndrome-related medical history, medications, comorbidities, and family history. All data were analyzed with a significance threshold of P < 0.05. RESULTS: Cognitive function quality of life was significantly lower (P < 0.001) in pediatric patients with Sturge-Weber syndrome compared with referenced control subjects. Male gender (P = 0.02) was associated with lower cognitive function Neuro-QoL. The extent of skin (R = -0.46, P = 0.04), total eyelid port-wine birthmark (R = -0.56, P = 0.007), eye (R = -0.58, P = 0.005), and total Sturge-Weber syndrome involvement (R = -0.63, P = 0.002) were negatively correlated with cognitive function Neuro-QoL. A younger age at seizure onset was associated with lower cognitive function Neuro-QoL (hazard ratio = 0.90, P = 0.004) even after controlling for extent of brain, skin, or eye involvement. Antidepressant use was associated with lower cognitive function Neuro-QoL (P = 0.005), and cognitive function Neuro-QoL was negatively correlated with depression Neuro-QoL; however, after adjusting for depression this relationship was no longer significant. CONCLUSIONS: The results suggest targeting cognitive function Neuro-QoL in treatment trials and reiterate the prognostic value of early seizure onset. In addition, sex-related differences were noted, which should be further studied.

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis.

BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of "kaposiform" spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies. PROCEDURE: Cells were obtained from the lungs of one patient isolated at autopsy and the spleen of two patients removed in surgery due to disease complications. A protein kinase array was performed on the KLA cell lysates and normal lymphatic endothelial cells. RESULTS: Higher activation of key signaling pathways in the KLA cells, including PRAS40, AKT1/2/3, and ERK-1/2, was identified by protein kinase array and confirmed by Western blot analysis. This indicated a role for highly activated PI3K-AKT and MAPK-ERK-1/2 signaling pathways in KLA cells. Cell proliferation studies assessed PI3K inhibitors (LY294002; BYL719), AKT inhibitor ARQ092, mTOR inhibitor rapamycin, and MAPK inhibitor U0126. These studies demonstrated that PI3K-AKT-mTOR and MAPK signaling are important mediators of KLA cell proliferation. BYL719 and rapamycin were more effective at inhibiting KLA cell proliferation than U0126. CONCLUSIONS: Our studies using cells from KLA patient lesions demonstrate that these cells are highly proliferative and the PI3K-AKT-mTOR and MAPK pathways are promising therapeutic targets. Development and clinical trials of PI3K, AKT, and MAPK inhibitors for cancer treatment and the data in this study lend support for early clinical trials assessing the efficacy of these inhibitors in KLA patients.

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

BACKGROUND: Sturge-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. METHODS: The questionnaire was collected from 277 participants (age: two months to 66 years) with SWS brain involvement at seven US sites. RESULTS: Bilateral 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. CONCLUSION: The 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 of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease.

BACKGROUND: Generalized lymphatic anomaly (GLA) and Gorham-Stout disease (GSD) are rare complicated lymphatic malformations that occur in multiple body sites and are associated with significant morbidity and mortality. Treatment options have been limited, and conventional medical therapies have been generally ineffective. Emerging data suggest a role for sirolimus as a treatment option for complex lymphatic anomalies. PROCEDURE: Disease response was evaluated by radiologic imaging, quality of life (QOL), and clinical status assessments in children and young adults with GLA and GSD from a multicenter systematic retrospective review of patients treated with oral sirolimus and the prospective phase 2 clinical trial assessing the efficacy and safety of sirolimus in complicated vascular anomalies (NCT00975819). Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Eighteen children and young adults with GLA (n = 13) or GSD (n = 5) received oral sirolimus. Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%). No patients with bone involvement had progression of bone disease, and the majority had symptom or functional improvement on sirolimus. Improvement of pleural and pericardial effusion(s) occurred in 72% and 50% of affected patients; no effusions worsened on treatment. CONCLUSIONS: Sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA and GSD. Functional impairment and/or QOL improved in the majority of individuals with GLA and GSD with sirolimus treatment.