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1 Tangtiphaiboontana, Jennifer MS1 Summer Basic, Biomedical, or Clinical and Translational Research Neurological Exam Findings of PHACE Syndrome and Associations with Posterior Fossa Abnormalities and Hemangioma Locations Completed: 4/11/ :26:32 AM Page 1 1) Check one only. These opportunities are mutually exclusive. Make sure you've reviewed eligibility and funding amounts on the PFA website before you make your selections. Summer (8 weeks fulltime if research funding, min. 4 weeks for OIP) Funding 2) First Name: Jennifer 3) Last Name: Tangtiphaiboontana 4) Are you currently enrolled in a Pathway to Discovery? No 5) Expected Date of Graduation? 05/17/2013 6) Applicant School Medicine Page 2 7) Check all that apply: Make sure you've reviewed eligibility and funding amounts on the PFA website before you make your selections. Basic, Biomedical, or Clinical and Translational Research Page 3 8) Applicant Level SOM1 Page 4 9) Project Title:

2 Neurological Exam Findings of PHACE Syndrome and Associations with Posterior Fossa Abnormalities and Hemangioma Locations 10) Infantile hemangiomas are benign neoplasms of the vascular endothelium. PHACE syndrome is a recently described syndrome, first reported in 1996, of large segmental cervicofacial hemangiomas associated with certain structural birth defects of the brain, cerebrovasculature, aorta, heart, or eyes. Past studies have demonstrated a strong correlation between hemangiomas and structural defects. Yet, there has been limited investigation of neurological abnormalities in this patient population. This study aims to characterize the specific neurological findings in patients diagnosed with PHACE syndrome. This is a retrospective, multicenter, cross sectional study of approximately 37 children diagnosed with PHACE syndrome at either UCSF Children s Hospital or Texas Children s Hospital (TCH). Neurological exam data will be extracted from medical records using a standardized data collection form created by the investigators. The study will also assess the association of posterior fossa malformations and hemangioma location (S1 through S4) with neurological abnormalities, defined as developmental delay or abnormalities on neurological exam. Imaging data previously collected and reviewed for another study will be used to identify posterior fossa and arterial abnormalities. Specific neurological outcomes include hypotonia and ataxia, and historical or exam evidence of motor delay. We will perform summary statistics and logistic regression tests to measure the associations; alpha will be set at < Upon literature review, a neurological exam study in PHACE syndrome patients has never been done. The purpose of the study is to further characterize PHACE syndrome and provide results that may help create a basis for future neurological studies. Page 5 11) Research Question or Hypothesis In 300 words or less, describe the specific research question you will undertake and your objectives. What are the neurological abnormalities seen in children with PHACE syndrome? Will posterior fossa abnormalities or hemangioma location predict neurological exam abnormalities, specifically hypotonia, ataxia, and motor delay? 12) Background and Review of the Literature In 800 words or less, describe the rationale for your research question through a review of relevant literature and any preliminary studies. Infantile hemangiomas are common benign neoplasms of the vascular endothelium that are absent at birth, grow rapidly during infancy, and slowly regress over time (1). Although they are benign, studies have shown that large, plaque-like segmental hemangiomas involving the face may be associated with several structural abnormalities (2,3). PHACE, an acronym proposed in 1996, is a neurocutaneous syndrome which describes the association of these infantile hemangiomas with one or more of the following structural abnormalities: posterior fossa brain malformations, arterial anomalies, cardiovascular anomalies, and eye anomalies. Diagnosis of PHACE requires the presence of a segmental hemangioma or hemangioma > 5 cm on the face or scalp in addition to one or more of the structural abnormalities listed. A study by Metry et al showed that 25 children in their cohort of 1196 with infantile hemangiomas met the criteria for PHACE syndrome. The authors argue that PHACE, although uncommon, is not a rare condition and may be as common as Sturge-Weber syndrome (3). Other reports have also suggested that some hemangiomas were mistakenly identified as port wine stains and given the diagnosis of atypical Sturge-Weber syndrome instead of the appropriate PHACE syndrome diagnosis (1,6,7). Of the associated abnormalities, structural cerebral and cerebrovascular anomalies are the most common features of PHACE. The common cerebral abnormalities observed include

3 malformations of the cerebellum and of the posterior fossa (8). A recent radiological imaging study by Hess et al found that 19 children out of a cohort of 60 who had PHACE syndrome also had posterior fossa abnormalities (9). These structural cerebral anomalies are associated with significant morbidity due to neurological sequelae that include seizures, stroke, and developmental delay (3). The developmental abnormalities noted include hypotonia and motor and language delays. There may also be a correlation between the location of the segmented hemangiomas on the face and the structural anomalies seen in patients with PHACE syndrome. Haggstrom et al showed a strong correlation between hemangiomas located over the upper half of the face (S1 or frontotemporal and S4 or frontonasal) and structural brain, cerebrovascular, and ocular anomalies (4,5). There have been many studies regarding the variety of anomalies seen in patients with PHACE syndrome however information regarding specific neurological exam findings in these patients is limited. To our knowledge, abnormal neurological exam findings have not been fully characterized for patients with PHACE syndrome. In our project, we will study a previously identified cohort of children with PHACE syndrome at UCSF and TCH. The neuroimaging findings in this cohort have already been described (9). We will now review medical charts for neurological findings and assess if abnormal radiological findings and/or the location of hemangiomas will serve as predictors of neurological abnormalities. We hypothesize that malformations of the posterior fossa will predict neurologic abnormalities, specifically hypotonia, ataxia, and/or motor delay. We also hypothesize that the location of the hemangioma will have no correlation with neurologic abnormalities as prior studies have shown that there is no association between the hemangioma location and arteriopathy (9). The co-investigators of this study include Dr. Heather Fullerton (pediatric vascular neurologist), Dr. Ilona Frieden (pediatric dermatologist), and Drs. Christopher Hess and A. James Barkovich (neuroradiologists) from UCSF; and Dr. Lisa El-Hakam (pediatric neurologist), Dr. Denise Metry (pediatric dermatologist), and a medical student (to be named) from TCH. The purpose of our study is to add to the current literature and create a foundation for other neurological studies to be done in PHACE patients. 13) Project or Research Plan In 1000 words or less, discuss your project design including appropriate methods, number and type of subjects, and data analysis. This is a retrospective, multicenter cross-sectional study of children with PHACE syndrome at UCSF Children s Hospital and TCH. IRB approval for this study has already been obtained at both sites. The study population includes children (<18 years of age) with PHACE syndrome. Inclusion criteria include: (1) diagnosis by a pediatric dermatologist at either UCSF or TCH, (2) parental consent for the on-going PHACE syndrome study, and (3) documented evaluation by a child neurologist at either UCSF or TCH. Our existing cohort of children with PHACE syndrome includes 22 from UCSF and 32 from TCH, all with signed parental consent for inclusion in the study. Of the 22 UCSF subjects, 15 (68%) have had neurological evaluations, and will therefore be included in the study. If we assume a similar proportion with neurological exams at TCH, we will have a sample of 37 subjects. Neurological exam data will be collected from medical records using a standardized data abstraction form and data abstraction instructions created by investigators at UCSF with input from our TCH collaborators. I will perform the data abstraction for the UCSF subjects, with the assistance of Dr. Fullerton. A medical student at TCH will perform the data abstraction for the TCH subjects, with the assistance of Dr. El-Hakam. We will apply the data form to a small sample (approximately 3 patients at each center) initially to review and make any necessary changes to the form. Once a revised form is completed, we will apply the form to all patients in our study. The outcome variables include motor delay, hypotonia, and ataxia. Motor delay is further divided into gross motor delay and fine motor delay. The predictor variables include posterior fossa abnormalities shown on imaging and the location of the hemangiomas on the face (S1-S4). We will use the previously collected dermatologic findings and imaging data for this study, which have been reported (9). These radiologic images have been subjected to review by two neuroradiologists at UCSF, Drs. Hess and Barkovich. Recently acquired PHACE

4 patients from TCH who were not included in the original radiological study will have imaging collected and reviewed in a similar fashion. All statistical analyses will be performed using STATA 10 (College Station, Texas) and alpha will be set at In our data analysis, we will: (1) describe the neurological findings in patients with PHACE syndrome; (2) measure an association between abnormal posterior fossa findings on imaging and neurological abnormalities (a dichotomous combined variable, defined as documentation of hypotonia, ataxia, and/or motor delay), and (3) measure an association between hemangioma location and neurological abnormalities. (1) A description of abnormal neurological exam findings in patients diagnosed with PHACE syndrome Using the data collected from the medical records, I will describe and make comments about neurological exam findings during the first year of life and after the first year of life. Our main outcome variables include hypotonia, ataxia, and gross and fine motor delays. For the first year of life, gross motor delay is defined as rolling over at greater than six months, sitting independently at great than or equal to eight months, and pulling to a stand at greater than or equal to 11 months. Fine motor delay for the first year of life is defined as reaching for a toy at greater than or equal to 6 months, raking grasp at greater than or equal to 8 months, and pincer grasp at greater than or equal to 11 months. Beyond the first year of life, gross motor delay is defined as walking at greater than or equal to 15 months and fine motor delay is defined as scribbling at greater than or equal to 18 months. For both time points, a documented physician diagnosis of fine or gross motor delay (with or without documentation of specific milestones) will also be used to classify a subject as having motor delay. Other aspects of a neurological assessment that will be described include language delay, weakness, cranial nerve palsy, Horner s Syndrome, and hemiatrophy. We will divide the data between the first year of life and after the first year of life to analyze what proportion of patients who were abnormal as infants went on to normalize. The descriptive portion of this project will comprise the bulk of the study. (2) Determination of posterior fossa abnormalities predictive of neurological exam abnormalities I will assess the correlation between posterior fossa abnormalities previously identified in another study and abnormal neurological exam findings. The predictor variable will be posterior fossa abnormalities which are defined as any abnormalities noted by the radiologists on review. Our primary outcome variable will be a combined dichotomous variable of neurological abnormalities, defined as documentation of hypotonia, ataxia, and/or motor delay. Secondary outcome variables will include hypotonia, ataxia, and motor delay, as defined above. I will analyze the proportions of children with versus without posterior fossa abnormalities who had these dichotomous outcome variables; I will compare these proportions using the chi-squared test or Fischer exact when appropriate. Logistic regression tests will be used to test for association and determine odd ratios and 95% confidence intervals. (3)Determination of hemangioma location predictive of neurological exam abnormalities I will assess the association between the features of the hemangiomas and neurological exam abnormalities. Predictor variables will be the location of hemangiomas within segment 1 (S1), segment 2 (S2), segment 3 (S3), or segment 4 (S4) on a facial map developed by Haggstrom, et al. S1 is defined as frontotemporal, S2 is maxillary, S3 is mandibular, and S4 is frontonasal. Outcome variables and analytic techniques will be the same as in section 2, described above. 14) Project Timeline: Develop a timeline including projected completion of preparations (including animal and human subjects protocol approvals); travel; preliminary studies; data collection; data analysis; write-up. Preparation: Create a draft of the data collection form with Dr. Fullerton. Obtain U-care and STOR log-in access. Follow up on IRB modification submission to add my name as an

5 investigator on the project. Week 1: Learn how to navigate U-care and STOR (online medical records system at UCSF). Test data collection form on 3 medical charts. Revise data collection form as appropriate to accommodate clinical data available. Apply final version of form to remaining patients and send final version to investigators at Texas Children s Hospital (TCH). Week 2: Continue to extract data from medical records and input data into database. Obtain clinical data and missing radiological imaging data from investigators at TCH. Send imaging data to radiologists at UCSF for review. Begin reviewing relevant literature in preparation for manuscript writing. Meet with mentor for project status check-in. Week 3: Obtain radiological imaging data from prior study and hemangioma location from records and add to database. Follow up on imaging data sent to radiologists. Begin organizing data for analysis. Begin drafting background section for manuscript and carefully document study methods. Week 4: Learn how to use statistical analysis system (STATA 10, College Station, Texas). Begin analysis of outcome and predictor variables using statistical and logistic regression tests. Continue drafting and revising background and methods sections. Meet with mentor for project status check-in. Week 5: Continue analyzing data and calculate statistical significance. Finalize background and methods sections and begin formulating results. Week 6: Finalize results and discuss with mentor on how to interpret the findings of the study. Begin drafting discussion section of manuscript. Meet with mentor for project status check-in. Present findings to other investigators in the study. Week 7: Begin drafting abstract section and finalize any other parts of the manuscript. Week 8: Have a final draft of the manuscript completed and ready for review by mentor and other experts in the field. Prepare a poster presentation for submission to the Annual Medical Student Research Poster Symposium. 15) In a personal statement of 700 words or less, please explain why you want to do research. Research plays a very important role in advancing medical knowledge and care. I want to do research this summer because I believe it will be a valuable learning experience for me and will contribute significantly to my progression toward becoming a fully developed physician. This summer research experience will also help me to assess whether I would want to incorporate research into my future career as a physician. As an undergraduate, I had meaningful but limited exposure to research. Now in medical school, it is my goal to take advantage of the opportunities at UCSF and gain more research experience. During college, my commitments as a four year student-athlete made it difficult to dedicate the time needed to carry out significant research. However, I was able to make time during my senior year and joined an ongoing clinical research project at the Center for Interdisciplinary Brain Sciences at Stanford University. The primary aim of this project was to look for cerebral structural abnormalities in patients with behavioral disorders. My responsibility was to process MRI scans of patients in the study and isolate areas of interest using a software program developed in the lab. Although I learned a lot about the brain and about raw data processing, this experience did not show me what clinical research really entails. I also lacked the guidance from a research mentor. I want to learn more about clinical research and develop strong research skills that may help me contribute to the advancement of medicine in the future.

6 I am very excited about my summer research project and the idea of being able to see a project through from start to finish. I have worked closely with my research mentor in refining the research question, developing the data extraction form that will be used during the project, and reading relevant literature. My work so far has allowed me to take some ownership in this project and I am looking forward to the results of the study. This project also caters to my interest in pediatrics and neurology. I have always been interested in pediatrics for my career and have volunteered at children's hospitals and shadowed pediatricians in the past. Being able to pursue a research opportunity within this specialty will allow me to experience the pediatric field in a new and exciting way. My previous research experience and classes have also sparked my interest in neurology and I hope it will continue to grow with my summer research project. I am excited to be able to learn and work closely with some of the leading investigators within the fields of pediatric neurology, dermatology, and neuroradiology. My goal for the summer is to work hard and learn about the different components of research, which include grant writing, data collection and analysis, interpretation, writing a paper, and creating a poster presentation. I also hope to be able to continue working on projects for the remainder of my time as a medical student at UCSF. Page 6 16) Literature Cited: (Not to exceed 700 words or approximately one single-spaced page) References: (1) Heyer GL, Millar WS, Ghatan S, Garzon MC. The neurologic aspects of PHACE: Case report and review of the literature. Pediatr Neurol 2006;35: (2) Frieden IJ, Reese V, Cohen D PHACE syndrome: The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol 132: (3) Metry DW, Haggstrom AN, Drolet, BA, Baselga E, Chamlin S, Garzon M, Horii K, Lucky A, Mancini AJ, Newell B, Nopper A, Heyer G, Frieden IJ A prospective study of PHACE syndrome in infantile hemangiomas: Demographic features, clinical findings, and complications. Am J Med Genet Part A 140A: (4) Haggstrom AN, Drolet BA, Baselga E, Chamlin S, Esterly NB, Garzon M, Horii KA, Lucky A, Mancini A, Metry D, Newell B, Nopper A, Frieden IJ Prospective study of infantile hemangiomas: Clinical characteristics predicting complications and treatment. Pediatrics 2006;118(3): (5) Haggstrom AN, Lammer EJ, Schneider RA, Marcucio R, Frieden IJ Patterns of infantile hemangiomas: New clues to hemangioma pathogenesis and embryonic facial development. Pediatrics 117: (6) Billson VR, Gillam GL. An unusual case of Sturge-Weber syndrome. Pathology 1984;16: (7) Loevner L, Quint DJ. Persistent trigeminal artery in a patient with Sturge-Weber syndrome. Am J Roentgenol 1992;158: (8) Metry DW, Heyer GL, Hess C, Garzon M, Haggstrom AN, Frommelt P, Adams D, Siegel D, Hall K, Powell J, Frieden IJ, Drolet BA. Consensus Statement on Diagnostic Criteria for PHACE Syndrome Pediatrics :

7 (9) Hess C, Fullerton HJ, Metry DW, Drolet BA, Siegel DH, Auguste KI, Gupta N, Frieden IJ, Barkovich AJ. Cerebrovascular Anomalies in PHACE Syndrome in 70 Patients: Neuroradiologic Findings and Proposed Pathogenesis. American Journal of Neuroradiology (under review). Page 7 17) Human Subjects Protections: Does your project require CHR approval? Yes Page 8 18) Please describe your timeline for obtaining CHR approval or if applicable, submit your PI's CHR no. CHR approval for study already obtained. CHR no. H Administrative modification form will be submitted before April 30th to add my name to the approved CHR. Page 9 19) UCSF Primary Project or Research Mentor Name: Your project or research must be sponsored by a UCSF-affiliated faculty member who will provide an evaluation of your application. If you are doing an international clinical elective, list the UCSF faculty contact. Dr. Heather Fullerton 20) Primary UCSF Project or Research Mentor Please note that you are responsible for ensuring that your mentor has the web link that will allow them to upload their endorsement and materials. The mentor endorsement is due on the same day as this application! FullertonH@neuropeds.ucsf.edu 21) Mentor Institutional Affiliation: Institution or UCSF School Department UCSF Pediatric Neurology 22) Confirmation: By checking this box, I confirm that I have notified my mentor(s) of their responsibility to submit their endorsement by 5:00 on April 15th. See information at the beginning of this survey for submission instructions. Check here to confirm Page 10

8 23) Current contact information: Current Street Address th Ave, Apt 6 Current City, State, and Postal Code San Francisco, CA UCSF Current Phone Number Jennifer.Tangtiphaiboontana@ucsf.edu 24) Please enter permanent contact information so that we can reach you even after you complete this project/program and your work at UCSF. We need to be in contact to report longitudinal data to funders, possibly including the federal government. Permanent Street Address th Ave, Apt 6 Permanent City, State, and Postal Code San Francisco, CA Permanent jtang67@gmail.com Permanent Phone Number (if appropriate, parents' phone no.) ) Emergency Contact: Emergency Contact Name Thomas Tangtiphaiboontana Relationship to you Brother Emergency Contact phone ) Are you in the MSTP Program? No 27) Please check the box that best reflects your citizenship: U.S. Citizen or U.S. Non-citizen National 28) Are you hispanic (or Latino)? No 29) What is your racial background? Please check all that apply Asian 30) Gender: Female 31) Date of Birth: (MM/DD/YYYY) 06/07/ ) Will you use independent study time to complete this project? Please inquire into the administrative procedures necessary for you to receive credit for independent study from your school and/or program. NOTE: To receive funding from PACCTR, students cannot be enrolled in any credit course or preceptorships. No