PeDRA

Pediatric Dermatology Research Alliance

Birthmark Studies

Long term outcomes and quality of life in PHACE syndrome

By

Fellow

Mitchell Braun
University of California, San Francisco

Mentor

Erin Mathes, MD
University of California, San Francisco

Overview

PHACE syndrome is a congenital neurocutaneous syndrome discovered in 1996 when Dr. Ilona Frieden synthesized the association between posterior fossa abnormalities, hemangiomas, arterial anomalies, cardiac anomalies, and eye anomalies. Although much has been discovered about PHACE’s clinical features, workup, and surveillance, there is little that is known about its natural history. Now that time has passed since first patients were diagnosed, we have the unique opportunity to study long-term outcomes, symptoms as patient age, and the impact this disease has on QoL. This project will serve as the next step in PHACE syndrome clinical management, answering questions about disease progression and long-term morbidity.

Our long-term goal is to provide details about the natural history of PHACE and define the impact of the disease on QoL. We hope to identify specific risk factors that may predict disease burden and QoL impact in older ages to ultimately establish preventative action or surveillance indications. Our central hypothesis is that all patients will continue to experience symptoms related to their individual constellation of disease findings in adolescence and adulthood and that those with more severe disease (eg more diagnostic criteria met, more severe anomalies) will report worse QoL. We are also aware of the possibility that this investigation will reveal aspects of PHACE syndrome that have otherwise not been defined in the literature.

Specific Aim 1: Establish a cohort of PHACE patients ages 10 and older and characterize symptoms of the disease and clinical outcomes through chart review and patient interviews.

Specific Aim 2: Assess the impact of PHACE syndrome on patient QoL using the Patient Reported Outcomes Measurement Information System (PROMIS) general global health, anxiety, depression, and social relationship domains.

Status

This project was funded through a 2021 PeDRA Research Fellowship Grant.

Multi Center Phenotype-Genotype Analysis of Vascular Overgrowth Syndromes

By

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Fellow

Ashley Ng
Medical College of Wisconsin

Mentor

Beth Drolet, MD
University of Wisconsin – Madison

Overview

Vascular anomalies represent a diverse group of developmental disorders and affect patient-reported quality of life globally, but particularly mental health and emotional well-being due to severe tissue overgrowth; chronic pain; functional impairment; and life-altering, stigmatizing disfigurement. Unfortunately, the care available to these patients suffers from large gaps in clinical practice. Misdiagnosis is common because vascular anomalies result in diverse clinical presentations. Even patients who are correctly diagnosed are likely to undergo invasive and often unsuccessful surgical procedures because no standardized treatment protocols or FDA-approved drugs have been developed to treat vascular anomalies.

We hypothesize that the spatially resolved transcriptome will elucidate shared expression patterns across three key signaling pathways and will accurately locate the depth of altered signaling within the tissue. This will guide molecularly targeted drug development and will help determine the best mechanism for drug delivery (e.g., topical, injectable, or oral). We will investigate our hypothesis through the following aims:

Aim 1: Clarify genotype–phenotype correlations by expanding the existing PeDRA national registry and leveraging cutting-edge 3D imaging technology

Aim 2: Determine the landscape of mRNA expression with spatial resolution in vascular anomalies

Status

This project was funded through a 2021 PeDRA Research Fellowship Grant.

Capillary Malformation-Arteriovenous Malformation Syndrome Guidelines

By


Project Lead:

Lara Wine Lee, MD, PhD
Medical University of South Carolina

Overview:

Patients diagnosed with Capillary Malformation – Arteriovenous Malformation Syndrome present with multiple, small, flat areas of red color change in their skin, known as capillary malformations. Some patients also have vascular malformations where the arteries and veins are not connected to one another properly. These vascular malformations can cause serious medical problems, including limb enlargement, heart problems, seizures, and even death. Unfortunately, there are currently no guidelines helping clinicians to uniformly diagnose or treat patients with this disease. The goal of our study is to review all the current research literature on this disease to create a guideline for physicians. We plan to answer questions such as what skin findings are necessary for diagnosis, when and how to order genetic testing, when to order imaging, whether imaging should be repeated, and how to treat patients with this syndrome.

Status:

This project was funded through a 2020 PeDRA Consensus Grant.

Examining How Virtual Reality Improves Children’s Coping During Dermatologic Procedures

By

Principal Investigator:

Annie Grossberg, MD
Johns Hopkins

Overview:

Children who play virtual reality games have been found to experience less pain and anxiety during vaccination and venipuncture. The immersive experience of virtual reality provides distraction and promotes play during an otherwise painful medical procedure. The aim of this study is to determine whether play with virtual reality games improves coping and decreases
pain and anxiety in children receiving dermatologic procedures. We will invite children to use a virtual reality headset during laser therapy or skin biopsies in our outpatient pediatric dermatology clinic. Our hope is that by distracting children with virtual reality we can help them experience improved coping and reduced pain and anxiety, and thereby give a more therapeutic medical
experience. This has implications on minimizing children’s medical trauma and building children’s resilience during painful procedures.

Status:

This project was funded by a 2019 PeDRA Research Grant.

Towards a precision-based treatment for facial port wine birthmarks

By

Principal Investigator:

Lisa Arkin, MD
University of Wisconsin, Madison

Overview:

Facial vascular stains affect 0.3-0.5% of newborns; they reduce quality of life due to soft tissue overgrowth, nodularity and life-altering, stigmatizing disfigurement. Laser treatment is the current standard of care and relies on selective destruction of aberrant vessels. Yet up to 50% are refractory to laser, and <25% clear entirely. Optimal laser settings require consideration of vessel diameter and depth. In treating patients, clinicians make a blind guess about these parameters, using the immediate endpoint of purpura as a visual marker for destruction. This endpoint, however, doesn’t guarantee vessel shut down or clearance of the vascular stain. Optical coherence tomography (OCT), which was FDA approved for skin-specific imaging in 2010, is a non-invasive imaging modality that uses multiple laser beams scanned simultaneously to enable rapid, non-invasive characterization of vessel diameter and depth. This novel imaging offers the potential for more precise laser destruction of vessels.

Recently, the genetic etiology of vascular stains has been elucidated. They are caused by mosaic mutations in genes that regulate the cell cycle and lead to tightly regulated cellular proliferation and growth. This discovery has transformed our fundamental understanding of the pathophysiology of these birthmarks. It provides a molecular explanation for the development of laser resistance, as these genes share oncogenic pathways that control cell growth, division and death. This underscores the observed resistance to laser as a single treatment modality, since residual mutated cells that escape complete destruction through photo coagulation will continue to multiply.

This proposal aims to leverage genotyping of vascular stains with deep, paired clinical phenotyping, to inform creation of a targeted laser algorithm. We will exploit existing institutional and Pediatric Dermatology Research Alliance (PeDRA) infrastructure to create a compelling cohort. In Aim 1, we will enroll patients, create a tissue biorepository and perform deep, paired clinical phenotyping including OCT to characterize median vessel diameter and depth. In Aim 2, we will correlate genotype with clinical phenotype, and integrate OCT data to create a targeted, laser algorithm to optimize laser destruction of mutated cells. The goal is to create a formula that could be applied by defining clinical phenotype of the stain – simply by examining the patient.

Upon completion, we will have refined genotype-phenotype correlations enhanced by novel imaging, all of which will accelerate precision-based treatments to prevent disfigurement and improve quality of life.

Status:

This study was funded through the 2019 PeDRA Research Hot Seat – A PeDRA Shark Tank.

Genomic and Non genomic Causes of Segmental Pigmentation Disorder

By

Principal Investigator:

Marcia Hogeling, MD
University of California, Los Angeles

Overview:

Segmental Pigmentation Disorder (SegPD) is an uncommon skin condition affecting young children. Segmental Pigmentation Disorder consists of white and brown pigmented birthmarks that appear as large patches on the body. The underlying cause of Segmental Pigmentation Disorder is not known, but it suspected to be due to genetic changes in these different areas of skin color, in the way that the skin cells produce pigment. The purpose of this study is to search for the cause of SegPD, by performing genetic testing of skin samples. Knowing the underlying cause of SegPD will allow us to better explain this skin problem to parents, and make informed recommendations on screening, monitoring and possibly treatments. Many birthmarks in children have the same mutations seen in cancer, and we think our study also might contribute to cancer research if SegPD has these mutations.

Status:

This study was funded as a 2018 PeDRA Pilot Grant and is currently underway.

Topical Sirolimus for the Treatment of Vascular Anomalies

By

Principal Investigator

Sheilagh Maguiness, MD
University of Minnesota

Overview:

There are growing reports regarding the efficacy of oral M-TOR inhibitors such as sirolimus in the treatment of complex combined vascular malformations. There is strong rationale for the use of sirolimus/M-TOR inhibitors in this setting given the genetic basis for many vascular malformations (including lymphatic malformations) which involve the PIK3CA signaling pathway. The use of topical sirolimus preparations have also been reported useful in the setting of facial angiofibromas and capillary malformations . We gathered retrospective data on the use of topical sirolimus for treatment of superficial vascular anomalies.

Status:

This study is complete, resulting in one publication (see publications page).

Participating Sites:

PHACE Risk Based on Clinical Characteristics of Large Facial Hemangiomas: A Retrospective Cohort Study

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Principal Investigators:

Victoria Barrio, MD
Rady Children’s Hospital

Colleen Cotton, MD
Medical University of South Carolina

Overview:

This is a retrospective, multicenter study across fifteen sites in the US and Canada examining all children who were evaluated for PHACE syndrome (whether or not they ultimately received the diagnosis) over a five year period. Objectives of the study are to assemble a multicenter retrospective cohort of patients with large facial hemangiomas evaluated for PHACE syndrome with data regarding epidemiology, hemangioma characteristics, and comorbid anomalies; to perform sub-group analyses of the categories outlined above by hemangioma depth and location, including parotid hemangiomas; and to determine the positive predictive value of clinical features that will provide more data-driven and cost-effective screening of children with large facial hemangiomas.

Status:

Data collection is complete and two manuscripts are in preparation.

This project received a 2019 PeDRA Study Support Grant to perform further statistical analysis to help identify clinical features that may be associated with high or low risk phenotypes in patients diagnosed with PHACE. The team also hopes to compare complication rates and treatment between PHACE and non-PHACE patients with large facial hemangiomas. All statistical analysis is being performed at the Children’s Hospital of Philadelphia.

Participating Sites: