Birthmark Studies

Principal Investigator:

Naiem Issa, MD, PhD
University of Miami Leonard M. Miller School of Medicine

Overview:

Sturge-Weber Syndrome (SWS) is a rare disease where a mutation causes abnormal capillary malformations affecting the skin, eyes, and brain leading to disfiguring skin changes, visual disturbances, as well as seizures and intellectual disability. A pharmacologic treatment at the root of SWS, the GNAQ (Gq) protein, is in critical need. Current drug development efforts have been focused on targeting proteins downstream of Gq. However, there is no small molecule drug that directly targets the Gq mutation causing SWS.

We discovered the drug NTI-001 to be the first small molecule inhibitor of Gq. This is a critical and historic milestone for not just SWS but also for G protein drug discovery at large as this is first-in-class and will serve as the framework for future drug discovery endeavors. Our proposal is to further assess NTI-001 as an inhibitor for the SWS-specific mutant of Gq known as the Gq R183Q mutant.

Status:

This project was funded by a 2021 PeDRA Research Grant.

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.

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.

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.

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.

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.