Multicenter Phenotype-Genotype Analysis of Vascular Stains to Optimize Treatment Utilizing Optical Coherence Tomography

Vascular stains, commonly called "port wine birthmarks," are vascular anomalies that affect 0.3-0.5% of newborns; they impact quality of life due to soft tissue overgrowth, nodularity and life-altering, stigmatizing disfigurement. Laser treatment is the standard of care and relies on photocoagulation of vessels. Yet less than 25% are reported to clear entirely; the reason for this lack of response is poorly understood. Recently, mosaic mutations in genes that control cell-cycle regulation including GNAQ, GNA11, PiK3CA and others were elucidated as a genetic cause for these birthmarks. This finding has transformed our fundamental understanding of their pathophysiology. It provides a molecular explanation for limited responsiveness to laser, as these genes share oncogenic pathways that result in synchronous, tightly regulated cellular proliferation and growth. Most importantly, this discovery has unlocked the potential to utilize pharmacologic blockade of activated downstream pathways to improve outcomes.

This proposal aims to utilize novel imaging to highlight differences in the vasculature of vascular birthmarks with genotyping and deep, paired clinical phenotyping, and to create a targeted laser algorithm based on genotype and age. In a small subset of patients with confirmed GNAQ/GNA11 genotyping, the investigators will utilize single cell spatial transcriptome profiling of affected tissue to drive drug discovery. Upon completion of this project, the investigators will have refined genotype-phenotype correlations enhanced by novel imaging of targeted tissue, elucidating differences in the vasculature by genotype, all of which may accelerate precision-based treatments to prevent disfigurement and improve quality of life. These results will provide critical data for implementation of clinical trials that will shift treatment paradigms from a single, ineffective destructive treatment modality to a targeted pharmacologic intervention coupled with light.

The investigators hypothesize that clearance of port wine birthmarks will require: 1) A precision-based approach including optimal laser dosimetry informed by novel angiographic imaging, age, and genotype, and 2) pathway specific-targeted pharmacologic blockade of activated pathways informed by investigation of downstream effectors. The long-term goal is to shift treatment paradigms from a single ineffective destructive modality to a targeted laser source coupled with targeted topical therapy.

Aim 1: Correlate genotype with clinical phenotype

• 1.1 Correlate genotype with comprehensive phenotyping on available participants in Strata A and Strata B. When stratified by participant age, the hypothesis is that genotype will influence vessel size, with greater cell-cycle activation associated with larger median vessel diameter and depth on OCT.
• 1.2 Correlate clinical phenotype with dynamic optical coherence tomography (OCT) in Strata A and Strata B. The investigators hypothesize that participant age will be the greatest predictor of median vessel size and depth on OCT. The investigators expect to see diversity in the architecture and patterning of the vasculature based on genotype. The hypothesis is GNAQ mutated patients will demonstrate significant vascular distortion, with drop out and vascular dilation as has been reported in the ocular OCT literature in patients with Sturge Weber Syndrome.
• 1.3 Collect both quantitative and qualitative outcomes in participants treated with OCT to evaluate the participant experience utilizing this adjuvant modality in treatment in Strata B.
• 1.4 Integrate OCT data to create a targeted laser algorithm by age and/or genotype to optimize photo-coagulation of mutated cells in Strata B.