PHTS-associated vascular anomalies

Introduction

Studies suggest that around 30 to 50% of people with PHTS develop vascular anomalies (VAs), often beginning in infancy or childhood. PHTS VAs can be associated with significant morbidity, and in severe cases mortality, and have a major impact on quality of life.

Addressing the major gaps in our knowledge of the mechanisms that drive the onset and progression of VAs is a key objective of PTEN Research. The three projects below, funded by PTEN Research, aim to advance understanding of VAs in PHTS by combining rigorously designed preclinical models and cutting-edge experimental methodology with analysis of clinical tissue samples from individuals with PHTS and VAs.

Collectively, these projects hold potential to guide new approaches to diagnosis and therapy and to translate scientific insight into improved care and better quality of life for those living with PHTS.

Project 1 goals

The objective of this project is to define and validate a classification system for PHTS VAs.

Project 1 overview

There is limited detailed research describing PHTS VAs, which leads to challenges in classification and makes identification of participants for future clinical trials and selection of appropriate trial endpoints challenging. Key opinion leaders hypothesise that VAs in PHTS are more severe and complex than VAs associated with other conditions.

This collaborative study involving international experts from universities and hospitals in the US and Europe aims to create and validate a classification system for PHTS related VAs through review of retrospective clinical data together with pathology and radiology imaging in what will likely represent the largest clinical cohort of PHTS associated VAs published to date. 

Project 2 goals

The types of VAs seen in individuals with PHTS vary, and not all share the same origin or pattern of progression. Some affect capillaries, veins, or lymphatic vessels, while others involve arteries and veins together. 

This study aims to characterise the variable origin of VAs occurring in PHTS and understand why and how these anomalies appear.

Project 2 overview

This study combines samples from people with PHTS, experimental models, and expert clinical insight to uncover the origins of VAs in PHTS. The team previously identified a specific genetic change in endothelial cells that results in loss of the second, normal copy of PTEN leading to abnormal vascular growth (Castillo S et al., 2025).

This new project extends this work to other vascular cell types, examining their contribution to the development of VAs in PHTS, and exploring the effect of external factors in this process. The study will also look at whether the presence of tumours and VAs together worsens disease outcomes.

Project 3 goals

This project aims to investigate the hypothesis that VAs develop when a germline change in the PTEN gene is combined with a second somatic hit. Together, these two genetic changes could trigger abnormal vasculature growth and the progression of VAs.

Project 3 overview

This study will characterise tissue samples from a variety of VAs and other lesions from people with PHTS. Through their clinical network in Australia, the team plans to recruit around 42 participants with confirmed or suspected PHTS.

The study will use droplet digital PCR and high depth gene panel or exome to interrogate 138 genes linked to VAs and cancer, including PTEN, to identify genetic changes associated with the development of VAs or other lesions.