Enhancing diagnosis of PHTS

Introduction

Like many rare diseases, PHTS presents significant diagnostic challenges. Variable phenotypic expression means individuals with PHTS present across multiple specialties, while many features such as macrocephaly, developmental delay and benign skin lesions are non-specific and relatively common in the general population. Limited disease awareness among clinicians further hinders recognition, underscoring the need for diagnostic approaches that go beyond traditional clinical recognition.

Delayed or missed diagnosis carries serious consequences given the substantially elevated lifetime cancer risks associated with PHTS. Evidence-based surveillance protocols can detect cancers earlier and improve outcomes, but only if individuals with PHTS are diagnosed correctly. Beyond individual health implications, timely diagnosis enables cascade testing and reproductive counselling for at-risk relatives.

PTEN Research is supporting enhanced PHTS diagnosis by funding the below two grants.

Project 1 goals

Immunohistochemistry (IHC) staining for specific protein markers has improved recognition of several hereditary cancer syndromes, such as Lynch syndrome. Similar approaches may help identify individuals with PHTS. 

This collaborative study between researchers at The Ohio State University (US), Cleveland Clinic Foundation (US) and Radboud University Medical Center (the Netherlands) aims to assess if PTEN IHC could help enhance diagnosis of PHTS.

Project 1 overview

PTEN expression in samples from individuals with PHTS will be compared to those from individuals with other hereditary cancer syndromes and individuals without known cancer predisposition using IHC. The project will evaluate nearly 1,000 non-malignant tissue samples from colorectal polyps, thyroid and breast tissue collected from individuals with PHTS in addition to matched controls.

Project 2 goals

This study aims to develop a computational phenotype for identifying adults with symptoms consistent with PHTS using electronic medical record data. 

A computational phenotype is an algorithm that uses diagnostic and billing codes and other clinical data to flag individuals whose phenotypes are consistent with a specific condition. Previously, the same team showed that this approach can be used to identify children who should be referred for PTEN genetic testing (doi:10.1186/s11689-022-09434-0). Given that the phenotype of adults with PHTS often differs from the paediatric phenotype and is likely to be more subtle than in children, the present study expands the computational phenotype to adults.

Project 2 overview

The project will develop a computational phenotype based on the Cleveland Clinic's adult PHTS criteria, supplemented by other published PHTS-associated manifestations, and apply it to large-scale clinical datasets. 

The algorithm will be developed and validated across three datasets comprising information from more than 240 million individuals from the US and UK, to evaluate its performance in identifying adults who meet criteria for PTEN genetic testing.