Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort

Madeline Pearson; Ruth McGowan; Philip Greene; Wayne Lam; Zofia Miedzybrodzka; Jonathan Berg

doi:10.1038/s41431-024-01607-w

Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort

Eur J Hum Genet. 2024 Apr 16. doi: 10.1038/s41431-024-01607-w. Online ahead of print.

Authors

Madeline Pearson¹, Ruth McGowan², Philip Greene³, Wayne Lam³, Zofia Miedzybrodzka⁴, Jonathan Berg⁵

Affiliations

¹ School of Medicine, University of Dundee, Dundee, Scotland, UK.
² West of Scotland Centre for Genomic Medicine, Glasgow, Scotland, UK.
³ South East of Scotland Clinical Genetics Service, Edinburgh, UK.
⁴ School of Medicine, Medical Sciences, Nutrition and Dentistry, University of Aberdeen, Aberdeen, UK.
⁵ School of Medicine, University of Dundee, Dundee, Scotland, UK. J.N.Berg@dundee.ac.uk.

PMID: 38627541
DOI: 10.1038/s41431-024-01607-w

Abstract

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.