No abstract

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial.

Background and study aim: In most patients with Juvenile Polyposis Syndrome, it is possible to detect a pathogenic germline variant in SMAD4 or BMPR1A. It is well known that patients with a pathogenic variant in SMAD4 have a higher risk of gastric polyposis and gastric cancer compared to BMPR1A carriers, but the natural history of gastric involvement is poorly described. We aimed to systematically review endoscopic and histopathological gastric findings in Danish patients with pathogenic variants in SMAD4. Patients and methods: The study is a retrospective, cross sectional study including endoscopic and histological gastric findings in all known Danish patients with pathogenic variants in SMAD4. The patients were identified by data from various registries as well as from clinical genetic departments and laboratories. Results: We identified 41 patients (2-72 years) with a pathogenic SMAD4 variant. In 31 patients, we were able to retrieve information on upper GI-endoscopy. Eighty-seven percent had at least one gastric abnormality including erythema (72%) and edema (72%). Half of the patients also had vulnerability of the mucosa and 68% had gastric polyposis. An increasing frequency of abnormalities were observed with increasing age. Gastric cancer was diagnosed in 5% of the cases and 22% had a gastrectomy mainly because of massive polyposis. Conclusion: This study shows that most patients with pathogenic SMAD4 variants have a distinct phenotype of the gastric mucosa, and with an increasing severity in the elderly patients. These findings provide new insights into the natural history of gastric manifestations in patients with pathogenic SMAD4 variants.