Phenotypic characterisation of SMAD4 variant carriers

Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of variants...

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Bibliographic Details
Published in:Journal of medical genetics Vol. 61; no. 8; p. 734
Main Authors: Caillot, Claire, Saurin, Jean-Christophe, Hervieu, Valérie, Faoucher, Marie, Reversat, Julie, Decullier, Evelyne, Poncet, Gilles, Bailly, Sabine, Giraud, Sophie, Dupuis-Girod, Sophie
Format: Journal Article
Language:English
Published: England 01-08-2024
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Summary:Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of variants followed in an HHT reference centre to further delineate the phenotype. Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database. Thirty-three participants from 15 families, out of 1114 patients with HHT, had an variant (3%).Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Curaçao criteria. Complication frequencies were as follows: epistaxis (n=27/33, 82%), cutaneous telangiectases (n=19/33, 58%), pulmonary arteriovenous malformations (n=17/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7/18, 39%), digestive angiodysplasia (n=13/22, 59%). No cerebral AVMs were diagnosed.Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer.Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation. We describe a large cohort of variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with gene variants and justify systematic cardiac ultrasound and skeletal complications screening.
ISSN:1468-6244
DOI:10.1136/jmg-2023-109632