Phenotypic characterisation of SMAD4 variant carriers

Abstract

Background: Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of SMAD4 variants followed in an HHT reference centre to further delineate the phenotype.

Methods: Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database.

Results: Thirty-three participants from 15 families, out of 1114 patients with HHT, had an SMAD4 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 et al 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.

Conclusion: We describe a large cohort of SMAD4 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 SMAD4 gene variants and justify systematic cardiac ultrasound and skeletal complications screening.

Keywords: genetics; patient care; pediatrics; vascular diseases.

Figure 1

SMAD4 in the transforming growth factor-beta (TGFβ) signalling pathway. SMAD4 is a central element in SMAD-dependent TGFβ signalling. For each ligand, specific receptors and receptor-associated SMADs are activated. BMPR1A and SMAD4 have been identified in juvenile polyposis syndrome, ALK1/ACVRL1, ENG and SMAD4 in hereditary haemorrhagic telangiectasia, TGFBR1, TGFBR2, SMAD2 and SMAD3 in connective tissue disorders (Loeys-Dietz syndrome).

Figure 2

Identified heterozygous SMAD4 variants. Variants in red are frameshift variants. Variants in black are missense variants. Variants in bold have been found in multiple families. The c.1245_1248del variant was present in 19 patients from 5 different families. c.1081C>T was found in three patients from three different families, with one proven de novo occurrence. Two gene deletions were identified, one by MLPA, the other with chromosomal microarray analysis. UTR, untranslated region.