Hereditary haemorrhagic telangiectasia in Danish patients with pathogenic variants inSMAD4:a nationwide study

Abstract

Background and aimsHereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by recurrent epistaxis, telangiectatic lesions in the skin and mucosal membranes, and arteriovenous malformations (AVMs) in various organs. In 3%–5% of patients, HHT is caused by pathogenic germline variants (PVs) in SMAD4, and these patients often have additional symptoms of juvenile polyposis syndrome and thoracic aneurysms. The phenotypic spectrum of SMAD4-associated HHT is less known, including the penetrance and severity of HHT. We aimed to investigate the phenotypic spectrum of HHT manifestations in Danish patients with PVs in SMAD4 and compare the findings with current literature.MethodsThe study is a retrospective nationwide study with all known Danish patients with PVs in SMAD4. In total, 35 patients were included. The patients were identified by collecting data from genetic laboratories, various databases and clinical genetic departments across the country. Clinical information was mainly collected from the Danish HHT-Centre at Odense University Hospital.ResultsTwenty-nine patients with PVs in SMAD4 (83%) were seen at the HHT-Centre. Seventy-six per cent of these fulfilled the Curaçao criteria, 86% experienced recurrent epistaxis and 83% presented with telangiectatic lesions at different anatomical localisations. Almost 60% had AVMs, mainly pulmonary and hepatic, while none was found to have cerebral AVMs. Fifteen per cent had thoracic aortic abnormalities.ConclusionWe present a nationwide study of one of the largest populations of patients with PVs in SMAD4 that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curaçao criteria.

Phenotypic characterisation ofSMAD4variant carriers

“…No cerebral AMVs were diagnosed in this study, but they have already been reported at a low level in other SMAD4 cohorts. 11 16 33 34 Seventy-five per cent of patients with at least one explored organ had a visceral AVM. Overall, these data are in line with published data on SMAD4 variant carriers and underlines the frequency of visceral AVMs in patients with SMAD4 , as well as the need for systematic screening.…”

“…8 The prevalence of SMAD4 variants in JPS is around 30%. [9][10][11] SMAD4 heterozygous loss-of-function mutations have been described in isolated JP 5 12 and combined JP-HHT syndrome. 4 13 In addition to those main phenotypes, connective tissue abnormalities such has aortic root dilation, mitral valve abnormalities and 'Marfan-like' phenotype with skeletal and cutaneous abnormalities have been described.…”

Course of Treatment of Chronic Bleeding and Anemia with Systemic Bevacizumab Treatment in Hereditary Hemorrhagic Telangiectasia: A Retrospective Cohort

“…Fifteen per cent had thoracic aortic abnormalities. 16 As a result of these processes, hemorrhages due to angiogenic dysregulation and the resulting anemia constitute the basic clinic of the disease. End-stage renal disease, sepsis, and catastrophic bleeding that occur with the progression of the disease are the most common causes of mortality.…”

Whole genome sequencing and disease pattern in patients with juvenile polyposis syndrome: a nationwide study

“…Patients with a pathogenic variant in SMAD4 ( SMAD4 -related JPS) often present with an additional phenotype not seen in patients with a pathogenic variant in BMPR1A ( BMPR1A -related JPS) or in patients with JPS with unknown etiology [ 9 ]. This additional phenotype includes symptoms of hereditary hemorrhagic telangiectasia (HHT) (recurrent epistaxis, AV-malformations primarily in the lungs, liver and brain, besides skin/mucosal telangiectasias) [ 10 ]. The patients also have an increased risk of aortic root dilatation [ 11 , 12 ].…”