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Phenotypes
Original research
Hereditary haemorrhagic telangiectasia in Danish patients with pathogenic variants in SMAD4: a nationwide study
  1. Anne Marie Jelsig1,
  2. Anette Kjeldsen2,
  3. Lise Lotte Christensen3,
  4. Birgitte Bertelsen4,
  5. John Gásdal Karstensen5,6,
  6. Klaus Brusgaard7,
  7. Pernille M Torring7
  1. 1 Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
  2. 2 Department of Otorhinolaryngology HHT-Centre, Odense University Hospital, Odense, Denmark
  3. 3 Department of Molecular Medicine, Aarhus Universitetshospital, Aarhus, Denmark
  4. 4 Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark
  5. 5 Danish Polyposis Registry, Gastro Unit, Hvidovre Hospital, Hvidovre, Denmark
  6. 6 Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  7. 7 Department of Clinical Genetics, Odense Universitetshospital, Odense, Denmark
  1. Correspondence to Dr Anne Marie Jelsig, Department of Clinical Genetics, Rigshospitalet, Copenhagen 2100, Denmark; Anne.Marie.Jelsig{at}regionh.dk

Abstract

Background and aims Hereditary 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.

Methods The 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.

Results Twenty-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.

Conclusion We 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.

  • Genetics
  • Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Data availability statement

No data are available.

https://doi.org/10.1136/jmg-2022-108766

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    Data availability statement

    No data are available.

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    Footnotes

    • Contributors AMJ planned, conducted, identified patients and data, analysed data and wrote the article, and is the corresponding author as weel as the guarantor of the work. AK identified patients, provided data, helped with data interpretation and commented on the article. LLC provided and analysed data, and commented on the final draft of the article. BB provided and analysed data, and commented on the final draft of the article. JGK provided and analysed data, and commented on the final draft of the article. KB provided and analysed data, and commented on the final draft of the article. PMT identified patients, provided data, helped with data interpretation and commented on the article.

    • Funding The project was supported by Copenhagen University Hospital, Rigshospitalet, Denmark.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.