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Short report
Seven cases of hereditary haemorrhagic telangiectasia-like hepatic vascular abnormalities associated with EPHB4 pathogenic variants
  1. Alexandre Guilhem1,
  2. Sophie Dupuis-Girod1,2,
  3. Olivier Espitia3,
  4. Sophie Rivière4,
  5. Julie Seguier5,
  6. Mallorie Kerjouan6,
  7. Christian Lavigne7,
  8. Hélène Maillard8,
  9. Pascal Magro9,
  10. Laurent Alric10,
  11. Dan Lipsker11,
  12. Antoine Parrot12,
  13. Vanessa Leguy13,
  14. Claire Vanlemmens14,
  15. Laurent Guibaud15,
  16. Miikka Vikkula16,
  17. Melanie Eyries17,
  18. Pierre-Jean Valette18,
  19. Sophie Giraud1
  1. 1 Service de Génétique, Centre de Référence pour la maladie de Rendu-Osler, CHU Lyon, Lyon, France
  2. 2 Laboratory Biology of Cancer and Infection, CEA de Grenoble, Grenoble, France
  3. 3 Department of Internal and Vascular Medicine, CHU Nantes, Nantes, France
  4. 4 Médecine Interne et Maladies Multi-Organiques, CHU Montpellier, Montpellier, France
  5. 5 Département de Médecine Interne, Hôpital de la Timone, Marseille, France
  6. 6 Service de Pneumologie, CHU Rennes, Rennes, France
  7. 7 Internal Medecine Department, CHU Angers, Angers, France
  8. 8 Service de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France
  9. 9 Service de Pneumologie, Hôpital Bretonneau, Tours, France
  10. 10 Médecine Interne, Département des Maladies Digestives, CHU Toulouse, Toulouse, France
  11. 11 Clinique Dermatologique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  12. 12 Service de Pneumologie, Hôpital Tenon, Paris, France
  13. 13 Service de Médecine Interne et Immunologie Clinique, CHU Dijon, Dijon, France
  14. 14 Service Hépatologie et soins intensifs digestifs, CHU Besancon, Besancon, France
  15. 15 Service d’Imagerie Médicale Pédiatrique et Foetale, CHU Lyon, Lyon, France
  16. 16 Human Molecular Genetics, de Duve Institute, Bruxelles, Belgium
  17. 17 Genetics, Groupe Hospitalier Pitié-Salpétrière, AP-HP, Paris, France
  18. 18 Service d'Imagerie Médicale et Interventionnelle, CHU Lyon, Lyon, France
  1. Correspondence to Dr Alexandre Guilhem, Service de Génétique, Hospices Civils de Lyon, Bron 69002, France; alexandre.guilhem{at}


Background EPHB4 loss of function is associated with type 2 capillary malformation–arteriovenous malformation syndrome, an autosomal dominant vascular disorder. The phenotype partially overlaps with hereditary haemorrhagic telangiectasia (HHT) due to epistaxis, telangiectases and cerebral arteriovenous malformations, but a similar liver involvement has never been described.

Methods Members of the French HHT network reported their cases of EPHB4 mutation identified after an initial suspicion of HHT. Clinical, radiological and genetic characteristics were analysed.

Results Among 21 patients with EPHB4, 15 had a liver imaging, including 7 with HHT-like abnormalities (2 female patients and 5 male patients, ages 43–69 years). Atypical epistaxis and telangiectases were noted in two cases each. They were significantly older than the eight patients with normal imaging (median: 51 vs 20 years, p<0.0006).

The main hepatic artery was dilated in all the cases (diameter: 8–11 mm). Six patients had hepatic telangiectases. All kind of shunts were described (arteriosystemic: five patients, arterioportal: two patients, portosystemic: three patients). The overall liver appearance was considered as typical of HHT in six cases.

Six EPHB4 variants were classified as pathogenic and one as likely pathogenic, with no specific hot spot.

Conclusion EPHB4 loss-of-function variants can be associated with HHT-like hepatic abnormalities and should be tested for atypical HHT presentations.

  • Cardiovascular Abnormalities
  • Phenotype
  • Liver Diseases

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  • Contributors AG, SD-G, MV, ME, PJV and SG conceived the study and analysed the data. SD-G, OE, SR, JS, MK, CL, HM, PM, LA, DL, AP, VL, CV and LG provided clinical cases. AG wrote the manuscript. SD-G, OE, CL, AP, ME, PJV and SG corrected the manuscript. All authors reviewed and approved the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • 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.