Press releases

A Genetic Cause of Tree Man Syndrome (Skin Papillomavirus) Identified for the First Time

02 Jul 2021 | By Inserm (Newsroom) | Genetics, genomics and bioinformatics


Papillomavirus. © Inserm/U190


Most of us carry human papillomaviruses (HPVs) – particularly skin papillomaviruses that generally cause warts or benign local lesions. However, on very rare occasions worldwide patients develop severe forms of these viral diseases, including “tree man” syndrome. This highly debilitating disease manifests as the uncontrolled growth of horn-like skin lesions for which surgery is ineffective. As part of an international collaboration, researchers from Inserm, teacher-researchers from Université de Paris, and doctors from AP-HP, all grouped at the Imagine Institute (Inserm/Université de Paris, Paris hospitals group AP-HP) located at Necker Hospital for Sick Children AP-HP, have been the first to reveal a genetic cause of tree man syndrome. This research was conducted by Vivien Béziat, under the supervision of Profs. Jean-Laurent Casanova and Laurent Abel, who run a laboratory with branches in Paris and New York’s Rockefeller University1. It was published on July 1, 2021, in the journal Cell.

There are over 200 human papillomaviruses (HPVs), with some causing benign skin lesions such as common or plantar warts, and others with the potential to cause cervical cancer. The Human Genetics of Infectious Diseases laboratory has focused on skin HPVs, working for several years to understand why these usually harmless infections take a severe turn in a few very rare cases.

A genetic mutation increases susceptibility to skin papillomaviruses

In a publication in the journal Cell, the team of Vivien Béziat, Inserm researcher in the Human Genetics of Infectious Diseases laboratory and first author of the publication, studied the genetic characteristics of an Iranian patient with tree man syndrome, and two members of his family presenting with a severe skin HPV infection involving large numbers of warts on their hands and feet, but who had not developed the syndrome. What the three patients were found to have in common was a mutation of the CD28 gene, which usually plays a major role in activating T cells – the immune cells that destroy the cells infected by a virus.

In these patients, the CD28 gene mutation prevents the immune system from recognizing the virus and from mounting an appropriate response. The virus then proliferates in the keratinocytes, the cells that make up the skin’s epidermis, causing the uncontrolled multiplication of skin warts and/or horn-like lesions. This is the first time that a genetic cause of tree man syndrome has been identified.

The CD28 gene, central for resisting certain skin papillomaviruses, but not for the immune system

However, it was when analyzing the CD28 mutation that the researchers made a different discovery. The CD28 gene, until now considered a mainstay in immune system function and T cell response, does not appear to play such a major role. The medical histories of the three patients showed exposure to several HPV types and to a very large number of other pathogens. Yet only the patient with tree man syndrome developed a severe reaction to HPV2, and only the two members of his family did so to HPV4.

“These patients only showed abnormally high susceptibility to certain papillomaviruses of the gamma-HPV and alpha-HPV genus. Based on the work done over the past 30 years, we thought that a CD28 gene dysfunction would actually make patients susceptible to many infectious agents. But even if their immune response is weakened, the patients defend themselves well against other pathogens,explains Béziat.

A discovery which therefore provides new insights into genetic susceptibility to HPVs and challenges the dogmas of T cell-mediated immune response.

“No treatment has so far been shown to be effective against tree man syndrome”. A hematopoietic stem cell transplant to replace the patient’s immune system is being considered. However, this major, costly treatment is not easily accessible to populations living in less developed countries, who will progress towards very severe forms of the disease, notably due to lack of access to care. By advancing research, the team hopes to accelerate access to treatment for these patients.


1 The Human Genetics of Infectious Diseases laboratory is directed by Jean-Laurent Casanova and Laurent Abel and is located at the Imagine Institute in Paris and Rockefeller University in New York. At both branches, Casanova heads up genetics and experimental immunology, whereas Abel heads up genetics and mathematical epidemiology.

Researcher Contact

Vivien Béziat

Chercheur Inserm

Equipe « Génétique Humaine des Maladies infectieuses »

Unité 1163 « Institut Imagine » (Inserm, AP-HP, Université de Paris)


Press Contact



Université de Paris





Humans with Inherited T cell CD28 deficiency are susceptible to Skin papillomaviruses but are otherwise healthy

Cell, 1er juillet 2021


Vivien Béziat1,2,@, Franck Rapaport2,*, Jiafen Hu3,*, Matthias Titeux1,*, Mathilde Bonnet des Claustres1,*, Mathieu Bourgey4,*, Heather Griffin5,*, Élise Bandet1,*, Cindy S. Ma6,7,*, Roya Sherkat8,*, Hassan Rokni-Zadeh9,*, David M. Louis10,*, Majid Changi-Ashtiani11,#, Ottavia M. Delmonte12,#, Toshiaki Fukushima13,#, Tanwir Habib14,#, Andrea Guenoun14,#, Taushif Khan14,#, Noemi Bender15,#, Mahbuba Rahman14,#, Frédégonde About1,#, Rui Yang2,#, Geetha Rao6,7,#, Claire Rouzaud1,16,#, Jingwei Li3,#, Debra Shearer3,#, Karla Balogh3,#, Fatima Al Ali14,#, Manar Ata14,#, Soroosh Dabiri17, Mana Momenilandi18, Justine Nammour1,  Marie-Alexandra Alyanakian16, Marianne Leruez-Ville16, David Guenat19, Marie Materna1, Léa Marcot1, Natasha Vladikine1, Christine Soret19, Hassan Vahidnezhad20, Leila Youssefian20, Amir Hossein Saeidian20, Jouni Uitto20, Émilie Catherinot21, Shadi Sadat Navabi22, Mohammed Zarhrate1, David T. Woodley23, Mohamed Jeljeli24, Thomas Abraham3, Serkan Belkaya2, Lazaro Lorenzo1, Jérémie Rosain1,16, Mousa Bayat17, Fanny Lanternier1,16, Olivier Lortholary1,16, Faramarz Zakavi25, Philippe Gros4,26, Gérard Orth27, Laurent Abel1,2, Jean-Luc Prétet19,&, Sylvie Fraitag16,&, Emmanuelle Jouanguy1,2,&, Mark M. Davis28,&, Stuart G. Tangye6,7,&, Luigi D. Notarangelo12,&, Nico Marr14,&, Tim Waterboer15,&, David Langlais4,26,&, John Doorbar5,&, Alain Hovnanian1,16,&, Neil Christensen3,§, Xavier Bossuyt18,§, Mohammad Shahrooei22,18,** and Jean-Laurent Casanova1,2,29,**,@


  1. University of Paris, Imagine Institute, INSERM U1163, 75015 Paris, France
  2. The Rockefeller University, New York 10065, NY, USA
  3. Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
  4. McGill University, Montreal, QC H3A 0G1, Canada
  5. University of Cambridge, CB2 1QP, UK.
  6. Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
  7. Vincent’s Clinical School, UNSW Sydney, NSW 2052, Australia
  8. Isfahan University of Medical Sciences, AIRC, Isfahan 81746-73461, Iran
  9. Zanjan University of Medical Sciences, Zanjan 45139-56184, Iran
  10. Stanford University Medical School, Stanford, California 94305, USA.
  11. Institute for Research in Fundamental Sciences (IPM), 19395-5746, Tehran, Iran
  12. National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
  13. Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
  14. Sidra Medicine, Doha, Qatar
  15. German Cancer Research Center, 69120 Heidelberg, Germany.
  16. Necker Hospital for Sick Children, AP-HP, 75015 Paris, France
  17. Zahedan University of Medical Sciences, 054 Zahedan, Iran
  18. University of Leuven, 3000 Leuven, Belgium
  19. Papillomavirus National Reference Center, Besançon Hospital, 25030 Besançon, France
  20. Thomas Jefferson University, Philadelphia, PA 19107, USA.
  21. Foch Hospital, 92150 Suresnes, France
  22. Shahrooei Lab, Ahvaz, Iran
  23. University of Southern California, Los Angeles, CA 90033, USA
  24. Cochin University Hospital, AP-HP, 75014 Paris, France.
  25. Ahvaz Jundishapur University of Medical Sciences, 061 Ahvaz, Iran
  26. McGill Research Centre on Complex Traits, Montreal, QC H3G 0B1, Canada
  27. Pasteur Institute, 75015 Paris, France
  28. HHMI, Stanford University Medical School, Stanford, California 94305, USA.
  29. HHMI, New York, NY 10065, USA

*,#,&,§, **: Equal contributions