ECTS Abstracts (2015) 1 OC6.5

The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism

Natacha Kadlub1,2, Marie-Paule Vazquez1,2, Louise Galmiche8, Aurore Coulomb L’Hermine3, Linda Dainese3, Tim Ulinski4, Brigitte Fauroux5, Ioana Pavlov2, Ariane Berdal1, Cécile Badoual7, Sandrine Marlin9, Marcel Deckert10, Vianney Descroix1,6, Arnaud Picard1,2 & Amélie Coudert1

1INSERM 1138, Team 5, Paris, France; 2APHP – Hopital Necker Enfant Maldes, Service de chirurgie maxillo-faciale, Paris, France; 3APHP – Hopital Arman Trousseau, Service de Cytologie et anatomopathologie, Paris, France; 4APHP – Hopital Arman Trousseau, Service de Néphrologie et transplantation, Paris, France, 5APHP – Hopital Necker Enfant Maldes, Service de Pneumologie, Paris, France; 6APHP – Hopital La Pitié Salpétrière, Service d’Odontologie, Paris, France; 7APHP – Hopital Européen Georges Pompidou, Service d’anatomopathologie, Paris, France; 8APHP – Hopital Necker Enfant Maldes, Service d’Anatomopathologie, Paris, France; 9APHP – Hopital Necker Enfant Maldes, Service de Génétique, Paris, France; 10INSERM U1065, NICE, France.

Cherubism is a rare genetic disorder characterised by extensive growth of a bilateral granuloma of the jaws, resulting in facial disfigurement. Cherubism is caused by gain-of-function mutations in the SH3BP2 gene, leading to over-activation of NFATc1-dependent osteoclastogenesis. Recent findings in human and mouse cherubism suggested that calcineurin inhibitors might be drug candidates in cherubism medical treatment. A 4-year-old boy with aggressive cherubism was treated with the calcineurin inhibitor tacrolimus for one year, and clinical, radiological, and molecular data were obtained. Immunohistological analysis was performed to compare pre- and post-operative NFATc1 staining and TRAP activity. Real-time PCR was performed to analyse the relative expression levels of OPG and RANKL. After tacrolimus therapy, the patient showed significant clinical improvement, including stabilisation of jaw size and intra-osseous osteogenesis. Immunohistological analyses on granuloma showed that tacrolimus caused a significant reduction in the number of TRAP positive osteoclasts and NFATc1 nuclear staining in multinucleated giant-cells. Molecular analysis showed that tacrolimus treatment also resulted in increased OPG expression. We present the first case of effective medical therapy in cherubism. Tacrolimus enhanced bone formation by stimulating osteogenesis and inhibiting osteoclastogenesis.

Disclosure: The authors declared no competing interests. This research was supported by the PHRC TEIOS, NK by AFDS (Association Française Développement de la Stomatologie) and AEC by ANR Osteodiversity (ANR-12-BSV1-0018).