title: The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism.
abstract: Cherubism is a rare genetic disorder characterized 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 overactivation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-dependent osteoclastogenesis. Recent findings in human and mouse cherubism have 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 1 year, and clinical, radiological, and molecular data were obtained. Immunohistologic analysis was performed to compare preoperative and postoperative NFATc1 staining and tartrate resistant acid phosphatase (TRAP) activity. Real-time PCR was performed to analyze the relative expression levels of OPG and RANKL. After tacrolimus therapy, the patient showed significant clinical improvement, including stabilization of jaw size and intraosseous osteogenesis. Immunohistologic 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS1138, Team Molecular Oral Pathophysiology, Cordeliers Research Center, University Paris-Diderot, University Paris-Descartes, and University Pierre and Marie Curie, Paris, France; Service de Chirurgie Maxillo-Faciale, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Unités de Formation et de Recherche (UFR) de Médecine Paris Descartes, Université Paris V, Paris, France; Centre de Références des Malformations de la Face et de la Cavité Buccale, Paris, France; Laboratoire de Physiopathologie Orale et Moléculaire, INSERM, UMRS 872, Equipe 5, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Kadlub
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Vazquez
authors.forename: Louise
authors.initials: L
authors.lastname: Galmiche
authors.forename: Aurore Coulomb
authors.initials: AC
authors.lastname: L'Herminé
authors.forename: Linda
authors.initials: L
authors.lastname: Dainese
authors.forename: Tim
authors.initials: T
authors.lastname: Ulinski
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fauroux
authors.forename: Ioana
authors.initials: I
authors.lastname: Pavlov
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Marcel
authors.initials: M
authors.lastname: Deckert
authors.forename: Nicolas
authors.initials: N
authors.lastname: Leboulanger
authors.forename: Ariane
authors.initials: A
authors.lastname: Berdal
authors.forename: Vianney
authors.initials: V
authors.lastname: Descroix
authors.forename: Arnaud
authors.initials: A
authors.lastname: Picard
authors.forename: Amélie E
authors.initials: AE
authors.lastname: Coudert
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D065095:Calcineurin Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count; D002636:Cherubism / Q000000981:diagnostic imaging / Q000188:drug therapy*; D002675:Child, Preschool; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D011859:Radiography; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D065095:Calcineurin Inhibitors; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D053244:Osteoprotegerin; D053245:RANK Ligand; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D016559:Tacrolimus
keywords: CENTRAL GIANT CELL GRANULOMA; CHERUBISM; NFATC1; OSTEOCLASTIC HYPERRESORPTIVE SYNDROMES; OSTEOCLASTOGENESIS; TACROLIMUS