Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

Abstract

Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.

• Authors: M Hero, A Suomalainen, J Hagström, P Stoor, R Kontio, H Alapulli, S Arte, S Toiviainen-Salo, P Lahdenne, O Mäkitie
• Journal: Bone (Bone) Vol. 52 Issue 1 Pg. 347-53 (Jan 2013) ISSN: 1873-2763 [Electronic] United States
• PMID: 23069372 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• SH3BP2 protein, human
• Tumor Necrosis Factor-alpha

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Animals
• Cherubism (diagnostic imaging, drug therapy, genetics, pathology)
• Child, Preschool
• Disease Models, Animal
• Female
• Humans
• Male
• Mice
• Radiography
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)