Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.
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.
Childrens' Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland. matti.hero@hus.fi
M
M
Hero
A
A
Suomalainen
J
J
Hagström
P
P
Stoor
R
R
Kontio
H
H
Alapulli
S
S
Arte
S
S
Toiviainen-Salo
P
P
Lahdenne
O
O
Mäkitie
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D002636:Cherubism / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D011859:Radiography; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; C109073:SH3BP2 protein, human; D014409:Tumor Necrosis Factor-alpha