acid-phosphatase and Cherubism

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.

Topics: Acid Phosphatase; Calcineurin Inhibitors; Cell Count; Cherubism; Child, Preschool; Humans; Isoenzymes; Male; Models, Biological; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Osteoprotegerin; Radiography; RANK Ligand; Tacrolimus; Tartrate-Resistant Acid Phosphatase

Cherubism is a rare developmental lesion of the jaw that is generally inherited as an autosomal dominant trait. Recent studies have revealed point mutations in the SH3BP2 gene in cherubism patients. In this study, we examined a 6-year-old Korean boy and his family. We found a Pro418Arg mutation in the SH3BP2 gene of the patient and his mother. A father and his 30-month-old younger brother had no mutations. Immunohistochemically, the multinucleated giant cells proved positive for CD68 and tartrate-resistant acid phosphatase (TRAP). Numerous spindle-shaped stromal cells expressed a ligand for receptor activator of nuclear factor kB (RANKL), but not in multinucleated giant cells. These results provide evidence that RANKL plays a critical role in the differentiation of osteoclast precursor cells to multinucleated giant cells in cherubism. Additionally, genetic analysis may be a useful method for differentiation of cherubism.

Topics: Acid Phosphatase; Adaptor Proteins, Signal Transducing; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cherubism; Child; Giant Cells; Humans; Isoenzymes; Male; Pedigree; Point Mutation; RANK Ligand; Tartrate-Resistant Acid Phosphatase

Cherubism (CBM) and central giant cell granuloma (CGCG) of the jaw and giant cell tumor (GCT) of the long bone are clinically different diseases. Histologically, they are all multinucleated giant cell (MGC)-containing lesions. This study aims to evaluate the expression of c-Src and cytologic features in CBM, CGCG and GCT and to clarify whether there is a common mechanism underlying the formation of multi-nucleated giant cells (MGCs) in these lesions. Specimens and paraffin blocks were collected from patients with CBM (12 cases), CGCG (24 cases) and GCT (37 cases). Histomorpho-metric differences in MGCs were compared among the three types of lesions. The expression of c-Src by immunohistochemistry and in situ hybridization and the expression of TRAP by enzyme histochemical staining were examined. Expression of c-Src mRNA and protein, as well as TRAP staining, was detected in both MGCs and a fraction of mononuclear cells in all investigated lesions. There are no quantitative differences for cytologic features and c-Src expression among the lesions. The results suggested that CBM, CGCG and GCT have overlapping cytological features at the histological level, and c-Src may be involved in the formation of MGCs in the three different diseases.

Topics: Acid Phosphatase; Adolescent; Adult; Bone Neoplasms; Cherubism; Child; Gene Expression; Giant Cell Tumor of Bone; Giant Cells; Granuloma, Giant Cell; Humans; Immunohistochemistry; In Situ Hybridization; Isoenzymes; Middle Aged; Proto-Oncogene Proteins pp60(c-src); Tartrate-Resistant Acid Phosphatase

Cherubism is a rare hereditary multilocular cystic disease of the jaws, characterized by its typical appearance. Although nonfamilial cases have been reported, it is difficult to distinguish nonfamilial cherubism from central giant cell granuloma. Recent studies have revealed the point mutations in the SH3BP2 gene on chromosome 4p16.3 in cherubism families. In this article, the SH3BP2 gene in nonfamilial cherubism was examined.. A 21-year-old Japanese woman with nonfamilial cherubism.. Genomic DNA was purified from a blood sample obtained from the patient and used for direct sequencing. In addition, a sample of the lesion, resected during surgery, was used for histologic and immunohistochemical purposes.. Genomic DNA sequencing found a Pro418Arg mutation in the SH3BP2 gene of the patient. In a histochemical analysis, the multinucleated giant cells proved to be strongly positive for PGM-1, KP-1, and tartrate-resistant acid phosphatase and faintly positive for osteopontin.. The missense mutation Pro418Arg was identified in the SH3BP2 gene from a nonfamilial case of cherubism. DNA diagnosis may play a significant role in the identification of cherubism.

Topics: Acid Phosphatase; Adaptor Proteins, Signal Transducing; Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Arginine; Biomarkers; Carrier Proteins; Cherubism; Chromosomes, Human, Pair 4; Female; Giant Cells; Humans; Isoenzymes; Macrophages; Mutation, Missense; Osteopontin; Phosphoproteins; Point Mutation; Proline; Sialoglycoproteins; src Homology Domains; Tartrate-Resistant Acid Phosphatase

Topics: Acid Phosphatase; Adolescent; Adult; Cherubism; Humans; Leucyl Aminopeptidase; Male; Mandible