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Abstract Context Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. Objective (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. Design Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). Results We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. Conclusions Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. Clinical Trial number NCT04969926

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by occurrence of parathyroid tumours, often atypical adenomas and carcinomas, ossifying jaw fibromas, renal tumours and uterine benign and malignant neoplasms. HPT-JT is caused by mutations of the cell division cycle 73 ( CDC73 ) gene, located on chromosome 1q31.2 and encodes a 531 amino acid protein, parafibromin. To facilitate in vivo studies of Cdc73 in tumourigenesis we generated conventional ( Cdc73 +/− ) and conditional parathyroid-specific ( Cdc73 +/L / PTH-Cre and Cdc73 L/L / PTH-Cre ) mouse models. Mice were aged to 18-21 months and studied for survival, tumour development and proliferation, and serum biochemistry, and compared to age-matched wild-type ( Cdc73 +/+ and Cdc73 +/+ /PTH-Cre ) littermates. Survival of Cdc73 +/− mice, when compared to Cdc73 +/+ mice was reduced ( Cdc73 +/− =80%; Cdc73 +/+ =90% at 18 months of age, P <0.05). Cdc73 +/− , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice developed parathyroid tumours, which had nuclear pleomorphism, fibrous septation and increased galectin-3 expression, consistent with atypical parathyroid adenomas, from 9 months of age. Parathyroid tumours in Cdc73 +/− , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice had significantly increased proliferation, with rates >fourfold higher than that in parathyroid glands of wild-type littermates ( P <0.0001). Cdc73 +/− , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73 +/− mice also had increased mean serum parathyroid hormone (PTH) concentrations. Parathyroid tumour development, and elevations in serum calcium and PTH, were similar in males and females. Cdc73 +/− mice did not develop bone or renal tumours but female Cdc73 +/− mice, at 18 months of age, had uterine neoplasms comprising squamous metaplasia, adenofibroma and adenomyoma. Uterine neoplasms, myometria and jaw bones of Cdc73 +/− mice had increased proliferation rates that were 2-fold higher than in Cdc73 +/+ mice ( P <0.05). Thus, our studies, which have established mouse models for parathyroid tumours and uterine neoplasms that develop in the HPT-JT syndrome, provide in vivo models for future studies of these tumours.

Ameloblastoma is a benign, epithelial cancer of the jawbone, which causes bone resorption and disfigurement to patients affected. The interaction of ameloblastoma with its tumour stroma drives invasion and progression. We used stiff collagen matrices to engineer active bone forming stroma, to probe the interaction of ameloblastoma with its native tumour bone microenvironment. This bone-stroma was assessed by nano-CT, transmission electron microscopy (TEM), Raman spectroscopy and gene analysis. Furthermore, we investigated gene correlation between bone forming 3D bone stroma and ameloblastoma introduced 3D bone stroma. Ameloblastoma cells increased expression of MMP-2 and -9 and RANK temporally in 3D compared to 2D. Our 3D biomimetic model formed bone nodules of an average surface area of 0.1 mm 2 and average height of 92.37 ± 7.96 μm over 21 days. We demonstrate a woven bone phenotype with distinct mineral and matrix components and increased expression of bone formation genes in our engineered bone. Introducing ameloblastoma to the bone stroma, completely inhibited bone formation, in a spatially specific manner. Multivariate gene analysis showed that ameloblastoma cells downregulate bone formation genes such as RUNX2 . Through the development of a comprehensive bone stroma, we show that an ameloblastoma tumour mass prevents osteoblasts from forming new bone nodules and severely restricted the growth of existing bone nodules. We have identified potential pathways for this inhibition. More critically, we present novel findings on the interaction of stromal osteoblasts with ameloblastoma.

Information on the heterogeneity of phosphaturic mesenchymal tumor, a rare entity associated with tumor-induced osteomalacia, is limited. In this retrospective analysis of 222 phosphaturic mesenchymal tumors, 22 cases exhibited mixed mesenchymal and epithelial elements, which we propose to term “phosphaturic mesenchymal tumor, mixed epithelial, and connective tissue type.” Phosphaturic mesenchymal tumor of the mixed epithelial and connective tissue type showed a distinctive and significant male predominance (male:female = 2.67:1), with most patients diagnosed at <40 years old. Moreover, all tumors were mainly located in the alveolar bone with focal invasion into surrounding soft tissue and oral mucosa, which could be detected preoperatively by oral examination. The mesenchymal component, composed of spindled cells resembling fibroblasts or myofibroblasts arranged in a storiform or fascicular pattern, exhibited a less prominent vasculature and lower cellularity than the typical phosphaturic mesenchymal tumor (mixed connective tissue type). The epithelial component was typically haphazardly and diffusely distributed throughout the tumor, forming small, irregular nests resembling odontogenic epithelial nests. All cases were immunoreactive for fibroblast growth factor-23, somatostatin receptor 2A, and NSE in both components. Mostly also demonstrated positive staining for CD99 (21/22, 96%), CD56 (16/22, 73%), Bcl-2 (21/22, 96%), and D2-40 (19/22, 86%) in one or both components. S100 was positive in both components in one of seven cases. Interestingly, immunoreactivity was typically stronger and more diffuse in the epithelial than in the paired mesenchymal components. The mesenchymal component was also diffusely positive for CD68 (17/17, 100%) and showed variable focal staining for SMA (15/22, 68%) and CD34 (9/19, 47 %). These results indicate that phosphaturic mesenchymal tumor of the mixed epithelial and connective tissue type has distinctive clinicopathological characteristics and a polyimmunophenotypic profile.

Ameloblastoma is a common odontogenic benign tumor located in the jaws and is characterized by severe local bone destruction. The current study aimed to investigate the effect of interactions between tumor cells and bone marrow stromal cells (BMSCs) on osteoclast formation in ameloblastoma. The impact of ameloblastoma/BMSC interactions on cytokine production, gene expression and osteoclastogenesis was examined using an immortalized ameloblastoma cell line that the authors' previously established. The results demonstrated that interactions between ameloblastoma cells and BMSCs increased interleukin (IL)-8 and activin A secretion by BMSCs. IL-8 expression in BMSCs was modulated by tumor-derived tumor necrosis factor-α and IL-8 contributed to osteoclast formation not only directly but also by stimulating receptor activator of NF-κB ligand (RANKL) expression in BMSCs. Activin A secretion in BMSCs was stimulated by ameloblastoma cells via cell-to-cell-mediated activation of c-Jun N-terminal kinase activation, acting as a cofactor of RANKL to induce osteoclast formation and function. The present study highlights the critical role of communication between BMSCs and ameloblastoma cells in bone resorption in ameloblastoma.

Objectives Odontoma—separated into complex (CxOD) and compound (CpOD) subtypes—represents the most frequent odontogenic malformation. Retention of permanent teeth is a common symptom. Therefore, in a series of odontomas, an analysis of the management of retained teeth was conducted. Materials and methods In a retrospective multicenter study of two University Medical Centers and one private praxis in Germany, demographic and clinical data regarding odontomas from 01/2000–03/2015 were obtained. In particular, the influence of operative therapy on the dentition and on the treatment of impacted teeth was analyzed. Results Forty-five patients with 15 CxOD and 30 CpOD were included. Initial symptoms were delayed eruption of permanent teeth ( n  = 11), pain ( n  = 4), and swellings ( n  = 2); 28 cases were discovered by incidence, all of them via panoramic radiographs. The mandible/maxilla ratio was about 1:0.55 (29/16). Thirty-five out of 45 odontomas were in close proximity of at least one tooth ( n  = 16 at molars). A total of 14 teeth were extracted (CxOD: n  = 5; CpOD: n  = 9). Extractions had to be conducted more often in older patients (mean age 39.8 vs. 25.6 years). Of the non-extracted teeth, 8 teeth were displaced and retained. Of those, 4 teeth were aligned in the dental arch via orthodontic help and 2 teeth erupted spontaneously after operation during the follow-up period. In all cases, no relapse was seen. Conclusion Odontomas can cause displacement as well as malformation and resorption of the adjacent teeth. Clinical relevance Mostly, removal of odontomas is conducted. Extirpation of odontoma can allow for normal tooth eruption, often rendering extractions avoidable. Orthodontic alignment, though sometimes challenging, is a reasonable therapeutic option. These findings underline the value of the panoramic radiograph in preventive dentistry in younger patients.

Mutations of the HRPT2 gene, which are responsible for hyperparathyroidism-jaw tumor (HPT-JT) syndrome, have been implicated in the development of a high proportion of parathyroid carcinomas. The aim of this study was to investigate differences in expression of the most important genes connected with parathyroid carcinoma between HPT-JT syndrome due to an HRPT2 splicing mutation, normal parathyroid tissue and sporadic parathyroid adenoma. Total RNAs were extracted from parathyroid carcinoma in HPT-JT syndrome harbouring HRPT2 splicing mutation or sporadic parathyroid adenoma and normal parathyroid gland, and subjected to Illumina DASL-based gene expression assay. Unsupervised hierarchical clustering analysis was used to compare gene expression in HPT-JT syndrome, sporadic parathyroid adenoma and normal parathyroid glands. We identified differentially regulated genes in HPT-JT syndrome and sporadic parathyroid adenoma relative to normal parathyroid glands using a combination of Welch's t-test and fold-change analysis. Quantitative PCR, RT-PCR and IHC were used for validation. Sixteen genes differentially regulated in the parathyroid carcinoma were associated with signal pathways, MAPK, regulation of actin cytoskeleton, prostate cancer and apoptosis. FGFR1 expression was confirmed to be significantly upregulated by validation experiments. Our gene expression profiling experiments suggest that upregulated FGFR1 expression appears to be associated with parathyroid carcinoma in HPT-JT syndrome due to an HRPT2 splicing mutation.

Background The reconstruction of mandibular defects after giant ameloblastoma resection is one of the most challenging problems facing reconstructive surgeons. Mandibular resection has been associated with a poor quality of life (QOL), particularly in adolescent patients reconstructed with a free fibula flap. This study aims to evaluate QOL outcomes in adolescent patients who have had mandibular resections of giant ameloblastoma and reconstruction with a free fibula flap and to collect information about their socio-cultural situation. Methods The present study assessed 45 adolescent patients who had undergone immediate mandible reconstruction with a free fibula flap for faint ameloblastoma using University of Washington Quality of Life (UW-QOL) and 14-item Oral Health Impact Profile (OHIP-14) questionnaires. Results Thirty-five of the 54 questionnaires were returned (64.81%). In the UW-QOL, of the twelve disease-specific domains, the best three scores from the patients related to pain, shoulder and appearance and the worst three scores related to chewing, anxiety and saliva. In the OHIP-14, the lowest-scoring domain was handicap, followed by physical pain and social disability. Conclusions Mandibular reconstruction with a free fibular flap significantly influenced the adolescent patients’ QOL. Adolescent patients pay more attention to postoperative facial appearance; this should be considered in surgical planning.

Keratocystic odontogenic tumors (KCOTs, previously known as odontogenic keratocysts) are aggressive jaw lesions that may occur in isolation or in association with nevoid basal cell carcinoma syndrome (NBCCS). Mutations in the PTCH1 (PTCH) gene are responsible for NBCCS and are related in tumors associated with this syndrome. Mutations in the SMO gene have been identified in basal cell carcinoma and in medulloblastoma, both of which are features of NBCCS. To clarify the role of PTCH1 and SMO in KCOTs, we undertook mutational analysis of PTCH1 and SMO in 20 sporadic and 10 NBCCS-associated KCOTs, and for SMO, 20 additional cases of KCOTs with known PTCH1 status were also included. Eleven novel (1 of which occurred twice) and 5 known PTCH1 mutations were identified. However, no pathogenic mutation was detected in SMO. Our findings suggest that mutations are rare in SMO, but frequent in PTCH1 in sporadic and NBCCS-associated KCOTs. Abbreviations: NBCCS, nevoid basal cell carcinoma syndrome; KCOTs, keratocystic odontogenic tumors; BCCs, basal cell carcinomas.

To present the case of a hyperparathyroidism-jaw tumor (HPT-JT) patient with a novel nonsense mutation of the CDC73 gene. We present the case of a patient with a history of three prior maxillectomies and two prior parathyroidectomies who presented with recurrent primary hyperparathyroidism (PHPT). We also briefly review the literature pertaining to HPT-JT. Genetic analysis revealed a novel nonsense mutation (c.85G>T; pGlu29) in exon 1 of CDC73. The patient's son underwent genetic testing for a CDC73 mutation and was found to be negative. HPT-JT is a rare condition characterized by PHPT and benign tumors of the mandible and maxilla. Up to 15% of HPT-JT patients with PHPT have parathyroid carcinoma. HPT-JT is associated with an inactivating mutation of CDC73, a gene that codes for the tumor suppressor protein parafibromin. This report expands our understanding of the genetics underlying this rare disorder and emphasizes the importance of early detection in order to prevent hypercalcemic complications such as parathyroid carcinoma.