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The Journal of Clinical Endocrinology... Dec 2017Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw...
CONTEXT
Heterozygous pathogenic germline variants in CDC73 predispose to the development of primary hyperparathyroidism (pHPT) and, less frequently, ossifying fibroma of the jaw and renal and uterine tumors. Clinical information on CDC73-related disorders has so far been limited to small case series.
OBJECTIVE
To assess the clinical manifestations and penetrance in CDC73-related disorders and to improve case detection in pHPT.
DESIGN
Nationwide retrospective Dutch cohort study.
SETTING
Tertiary referral center.
PATIENTS
We studied 89 patients with pHPT referred for germline CDC73 analysis and 43 subsequently tested relatives who proved to be mutation carriers.
INVESTIGATION
Germline CDC73 mutation analysis.
MEAN OUTCOME
CDC73 mutation detection yield, referral rate, and CDC73-related disease penetrance.
RESULTS
Pathogenic germline CDC73 variants were identified in 11 of the 89 referred pHPT patients (12.4%), with (suspected) hyperparathyroidism-jaw tumor (HPT-JT) syndrome (n = 3), familial isolated pHPT (n = 5), apparently sporadic parathyroid carcinoma (n = 2), and apparently sporadic parathyroid adenoma (n = 1). The estimated penetrance of CDC73-related disorders was 65% at age 50 years (95% confidence interval, 48% to 82%) in 43 nonindex mutation carriers.
CONCLUSIONS
Germline CDC73 analysis is recommended in individuals with (suspected) HPT-JT syndrome, familial isolated pHPT, atypical or malignant parathyroid histology, and young individuals with pHPT. These criteria would increase germline CDC73 mutation detection, enabling optimal clinical management of pHPT as well as genetic counseling and surveillance for family members at risk for developing CDC73-related disorders.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Cohort Studies; Female; Germ-Line Mutation; Heterozygote; Humans; Hyperparathyroidism, Primary; Jaw Neoplasms; Male; Middle Aged; Mutation; Netherlands; Parathyroid Neoplasms; Penetrance; Retrospective Studies; Tumor Suppressor Proteins; Young Adult
PubMed: 29040582
DOI: 10.1210/jc.2017-01249 -
The British Journal of Radiology May 2012Calcifying cystic odontogenic tumour (CCOT) is a rare disorder of the jaw. A comparison between conventional radiographs and CT images in CCOTs has not been reported.... (Comparative Study)
Comparative Study
OBJECTIVES
Calcifying cystic odontogenic tumour (CCOT) is a rare disorder of the jaw. A comparison between conventional radiographs and CT images in CCOTs has not been reported. The purposes of this study were to analyse conventional radiographs and CT images of CCOTs, establish CT images of CCOTs and assess the utility of CT in the diagnosis of CCOTs.
METHODS
Nine patients with a histopathologically confirmed CCOT who had both conventional radiographs and CT images were enrolled.
RESULTS
CT was superior to conventional radiographs in detecting buccolingual expansion, odontomas and radio-opaque bodies.
CONCLUSION
The characteristic CT appearances of CCOT were that radio-opaque bodies were typically located in the periphery of the lesion and the shape of radio-opaque bodies was linear and/or spotted. CT was useful in diagnosing a CCOT.
Topics: Adolescent; Adult; Child; Female; Humans; Jaw Neoplasms; Male; Middle Aged; Odontogenic Cyst, Calcifying; Reproducibility of Results; Tomography, X-Ray Computed; Young Adult
PubMed: 21828147
DOI: 10.1259/bjr/19841479 -
PloS One 2017Calcifying cystic odontogenic tumors (CCOTs) are benign cystic tumors that form abnormally keratinized ghost cells. Mutations in CTNNB1, which encodes beta-catenin, have...
Calcifying cystic odontogenic tumors (CCOTs) are benign cystic tumors that form abnormally keratinized ghost cells. Mutations in CTNNB1, which encodes beta-catenin, have been implicated in the development of these tumors, but a causal relationship has not been definitively established. Thus, mutational hot spots in 50 cancer genes were examined by targeted next-generation sequencing in 11 samples of CCOT. Mutations in CTNNB1, but not in other genes, were observed in 10 of 11 cases. These mutations constitutively activate beta-catenin signaling by abolishing the phosphorylation sites Asp32, Ser33, or Ser37, and are similar to those reported in pilomatrixoma and adamantinomatous craniopharyngioma. In contrast, BRAF or NRAS mutations were observed in 12 and two control samples of ameloblastoma, respectively. In HEK293 cells, overexpression of mutated CTNNB1 also upregulated hair keratin, a marker of ghost cells. Furthermore, ghost cells were present in two cases of ameloblastoma with BRAF and CTNNB1 mutations, indicating that ghost cells form due to mutations in CTNNB1. The data suggest that mutations in CTNNB1 are the major driver mutations of CCOT, and that CCOT is the genetic analog of pilomatrixoma and adamantinomatous craniopharyngioma in odontogenic tissue.
Topics: Adolescent; Adult; Aged; Ameloblastoma; Blotting, Western; Child; DNA, Neoplasm; Female; HEK293 Cells; High-Throughput Nucleotide Sequencing; Humans; Jaw Neoplasms; Male; Middle Aged; Mutation, Missense; Odontogenic Cyst, Calcifying; Polymerase Chain Reaction; Proto-Oncogene Proteins B-raf; Young Adult; beta Catenin
PubMed: 28658279
DOI: 10.1371/journal.pone.0180224 -
American Journal of Human Genetics Nov 2016Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid...
Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP.
Topics: Adenoma; Adolescent; Adult; Aged; Amino Acid Sequence; Exome; Female; Fibroma; Genetic Variation; Germ-Line Mutation; Humans; Hyperparathyroidism; Hyperparathyroidism, Primary; Jaw Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Nuclear Proteins; Parathyroid Hormone; Pedigree; Proto-Oncogene Mas; Proto-Oncogenes; Sequence Analysis, DNA; Transcription Factors; Young Adult
PubMed: 27745835
DOI: 10.1016/j.ajhg.2016.08.018 -
BMJ Case Reports Apr 2021We report the case of a 25-year-old man with a maxillary ghost cell odontogenic carcinoma (GCOC). The patient presented to the maxillofacial and head and neck surgery...
We report the case of a 25-year-old man with a maxillary ghost cell odontogenic carcinoma (GCOC). The patient presented to the maxillofacial and head and neck surgery clinic with a growing lump in the left maxilla. Initial workup with CT revealed a cystic lesion in the left upper jaw with associated bone erosion and an enhancing soft-tissue component. Enucleation showed a GCOC associated with a calcifying odontogenic cyst. After the diagnosis was obtained, the patient underwent widening of the first surgical resection. GCOCs are rare odontogenic neoplasms with unspecific clinical and imaging presentation, whose definitive characterisation is based on pathology. Current treatment approaches mainly involve surgical excision, but the prognosis is highly unpredictable due to intertumoral heterogeneity. As tumour recurrences occur in 73% of cases, radical surgery with negative margins is highly recommended. Therefore, it is essential to recognise this entity to offer patients adequate management.
Topics: Adult; Carcinoma; Humans; Male; Maxilla; Maxillary Neoplasms; Neoplasm Recurrence, Local; Odontogenic Cyst, Calcifying; Odontogenic Tumors
PubMed: 33888482
DOI: 10.1136/bcr-2021-242445 -
Medicina Oral, Patologia Oral Y Cirugia... Mar 2018Mismatch repair proteins (MMRPs) are a group of nuclear enzymes that participate in the repair of base mismatches that occur during DNA replication in all proliferating...
BACKGROUND
Mismatch repair proteins (MMRPs) are a group of nuclear enzymes that participate in the repair of base mismatches that occur during DNA replication in all proliferating cells. The most studied MMRPs are hMSH2 and hMLH1, which are known to be highly expressed in normal tissues. A loss of MMRPs leads to the accumulation of DNA replication errors in proliferating cells. Ki-67 is a biomarker regarded to be the gold-standard tool for determining cell proliferation by immunohistochemical methods. The aim of this study was to investigate the immunohistochemical expression of hMLH1, hMSH2 and Ki-67 proteins in ameloblastomas and tooth germs, to contribute to the understanding of the development of this odontogenic neoplasm.
MATERIAL AND METHODS
Immunohistochemical assays to determine the presence of proteins hMSH2, hMLH1 and Ki-67 were performed in 80 ameloblastomas (40 solid and 40 unicystic) and five tooth germs.
RESULTS
Unicystic ameloblastomas showed higher MMRP expression (hMLH1: 62.5 ± 43.4; hMSH2: 83.3 ± 47.8) than did solid ameloblastomas (hMLH1: 59.4 ± 13.5; hMSH2: 75.8 ± 40.2). Additionally, the cell proliferation index assessed by Ki-67 was inversely proportional to the expression of MMRP. Comparison between tooth germs and ameloblastoma revealed significantly higher expression of hMLH1, hMSH2 and Ki-67 in tooth germs (p=0.02).
CONCLUSIONS
The differences of MMRP and Ki-67 immunoexpression between ameloblastomas and tooth germ suggest that alterations in the MMRP mechanisms could participate in the biological behavior of ameloblastomas.
Topics: Ameloblastoma; Humans; Immunohistochemistry; Jaw Neoplasms; Ki-67 Antigen; MutL Protein Homolog 1; MutS Homolog 2 Protein; Tooth Germ
PubMed: 29476681
DOI: 10.4317/medoral.22210 -
Journal of Cranio-maxillo-facial... Aug 2016Metastatic solid tumors to the oral cavity are rare, frequently indicative of an end-stage disease process, and associated with poor survival rates. We performed a...
PURPOSE
Metastatic solid tumors to the oral cavity are rare, frequently indicative of an end-stage disease process, and associated with poor survival rates. We performed a 20-year retrospective clinical analysis of our institution's cases of solid metastases to the oral cavity, and investigated these patients' clinical outcomes.
MATERIAL AND METHODS
A retrospective study of patients with metastatic solid tumors to the oral cavity over a 20-year period (October 1996 to September 2015) was conducted at Memorial Sloan Kettering Cancer Center. Patients were selected if they had a histopathologically confirmed diagnosis. Demographic, pathologic, and clinical information were reviewed to identify patient outcomes.
RESULTS
A total of 44 patients with metastatic non-melanocytic non-hematopoietic tumor to the oral cavity were identified: 24 males and 20 females (39 adults and 5 children) with a mean age of 54.3 years. In all, 24 cases involved the jaw and 20 cases involved the oral soft tissue. Eight patients (18.2%) had oral cavity metastases as the first indication of an occult malignancy. In adult patients, the common primary sites were the lungs (n = 9, 20%), kidney (n = 7, 16%), breast (n = 5, 11%), and colon (n = 4, 9%); and in pediatric patients the adrenal gland (3/5) was the most common site. Of the adult patients, 33 (84.6%) died of disease. From the time of metastasis diagnosis, patients with jaw metastases had a median and mean survival of 12 months and 27.7 months, respectively. In comparison, patients with oral soft tissue metastases had a median survival time of 5 months, and mean of 8 months. One pediatric patient (20%) died of disease 8 months after metastasis diagnosis.
CONCLUSION
Metastatic solid tumors to the oral cavity can be the first sign of a malignancy. Pediatric patients with oral cavity metastases have a better prognosis compared to adult patients. In this series, adults with oral soft tissue involvement had shorter survival times compared to patients with jaw involvement.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Humans; Infant; Jaw Neoplasms; Male; Middle Aged; Mouth Neoplasms; Prognosis; Retrospective Studies; Survival Analysis
PubMed: 27270028
DOI: 10.1016/j.jcms.2016.05.013 -
International Journal of Molecular... Jun 2019Ameloblastoma 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...
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.
Topics: Activins; Adult; Ameloblastoma; Cells, Cultured; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Jaw Neoplasms; Male; Mesenchymal Stem Cells; Osteoclasts; Osteolysis; Tumor Cells, Cultured; Up-Regulation; Young Adult
PubMed: 31017256
DOI: 10.3892/ijmm.2019.4171 -
Indian Journal of Dental Research :... 2017This study aims to report of two variants of gnathic osteosarcoma with highlights on the varied histopathological presentation of osteosarcomas (OS). OS present with... (Review)
Review
This study aims to report of two variants of gnathic osteosarcoma with highlights on the varied histopathological presentation of osteosarcomas (OS). OS present with diverse histological appearances. Despite significant advances in molecular pathogenesis and biomarkers, clinicopathologic correlation is still considered as the important criteria in diagnosis. Chondroblastic osteosarcoma in a 52-year-old female and fibroblastic osteosarcoma in a 35-year-old female. Osteosarcoma is a relatively rare disease of the oral and maxillofacial region. Regular screening and follow-up is highly recommended, as recurrence rates are higher. Thorough understanding of the histologic spectrum of osteosarcoma reduces the diagnostic difficulties in categorizing the OS and separating these neoplasms from benign bone diseases.
Topics: Adult; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Jaw Neoplasms; Mandibular Neoplasms; Middle Aged; Osteosarcoma; Periapical Tissue; Radiography, Panoramic; Statistics as Topic
PubMed: 28393823
DOI: 10.4103/ijdr.IJDR_792_14 -
PloS One 2015Ameloblastoma is the second most common odontogenic tumor, known to be slow-growing, persistent, and locally aggressive. Recent data suggests that ameloblastoma is best... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Ameloblastoma is the second most common odontogenic tumor, known to be slow-growing, persistent, and locally aggressive. Recent data suggests that ameloblastoma is best treated with wide resection and adequate margins. Following primary excision, bony reconstruction is often necessary for a functional and aesthetically satisfactory outcome, making early diagnosis paramount. Despite earlier diagnosis potentially limiting the extent of resection and reconstruction, an understanding of the growth rate and natural history of ameloblastoma has been notably lacking from the literature.
METHOD
A systematic review of the literature was conducted by reviewing relevant articles from PubMed and Web of Science databases. Each article's level of evidence was formally appraised according to the Centre of Evidence Based Medicine (CEBM), with data from each utilized in a meta-analysis of growth rates for ameloblastoma.
RESULTS
Literature regarding the natural history of ameloblastoma is limited since the tumor is immediately acted upon at its initial detection, unless the patient voluntarily refuses a surgical intervention. From the limited data, it is derived that the highest estimated growth rate is associated with solid, multicystic type and the lowest rate with peripheral ameloblastomas. After meta-analysis, the calculated mean specific grow rate is 87.84% per year.
CONCLUSION
The growth rate of ameloblastoma has been demonstrated, offering prognostic and management information, particularly in cases where a delay in management is envisaged.
Topics: Adult; Aged; Ameloblastoma; Female; Humans; Jaw Neoplasms; Male; Middle Aged; Young Adult
PubMed: 25706407
DOI: 10.1371/journal.pone.0117241