Two Cases of Temporomandibular Synovial Chondromatosis Associated with Gli1 Gene Mutation.

Synovial chondromatosis (SC) is a rare benign disease involving multifocal generation of ectopic cartilage in the synovial tissue. Herein, we report two cases of SC in the temporomandibular joint: a 38-year-old woman (patient 1) and 39-year-old woman (patient 2). Both patients had trismus, jaw joint noises, and jaw-opening pain in the temporomandibular joint. Cone-beam computed tomography (CT) and magnetic resonance imaging (MRI) in patient 1 showed multiple calcified loose bodies around the right mandibular condyle. In addition, CT and MRI in patient 2 showed multiple calcified loose bodies around the left mandibular condyle and temporal bone perforation. Following establishing a diagnosis of SC, both patients underwent tumor resection via open surgery. In immunohistochemical examinations of the resected tissues, tumor cells showed intense nuclear staining with labeled anti-Gli1 antibody. Gene sequencing revealed that both patients had a homozygous mutation in the Gli1 gene (rs2228226 G>C). In conclusion, we suggest that the Gli1 gene (rs2228226 G>C) may be involved in the etiology of SC.

What is new about the molecular genetics in matrix-producing soft tissue tumors? -The contributions to pathogenetic understanding and diagnostic classification.

Soft tissue tumors encompass a wide variety of mesenchymal neoplasms exhibiting diverse clinical, pathologic, and molecular features. Among these, osteoid and/or chondroid matrix deposition in some soft tissue tumors represents a noticeable characteristic. Unlike matrices present in bone tumors where they likely reveal the respective cells of origin (i.e., osteoblastic or chondroblastic precursors), those existing in soft tissue tumors more often denote a metaplastic phenomenon and reflect the diversity of differentiation these tumors can display. While many soft tissue tumor types can occasionally harbor metaplastic bone or cartilage as an incidental component or heterologous differentiation, in some other tumor types, the production of these matrices is a frequent and distinctive, if not diagnostic, feature. This review focuses on the latter tumor types where emerging immunohistochemical and molecular evidence has significantly improved our understanding of their respective pathogenesis and histopathological spectra. These tumor types include ossifying fibromyxoid tumor, phosphaturic mesenchymal tumor, synovial chondromatosis, soft tissue chondroma, calcifying aponeurotic fibroma, giant cell tumor of soft tissue, myositis ossificans and related diseases, mesenchymal chondrosarcoma, and extraskeletal osteosarcoma.

Synovial chondromatosis and soft tissue chondroma: extraosseous cartilaginous tumor defined by FN1 gene rearrangement.

A fusion between fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) has been reported previously in isolated cases of the synovial chondromatosis. To analyze further and validate the findings, we performed FISH and demonstrated recurrent FN1-ACVR2A rearrangements in synovial chondromatosis (57%), and chondrosarcoma secondary to synovial chondromatosis (75%), showing that FN1 and/or AVCR2A gene rearrangements do not distinguish between benign and malignant synovial chondromatosis. RNA sequencing revealed the presence of the FN1-ACVR2A fusion in several cases that were negative by FISH suggesting that the true prevalence of this fusion is potentially higher than 57%. In soft tissue chondromas, FN1 alterations were detected by FISH in 50% of cases but no ACVR2A alterations were identified. RNA sequencing identified a fusion involving FN1 and fibroblast growth factor receptor 2 (FGFR2) in the case of soft tissue chondroma and FISH confirmed recurrent involvement of both FGFR1 and FGFR2. These fusions were present in a subset of soft tissue chondromas characterized by grungy calcification, a feature reminiscent of phosphaturic mesenchymal tumor. However, unlike the latter, fibroblast growth factor 23 (FGF23) mRNA expression was not elevated in soft tissue chondromas harboring the FN1-FGFR1 fusion. The mutual exclusivity of ACVR2A rearrangements observed in synovial chondromatosis and FGFR1/2 in soft tissue chondromas suggests these represent separate entities. There have been no reports of malignant soft tissue chondromas, therefore differentiating these lesions will potentially alter clinical management by allowing soft tissue chondromas to be managed more conservatively.

Transforming growth factor beta 3 involved in the pathogenesis of synovial chondromatosis of temporomandibular joint.

Synovial chondromatosis (SC) of temporomandibular joint is rare proliferative disorder featured by the formation of cartilaginous nodules in synovium and joint space. Transforming growth factor beta 3 (TGF-ß3) is closely related to chondrogenic differentiation, and might participate in pathogenesis of SC. We discovered that increased quantity of synoviocytes and blood vessels were observed in SC synovium. The vessel wall and sublining fibroblasts were stained positively by the antibodies against TGF-ß3, fibroblast growth factor 2 (FGF-2), and CD34. In loose bodies (LBs), TGF-ß3 was mainly expressed in chondrocytes and FGF-2 was expressed in chondrocytes, fibroblasts, and vessel walls. Expressions of TGF-ß1, TGF-ß3, FGF-2, Sox9, Wnt-4, Foxc2, and VEGF-A mRNA were significantly higher in SC synovium. Stimulation of TGF-ß3 on synoviocytes increased alkaline phosphatase (ALP) activity and expressions of chondrogenic genes (Sox9, Col2α1, Aggrecan, Wnt-4, and Wnt-11), osteogenic genes (Runx2, Foxc2, osteocalcin, and Col1α1), and VEGF-A, but failed to influence FGF-2 expression. However, the addition of FGF-2 increased TGF-ß3 expression. In conclusion, TGF-ß3 existed in synovium and LBs of SC, and was responsible for the pathogenesis of SC.

Translocaciones cromosómicas en los sarcomas de partes blandas: de la biología molecular a la aplicación clínica / Chromosomal translocations in soft tissue sarcomas: from molecular biology to clinical application

Los avances recientes en el campo de la biología molecular de los sarcomas pediátricos, en especial el descubrimiento y caracterización de translocaciones cromosómicas específicas, han sentado las bases para la implantación de nuevas herramientas diagnósticas. En esta revisión se repasan las principales translocaciones asociadas a tumores pediátricos y se resumen sus características moleculares en relación a su capacidad oncogénica, su posible utilidad como herramientas de diagnóstico diferencial así como su posible relación con parámetros clínicos(AU)

Recent advances in the knowledge of the molecular biology of paediatric sarcomas, especially the characterisation of chromosomal translocations associated specifically with particular types of cancer, have established bases for the introduction of new diagnostic tools. This article reviews the main chromosomal translocations associated with paediatric tumours, and summarises their molecular characteristics regarding their oncogenic capabilities, possible usefulness as a differential diagnostic tools and possible correlation with clinical parameters(AU)

Progressive pseudorheumatoid chondrodysplasia of childhood.

Progressive pseudorheumatoid chondrodysplasia is an autosomal recessively inherited skeletal dysplasia, characterised by platyspondyly and progressive arthropathy. We report a 26-year-old woman who presented with a history of waddling gait, progressive restriction of movements of several joints and swelling of interphalangeal joints since her late childhood. She was diagnosed to have progressive pseudorheumatoid chondrodysplasia associated with synovial osteochondromatosis.

Dysregulation of hedgehog signalling predisposes to synovial chondromatosis.

Synovial chondromatosis is a condition affecting joints in which metaplastic cartilage nodules arise from the synovium, causing pain, joint dysfunction, and ultimately joint destruction. Because dysregulation of hedgehog signalling is a feature of several benign cartilaginous tumours, expression of the hedgehog target genes PTC1 and GLI1 was examined in this study in samples from human synovial chondromatosis. Significantly higher expression levels were found in synovial chondromatosis than in the synovium, from which it arises. To determine if hedgehog-mediated transcription predisposes to synovial chondromatosis, the extra-toes mutant mouse, which harbours a heterozygous mutation in the hedgehog transcriptional repressor, Gli3, resulting in decreased expression of Gli3 protein, was studied. The extra-toes mutant mouse has a phenotype consistent with overactive hedgehog signalling, suggesting that Gli3 acts as a transcriptional repressor of limb development. Eighty-five per cent of Gli3 mutant mice developed synovial chondromatosis at 18 months of age, compared with 30% of wild-type littermates (p < 0.05). Three of the ten Gli3 mutant mice treated with triparanol, which blocks hedgehog signalling upstream of the Gli transcription factors, developed synovial chondromatosis, compared with eight of ten control mice. These data demonstrate that hedgehog signalling plays an important role in the development of synovial chondromatosis and suggest that blockade of hedgehog signalling may be a potential treatment for this disorder.

Genetics of chondrosarcoma and related tumors.

PURPOSE OF REVIEW: The burgeoning body of information on the genetic changes present in and underlying the development and biology of human cancers has carried implications regarding the possible genetic events that are responsible for not only the genesis of these cancers but also the hope of the cure for these cancers. Chondrosarcomas are a group of tumors that fall into this category. The purpose of this review is to summarize the genetic findings in these tumors. RECENT FINDINGS: The histopathologic variability of chondrosarcomas is reflected in the complexity and lack of specificity of their cytogenetic and molecular genetic findings, except for extraskeletal myxoid chondrosarcomas. These are characterized in the preponderant number of cases by a translocation, t(9;22)(q22;q12), and in a small number of cases by variant translocations t(9;17)(q22;q11) and t(9;15)(q22;q21). These translocations lead to the formation of abnormal fusion genes and gene products (proteins). In each of these translocations, the CHN gene is involved, resulting in the chimeric fusion genes EWS/CHN, RBP56/CHN, and TCF12/CHN, respectively. The specific translocations and their associated molecular genetic changes are diagnostic of extraskeletal myxoid chondrosarcomas. The abnormal proteins resulting from these fusion genes aberrantly affect gene transcription and cellular signaling pathways thought to be responsible for initiating sarcoma formation. In skeletal (central) chondrosarcomas of varying histopathologic types, the cytogenetic and molecular genetic findings are variable, complex, and apparently lacking in specificity. These changes may reflect a stepwise process (or processes) of oncogenesis involving an array of genes. SUMMARY: Although some cartilaginous tumors are characterized by specific or recurrent chromosome alterations and molecular genetic changes, much is yet to be learned about the nature and sequence of these genetics events and about their unique role in the stepwise process involved in the development and biology of each tumor type, both malignant and nonmalignant. Until such time, some of the genetic changes, particularly the presence of specific translocations, can be of definite diagnostic value.

Articular chondromatosis and chrondroid metaplasia in transgenic TAg mice.

The C3(1)/SV40 T antigen transgenic mouse model for which rapid mammary and prostate tumor development has been documented uses the FVB/N mouse as a background strain. In this study, where the background strain used was the C57BL/6J mouse, neither mammary nor prostate tumors developed over periods of up to 40 weeks. However, a disturbance of hyaline cartilage in joints was observed similar to that found in synovial chondromatosis in humans. In addition, cartilage thickening in the external ears and cartilaginous metaplasia of the ascending aorta also occurred. This suggests that rearrangement of the transgene occurred in breeding on the C57BL background, thus modifying its expression. It raises the possibility that the genetic changes induced by the SV40 T antigen transforming sequence are important in cartilage homeostasis.

Primary synovial chondromatosis of the subtalar joint affecting two brothers.

Primary synovial chondromatosis is a rare benign condition characterized by the formation of multiple cartilaginous nodules in the synovium of joints and on occasions tendon sheaths or bursae. A case of primary synovial chondromatosis affecting the subtalar joint is reported. The patient's brother developed the same condition affecting the same joint 2 years later. The proposed etiologies are discussed including the presence of the proto-oncogene C-erb B-2.

Synovial osteochondromatosis in hereditary arthro-ophthalmopathy (Wagner-Stickler syndrome).

A case of bilateral synovial osteochondromatosis in a patient with hereditary arthro-ophthalmopathy is presented. The osteochondral lesions were largely calcified in one joint and largely chondromatous in the other. Typical features of hereditary arthro-ophthalmopathy are reviewed and it is hypothesised that the abnormal collagen in this syndrome is responsible for the development of synovial osteochondromatosis. Synovial manifestations of skeletal dysplasias have to our knowledge not been described previously but we suggest that synovial osteochondromatosis can be the manifestation of an underlying skeletal dysplasia.

Chromosome 6 abnormalities are recurrent in synovial chondromatosis.

Synovial chondromatosis, a lesion composed of multiple nodules of cartilage involving articular or tendon sheath synovial membranes, has traditionally been considered a metaplastic condition. A specific or characteristic chromosomal anomaly has not yet been identified in synovial chondromatosis. Cytogenetic and molecular cytogenetic analyses of three cases of synovial chondromatosis revealed clonal karyotypic abnormalities in all three cases including structural abnormalities of chromosome 6 in two. Anomalies of chromosome 6 have been observed in three of five previously reported synovial chondromatosis cases. These findings support a neoplastic origin for synovial chondromatosis and suggest that chromosome 6 aberrations are recurrent in this lesion.

Synovial chondromatosis: clonal chromosome changes provide further evidence for a neoplastic disorder.

Synovial chondromatosis is a rare lesion, which is still believed by most authors to be reactive rather than neoplastic. We report on a case of synovial chondromatosis with clonal chromosomal changes [43,XX,der (1) t (1;13) (p21-22;q21),-6,-13,-14, add(21) (q21)]. The presence of clonal chromosomal changes in this and in three previously reported cases suggests that synovial chondromatosis is a true neoplastic lesion.

Chromosome rearrangements in synovial chondromatous lesions.

Short-term cultures from one synovial chondroma and three cases of synovial chondromatosis, a lesion for which no previous karyotypic information exists, were cytogenetically analysed. Whereas the chondroma displayed the relatively simple karyotype 46,XY,add(12)(q13),der(17)t(12;17)(q13;q21), more complex changes were found in the three cases of chondromatosis: case 1, 47,XY,der(1)inv(1)(p13q25)del (1)(q25q32), t(1;12)(q25;q13), + 5,der(12)add(12)(p11)t(1;12)(p22;q13); case 2, 47,XY,add(10)(q26), + 20/46 idem,-6/46,XY,t(2;4)(q33;q21), add(21)(p11); and case 3, 44,XY,add(1)(p36), del(1)(p13p22),add(6)(p25), del(7) (q22q32),del(10)(q21),add(11)(q13),-17,-18. The cytogenetic findings strongly suggest that synovial chondro-matosis is a clonal proliferation. Apart from a near-diploid chromosome number, the only recurrent cytogenetic features among the four cases were loss of band 10q26 and rearrangements of 1p13 and 12q13, found in two cases each. While chromosome bands 1p13 and 10q26 have not been reported to be involved in other types of benign chondromatous lesions, the 12q13-15 segment is recurrently rearranged in a variety of chondromatous tumours, e.g. pulmonary chondroid hamartomas. The present finding of translocations affecting band 12q13 in two of the cases emphasises that, irrespective of the anatomical localisation of the tumours, rearrangements of genes in 12q13-15 are important in the development of a large subset of benign and malignant cartilage-forming tumours.

p53 expression and DNA ploidy of cartilage lesions.

The aim of this study was to investigate the expression of a tumor suppressor gene (p53) in cartilage lesions of bone and its relationship to their histological grade and DNA ploidy. An immunohistochemical assay for p53 and Feulgen-stained DNA preparations was subjected to computerized image analysis. Enchondromas, synovial chondromatosis, and low grade (grade I and II) chondrosarcomas were diploid. High grade (grade III) chondrosarcomas and high grade sarcomatous components of dedifferentiated chondrosarcomas were aneuploid. Well differentiated cartilaginous components of dedifferentiated chondrosarcomas were diploid. Microscopic examination showed weak focal positivity for p53 in one of 10 enchondromas one of six examples of synovial chondromatosis, and three of four low grade (grade I and II) chondrosarcomas. All three high grade (grade III) chondrosarcomas were strongly positive for p53. The high grade sarcomatous component of all four dedifferentiated chondrosarcomas was strongly positive for p53, whereas only focal weak positivity was noted in the well differentiated cartilaginous areas. These results were confirmed by quantitative computer-assisted image analysis, which showed that high grade aneuploid cartilage tumors demonstrated strikingly higher levels of p53 than did diploid low grade malignant tumors or benign cartilage lesions.

Metachondromatosis: a report of two cases in a family.

We have described a 10-year-old Japanese boy and his father with metachondromatosis characterized by multiple exostoses, enchondromas, and periarticular calcification or ossification and reviewed the literature on this condition. The boy developed bilateral epiphyseal changes in the hips mimicking Perthes' disease. These cases are the first Japanese individuals with this disorder. The natural history and the associated disorders of metachondromatosis are also discussed in this paper. Metachondromatosis is an inherited skeletal dysplasia characterized by multiple cartilaginous exostoses, multiple enchondromas, and periarticular calcification or ossification. The mode of inheritance of the disease is autosomal dominant. In 1971, Maroteaux first described the disorder in 6 patients of 2 kindreds. Since then, 22 cases have been reported. However, no Japanese patient with this disorder has been described to date. We herein report a Japanese boy and his father with this rare bone dysplasia. The boy developed bilateral epiphyseal lesions in the femoral heads mimicking Perthes' disease.

Familial synovial chondromatosis combined with dwarfism.

In a family with synovial chondromatosis affecting at least three, presumably five members, the articular disorder was combined with dwarfism. The persons with joint disorders were below the third percentile in body height, but family members with normal articular function had normal height. We believe this to be the first description of a combination of synovial chondromatosis with genetically caused dwarfism.