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Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.

Ollier disease and Maffucci syndrome are rare, nonhereditary skeletal disorders characterized by the presence of multiple enchondromas with (Maffucci) or without (Ollier) co-existing multiple hemangiomas of soft tissue. Enchondromas can progress toward central chondrosarcomas. PTH1R mutations are found in a small subset of Ollier patients. The genetic deficit in Maffucci syndrome is unknown. Here, we report the first genome-wide analysis using Affymetrix SNP 6.0 array on Maffucci enchondromas (n = 4) and chondrosarcomas (n = 2) from four cases. Results were compared to a previously studied cohort of Ollier patients (n = 37). We found no loss of heterozygosity (LOH) or common copy number alterations shared by all enchondromas, with the exception of some copy number variations. As expected, chondrosarcomas were found to have multiple genomic imbalances. This is similar to conventional solitary and Ollier-related enchondromas and chondrosarcomas and supports the multistep genetic progression model. Expression profiling using Illumina BeadArray-v3 chip revealed that cartilaginous tumors in Maffucci patients are more similar to such tumors in Ollier patients than to sporadic cartilage tumors. Point mutations in a single gene or other copy number neutral genomic changes might play a role in enchondromagenesis., (Copyright © 2011 Wiley-Liss, Inc.)

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome., Competing Interests: The authors have declared that no competing interests exist.

Background: Ollier disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier disease is unknown., Methods: We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina BeadArray v3.0 for 7 ECs of 6 patients., Results: Non-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identified loss as well as down regulation of POU5F1 and gain as well as up regulation of NIPBL. None of these candidate regions were affected in more than two Ollier patients suggesting these changes to be random secondary events in EC development. An increased number of genetic alterations and LOH were found in Ollier CS which mainly involves chromosomes 9p, 6q, 5q and 3p., Conclusions: We present the first genome-wide analysis of the largest international series of Ollier ECs and CS reported so far and demonstrate that copy number alterations and LOH are rare and non-recurrent in Ollier ECs while secondary CS are genetically unstable. One could predict that instead small deletions, point mutations or epigenetic mechanisms play a role in the origin of ECs of Ollier disease.

Background: Enchondromatosis is characterized by the presence of multiple benign cartilage lesions in bone. While Ollier disease is typified by multiple enchondromas, in Maffucci syndrome these are associated with hemangiomas. Studies evaluating the predictive value of clinical symptoms for development of secondary chondrosarcoma and prognosis are lacking. This multi-institute study evaluates the clinical characteristics of patients, to get better insight on behavior and prognosis of these diseases., Method: A retrospective study was conducted using clinical data of 144 Ollier and 17 Maffucci patients from 13 European centers and one national databank supplied by members of the European Musculoskeletal Oncology Society., Results: Patients had multiple enchondromas in the hands and feet only (group I, 18%), in long bones including scapula and pelvis only (group II, 39%), and in both small and long/flat bones (group III, 43%), respectively. The overall incidence of chondrosarcoma thus far is 40%. In group I, only 4 patients (15%) developed chondrosarcoma, in contrast to 27 patients (43%) in group II and 26 patients (46%) in group III, respectively. The risk of developing chondrosarcoma is increased when enchondromas are located in the pelvis (odds ratio, 3.8; p = 0.00l)., Conclusions: Overall incidence of development of chondrosarcoma is 40%, but may, due to age-dependency, increase when considered as a lifelong risk. Patients with enchondromas located in long bones or axial skeleton, especially the pelvis, have a seriously increased risk of developing chondrosarcoma, and are identified as the population that needs regular screening on early detection of malignant transformation.

Enchondromatosis is a rare, heterogeneous skeletal disorder in which patients have multiple enchondromas. Enchondromas are benign hyaline cartilage forming tumors in the medulla of metaphyseal bone. The disorder manifests itself early in childhood without any significant gender bias. Enchondromatosis encompasses several different subtypes of which Ollier disease and Maffucci syndrome are most common, while the other subtypes (metachondromatosis, genochondromatosis, spondyloenchondrodysplasia, dysspondyloenchondromatosis and cheirospondyloenchondromatosis) are extremely rare. Most subtypes are non-hereditary, while some are autosomal dominant or recessive. The gene(s) causing the different enchondromatosis syndromes are largely unknown. They should be distinguished and adequately diagnosed, not only to guide therapeutic decisions and genetic counseling, but also with respect to research into their etiology. For a longtime enchondromas have been considered a developmental disorder caused by the failure of normal endochondral bone formation. With the identification of genetic abnormalities in enchondromas however, they were being thought of as neoplasms. Active hedgehog signaling is reported to be important for enchondroma development and PTH1R mutations have been identified in approximately 10% of Ollier patients. One can therefore speculate that the gene(s) causing the different enchondromatosis subtypes are involved in hedgehog/PTH1R growth plate signaling. Adequate distinction within future studies will shed light on whether these subtypes are different ends of a spectrum caused by a single gene, or that they represent truely different diseases. We therefore review the available clinical information for all enchondromatosis subtypes and discuss the little molecular data available hinting towards their cause.

Conventional central chondrosarcomas are malignant cartilaginous tumours, occasionally arising secondary to either solitary or multiple (Ollier disease) enchondromas. Recurrences may have progressed in grade. The aims of the present study were to identify putative differences in gene expression between solitary and Ollier disease-related tumours, and to elucidate signalling pathways involved in tumour progression by genome-wide cDNA expression analysis. Arrays enriched for cartilage-specific cDNAs and genes involved in general tumourigenesis were used to analyse enchondromas (n = 3, two with Ollier disease), chondrosarcomas of different grades (n = 19, three with Ollier disease), normal resting-zone cartilage (n = 2), and chondrosarcoma cells in culture (n = 7). The arrays were analysed by unsupervised hierarchical clustering, significant analysis of microarray, and T-tests. Confirmation of data was performed by immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Ollier disease cases and solitary tumours revealed similar expression profiles, suggesting that the same signalling pathways are involved in tumourigenesis. Interestingly, JunB protein expression was significantly higher in grade I chondrosarcomas than in enchondromas (p = 0.009), which could be of diagnostic relevance. Upon chondrosarcoma progression, matrix-associated genes are down-regulated, reflecting the histology of high-grade tumours. An increase in glycolysis-associated, and a decrease in oxidative phosphorylation-related, genes was found in high-grade tumours. These findings suggest an adaptation in energy supply upon progression towards higher grade., (Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Enchondromas and conventional central chondrosarcomas are, respectively, benign and malignant hyaline cartilage-forming tumours that originate in the medulla of bone. In order to gain a better understanding of the molecular process underlying malignant transformation of enchondroma, and to investigate whether there is a biological difference between conventional central cartilaginous tumours and those of enchondromatosis or with phalangeal localization, a series of 64 enchondromas (phalanx, n = 21; enchondromatosis, n = 15) and 89 chondrosarcomas (phalanx, n = 17; enchondromatosis, n = 13) was collected. Indian Hedgehog (IHH)/parathyroid hormone related peptide (PTHrP) signalling, an important pathway in chondrocyte proliferation and differentiation within the normal growth plate, was studied by immunohistochemical analysis of the expression of PTHrP, PTHR1, Bcl-2, p21, cyclin D1, and cyclin E. Quantitative real-time PCR for IHH, PTCH, SMO, and GLI2 was performed on a subset of tumours. The data show that IHH signalling is absent in enchondromas and central chondrosarcomas, while PTHrP signalling is active. There was no difference in the expression of any of the molecules between 35 enchondromas and 26 grade I central chondrosarcomas, indicating that PTHrP signalling is not important in malignant transformation of enchondroma. Higher expression of PTHR1 and Bcl-2 was associated with increasing histological grade in chondrosarcoma, suggesting involvement in tumour progression. No difference was found between samples from enchondromatosis patients and solitary cases, suggesting no difference in PTHrP signalling. A small subset of phalangeal chondrosarcomas demonstrated down-regulation of PTHrP, which may be related to its more indolent clinical behaviour. Thus, in both enchondromas and central chondrosarcomas, PTHrP signalling is active and independent of IHH signalling, irrespective of the presence or absence of enchondromatosis.

Enchondromatosis (Ollier disease, Maffucci syndrome) is a rare developmental disorder characterized by multiple enchondromas. Not much is known about its molecular genetic background. Recently, an activating mutation in the parathyroid hormone receptor type 1 (PTHR1) gene, c.448C>T (p.R150C), was reported in two of six patients with enchondromatosis. The mutation is thought to result in upregulation of the IHH/PTHrP pathway. This is in contrast to previous studies, showing downregulation of this pathway in other cartilaginous tumors. Therefore, we investigated PTHR1 in enchondromas and chondrosarcomas from 31 enchondromatosis patients from three different European countries, thereby excluding a population bias. PTHR1 protein expression was studied using immunohistochemistry, revealing normal expression. The presence of the described PTHR1 mutation was analyzed, using allele-specific oligonucleotide hybridization confirmed by sequence analysis, in tumors from 26 patients. In addition, 11 patients were screened for other mutations in the PTHR1 gene by sequence analysis. Using both allele-specific oligonucleotide hybridization and sequencing, we could neither confirm the previously found mutation nor find any other mutations in the PTHR1 gene. These results indicate that the PTHR1 gene is not, in contrast to previous suggestions, the culprit for enchondromatosis., (Copyright 2004 Wiley-Liss, Inc.)

Multiple enchondromatosis (Ollier's disease) is a nonhereditary disease characterized by multiple central (medullary) cartilaginous bone tumors of unknown pathogenesis. It usually involves the extremities with a unilateral predominance, and sarcomatous transformation may occur. We report an autopsy-based genetic study of a 34-year-old man presenting in early adolescence with multiple enchondromas of the extremities, predominantly left-sided, compatible with Ollier's disease. Twelve years after presentation, malignant transformation to a high grade chondrosarcoma occurred in a tibial enchondroma. The patient died after widespread metastatic disease. Loss of heterozygosity (LOH), in the tibial chondrosarcoma and its metastases, was identified exclusively on chromosome bands 13q14 and 9p21, while being absent in the femoral enchondroma analyzed. Similarly, p53 overexpression was identified immunohistochemically in the tibial chondrosarcoma and its metastases, while being absent in the femoral enchondroma; LOH at 17p13 however, was not demonstrable. It is hypothesized that inactivation of putative tumor suppressor genes at 9p21 and 13q14, and overexpression of p53, identified in the chondrosarcoma and its metastases, but absent in enchondroma, may be related to sarcomatous transformation in Ollier's disease.