Multiple Joint Arthroplasty in Hip and Knee Osteoarthritis Patients: A National Longitudinal Cohort Study.

BACKGROUND: Many patients suffer from osteoarthritis (OA) in multiple joints, possibly resulting in multiple joint arthroplasties (MJAs). Primarily, we determined the cumulative incidence (Cin) of MJA in hip and knee joints up to 10 years. Secondly, we calculated the mean time between the first and subsequent joint arthroplasty, and evaluated the different MJA trajectories. Lastly, we compared patient characteristics and outcomes (functionality and pain) after surgery between MJA patients and single hip arthroplasty or knee arthroplasty (HA and KA) patients. METHODS: Primary index (first) HA or KA for OA were extracted from the Dutch Arthroplasty Register. The 1, 2, 5, and 10-year Cin (including competing risk death) of MJA, mean time intervals, and MJA-trajectories were calculated and stratified for primary index HA or KA. Sex, preoperative age, and body mass index were compared using ordinal logistic regression. Outcomes, measured preoperatively, 3, 6, and 12 months postoperatively (function: Hip Disability or Knee Injury and OA Outcome Score; Pain: Numerical Rating Scale), were compared using linear regression. RESULTS: A total of 140,406 HA-patients and 140,268 KA-patients were included. One, 2, 5, and 10-year Cin for a second arthroplasty were respectively 8.9% [95% confidence interval (CI): 8.7 to 9.0], 14.3% [95% CI: 14.1 to 14.5], 24.0% [95% CI: 23.7 to 24.2], and 32.7% [95% CI: 32.2 to 33.1] after index HA, and 9.5% [95% CI: 9.4 to 9.7], 16.0% [95% CI: 15.9 to 16.2], 26.4% [95% CI: 26.1 to 26.6], and 35.8% [95% CI: 35.4 to 36.3] after index KA. The 10-year Cin for > 2 arthroplasties were small in both the index HA and KA groups. Time-intervals from first to second, third, and fourth arthroplasty were 26 [95% CI: 26.1 to 26.7], 47 [95% CI: 46.4 to 48.4], and 58 [95% CI: 55.4 to 61.1] months after index HA, and 26 [95% CI: 25.9 to 26.3], 52 [95% CI: 50.8 to 52.7], and 61 [95% CI: 58.3 to 63.4] months after index KA. There were 83% of the second arthroplasties placed in the contralateral cognate joint (ie, knee or hip). Differences in postoperative functionality and pain between MJAs and single HAs and KAs were small. CONCLUSIONS: The 10-year Cin showed that about one-third of patients received a second arthroplasty after approximately 2 years, with the majority in the contralateral cognate joint. Few patients received > 2 arthroplasties within 10 years. Being a women, having a higher body mass index, and being younger increased the odds of MJA. Postoperative outcomes were slightly negatively affected by MJA.

Activities and participation after primary total hip arthroplasty; posterolateral versus direct anterior approach in 860 patients.

BACKGROUND AND PURPOSE: In the past decade, a shift occurred in surgical total hip arthroplasty (THA) approaches to the posterolateral (PLA) and direct anterior approach (DAA). Comparisons of postoperative activities and participation between surgical approaches for THA are sparse. We therefore investigated the association between PLA and DAA for THA regarding the construct "activity and participation" (ICF model) during the first postoperative year. PATIENTS AND METHODS: This was an observational cohort study on osteoarthritis patients scheduled for primary THA in 2 hospitals. Questionnaires to assess the ICF domain "activity and participation" were completed preoperatively, and 3, 6, and 12 months postoperatively (HOOS Activities of daily living (ADL) and Sport and Recreation Function (SR), Hospital for Special Surgery Hip Replacement Expectations Survey, and questions regarding return to work). Each hospital exclusively performed one approach (PLA [Alloclassic-Zweymüller stem] or DAA [Taperloc Complete stem]) for uncemented THA. Hospital was included as instrumental variable, thereby addressing bias by (un)measured confounders. Adjusted mixed-effect models were used, stratified by employment. RESULTS: Total population: 238 PLA (24% employed) and 622 DAA (26% employed) patients. At 12 months, the PLA group had a lower ADL score (-7, 95% CI -12 to -2 points). At 6 months, significantly fewer PLA patients had fulfillment of the expectation sports-performance (OR = 0.3, CI 0.2-0.7]. Other outcomes were comparable. Employed population: At 6 and 12 months, PLA patients scored clinically lower on ADL (respectively -10, CI -19 to 0 and -9, CI -19 to 0 points) and SR (respectively -13, CI -21 to -4 and -9, CI -18 to -1 points). At 6 months, fewer PLA patients fulfilled the expectation joining recreational activities (OR = 0.2, CI 0.1-0.7]. Fulfillment of other expectations was comparable between groups. PLA patients less often returned to work within 3 months (31% vs. 45%), but rates were comparable at 12 months (86% vs. 87%). INTERPRETATION: Overall, functional recovery regarding "activity and participation" was comparable for PLA and DAA. Among employed patients, DAA resulted in better functional recovery and more fulfillment of expectations compared with PLA patients. DAA might also facilitate faster return to work.

Feasibility of Collecting Multiple Patient-Reported Outcome Measures Alongside the Dutch Arthroplasty Register.

BACKGROUND: Compliance rates with patient-reported outcome measures (PROMs) collected alongside arthroplasty registries vary in the literature. We described the feasibility of a routinely collected set PROMs alongside the Dutch Arthroplasty Register. METHODS: The longitudinal Leiden Orthopaedics Outcomes of OsteoArthritis Study is a multicenter (7 hospitals), observational study including patients undergoing total hip or total knee arthroplasty (THA or TKA). A set of PROMs: Short Form-12, EuroQol 5 Dimensions, Hip/Knee injury and Osteoarthritis Outcome Score, Oxford Hip/Knee Score was collected preoperatively and at 6, 12, 24 months, and every 2 years thereafter. Participation rates and response rates were recorded. RESULTS: Between June 2012 and December 2014, 1796 THA and 1636 TKA patients were invited, of whom 1043 THA (58%; mean age 68 years [standard deviation, SD: 10]) and 970 TKA patients (59%; mean age 71 years [SD 9.5]) participated in the study. At 6 months, 35 THA/38 TKA patients were lost to follow-up. Response rates were 90% for THA (898/1000) and 89% for TKA (827/932) participants. At 1 and 2 years, 8 and 18 THA and 17 and 11 TKA patients were lost to follow-up, respectively. The response rates among those eligible were 87% (866/992) and 84% (812/972) for THA and 84% (771/917) and 83% (756/906) for TKA patients, respectively. The 2-year questionnaire was completed by 78.5% of the included THA patients and by 77.9% of the included TKA patients. CONCLUSIONS: About 60% of patients undergoing THA or TKA complete PROMs preoperatively, with more than 80% returning follow-up PROMs. To increase the participation rates, more efforts concerning the initial recruitment of patients are needed.

Association of handgrip strength with patient-reported outcome measures after total hip and knee arthroplasty.

About 33% patients with osteoarthritis undergoing total hip/knee arthroplasty are not satisfied with the outcome, warranting the need to improve patient selection. Handgrip strength (HGS) has been suggested as a proxy for overall muscle strength and may be associated with post-arthroplasty function. This study aims to assess the association of pre-operative HGS with change in hip/knee function and quality of life in patients with arthroplasty. 226 hip (THA) and 246 knee (TKA) arthroplasty patients were included in this prospective cohort study. Pre-operative HGS was assessed by means of a dynamometer and the HOOS/KOOS and SF-36 questionnaires were collected before arthroplasty and 1 year thereafter. The association of HGS with score change on each sub-domain of the included questionnaires was assessed by linear regression models, adjusting for sex, body mass index and baseline score. Mean pre-operative HGS was 26 kg for patients undergoing THA and 24 kg for those undergoing TKA. HGS was positively associated with an increased improvement score on "function in sport and recreation"-domain in hip (ß = 0.68, P = 0.005) and knee (ß = 0.52, P = 0.049) and "symptoms"-domain in hip (ß = 0.56, P = 0.001). For patients with THA, HGS was associated with the "quality of life" domain (ß = 0.33, P = 0.033). In patients with TKA, HGS was associated with the physical component score (ß = 0.31, P = 0.001). All statistically significant effects were positive, indicating that with greater pre-operative HGS, an increased gain in 1-year post-surgery score was observed. HGS can be used as a tool to inform patients with OA who are future candidates for a prosthesis about the possible improvements of certain aspects of life after arthroplasty.

Preoperative Radiographic Osteoarthritis Severity Modifies the Effect of Preoperative Pain on Pain/Function After Total Knee Arthroplasty: Results at 1 and 2 Years Postoperatively.

BACKGROUND: Osteoarthritis (OA) severity as demonstrated by preoperative radiographs and preoperative pain play an important role in the indication for total knee arthroplasty (TKA). We investigated whether preoperative radiographic evidence of OA severity modified the effect of preoperative self-reported pain on postoperative pain and function 1 and 2 years after TKA for OA. METHODS: Data from the Longitudinal Leiden Orthopaedics Outcomes of Osteoarthritis Study (LOAS), a multicenter cohort study on outcomes after TKA, were used. OA severity was assessed radiographically with the Kellgren and Lawrence (KL) score (range, 0 to 4). Pain and function were evaluated with the Knee injury and Osteoarthritis Outcome Score (KOOS). After adjustment for body mass index (BMI), age, sex, and the Mental Component Summary scores from the Short Form-12, multivariate linear regression analyses with an interaction term between the preoperative KL score and preoperative pain were performed. RESULTS: The study included 559 patients. The preoperative KL score was independently associated with 1-year postoperative pain and function (ß = 5.4, 95% confidence interval [CI] = 1.4 to 9.4, and ß = 7.7, 95% CI = 3.2 to 12.2), while preoperative pain was associated only with postoperative pain (ß = 0.3, 95% CI = 0.1 to 0.6) and not with postoperative function (ß = 0.2, 95% CI = -0.2 to 0.5). Comparable associations were found between 2-year postoperative pain and KL score (ß = 8.0, 95% CI = 3.2 to 12.7) and preoperative pain (ß = 0.5, 95% CI = 0.1 to 0.8) and between 2-year postoperative function and KL score (ß = 7.7, 95% CI = 3.2 to 12.2). The study showed a trend toward the KL score modifying the effect of preoperative pain on 1-year postoperative pain (ß = -0.1, 95% CI = -0.1 to 0.0) and 2-year postoperative pain (ß = -0.1, 95% CI = -0.2 to 0.0) and on 1 and 2-year function (ß = -0.1, 95% CI = -0.2 to 0.0 for both), with the effect of preoperative pain on postoperative pain and function seeming to become less important when there was radiographic evidence of greater preoperative OA severity. CONCLUSIONS: Patients with less pain and higher KL grades preoperatively had better function and pain outcomes 1 and 2 years after TKA. However, the effect of preoperative pain on the postoperative outcomes seems to become less important when the patient has radiographic evidence of more severe OA. We believe that analysis of the severity of preoperative pain is an important proxy for optimal postoperative patient outcome. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Patients' pre-operative general and specific outcome expectations predict postoperative pain and function after total knee and total hip arthroplasties.

Background and aims Previous studies have suggested there is an association between preoperative expectations about the outcome and outcomes of total knee and total hip arthroplasty (TKA/THA). However, expectations have been rarely examined on their clinical relevance relative to other well-known predictive factors. Furthermore expectations can be measured on a more generic level (e.g. does one expect their symptoms to improve after surgery) or on a more specific level (e.g. does one expect to be able to squat again after surgery). Aim of this study was to examine whether patients' general and specific preoperative outcome expectations predict function and pain 12-months after TKA/THA, when assessed as one of the candidate predictive variables alongside other relevant clinical and sociodemographic variables. Moreover, we explored whether a more generic or a more specific assessment of expectations would better predict outcome. Methods A prospective cohort study on consecutive TKA/THA patients, with assessments done preoperatively and 12-months postoperative. Primary outcomes were the knee injury and osteoarthritis outcome score (KOOS) and hip injury and osteoarthritis outcome score (HOOS) activities of daily living (ADL) and pain subscale scores at 12-months. The pain subscales consist of nine-(KOOS) and 10-(HOOS) items and the ADL of 17 items. Patients' preoperative outcome expectations were measured with the credibility expectancy questionnaire (CEQ), which contains three items scored on a 0-9 scale and sum score 0-27 and the Hospital for Special Surgery expectations surveys (HSS expectation surveys) for 17(TKA) or 18(THA) outcomes on 0-4 scale. Other candidate predictors: preoperative pain and function as measured with HOOS/KOOS, sex, age, education level, body mass index, Kellgren/Lawrence score, preoperative mental health and treatment credibility as measured with CEQ. Eight prediction models were constructed using multivariate linear regression analysis with a backward selection procedure. Results The 146 TKA patients included in this study had a mean age of 66.9 years (SD 9.2) and 69% was female. The 148 THA patients had a mean age 67.2 (SD 9.5) and 57% was female. Mean outcomes: postoperative HOOS-ADL 84.3 (SD 16.6), pain 88.2 (SD 15.4), KOOS-ADL 83.9 (SD 15.8) and pain 83.6 (SD 17.1). CEQ-expectancy median was in THA 23 (IQR 21;24) and TKA 23 (IQR 20;24). HSS-expectation surveys function was for THA 21.0 (18.0;24.0) and 19.0 (14.0;22.0) in TKA. Patients' outcome expectations were consistently part of the combination of variables that best predicted outcomes for both TKA/THA 1-year post-operatively. Expectations alone explained between 17.0 and 30.3% of the variance in outcomes. The CEQ expectancy subscale explained more variance of postoperative function in TKA and of function and pain in THA as compared to the HSS expectation surveys. Conclusions In planning of surgical treatment, orthopedic surgeons should take a range of variables into account of which the patient's expectations about outcome of surgery is one. The CEQ expectancy subscale predicted outcomes slightly better as the HSS expectation surveys, but differences in predictive value of the two measurements were too small to prefer between the two. Future studies are advised to replicate these findings and externally validate the models presented.

Frailty in end-stage hip or knee osteoarthritis: validation of the Groningen Frailty Indicator (GFI) questionnaire.

Frailty is highly prevalent in the elderly, increasing the risk of poor health outcomes. The Groningen Frailty Indicator (GFI) is a 15-item validated questionnaire for the elderly. Its value in patients with end-stage hip or knee osteoarthritis (OA) has not yet been determined. This study assesses the validity of the GFI in this patient group. End-stage hip or knee OA patients completed the GFI (range 0-15, ≥ 4 = frail) before arthroplasty surgery. Convergent validity was determined by Spearman-rank correlation between the SF-12 physical (PCS) and mental (MCS) component scores and the physical and mental GFI-domains, respectively. Discriminant validity was assessed by means of overall GFI-score and the pain-domain of the Hip/Knee Osteoarthritis Outcome Score (HOOS/KOOS). Altogether 3275 patients were included of whom 2957 (90.3%) completed the GFI. Mean GFI-scores were 2.78 (2.41) and 2.28 (1.99) in hip and knee OA-patients, respectively, with 570 (35.9%) of hip and 344 (24.1%) of knee patients considered frail. The convergent validity was moderate to strong (physical domain R = - 0.4, mental domain R = - 0.6) and discriminant validity low (R HOOS/KOOS-pain domain = - 0.2), confirming the validity of the GFI-questionnaire in this population. With 90% of participants completing the GFI, it is a feasible and valid questionnaire to assess frailty in end-stage hip and knee OA-patients. One-third (33.3%) of the patients undergoing hip arthroplasty and a quarter (24.1%) of those undergoing knee arthroplasty are frail. Whether this is associated with worse outcomes and can thus be used as a pre-operative predictor needs to be explored.

No associations between self-reported knee joint instability and radiographic features in knee osteoarthritis patients prior to Total Knee Arthroplasty: A cross-sectional analysis of the Longitudinal Leiden Orthopaedics Outcomes of Osteo-Arthritis study (LOAS) data.

BACKGROUND: To describe the prevalence of self-reported knee joint instability in patients with pre-surgery knee osteoarthritis (OA) and to explore the associations between self-reported knee joint instability and radiological features. METHODS: A cross-sectional study including patients scheduled for primary Total Knee Arthroplasty (TKA). Self-reported knee instability was examined by questionnaire. Radiological features consisted of osteophyte formation and joint space narrowing (JSN), both scored on a 0 to three scale. Scores >1 are defined as substantial JSN or osteophyte formation. Regression analyses were provided to identify associations of radiological features with self-reported knee joint instability. RESULTS: Two hundred and sixty-five patients (mean age 69years and 170 females) were included. Knee instability was reported by 192 patients (72%). Substantial osteophyte formation was present in 78 patients (41%) reporting and 33 patients (46%) not reporting knee joint instability. Substantial JSN was present in 137 (71%) and 53 patients (73%), respectively. Self-reported knee instability was not associated with JSN (relative to score 0, odds ratios (95% CI) of score 1, 2 and 3 were 0.87 (0.30-2.54), 0.98 (0.38-2.52), 0.68 (0.25-1.86), respectively) or osteophyte formation (relative to score 0, odds ratios (95% CI) of score 1, 2 and 3 were 0.77 (0.36-1.64), 0.69 (0.23-1.45), 0.89 (0.16-4.93), respectively). Stratified analysis for pain, age and BMI showed no associations between self-reported knee joint instability and radiological features. CONCLUSION: Self-reported knee joint instability is not associated with JSN or osteophyte formation.

Unfulfilled Expectations After Total Hip and Knee Arthroplasty Surgery: There Is a Need for Better Preoperative Patient Information and Education.

BACKGROUND: The aims of this study were to assess patients' preoperative expectations of the outcome of total hip or knee arthroplasty (THA/TKA) regarding specific aspects of functioning and to determine to what extent each expectation was fulfilled after 1 year. METHODS: This was a prospective cohort study. Preoperative expectations and their fulfillment after 1 year were measured with the Hospital for Special Surgery Hip/Knee arthroplasty Expectations Surveys. Preoperative and postoperative scores were subtracted to calculate whether expectations were unfulfilled, fulfilled, or exceeded. RESULTS: A total of 343 THA and 322 TKA patients with complete follow-up were included. Preoperatively, >60% of patients (both THA/TKA) expected to get back to normal or have much improvement in 19 of 20 (THA) and 12 of 19 (TKA) items. Expectations were fulfilled or exceeded in >60% of patients in all 20 items for THA and 17 of 19 items for TKA. In THA, items with the largest proportions patients with unfulfilled expectations (>30%) were "improvement in walking ability: long distances" (31%), "walking stairs" (33%), and "improve ability to cut toenails" (38%). In TKA, expectations for 12 of 19 items were unfulfilled in >30% of patients, with the largest proportions seen for "being able to kneel down" (44%) and "being able to squat" (47%). CONCLUSION: Although for most items, >60% of THA and TKA patients indicated that their expectations were met or exceeded, there was a substantial number of patients, particularly TKA patients, having unfulfilled expectations. These need more attention in preoperative patient information and education.

Outcome of total hip arthroplasty, but not of total knee arthroplasty, is related to the preoperative radiographic severity of osteoarthritis. A prospective cohort study of 573 patients.

BACKGROUND AND PURPOSE: There is no consensus on the impact of radiographic severity of hip and knee osteoarthritis (OA) on the clinical outcome of total hip arthroplasty (THA) and total knee arthroplasty (TKA). We assessed whether preoperative radiographic severity of OA is related to improvements in functioning, pain, and health-related quality of life (HRQoL) 1 year after THA or TKA. PATIENTS AND METHODS: This prospective cohort study included 302 THA patients and 271 TKA patients with hip or knee OA. In the THA patients, preoperatively 26% had mild OA and 74% had severe OA; in the TKA patients, preoperatively 27% had mild OA and 73% had severe OA. Radiographic severity was determined according to the Kellgren and Lawrence (KL) classification. Clinical assessments preoperatively and 1 year postoperatively included: sociodemographic characteristics and patient-reported outcomes (PROMs): Oxford hip/knee score, hip/knee injury and osteoarthritis outcome score (HOOS/KOOS), SF36, and EQ5D. Change scores of PROMs were compared with mild OA (KL 0-2) and severe OA (KL 3-4) using a multivariate linear regression model. RESULTS: Adjusted for sex, age, preoperative scores, BMI, and Charnley score, radiographic severity of OA in THA was associated with improvement in HOOS "Activities of daily living", "Pain", and "Symptoms", and SF36 physical component summary ("PCS") scale. In TKA, we found no such associations. INTERPRETATION: The decrease in pain and improvement in function in THA patients, but not in TKA patients, was positively associated with the preoperative radiographic severity of OA.

Low-grade chondrosarcoma of long bones treated with intralesional curettage followed by application of phenol, ethanol, and bone-grafting.

BACKGROUND: A common treatment of low-grade cartilaginous lesions of bone is intralesional curettage with local adjuvant therapy. Because of the wide variety of different diagnoses and treatments, there is still a lack of knowledge about the effectiveness of the use of phenol as local adjuvant therapy in patients with grade-I central chondrosarcoma of a long bone. METHODS: A retrospective study was done to assess the clinical and oncological outcomes after intralesional curettage, application of phenol and ethanol, and bone-grafting in eighty-five patients treated between 1994 and 2005. Inclusion criteria were histologically proven grade-I central chondrosarcoma and location of the lesion in a long bone. The average age at surgery was 47.5 years (range, 15.6 to 72.3 years). The average duration of follow-up was 6.8 years (range, 0.2 to 14.1 years). Patients were evaluated periodically with conventional radiographs and gadolinium-enhanced magnetic resonance imaging (Gd-MRI) scans. When a lesion was suspected on the basis of the MRI, the patient underwent repeat intervention. Depending on the size of the recurrent lesion, biopsy followed by radiofrequency ablation (for lesions of <10 mm) or repeat curettage (for those of ≥10 mm) was performed. RESULTS: Of the eighty-five patients, eleven underwent repeat surgery because a lesion was suspected on the basis of the Gd-MRI studies during follow-up. Of these eleven, five had a histologically proven local recurrence (a recurrence rate of 5.9% [95% confidence interval, 0.9% to 10.9%]), and all were grade-I chondrosarcomas. General complications consisted of one superficial infection, and two femoral fractures within six weeks after surgery. CONCLUSIONS: This retrospective case series without controls has limitations, but the use of phenol as an adjuvant after intralesional curettage of low-grade chondrosarcoma of a long bone was safe and effective, with a recurrence rate of <6% at a mean of 6.8 years after treatment.

Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients.

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.

Maffucci syndrome: a genome-wide analysis using high resolution single nucleotide polymorphism and expression arrays on four cases.

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.

Genome-wide analysis of Ollier disease: Is it all in the genes?

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.