Hereditary multiple exostoses: anatomical distribution and burden of exostoses is dependent upon genotype and gender.

BACKGROUND AND AIMS: We describe the novel anatomical distribution of exostoses in patients with hereditary multiple exostoses according to their gender and genotype. METHODS AND RESULTS: A prospective database of 143 patients from 65 families with hereditary multiple exostoses was compiled. Patient demographics, genotype and number of exostoses according to anatomical site were recorded. The hand was affected by the greatest proportion of exostoses for both EXT1 (19%) and EXT2 (14%) genotypes and was the most prevalent site for exostoses in patients with an EXT1 genotype (92%). Patients with an EXT1 genotype had a significantly greater number of exostoses compared to those with an EXT2 genotype (2680 vs. 1828, p = 0.006); however, this was only significantly different for 10 of the 19 anatomical regions examined. Male patients with an EXT1 genotype had a significantly (p < 0.05) greater number of exostoses affecting their hands, distal radius, proximal humerus, scapular and ribs compared to female patients with the same genotype and males with an EXT2 genotype. CONCLUSION: The anatomical distribution of exostoses varies according to genotype and gender; however, the reason for this difference is not clear and may relate to different biochemical pathways.

Can deformity of the knee and longitudinal growth of the leg be predicted in patients with hereditary multiple exostoses? A cross-sectional study.

BACKGROUND: There is a high rate of knee deformity in patients with hereditary multiple exostoses (HME), and a quarter of patients have a limb length discrepancy. METHODS: A prospective database of 172 patients with HME was compiled. Patient demographics, knee deformity and range of movement, leg length and height, and number of exostoses around the knee were recorded. RESULTS: Nine out of 10 patients with HME were affected by exostoses around the knee, of which the distal femur was the most common site to be involved. Approximately 20% of patients had a valgus deformity and 16% had a fixed flexion deformity of the knee, with 25% having a diminished range of movement. Height was directly proportional to leg length and a quarter of patients were below the 10th centile for height. The presence of a distal femoral exostosis was an independent predictor of knee deformity (p=0.002), diminished range of movement (ROM) (p<0.001), and smaller stature (p<0.001) on multivariate analysis. In addition increasing age, prior surgery, genotype, and gender were also intendant predictors of ROM and height. CONCLUSION: Future studies analysing if surgical excision improves knee function and limits deformity would need to assess whether this is dependent upon anatomical site, as our results suggest that distal femoral exostoses may have the greatest affect upon these outcomes. LEVEL OF EVIDENCE: Level II.

Nontraumatic Lesions of the Clavicle in a Paediatric Population: Incidence and Management.

Background. The incidence of paediatric nontraumatic clavicle lesions is unknown and there is limited literature regarding the management of such patients. Methods. A review of a prospectively complied radiological database held at the study was conducted for a defined 10-year period. The study centre is the only paediatric service available for a defined catchment population. The case notes of all patients with nontraumatic lesions were reviewed, and the mode of presentation, the diagnostic dilemmas, and the management were recorded. Results. A total of 2133 clavicle radiographs were performed during the study period, with only five having a nontraumatic history. The overall incidence of paediatric nontraumatic clavicle lesions was 0.38 per 100,000 per year. Three patients were diagnosed with chronic recurrent osteomyelitis, one with chronic bifocal osteomyelitis, and one with Langerhans cell histiocytosis. All patients with osteomyelitis demonstrated a typical natural history of a chronic relapsing remitting infection. Three underwent bone biopsy; however, no organism was identified. Conclusion. This study demonstrated that the incidence of nontraumatic clavicle lesions is small, and those patients presenting with osteomyelitis should not routinely undergo a bone biopsy and close observation with the appropriate antibiotic therapy is advised.

Forearm deformity in patients with hereditary multiple exostoses: factors associated with range of motion and radial head dislocation.

BACKGROUND: There is a high rate of forearm deformity in patients with hereditary multiple exostoses, with many patients developing radial head dislocation associated with ulnar shortening. METHODS: One hundred and six patients with hereditary multiple exostoses who were fifteen years of age or older were identified with use of a previously compiled database. An independent observer measured flexion and extension of the elbow and wrist as well as supination and pronation of the forearm and recorded the number of exostoses affecting the forearm. Proportional ulnar length was calculated as a percentage of the measured height of the patient ([ulnar length/height] ×100). RESULTS: Exostoses were identified in 183 (86%) of the 212 forearms that were examined. The distal part of the radius was the most common site and was affected in 73% of the patients. One in seven patients had a dislocated radial head, which was associated with reduced proportional ulnar length (p < 0.001). Both radial head dislocation (p < 0.001) and proportional ulnar length (p < 0.001) were confirmed to be independent risk factors associated with forearm rotation on multivariate regression analysis. In conjunction with other risk factors, both of these factors could be used to predict forearm motion. In addition, a reduced proportional ulnar length was also an independent risk factor for radial head dislocation (p < 0.001). CONCLUSIONS: Proportional ulnar length could be used as a tool to identify patients who are at risk for diminished forearm motion and radial head dislocation during childhood. Surgical intervention could potentially be offered before deterioration in function and dislocation of the radial head occurs.

Risk of cancer following primary total hip replacement or primary resurfacing arthroplasty of the hip: a retrospective cohort study in Scotland.

BACKGROUND: Release and dispersion of particles arising from corrosion and wear of total hip arthroplasty (THA) components has raised concerns about a possible increased risk of cancer. Concerns have been heightened by a recent revival in the use of metal-on-metal (MoM) hip prostheses. METHODS: From a linked database of hospital discharge, cancer registration, and mortality records, we selected a cohort of patients who underwent primary THA (1990-2009) or primary resurfacing arthroplasty (mainly 2000-2009) in Scotland, with follow-up to the end of 2010. Available operation codes did not enable us to distinguish MoM THAs. Indirectly standardised incidence ratios (SIRs) were calculated for selected cancers with standardisation for age, sex, deprivation, and calendar period. RESULTS: The study cohort included 71 990 patients yielding 547 001 person-years at risk (PYAR) and 13 946 cancers diagnosed during follow-up. For the total period of observation combined, the risks of all cancers (SIR: 1.05; 95% CI: confidence interval 1.04-1.07), prostate cancer (SIR: 1.07; 95% CI: 1.01-1.14), and multiple myeloma (SIR: 1.22; 95% CI: 1.06-1.41) were increased. These modest increases in risk emerged in the context of effectively multiple tests of statistical significance, and may reflect inadequate adjustment for confounding factors. For 1317 patients undergoing primary resurfacing arthroplasty between 2000 and 2009 (PYAR=5698), the SIR for all cancers (n=39) was 1.23 (95% CI: 0.87-1.68). CONCLUSION: In the context of previous research, these results do not suggest a major cause for concern. However, the duration of follow-up of patients receiving recently introduced, new-generation MoM prostheses is too short to rule out a genuinely increased risk of cancer entirely.

Retention of forearm plates: risks and benefits in a paediatric population.

Most surgeons favour removing forearm plates in children. There is, however, no long-term data regarding the complications of retaining a plate. We present a prospective case series of 82 paediatric patients who underwent plating of their forearm fracture over an eight-year period with a minimum follow-up of two years. The study institution does not routinely remove forearm plates. A total of 116 plates were used: 79 one-third tubular plates and 37 dynamic compression plates (DCP). There were 12 complications: six plates (7.3%) were removed for pain or stiffness and there were six (7.3%) implant-related fractures. Overall, survival of the plates was 85% at 10 years. Cox regression analysis identified radial plates (odds ratio (OR) 4.4, p = 0.03) and DCP fixation (OR 3.2, p = 0.02) to be independent risk factors of an implant-related fracture. In contrast ulnar plates were more likely to cause pain or irritation necessitating removal (OR 5.6, p = 0.04). The complications associated with retaining a plate are different, but do not occur more frequently than the complications following removal of a plate in children.

Multifocal primary bone sarcoma in the elderly: a rare case and review of the literature.

To our knowledge there are no reports of a primary multifocal spindle cell sarcoma affecting both long bones of the lower limb in an elderly patient. An 83-year-old man presented with a progressively painful right ankle, without a history of trauma. Radiographs demonstrated a pathological fracture through a mixed lytic and sclerotic lesion in the distal tibia. Staging investigations, including bone scintigraphy and magnetic resonance imaging, revealed a second lytic lesion in the right distal femur. A provisional diagnosis of metastatic disease was favoured and intramedullary nailing was considered. However, computed tomography of the chest, abdomen and pelvis, and relevant blood tests revealed no evidence of a primary malignancy. Open biopsy of the tibial lesion showed high-grade pleomorphic spindle cells consistent with a primary bone sarcoma. The patient was treated successfully with a right trans-femoral amputation. In conclusion, we recommend early bone biopsy to allow accurate diagnosis and appropriate skeletal management in elderly patients.

Isolation of faecal coliform bacteria from the American alligator (Alligator mississippiensis).

AIMS: To determine whether American alligators (Alligator mississippiensis) are an unrecognized poikilothermic source of faecal coliform and/or potential pathogenic bacteria in South Carolina's coastal waters. METHODS AND RESULTS: Bacteria from the cloaca of American alligators, as well as bacteria from surface water samples from their aquatic habitat, were isolated and identified. The predominant enteric bacteria identified from alligator samples using biochemical tests included Aeromonas hydrophila, Citrobacter braakii, Edwardsiella tarda, Escherichia coli, Enterobacter cloacae, Plesiomonas shigelloides and putative Salmonella, and these were similar to bacteria isolated from the surface waters in which the alligators inhabited. Based on most-probable-number enumeration estimates from captive alligator faeces, faecal coliform bacteria numbered 8.0x10(9) g(-1) (wet weight) of alligator faecal material, a much higher concentration than many other documented endothermic animal sources. CONCLUSIONS: A prevalence of enteric bacteria, both faecal coliforms and potential pathogens, was observed in American alligators. The high faecal coliform bacterial density of alligator faeces may suggest that alligators are a potential source of bacterial contamination in South Carolina coastal waters. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings help to increase our understanding of faecal coliform and potential pathogenic bacteria from poikilothermic reptilian sources, as there is the potential for these sources to raise bacterial water quality levels above regulatory thresholds.

Survival in Malignant Peripheral Nerve Sheath Tumours: A Comparison between Sporadic and Neurofibromatosis Type 1-Associated Tumours.

We studied 123 patients with malignant peripheral nerve sheath tumours (MPNSTs) between 1979 and 2002. However, 90 occurred sporadically whereas 33 were associated with neurofibromatosis type 1 (NF1). Survival was calculated using Kaplan-Meier survival curves and we used Cox's proportional hazards model to identify independent prognostic factors. A 5-year survival for 110 nonmetastatic patients was 54%; (33% NF1 and 63% sporadic P = .015). Tumour stage and site were significant prognostic indicators after univariate analysis. After multivariate analysis, however, only NF1 (P = .007) and tumour volume more than 200 m (P = .015) remained independent predictors of poor outcome. We recommend that NF1 be taken into account during MPNST staging. As the survival rate in the NF group was dependant on tumour volume, routine screening of these patients with FDG PET and/or MRI may be warranted, thereby staging and controlling them at the earliest possible opportunity.

Malignant peripheral nerve sheath tumour in the ischio-rectal fossa.

Primary sarcomas in the ischiorectal fossa are occasionally reported and represent a significant challenge due to the proximity of rectum, levator muscles and pudendal neurovascular structures. We report a case in which the diagnosis changed between biopsy (desmoid tumour) and resection (malignant peripheral nerve sheath tumour), requiring a multidisciplinary surgical approach involving different sub-specialties. It also illustrates the importance of undertaking sarcoma surgery in a recognized sarcoma centre with sarcoma expertise available across a range of disciplines.

Acute Q-fever and history taking--a lesson learned.

A 50-year-old patient underwent a routine primary total hip replacement. Soon after surgery, he developed acute respiratory failure from post-operative sepsis. His condition deteriorated rapidly despite supportive management and he required admission into intensive care unit for assisted ventilation. It took almost one week before the underlying cause of the deterioration was determined to be unrelated to complications of surgery. A diagnosis of Q-fever was made following detailed attention to the clinical history. Appropriate treatment was started and the patient made a full recovery. The diagnosis was confirmed later following discharge from hospital.

Twentieth-century survival from osteosarcoma in childhood. Trends from 1933 to 2004.

We have reviewed the data from our regional Bone Tumour Registry on patients with osteosarcoma diagnosed between 1933 and 2004 in order to investigate the relationship between survival and changes in treatment. There were 184 patients with non-metastatic appendicular osteosarcoma diagnosed at the age of 18 or under. Survival was calculated using Kaplan-Meier curves, and multivariate analysis was performed using the Cox regression proportional hazards model. The five-year survival improved from 21% between 1933 and 1959, to 62% between 1990 and 1999. During this time, a multi-disciplinary organisation was gradually developed to manage treatment. The most significant variable affecting outcome was the date of diagnosis, with trends in improved survival mirroring the introduction of increasingly effective chemotherapy. Our experience suggests that the guidelines of the National Institute for Clinical Excellence on the minimum throughput of centres for treatment should be enforced flexibly in those that can demonstrate that their historical and contemporary results are comparable to those published nationally and internationally.

Delay increases the need for open reduction of type-III supracondylar fractures of the humerus.

Recent reports have suggested that a delay in the management of type-III supracondylar fractures of the humerus does not affect the outcome. In this retrospective study we examined whether the timing of surgery affected peri-operative complications, or the need for open reduction. There were 171 children with a closed type-III supracondylar fracture of the humerus and no vascular compromise in our study. They were divided into two groups: those treated less than eight hours from presentation to the Accident and Emergency Department (126 children), and those treated more than eight hours from presentation (45 children). There were no differences in the rate of complications between the groups, but children waiting more than eight hours for reduction were more likely to undergo an open reduction (33.3% vs 11.2%, p < 0.05) and there was a weak correlation (p = 0.062) between delay in surgery and length of operating time. Consequently, we would still recommend treating these injuries at the earliest opportunity.

Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study.

We performed a prospective genotype-phenotype study using molecular screening and clinical assessment to compare the severity of disease and the risk of sarcoma in 172 individuals (78 families) with hereditary multiple exostoses. We calculated the severity of disease including stature, number of exostoses, number of surgical procedures that were necessary, deformity and functional parameters and used molecular techniques to identify the genetic mutations in affected individuals. Each arm of the genotype-phenotype study was blind to the outcome of the other. Mutations EXT1 and EXT2 were almost equally common, and were identified in 83% of individuals. Non-parametric statistical tests were used. There was a wide variation in the severity of disease. Children under ten years of age had fewer exostoses, consistent with the known age-related penetrance of this condition. The severity of the disease did not differ significantly with gender and was very variable within any given family. The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations in three of five parameters of severity (stature, deformity and functional parameters). A single sarcoma developed in an EXT2 mutation carrier, compared with seven in EXT1 mutation carriers. There was no evidence that sarcomas arose more commonly in families in whom the disease was more severe. The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable.

The hip in hereditary multiple exostoses.

We defined the characteristics of dysplasia and coxa valga in hereditary multiple exostoses (HME) by radiological analysis of 24 hips in 12 patients. The degree and effect of the 'osteochondroma load' around the hip were quantified. We investigated the pathology of the labrum and the incidence of osteoarthritis and of malignant change in these patients. Coxa valga and dysplasia were common with a median neck-shaft angle of 156 degrees, a median centre-edge angle of 23 degrees and Sharp's acetabular angle of 44 degrees. There was overgrowth of the femoral neck with a significantly greater ratio of the neck/shaft diameter in HME than in the control hips (p < 0.05), as well as correlations between the proximal femoral and pelvic osteochondroma load (p < 0.05) and between the proximal femoral osteochondroma load and coxa valga (p < 0.01). Periacetabular osteochondromas are related to Sharp's angle as an index of dysplasia (p < 0.05), but not coxa valga. No correlation was found between dysplasia and coxa valga. These data suggest that HME may cause anomalies of the hip as a reflection of a generalised inherited defect, but also support the theory that osteochondromas may themselves precipitate some of the characteristic features of HME around the hip.

Clinical and radiographic analysis of osteochondromas and growth disturbance in hereditary multiple exostoses.

Hereditary multiple exostoses (HME) is traditionally described as a skeletal dysplasia. However, the discovery that the EXT family of tumour suppressor genes are responsible for HME suggests that it is more appropriate to classify HME as a familial neoplastic trait. In a clinical and radiographic analysis of paired bone length and exostoses number and dimensions in a HME cohort, the local presence of osteochondromas was consistently associated with growth disturbance. In particular, an inverse correlation between osteochondroma size and relative bone length (p<0.01) was found. These data suggest that the growth retardation in HME may result from the local effects of enlarging osteochondromas rather than a skeletal dysplasia effect. This study provides the first clinical rationale for ablation of rapidly enlarging exostoses to reduce growth disturbance.

Comparison of fluorescent single-strand conformation polymorphism analysis and denaturing high-performance liquid chromatography for detection of EXT1 and EXT2 mutations in hereditary multiple exostoses.

EXT1 and EXT2 are two genes responsible for the majority of cases of hereditary multiple exostoses (HME), a dominantly inherited bone disorder. In order to develop an efficient screening strategy for mutations in these genes, we performed two independent blind screens of EXT1 and EXT2 in 34 unrelated patients with HME, using denaturing high-performance liquid chromatography (DHPLC) and fluorescent single-strand conformation polymorphism analysis (F-SSCP). The mutation likely to cause HME was found in 29 (85%) of the 34 probands: in 22 of these (76%), the mutation was in EXT1; seven patients (24%) had EXT2 mutations. Nineteen of these disease mutations have not been previously reported. Of the 42 different amplicon variants identified in total in the cohort, 40 were detected by DHPLC and 39 by F-SSCP. This corresponds to mutation detection efficiencies of 95% and 93% respectively. We have also found that we can confidently distinguish between different sequence variants in the same fragment using F-SSCP but not DHPLC. In light of this, and the similarly high sensitivities of the two techniques, we propose to continue screening with F-SSCP.