Daniel Porter

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.

Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.

Hereditary multiple exostoses (HME), the most frequent of all skeletal dysplasias, is an autosomal dominant disorder characterized by the presence of multiple exostoses localized mainly at the end of long bones. HME is genetically heterogeneous, with at least three loci, on 8q24.1 (EXT1), 11p11-p13 (EXT2), and 19p (EXT3). Both the EXT1 and EXT2 genes have been cloned recently and define a new family of potential tumor suppressor genes. This is the first study in which mutation screening has been performed for both the EXT1 and EXT2 genes prior to any linkage analysis. We have screened 17 probands with the HME phenotype, for alterations in all translated exons and flanking intronic sequences, in the EXT1 and EXT2 genes, by conformation-sensitive gel electrophoresis. We found the disease-causing mutation in 12 families (70%), 7 (41%) of which have EXT1 mutations and 5 (29%) EXT2 mutations. Together with the previously described 1-bp deletion in exon 6, which is present in 2 of our families, we report five new mutations in EXT1. Two are missense mutations in exon 2 (G339D and R340C), and the other three alterations (a nonsense mutation, a frameshift, and a splicing mutation) are likely to result in truncated nonfunctional proteins. Four new mutations are described in EXT2. A missense mutation (D227N) was found in 2 different families; the other three alterations (two nonsense mutations and one frameshift mutation) lead directly or indirectly to premature stop codons. The missense mutations in EXT1 and EXT2 may pinpoint crucial domains in both proteins and therefore give clues for the understanding of the pathophysiology of this skeletal disorder.

Inflammatory pseudotumor associated with femoral nerve palsy following metal-on-metal resurfacing of the hip. A case report.

Metal-on-metal resurfacing arthroplasty of the hip has been used increasingly in Europe over the last ten years for the treatment of osteoarthritis of the hip in younger (<65 years of age), active patients. In 2005, 6,153 procedures were performed in England and Wales1. Marketing of the Birmingham hip replacement for resurfacing arthroplasty was approved by the United States Food and Drug Administration in May 2006. Metal-on-metal resurfacing of the hip is known to be associated with elevated concentrations of metal ions within the hip joint and systemically, but, to our knowledge as of this writing, no adverse effects of this process have been identified. However, the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) issued an alert in June 2007 about the Ultima metal-on-metal bearing total hip arthroplasty prosthesis (DePuy International, Leeds, United Kingdom) following reports of the need for early revision due to periprosthetic soft-tissue necrosis2. The bearing in question was a cobalt-chromium-molybdenum alloy similar to that used in the Birmingham hip replacement. We report the development of an ipsilateral mass associated with markedly elevated intralesional cobalt and chromium levels and a femoral nerve palsy in a patient who underwent a Birmingham metal-on-metal resurfacing arthroplasty of the hip one year previously. Our patient was informed that data concerning the case would be submitted for publication, and she consented. A sixty-three-year-old woman presented to another institution with painful idiopathic osteoarthrosis of the right hip. She had undergone a total abdominal hysterectomy, oophorectomy, and lysis of bowel adhesions five years previously but had no other contributory medical history. She underwent metal-on-metal resurfacing arthroplasty of the hip with the Birmingham hip replacement (Smith and Nephew Orthopaedics, Warwick, United Kingdom) in June 2005 (Fig. 1). The surgery and the early postoperative recovery were uncomplicated. Fig. 1 Pelvic radiograph made one …

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 Coxs 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.

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.

MRI surveillance after resection for primary musculoskeletal sarcoma

This study reports the experience of one treatment centre with routine surveillance MRI following excision of musculoskeletal sarcoma. The case notes, MRI and histology reports for 57 patients were reviewed. The primary outcome was local tumour recurrence detected on either surveillance MRI in asymptomatic patients, or interval MRI in patients with clinical concern. A total of 47 patients had a diagnosis of soft-tissue sarcoma and ten of a primary bone tumour. A total of 13 patients (22%) had local recurrence. Nine were identified on a surveillance scan, and four by interval scans. The cost of surveillance is estimated to be pound4414 per recurrence detected if low-grade tumours with clear resection margins are excluded. Surveillance scanning has a role in the early detection of local recurrence of bone and soft-tissue sarcoma.

Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses

AbstractHereditary multiple exostoses (EXT) is an autosomal dominantly inherited disease characterized by the formation of cartilage-capped prominences (exostoses) that develop from the juxtaepiphyseal regions of the long bones. Recently, EXT1 and EXT2 genes were cloned and germline mutations of EXT1 and EXT2 were identified in EXT families. In this study, we performed a mutational analysis of EXT1 and EXT2 genes in eight unrelated Korean EXT families by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis followed by direct DNA sequencing. As a result, we were able to identify one family (SNU-OC3) with the EXT1 mutation and another family (SNU-OC15) with the EXT2 mutation. The EXT1 mutation was a 10-bp deletion at the 3′ end of exon 5 (CTAATTTAGg) including the splice site of this exon. The EXT2 mutation identified in the SNU-OC15 family was a missense mutation at codon 85 of exon 2 (TGC→CGC), resulting in an amino acid change from cysteine to arginine. This missense mutation cosegregated with the disease phenotype in this family, suggesting that it is the disease-causing mutation. These two mutations identified in EXT1 and EXT2 are novel ones.

The pediatric fracture of the scaphoid in patients aged 13 years and under: an epidemiological study.

Background: Fractures of the scaphoid are uncommon in the pediatric population. Despite their rarity, a significant number of children are referred to the fracture clinic for a suspected scaphoid fracture. The aim of this study was to report on the current incidence, pattern of injury, and the long-term outcomes following this injury in the pediatric population. Methods: Analysis of all pediatric scaphoid fractures presenting to a tertiary pediatric hospital (aged 13 y and under) over a 5-year period was performed. The case notes, radiographs, and other imaging studies for these patients were reviewed. Long-term functional outcome was assessed using Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. Results: Fifty-six patients of the 838 (6.7%) referred for a suspected scaphoid fracture were identified as having a confirmed diagnosis of a scaphoid fracture, giving an average annual incidence of 11 per 100,000. This group consisted of 39 boys (70%) and 17 girls (30%). The average age of incidence in boys was 12.2 years and in girls was 10.3 years (P<0.001). No scaphoid fractures were observed in boys below the age of 11 years and in girls below the age of 9 years. The most common type of fracture was a distal pole fracture (45 patients). One patient sustained a proximal pole fracture and went on to develop a nonunion. The duration of treatment in cast was shorter in distal pole fractures than in other types (P<0.001). At a mean follow-up of 70 months (range, 46 to 104 mo), 60% reported no limitation or impact when reporting a range of daily functional activities (mean DASH score=3.0). Conclusions: There is a suggestion that the overall incidence of scaphoid fractures in the pediatric population is increasing, but children aged 13 years and under continue to maintain a distinct fracture pattern when compared with adolescents and adults. The majority involves the distal third of the scaphoid and carries a good prognosis with conservative management. Level of Evidence: Prognostic study, Level 4.

Skeletal growth patterns in hereditary multiple exostoses: a natural history

Hereditary multiple exostoses (HME) is a commonly inherited musculoskeletal condition and is associated with a diminished stature. We demonstrated that adults with HME were significantly shorter when compared with a control group (P<0.001); preadolescents, however, were significantly taller than predicted (P=0.01). This was reflected by their height centile; 58% of the adults were under the 25th centile, whereas 53% of the preadolescence group were above the 75th centile. Stature was more severely affected in patients with an EXT1 mutation (P=0.008). This study illustrates a novel age-related growth pattern associated with HME, which is also affected by genotype.

A micro-architectural evaluation of osteoporotic human femoral heads to guide implant placement in proximal femoral fractures

Background and purpose The micro-architecture of bone has been increasingly recognized as an important determinant of bone strength. Successful operative stabilization of fractures depends on bone strength. We evaluated the osseous micro-architecture and strength of the osteoporotic human femoral head. Material and methods 6 femoral heads, obtained during arthroplasty surgery for femoral neck fracture, underwent micro-computed tomography (microCT) scanning at 30 μm, and bone volume ratio (BV/TV), trabecular thickness, structural model index, connection density, and degree of anisotropy for volumes of interest throughout the head were derived. A further 15 femoral heads underwent mechanical testing of compressive failure stress of cubes of trabecular bone from different regions of the head. Results The greatest density and trabecular thickness was found in the central core that extended from the medial calcar to the physeal scar. This region also correlated with the greatest degree of anisotropy and proportion of plate-like trabeculae. In the epiphyseal region, the trabeculae were organized radially from the physeal scar. The weakest area was found at the apex and peripheral areas of the head. The strongest region was at the center of the head. Interpretation The center of the femoral head contained the strongest trabecular bone, with the thickest, most dense trabeculae. The apical region was weaker. From an anatomical and mechanical point of view, implants that achieve fixation in or below this central core may achieve the most stable fixation during fracture healing.