Myositis ossificans progressiva.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
D E Porter
Publications and source records attributed to D E Porter.
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.
Adolescent↗
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.
Adolescent↗
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.
Adolescent↗
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.
Chromatography, High Pressure Liquid↗
The neoplastic pathogenesis of solitary and multiple osteochondromas.
Many theories of osteochondroma pathogenesis have been advanced. Genetic research into the inherited multiple form, hereditary multiple exostoses, has revealed a new family of tumour suppressor genes denoted EXT. Patterns of EXT gene mutation in hereditary multiple exostoses, in solitary and multiple osteochondromas, and in chondrosarcoma are analogous to those found in other tumour suppressor genes responsible for family cancer traits and associated malignancies. With one exception, most features of osteochondroma behaviour are comparable to those of benign neoplasms. The neoplastic pathogenesis of osteochondromas provides an alternative to the traditional 'skeletal dysplasia' theory to explain the growth disturbance associated with hereditary multiple exostoses. Recent studies on the physiological function of EXT genes are reviewed and implications for osteochondroma 'cell-of-origin' theories are discussed.
Bone Neoplasms↗
Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses.
Hereditary 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.
Child, Preschool↗
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.
Electrophoresis, Polyacrylamide Gel↗
Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation in families linked to BRCA1 on chromosome 17q12-21.
Eight breast cancer pedigrees with a high probability of containing individuals with the BRCA1 gene mutation (odds 79.2-99.9 per cent) were identified through genetic linkage analysis using probes located within q12-22 on the long arm of chromosome 17. Some 102 female relatives were successfully typed with one or both of adjacent markers D17S588 and D17S579, and 41 were probable non-BRCA1 mutation carriers. Of the remaining 61 women classified as probable BRCA1 carriers, breast cancer was diagnosed in 35. As expected from epidemiological segregation analysis studies, 13 of these had bilateral disease. Approximately two-thirds of women unaffected by malignancy and alive at the time of observation were non-BRCA1 carriers. Lifetime disease penetrance of the BRCA1 gene was 88 per cent and this plateau was reached earlier (by age 65 years) than that estimated in segregation analysis. The survival curve of patients with breast cancer was less steep in BRCA1 gene carriers than that in the general population; 5-, 10- and 20-year survival rates unadjusted for non-cancer deaths were 83, 63 and 41 per cent respectively. The 5-year survival rate was significantly higher in BRCA1 carriers than that in an age-matched Scottish population (P < 0.05).
Adult↗
Linkage mapping in familial breast cancer: improved localisation of a susceptibility locus on chromosome 17q12-21.
Fifteen pedigrees with a total of 75 cases of breast cancer, 10 of ovarian cancer and 53 of other cancers have been collected. Polymorphic markers on chromosome 17q have been screened to locate a putative breast-cancer gene using DNA from relevant individuals within these families. Pairwise LOD scores have been calculated for markers CMM86, NM23, 42D6 and MFD188. The maximal summated LOD for the 15 families is 4.45 at theta = 0.025 using 42D6. All cases of bilateral breast cancer and ovarian cancer appear to be linked to this region. Recalculating LOD scores on the assumption of linkage in these cases increases the maximal summated LOD to 5.62 at theta = 0.025 using 42D6. A genetic exclusion map of critical recombinants in linked families suggests that the gene is flanked by markers 42D6 and MFD188, a region 5 to 10 cm in length.
Adult↗
Breast cancer survival in BRCA1 carriers.
Explore the source record for details and available documents.
Breast Neoplasms↗
Genetic linkage analysis applied to unaffected women from families with breast cancer can discriminate high- from low-risk individuals.
Up to 20 per cent of cases of breast cancer diagnosed in women under the age of 45 years may be caused by an autosomal dominant gene. A present difficulty is differentiation of mutation carriers from non-mutation carriers in high-risk families. Genetic linkage analysis has been used to localize a susceptibility gene (BRCA1) on chromosome 17q12-21 between markers 42D6 and MFD188, a region 5-10 million base pairs in length. Odds in favour of linkage to this region were greater than 100,000:1 in 15 families with breast cancer. In eight families in which the probability of linkage was above 75 (range 79.2-99.9) per cent, 19 women were identified who were at high lifetime risk of breast cancer (range 80.6-87.2 per cent) and 37 whose risk was similar to that for the general population (range 9.8-16.4 per cent). Genetic risk prediction of this kind may enable high-risk screening clinic resources to be concentrated on those most likely to benefit.
Adult↗
Recent advances in the genetics of heritable breast cancer.
Explore the source record for details and available documents.
Breast Neoplasms↗
Linkage of a major breast cancer gene to chromosome 17q12-21: results from 15 Edinburgh families.
DNA from members of 15 pedigrees each containing between three and eight cases of breast cancer have been collected from southeastern Scotland. Polymorphic markers on chromosome 17q were screened to locate a putative breast cancer gene by using DNA from relevant individuals within these families. Pairwise LOD scores were calculated for markers D17S74, NM23, D17S588, and D17S579. The maximal summated LOD for the 15 families was 5.44 at theta = .034, when D17S588 (42D6) was used. In these breast cancer families, a subset which did not give evidence for linkage to this region could be identified.
Adult↗
A significant proportion of patients with osteosarcoma may belong to Li-Fraumeni cancer families.
We studied the pedigrees of 17 index patients with osteosarcoma, recording malignant disease and cause of death for first- and second-degree relatives. There were seven cancers and five cancer deaths per 2151.5 person-years in first-degree relatives of osteosarcoma patients under the age of 50 years, a significantly greater incidence than in an age- and sex-matched population group (p < 0.001). This excess of malignancy was largely due to two families which fulfilled the criteria for the Li-Fraumeni cancer family syndrome. Both of these families were shown to have the genetic alterations in the p53 gene which have been implicated in this syndrome. Our study suggests that orthopaedic surgeons seeing new cases of osteosarcoma should arrange screening for familial malignancy.
Adolescent↗
Familial breast cancer.
Familial clustering of breast cancer has been recognised for over a century but until recently a genetic basis has been suspected rather than proven. Epidemiological studies have tended to support the view that an autosomal dominant gene, with high but incomplete penetrance, accounts for most breast cancer families. However, it is likely that several different predisposing genes are present within most populations. Difficulties arise in a conventional 'linkage mapping' approach to identifying these genes, first, because it is not clear that genetically homogeneous groups of families can be recognised on the basis, for example, of mean age of onset or pattern of other cancers within the kindred and, second, because breast cancer is so common (affecting almost one in twelve women) that large affected kindreds are likely to include an admixture of sporadic (non-genetic) cases. Cytogenetic and 'Loss of Heterozygosity' (LOH) studies in sporadic breast cancers have pointed to several candidate loci for breast cancer genes but there is no clear consensus from these two approaches that might direct attention to any prime target region. Recent reports of tight linkage between familial breast cancer (early onset) and breast/ovarian cancer (regardless of mean age of onset) and a locus on chromosome 17q21 defined by the anonymous probe CMM86, have not been confirmed in detail but have led to the identification of a locus some 15 Mb centromeric of CMM86 that gives a high positive lod at very low recombination fraction in fifteen Edinburgh breast and breast/ovarian cancer families. The disease in the majority of such families therefore appears to be attributable to a mutant gene at 17q12-21. A much smaller proportion of familial breast cancer is accounted for by mutations in the p53 gene (17p13). Not all such families fulfil the criteria for Li-Fraumeni syndrome and not all of the inherited mutations lie within exon 7 of p53. Counselling of members of breast cancer families becomes more exacting as these genetic lesions are identified. It is essential to extend the collection of data and tissue (blood or fixed pathology material) as widely as possible to confirm linkage to a specific locus within each individual kindred, to define the precise mutation and to establish the cancer phenotype and its penetrance. In the course of these studies a substantial population of women at high risk of breast (and other) cancer will be identified. Resources should be directed to this population so that optimum procedures for screening and prevention can be developed.
Breast Neoplasms↗
The vertebral canal: II. Health and academic status, a clinical study.
This study was designed to test the concept that a shallow vertebral canal in the adult may act as a marker of impaired development in early life. If that same impaired development also affected the immune and central nervous systems, there could be a relationship between the vertebral canal size, health, and academic status. A retrospective analysis was made of the general practitioner records of 94 patients, some with very narrow canals and some with wide canals. There were significantly more episodes and total attendances with infections, more episodes of low-back pain, and more attendances with trauma in those with small canals. A prospective study compared the GCE examination results of 331 children whose canals had been measured by ultrasound 3 years previously. The children in the highest three deciles for canal size performed significantly better than those in the lowest decile (P less than 0.01). There is evidence that a relation may exist between the sagittal diameter of the lumbar vertebral canal and health and academic status.
Adolescent↗
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.
Adolescent↗