Association of ENPP1 gene polymorphisms with hand osteoarthritis in a Chuvasha population.
Periarticular calcification is a common attendant symptom of generalized arterial calcification of infancy, a rare Mendelian disorder caused by mutations of the gene coding for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This prompted us to perform a family-based association study to test the hypothesis that genetic variation at the ENPP1 locus is involved in the etiology of osteoarthritis of the hand. The study population comprised 126 nuclear families with 574 adult individuals living in small villages in the Chuvasha and Bashkirostan autonomies of the Russian Federation. The extent of osteoarthritis was determined by analyzing plain hand radiographs. The outcome of a principal component analysis of osteoarthritis scores of a total of 28 joints of both hands was used as a primary phenotype in this study. Maximum likelihood estimates of the variance component analysis revealed a substantial contribution of genetic factors to the overall trait variance of about 25% in this homogeneous population. Three short tandem repeat (STR) polymorphisms--one intragenic and two flanking markers--and four single-nucleotide polymorphisms were tested. The markers tagged the ENPP1 locus at nearly equal intervals. We used three different transmission disequilibrium tests and obtained highly significant association signals. Alleles of the upstream microsatellite marker as well as several single-nucleotide polymorphism haplotypes consistently revealed the association. Thus, our data highlights variability of ENPP1 as an important genetic factor in the pathogenesis of idiopathic osteoarthritis. (+info)
Crystals in hand.
A genetic association of the ENPP1 gene with primary hand osteoarthritis was recently reported in this journal. ENPP1 encodes an enzyme that regulates soft tissue calcification. The study as it stands is far from complete because the actual causal variant(s) within ENPP1 has not been identified and no functional study on the activity of the enzyme in hand osteoarthritis was presented. Nevertheless, the study stimulates interest and will encourage others in the field to test ENPP1 as a possible osteoarthritis susceptibility gene in their cohorts. The genetic basis of osteoarthritis is slowly being uncovered, and this report constitutes another interesting find. (+info)
Hand bone loss in early undifferentiated arthritis: evaluating bone mineral density loss before the development of rheumatoid arthritis.
OBJECTIVES: (1) To examine the change in regional bone mineral density (BMD), including the hands, and assess its role as a predictor of outcome in patients presenting with an early undifferentiated inflammatory arthritis; (2) to examine for associations with the changes in hand BMD. METHODS: 74 patients with undifferentiated hand arthritis of less than 12 months' duration were examined at baseline and then at three, six, and 12 months follow up, including BMD measurement of the femoral neck, spine (L2-4), and the whole hands using dual energy absorptiometry (DXA). RESULTS: During the study, 13 patients were diagnosed as having rheumatoid arthritis, 19 as having inflammatory non-rheumatoid joint disorders, and 42 as having non-inflammatory joint disorders. At the femoral neck and lumbar spine no significant bone loss was seen in any of the three subgroups. At the 12 months follow up the mean (95% confidence interval) hand BMD loss in the patients with rheumatoid arthritis was -4.27% (-1.41 to -7.13); in the inflammatory non-rheumatoid group, -0.49% (-1.33 to +0.35); and in the non-inflammatory joint disorder group, -0.87% (-1.51 to -0.23). In a multivariate linear regression model (including age, rheumatoid factor, mean C reactive protein, mean HAQ score, and cumulative glucocorticoid dose), only mean C reactive protein (p<0.001) and rheumatoid factor (p = 0.04) were independently associated with change in hand BMD during follow up. CONCLUSIONS: Hand DXA provides a very sensitive tool for measuring bone loss in early rheumatoid arthritis and may be useful in identifying patients at high risk of developing progressive disease. Further studies are needed to evaluate the role of hand bone loss as a prognostic factor and outcome measure in rheumatoid arthritis. (+info)
Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis.
OBJECTIVES: To examine whether treatment with anti-tumour necrosis factor (TNF) alpha prevents loss of bone mineral density (BMD) at the spine and hip (generalised) and in the hands (local) of patients with rheumatoid arthritis, and to study the changes in markers of bone metabolism, including receptor activator of the NFkappaB ligand (RANKL) and osteoprotegerin (OPG), during anti-TNF treatment. PATIENTS AND METHODS: 102 patients with active rheumatoid arthritis, who were treated with infliximab during 1 year, were included in this open cohort study. The BMD of the spine and hip (dual x ray absorptiometry) and hands dual x ray radiogrammetry was measured before the start of treatment and after 1 year. Changes in osteocalcin formation, beta-isomerised carboxy terminal telopeptide of type 1 collagen (beta-CTx, resorption), RANKL and OPG were determined at 0, 14, 30 and 46 weeks. RESULTS: The BMD of the spine and hip was unchanged during treatment with infliximab, whereas BMD of the hand decreased significantly by 0.8% (p<0.01). The BMD of the hip in patients with a good European League Against Rheumatism response showed a favourable change compared with patients not achieving such a response. Serum beta-CTx and RANKL were both considerably decreased compared with baseline at all time points. The decrease in beta-CTx was associated with the decrease in Disease Activity Score of 28 joints and C reactive protein during the 0-14 weeks interval. CONCLUSION: In patients with rheumatoid arthritis treated with infliximab, spine and hip bone loss is arrested, whereas metacarpal cortical hand bone loss is not stopped. The outcome of the study also supports a relationship between clinical response, in terms of reduced inflammatory activity, and changes in bone loss of the spine, hip and hands. (+info)
Computerized digital imaging techniques provided by digital X-ray radiogrammetry as new diagnostic tool in rheumatoid arthritis.
PURPOSE: Our study evaluates digital x-ray radiogrammetry (DXR) and Radiogrammetry Kit (RK) as a new diagnostic method for the measurement of disease-related osteoporosis including quantification of joint space narrowing dependent on the severity of rheumatoid arthritis (RA). MATERIALS AND METHODS: A total of 172 unselected patients with RA underwent computerized measurements of bone mineral density (BMD) and metacarpal index (MCI) by DXR, as well as a semiautomated measurement of joint space distances at the metacarpal-phalangeal articulation (JSD-MCP 2-5), both were analyzed from plain radiographs of the nondominant hand. RESULTS: Correlations between DXR-BMD and DXR-MCI vs. parameters of RK were all significant (0.34 < R < 0.61; p < 0.01). An expected negative association was observed between RK parameters and the different scoring methods (-0.27 < R < -0.59). The maximum relative decrease in BMD vs. MCI as measured by DXR between the highest and lowest RA severity group was -27.7% vs. -27.5% (p < 0.01) for the modified Larsen Score, whereas the minimal value of relative DXR-BMD and DXR-MCI reduction could be documented for the Sharp Erosion Score (-20.8% vs. -26.8%; p < 0.01). The relative reduction of mean JSD-MCP using RK significantly varied from -25.0% (Sharp Erosion Score) to -41.2% (modified Larsen Score). In addition, an excellent reproducibility of DXR and RK could be verified. CONCLUSION: DXR in combination with RK could be a promising, widely available diagnostic tool to supplement the different scoring methods of RA with quantitative data, allowing an earlier and improved diagnosis and more precision in determining disease progression. (+info)
A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene.
Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance. (+info)
Factors influencing osteological changes in the hands and fingers of rock climbers.
This study examines the osteological changes in the hands and fingers of rock climbers that result from intense, long-term mechanical stress placed on these bones. Specifically, it examines whether rock climbing leads to metacarpal and phalange modelling in the form of increased cortical thickness as well as joint changes associated with osteoarthritis. This study also attempts to identify specific climbing-related factors that may influence these changes, including climbing intensity and frequency of different styles of climbing. Radiographs of both hands were taken for each participant and were scored for radiographic signs of osteoarthritis using an atlas method. Total width and medullary width were measured directly on radiographs using digital calipers and used to calculate cross-sectional area and second moment of area based on a ring model. We compared 27 recreational rock climbers and 35 non-climbers for four measures of bone strength and dimensions (cross-sectional area, second moment of area, total width and medullary width) and osteoarthritis. A chi-squared test for independence was used to compare climber and non-climber osteoarthritis scores. For each measure of bone strength climbers and non-climbers were compared using a manova test. Significant manova tests were followed by principal components analysis (PCA) and individual anova tests performed on principal components with eigenvalues greater than one. A second PCA was performed on the climber subsample and the first principal component was then used as the dependent variable in linear regression variable selection procedures to determine which climbing-related variables affect bone thickness. The results suggest that climbers are not at an increased risk of developing osteoarthritis compared with non-climbers. Climbers, however, do have greater cross-sectional area as well as second moment of area. Greater total width, but not meduallary width, indicates that additional bone is deposited subperiosteally. The strength of the finger and hand bones are correlated with styles of climbing that emphasize athletic difficulty. Significant predictors include the highest levels achieved in bouldering and sport climbing. (+info)
Diagnosis of post-traumatic complex regional pain syndrome of the hand: current role of sympathetic skin response and three-phase bone scintigraphy.
PURPOSE: To evaluate the role of sympathetic skin response (SSR) and three-phase bone scintigraphy (TPBS) in the diagnosis of complex regional pain syndrome (CRPS). METHODS: 60 patients with CRPS of the hand were recruited. TPBS was performed using a bolus injection of 20 mCi of Tc-99m methylene diphosphonate in an antecubital vein and blood flow (first phase) image, blood pool (second phase) image, and delayed (third phase) image obtained. Patients were considered to have CRPS when the blood pool and blood flow images showed diffuse asymmetric uptake, or when the delayed image indicated increased asymmetric periarticular uptake. SSR was measured simultaneously in the affected and unaffected hands. Standard surface electromyogram disc electrodes were applied to the palm and dorsum of both hands. Electrical stimuli were applied to the skin at the base of little and ring fingers of the unaffected hand. Patients were considered abnormal when response was absent or the peak-to-peak amplitude was <50% of the contralateral hand in at least 2 readings. RESULTS: The delayed phase of TPBS tested positive in all; the first and second phases tested positive in 54 (90%) and 56 (93%) of the patients, respectively. Four of the 6 patients with a negative first phase had had symptoms persisting for more than 6 months, and the other 2 for about 3 to 6 months. No patient presenting within 3 months had a negative scan. SSR was absent in 16 (27%) patients and normal in 44 (73%). 11 (79%) of 14 patients who presented more than 6 months after symptom onset displayed an abnormal SSR, while only 10% of those presenting within 3 to 6 months and 11% of those presenting within 3 months had an abnormal SSR. 12 (75%) of the 16 patients with abnormal SSR had associated decreased sweating, compared with 2 (4.5%) of the 44 patients with a normal SSR. CONCLUSION: TPBS is a very sensitive corroborative test to confirm the clinical suspicion of CRPS during the initial stages, but not in late cases. SSR can be used to document the sympathetic dysfunction in cases having an associated sweating abnormality and may have some diagnostic value in late cases of CRPS, when TPBS is less reliable. (+info)