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Ectopic calcification among families in the Azores: Clinical and radiologic manifestations in families with diffuse idiopathic skeletal hyperostosis and chondrocalcinosis
Abstract
Twelve families that were multiply affected with diffuse idiopathic skeletal hyperostosis (DISH) and/or chondrocalcinosis, were identified on the island of Terceira, The Azores, potentially supporting the hypothesis that the 2 disorders share common etiopathogenic factors. The present study was undertaken to investigate this hypothesis.
One hundred three individuals from 12 unrelated families were assessed. Probands were identified from patients attending the Rheumatic Diseases Clinic, Hospital de Santo Espírito, in The Azores. Family members were assessed by rheumatologists and radiologists. Radiographs of all family members were obtained, including radiographs of the dorsolumbar spine, pelvis, knees, elbows, and wrists, and all cases were screened for known features of chondrocalcinosis.
Ectopic calcifications were identified in 70 patients. The most frequent symptoms or findings were as follows: axial pain, elbow, knee and metacarpophalangeal (MCP) joint pain, swelling, and/or deformity, and radiographic enthesopathic changes. Elbow and MCP joint periarticular calcifications were observed in 35 and 5 patients, respectively, and chondrocalcinosis was identified in 12 patients. Fifteen patients had sacroiliac disease (ankylosis or sclerosis) on computed tomography scans. Fifty-two patients could be classified as having definite (17%), probable (26%), or possible (31%) DISH. Concomitant DISH and chondrocalcinosis was diagnosed in 12 patients. Pyrophosphate crystals were identified from knee effusions in 13 patients. The pattern of disease transmission was compatible with an autosomal-dominant monogenic disease. The mean age at which symptoms developed was 38 years.
These families may represent a familial type of pyrophosphate arthropathy with a phenotype that includes peripheral and axial enthesopathic calcifications. The concurrence of DISH and chondrocalcinosis suggests a shared pathogenic mechanism in the 2 conditions.
... Main symptom Epidemiology DISH Calcification and ossification of the anterior longitudinal ligament affecting, in particular, the right side of the spine with preservation of the intervertebral disc space. Peripheral joints, such as elbow, shoulder, hip, knee and heel are commonly affected (Okazaki et al., 1976;Gorman et al., 2005;Bruges-Armas et al., 2006;Couto et al., 2017;Parreira et al., 2020) Dysphagia (Beardwell, 1969). Axial pain, elbow, knee and metacarpophalangeal pain, swelling and deformity (Okazaki et al., 1976) Elderly males are mostly affected. ...
... In Azores region, twelve families were identified presenting early onset (third decade) of DISH and/or Chondrocalcinosis (CC). The affected members had a pyrophosphate arthropathy showing exuberant axial and peripheral enthesopathic calcifications, meaning calcification of the connective tissues in the attachments of tendons or ligaments to the bones, in joints other than the spine (Bruges-Armas et al., 2006). Genetic studies in these families suggest that the phenotype DISH/CC is polygenic and influenced by the interaction of several, small-effect gene variants and possibly by unidentified environmental factors (Couto et al., 2017;Parreira et al., 2020). ...
... Genetic studies in these families suggest that the phenotype DISH/CC is polygenic and influenced by the interaction of several, small-effect gene variants and possibly by unidentified environmental factors (Couto et al., 2017;Parreira et al., 2020). Similar cases, of patients with CPPD and/or CC and DISH, were mentioned in other studies (Okazaki et al., 1976), also showing familial aggregation (van der Korst et al., 1974;Bruges-Armas et al., 2006). ...
Diffuse Idiopathic Skeletal Hyperostosis (DISH) and Ossification of the Posterior Longitudinal Ligament (OPLL) are common disorders characterized by the ossification of spinal ligaments. The cause for this ossification is currently unknown but a genetic contribution has been hypothesized. Over the last decade, many studies on the genetics of ectopic calcification disorders have been performed, mainly on OPLL. Most of these studies were based on linkage analysis and case control association studies. Animal models have provided some clues but so far, the involvement of the identified genes has not been confirmed in human cases. In the last few years, many common variants in several genes have been associated with OPLL. However, these associations have not been at definitive levels of significance and evidence of functional significance is generally modest. The current evidence suggests a multifactorial aetiopathogenesis for DISH and OPLL with a subset of cases showing a stronger genetic component.
... Based on family research, some studies have suggested that DISH could be related to some genetic or immunological factors not linked to the HLA system (Bruges-Armas et al., 2006;Gorman et al., 2005;Spagnola et al., 1978). Tsukahara et al. (2005) showed correlation between single nucleotide polymorphisms in COL6A1 genes and the development of DISH in the Japanese population, but this correlation was not observed in Czech populations, so it has been argued that this genetic factor in the development of DISH could be population specific. ...
... This constancy in the prevalence of DISH in some ancient populations through time and across regions supports the hypothesis that there may be an underlying genetic factor (Crubézy, 1996). Some clinical studies also suggest that DISH could have a genetic component that could be population or even family-specific (Bruges-Armas et al., 2006;Gorman et al., 2005;Spagnola et al., 1978;Tsukahara et al., 2005;Villari et al., 2009). Spencer (2008 attempted to directly investigate this genetic component by aDNA analysis; the results showed that DISH is not related to the maternal genealogic lineage, but other pathways of inheritance could be involved in the development DISH. ...
Objective
Evaluate the prevalence of DISH through time from the Roman to the post-Medieval period in England and Catalonia.
Material
281 individuals from England and 247 from Catalonia were analyzed.
Methods
Adult individuals with at least three well-preserved lower thoracic vertebral bodies were analyzed. DISH was assessed considering the early stages of development. Diachronic and geographical dietary shifts were investigated using reported light isotope data, archaeological reports and historical documentation.
Results
Males and older individuals showed consistently higher prevalence of DISH, however, only the English sample showed a significant difference between males and females in the prevalence of DISH. No significant difference was found in the prevalence of DISH though time (from Roman to post medieval periods) nor across regions (England and Catalonia).
Conclusion
The development of DISH is probably influenced by a combination of factors including increasing age and sex.
Significance
This is the first exhaustive analysis of DISH in ancient Catalan populations and the first that considers the early stages of DISH.
Limitations
Reduced sample size, particularly in post-medieval samples, as a result of the available excavated samples and the inclusion criteria adopted.
Future Research
Include rural, religious and high-status samples in the analysis of DISH. Re-assess the prevalence of DISH in post-medieval populations.
... A formal segregation study in these families suggested that the condition was caused by a Mendelian inherited disorder with an autosomaldominant model of transmission. 32 Therefore, we performed a whole-genome linkage analysis followed by 'identity-by-state (IBS)/identity-by-descent (IBD)' mapping to determine the genetic cause of this phenotype. IBD mapping is a statistical method for the detection of genetic loci that share an ancestral segment among 'unrelated' affected pairs of individuals. ...
... The concurrence of DISH and CC suggests a shared pathogenic mechanism. 32 The etiology of DISH/CC is unknown. However, because it is a bone-forming disease, it is expected that genes related to the calcification and ossification process are implicated in its etiology. ...
Twelve families with exuberant and early-onset calcium pyrophosphate dehydrate chondrocalcinosis (CC) and diffuse idiopathic skeletal hyperostosis (DISH), hereafter designated DISH/CC, were identified in Terceira Island, the Azores, Portugal. Ninety-two (92) individuals from these families were selected for whole-genome-wide linkage analysis. An identity-by-descent (IBD) analysis was performed in 10 individuals from 5 of the investigated pedigrees. The chromosome area with the maximal logarithm of the odds score (1.32; P=0.007) was not identified using the IBD/identity-by-state (IBS) analysis; therefore, it was not investigated further. From the IBD/IBS analysis, two candidate genes, LEMD3 and RSPO4, were identified and sequenced. Nine genetic variants were identified in the RSPO4 gene; one regulatory variant (rs146447064) was significantly more frequent in control individuals than in DISH/CC patients (P=0.03). Four variants were identified in LEMD3, and the rs201930700 variant was further investigated using segregation analysis. None of the genetic variants in RSPO4 or LEMD3 segregated within the studied families. Therefore, although a major genetic effect was shown to determine DISH/CC occurrence within these families, the specific genetic variants involved were not identified.
... Moreover, involvement of the C-spine varies between inflammatory conditions (such as rheumatoid arthritis and spondyloarthropathies) and degenerative conditions, the upper section (C1-C2) being more prone to inflammatory diseases and the lower (C5-C7) to degenerative changes (Kim et al., 2018). DISH in the C-spine could also be linked to conditions such as gout and Paget disease (Bruges-Armas et al., 2006). There is a significant correlation between DISH and metabolic disorders, notably obesity, and diabetes; prolonged metabolic imbalance could boost the production of growth factors including insulin-like growth factor 1, contributing to DISH development (Jun et al., 2017). ...
Osseous bridging (OB) in three or more segments of motions (SOMs) of the mobile spine was initially defined as diffuse idiopathic skeletal hyperostosis (DISH), located particularly in the thoracic spine (T‐spine). This pathological phenomenon is often characterized by calcification and ossification, which take place simultaneously or separately. The soft tissues, mainly ligaments and entheses, are calcified, with bone formation not originating from the anterior longitudinal ligament (ALL). DISH formation can involve osteophytes, which are created by the ossification process and can involve soft tissue such as the ALL. The ALL can also be calcified. Until recently, the prevalence of DISH in the general population was considered low (0%–5%) and rare in the cervical spine (C‐spine). In a cross‐sectional observational skeletal study, we investigated the prevalence and location of C‐spine OB between vertebral bodies with fewer than three SOMs. We tested a large sample (n = 2779) of C‐spines housed in the Cleveland Museum of Natural History (Ohio, USA). The human sources of the samples had died between the years 1912 and 1938 and represented both sexes and two different ethnic groups: Black Americans and White Americans. The process development can be seen on the ALLs as calcification, osteophytosis, and candle‐shaped. Among all of the specimens, 139 (5%) were affected by OB, mostly in one SOM. Prevalence tended to be higher in women, White Americans, and the older age group. The levels most affected were C3–C4, followed by C2–C3 and subsequently, C5–C6. OB involving two consecutive SOMs was found only at C5–C7. We believe it is important to respond to the presence of a single SOM with a presumptive diagnosis of OB and to follow up, identify whether the diagnosis is correct, and take preventive action if possible. There is a need for updated diagnostic criteria and research approaches that reflect contemporary lifestyle factors and their impact on spine health.
... Furthermore, comorbidities such as obesity, diabetes mellitus, and arterial hypertension are associated with DISH [6]. A genetic predisposition has been observed in a number of families affected by the disease [7,8]. At the same time, single nucleotide polymorphisms in the COL6A1 [9] and FGF2 genes [10] were reported to be associated with the occurrence of DISH. ...
Zusammenfassung
Einleitung Die vorliegende Studie hatte das Ziel, Erkenntnisse über Veränderungen in der Knochendichte und der kortikale Dicke bei Patienten mit diffuser idiopathischer skelettaler Hyperostose (DISH) und Osteoporose zu gewinnen, um das Verständnis für Risikobereiche für das Auftreten von Insuffizienzfrakturen am Achsenskelett zu verbessern.
Fallbeschreibung und Ergebnisse Eine weibliche 83-Jährige Körperspenderin mit DISH und Osteoporose wurde mittels CT/QCT- sowie Mikro-CT-Bildgebung untersucht. Die kortikale Dicke wurde an den Endplatten und der kortikalen Schale von 15 Wirbelkörpern an 1800 Messpunkten ermittelt, um Unterschiede zwischen den Wirbelsäulen Abschnitten festzustellen. Alle erhobenen Daten wurden mit dem Softwarepaket SPSS, Version 24.0 (Armonk, New York: IBM Corp., USA) analysiert. Es zeigte sich eine signifikant höhere kortikale Dicke in der Brustwirbelsäule im Vergleich zur Hals- (p=0,001) und Lendenwirbelsäule (p<0,001). Die Kortikalisdicke ist an der Hinterkante in den verschiedenen Abschnitten am geringsten ausgeprägt. Der spongiöse Knochenmineralgehalt steigt in den von DISH betroffenen Wirbelkörpern an. Obwohl die Halswirbelsäule nicht von DISH betroffen war, fand sich dort die höchste Knochendichte der gesamten Wirbelsäule.
Schlussfolgerungen Die signifikant höhere kortikale Dicke und der erhöhte spongiöse Knochenmineralgehalt in der Brustwirbelsäule bei DISH könnte auf eine erhöhte Stabilität und ein geringeres Frakturrisiko in diesem Bereich hinweisen. Die hohe Knochendichte im HWS-Bereich scheint auch bei vorliegender Osteoporose am Achsenskelett einen kritischen Frakturschwellenwert nicht zu unterschreiten.
... We could not find an association of DISH with CPPA in gout patients, what could be explained by the association of CPPA itself with aging [16]. CPPA and DISH have been shown to be associated in some populations [17], and even genetic variants identified for such a phenotype [18]. ...
Aim: To evaluate the prevalence, associated factors, and the impact of diffuse idiopathic skeletal hyperostosis (DISH) in patients with gout. Methods: Patients with gout entering into an inception cohort were evaluated for either spinal or peripheral hyperostosis from January 2022 to April 2023. Age, gender, along with comorbid conditions associated to gout and DISH were analyzed, including the presence either axial or peripheral hyperostosis and associated calcium pyrophosphate arthritis (CPPA). Results: The prevalence of DISH was 25.6% (31/121) patients, neat peripheral joint hyperostosis affecting 51.6% (16/31). CPPA was also present in 11.6% (14/121) patients. Only older age and male gender were independently associated to the presence of DISH. The presence of hyperostosis in peripheral joints was not associated to a worse initial evaluation of the severity of gout. Conclusions: The presence of DISH in patients with gout seems to be related mostly to aging. Conditions apparently associated to DISH in gout patients seem therefore to be related to aging.
... Furthermore, it is associated with fractures of the vertebral body, even with minor trauma, because of the loss of flexibility, which is problematic [2][3][4]. Computed tomography (CT) has made it possible to easily diagnose the morphology of ossification [5,6]. Previous studies added the thickness of the bony ridge as a diagnostic criterion [7]. ...
Patients with diffuse idiopathic skeletal hyperostosis (DISH) develop fractures of the vertebral bodies, even in minor trauma, because of the loss of flexibility, which causes difficulties in fusing vertebrae; therefore, the diagnosis of spine injuries may be delayed. We used the three-dimensional finite element method to add data on ossification to the healthy vertebral model in order to investigate how stress in intervertebral discs changes with bone shape and whether these changes present any risk factors. A healthy spine model and a DISH flat model (T8–sacrum) were generated from medical images. As an ossified hypertrophic model, T11–T12 was cross-linked with hypertrophic ossification, and hypertrophy was found to be 5 and 10 mm. An ossifying hypertrophic groove model (5 and 10 mm) was created at T11–T12 and T11–L1. A groove was created at the center of T12, and the radius of curvature of the groove was set to 1 and 2.5 mm. An extension force and flexion force were applied to the upper part of T8, assuming that external forces in the direction of flexion and extension were applied to the spine. Stresses were greater in the DISH flat model than in the healthy model. In the hypertrophic ossification model, the stress on the vertebral body was similar to greater ossification in extension and flexion. In the ossified hypertrophic groove model, the stress at the center of the groove increased. In DISH, vertebrae are more susceptible to stress. Furthermore, depending on the morphology of ossification, stresses on the vertebrae and intervertebral discs differed even with similar loads. An examination of ossification geometry may help surgeons decide the thoracolumbar spine’s stress elevated position in patients with DISH, thereby contributing to the understanding of the pathogenesis of pain.
... The genetics of DISH are still in their early days, although there is some information already available on this subject. Several reports of familial DISH have been published [17][18][19][20]. DISH has a higher prevalence in older male dogs in the boxer breed, and a lower prevalence in other genetic breeds suggests a genetic influence [21]. ...
Purpose of Review
Diffuse Idiopathic Skeletal Hyperostosis (DISH) is considered a metabolic condition, characterized by new bone formation affecting mainly at entheseal sites. Enthesitis and enthesopathies occur not only in the axial skeleton but also at some peripheral sites, and they resemble to some extent the enthesitis that is a cardinal feature in spondyloarthritis (SpA), which is an inflammatory disease.
Recent Findings
We review the possible non-metabolic mechanism such as inflammation that may also be involved at some stage and help promote new bone formation in DISH. We discuss supporting pathogenic mechanisms for a local inflammation at sites typically affected by this disease, and that is also supported by imaging studies that report some similarities between DISH and SpA.
Summary
Local inflammation, either primary or secondary to metabolic derangements, may contribute to new bone formation in DISH. This new hypothesis is expected to stimulate further research in both the metabolic and inflammatory pathways in order to better understand the mechanisms that lead to new bone formation. This may lead to development of measures that will help in earlier detection and effective management before damage occurs.
... A genetic predisposition for the development of DISH was described in different affected families with DISH [50,51]. In dogs, the boxer breed has been shown to have a significantly higher prevalence of DISH (40%) compared to all other dogs (4%) [52,53]. ...
Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic bone-forming condition characterized by the presence of at least three bony bridges at the anterolateral spine. The aim of this review was to address the present state of pathophysiological knowledge, the clinical relevance, and diagnosis of DISH. The pathogenesis of DISH is currently unknown. The presence of DISH has been associated with older age, male sex, obesity, hypertension, atherosclerosis, and diabetes mellitus. Because the new bone forms mainly at entheseal sites, local fibroblasts, chondrocytes, collagen fibers, and calcified matrix are probably influenced by genetic, vascular, metabolic, and mechanical factors. Diagnosing the presence of DISH is of clinical importance, because the risk of a spinal fracture increases and associations with the metabolic syndrome, coronary and aortic disease, and respiratory effects are strong. Unravelling the pathogenesis of DISH can impact the field of regenerative medicine and bone tissue regeneration.
... Phenotypic heterogeneity of kindreds with familial CPPD, even with mutations limited to ANKH (29), could allow genomics to potentially illuminate idiopathic and OAassociated CPPD pathogeneses. Examples include kindreds with mixed phenotypes of chondrocalcinosis and features such as premature OA, spondyloepiphyseal dysplasia, and skeletal deformities and hyperostosis (30). Genetic linkages to mutation of TNFRSF11B (which encodes osteoprotegerin) (31) and procollagen II (32) have been reported in some such kindreds with CPPD. ...
Calcium pyrophosphate (CPP) crystal deposition (CPPD) is prevalent, and can be associated with synovitis and joint damage. The older‐aged population predominantly affected by CPPD is growing rapidly. Since shortfalls exist in many aspects of CPPD, we conducted an anonymous survey of CPPD unmet needs, prioritized by experts from the Gout, Hyperuricemia and Crystal‐Associated Disease Network (G‐CAN). We provide our perspectives on the survey results, and propose several CPPD basic and clinical translational research pathways. Chondrocyte and cartilage culture systems for generating CPP crystals in vitro, and transgenic small animal CPPD models are needed to better define CPPD mechanism paradigms and help guide new therapies. CPPD recognition, clinical research, and care would be improved by international consensus on CPPD nomenclature and disease phenotype classification, better exploitation of advanced imaging, and pragmatic new point‐of‐care crystal analytic approaches for detecting CPP crystals. Clinical impact of CPP crystals in OA, and in asymptomatic joints in the aged, remain major unanswered questions, rendered more difficult by current inability to therapeutically limit or dissolve the crystal deposits and assess consequent clinical outcome. Going forward, CPPD clinical research studies should define clinical settings in which articular CPPD does substantial harm, and include analyses of diverse clinical phenotypes and populations. Clinical trials should identify the best therapeutic targets to limit CPP crystal deposition and associated inflammation, and include assessment of intra‐articular agents. Our perspective is that such advances in basic and clinical science in CPPD are now within reach, and can lead to better treatments for this disorder.
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... Three main forms of CPPD are usually described: acute pseudogout, inflammatory chronic arthropathy, and osteoarthritis-like disease [1]. An additional CPPD phenotype characterized by peripheral and axial enthesopathic calcifications was described by Resnick and others [2][3][4][5]. Pseudogout, characterized by acute attacks of inflammatory arthritis, mainly in wrists and knees, is sometimes severe and can be refractory to current nonbiological treatments. Treatment of CPPD depends on the clinical manifestations and disease severity, and several drugs may be used, like nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular or systemic steroids, methotrexate, hydroxychloroquine, and colchicine [6]. ...
Objectives. To investigate the efficacy of infliximab in the treatment of severe calcium pyrophosphate deposition diseases (CPPD). Methods. Two patients with severe CPPD and diffuse idiopathic skeletal hyperostosis- (DISH-) like phenotype are described. Both patients were resistant to therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). Both patients were treated with infliximab, a TNF-α receptor antagonist, for nine years.
Results. Treatment with infliximab resulted in major clinical and laboratory improvements without relevant side effects.
Conclusions. These results suggest that infliximab may be an effective treatment of severe CPDD.
... Moreover, familial clustering of the condition and early onset (in the third decade of life) in some affected families have been observed, which are also suggestive of a genetic contribution to the disease. 50,51 Studies in dogs have revealed the overall prevalence of canine DISH to be 3.8%, whereas in the Boxer breed it is >40%, which further supports the existence of a genetic component in the risk of developing DISH. 52 So far, however, only one potential susceptibility gene (namely COL6A1, which encodes type VI collagen α chain) has been identified. ...
Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic condition characterized by the ossification and calcification of ligaments and entheses. DISH is observed on all continents and in all races, but most commonly in men over 50 years of age. Although DISH is asymptomatic in most individuals, the condition is often an indicator of underlying metabolic disease, and the presence of spinal or extraspinal ossifications can sometimes lead to symptoms including pain, stiffness, a reduced range of articular motion, and dysphagia, as well as increasing the risk of unstable spinal fractures. The aetiology of DISH is poorly understood, and the roles of the many factors that might be involved in the development of excess bone are not well delineated. The study of pathophysiological aspects of DISH is made difficult by the formal diagnosis requiring the presence of multiple contiguous fully formed bridging ossifications, which probably represent advanced stages of DISH. In this Review, the reader is provided with an up-to-date discussion of the epidemiological, aetiological and clinical aspects of DISH. Existing classification criteria (which, in the absence of diagnostic criteria, are used to establish a diagnosis of DISH) are also considered, together with the need for modified criteria that enable timely identification of early phases in the development of DISH.
... Other conditions that may be associated with DISH include gout, 11 rheumatoid arthritis, 12 Paget's disease 13 and chondrocalcinosis. 14 Evaluation of progressive dysphagia should include speech and swallow evaluation, barium swallow studies, motility studies, otolaryngologic examination, and other radiological studies, which include CT and MRI of the head and neck. Endoscopy should be utilized with caution as this may cause perforation of esophagus. ...
A 72-year-old gentleman presented to the hospital with progressively worsening dysphagia to soft foods and liquids. He was diagnosed with severe pharyngeal dysphagia by modified barium swallow. A CT scan of the neck with IV contrast showed anterior flowing of bridging osteophytes from C3-C6, indicative of DISH, resulting in esophageal impingement. He underwent resection of the DISH segments. Following the surgery, a PEG tube for nutrition supplementation was placed. However, the PEG tube was removed after five months when the speech and swallow evaluation showed no residual dysphagia. DISH is a rare non-inflammatory condition that results in pathological ossification and calcification of the anterolateral spinal ligaments.
... The propensity for new bone formation in patients with DISH has emerged in descriptions of large sesamoid bones, thickened cortical bone, enlarged fingers' distal tufts, hyperostosis of ribs and the tendency for heterotopic ossifications following orthopaedic surgery [10,[16][17][18]. Concomitant chondrocalcinosis, ectopic entheseal calcifications or nephrolithiasis have been reported in familial cases of DISH [19]. This information suggests that the same, yet unknown, pathogenetic factors operating in DISH might influence structures other than bone. ...
DISH is a condition characterized by calcification and/or ossification of soft tissues, mainly entheses, ligaments and joint capsules. Its prevalence increases with age and, therefore, DISH is a relatively common entity in the elderly. The classical site of involvement is the spinal column with right anterolateral soft tissue ossification being the most characteristic feature. However, DISH is not limited to the spine, and may affect multiple peripheral sites independently. Extraspinal entheseal ossifications are common and observing their isolated presence may lead to the diagnosis of DISH. Furthermore, hypertrophic or atypical OA observed in joints usually not affected by primary OA has frequently been reported in DISH. Several metabolic derangements and concomitant diseases have been suggested to be associated with DISH including obesity, increased waist circumference, hypertension, dyslipidaemia, diabetes mellitus (DM), hyperuricaemia, metabolic syndrome and an increased risk for cardiovascular diseases. Witnessing the present increase in lifespan, obesity, DM and metabolic syndrome in the Western population, the prevalence of DISH should be expected to rise. In order to increase the awareness for DISH, this review focuses on the extraspinal features of the condition.
Background:
Diffuse idiopathic skeletal hyperostosis (DISH) is an incompletely defined disease process with no known unifying pathophysiological mechanism.
Objective:
To our knowledge, no genetic studies have been performed in a North American population. To summarize genetic findings from previous studies and to comprehensively test for these associations in a novel and diverse, multi-institutional population.
Methods:
Cross-sectional, single nucleotide polymorphism (SNP) analysis was performed in 55 of 121 enrolled patients with DISH. Baseline demographic data were available on 100 patients. Based on allele selection from previous studies and related disease conditions, sequencing was performed on COL11A2, COL6A6, fibroblast growth factor 2 gene, LEMD3, TGFB1, and TLR1 genes and compared with global haplotype rates.
Results:
Consistent with previous studies, older age (mean 71 years), male sex predominance (80%), a high frequency of type 2 diabetes (54%), and renal disease (17%) were observed. Unique findings included high rates of tobacco use (11% currently smoking, 55% former smoker), a higher predominance of cervical DISH (70%) relative to other locations (30%), and an especially high rate of type 2 diabetes in patients with DISH and ossification of the posterior longitudinal ligament (100%) relative to DISH alone (100% vs 47%, P < .001). Compared with global allele rates, we found higher rates of SNPs in 5 of 9 tested genes (P < .05).
Conclusion:
We identified 5 SNPs in patients with DISH that occurred more frequently than a global reference. We also identified novel environmental associations. We hypothesize that DISH represents a heterogeneous condition with both multiple genetic and environmental influences.
Coined in 1975 by Resnick et al., diffuse idiopathic skeletal hyperostosis describes a systemic condition that is mainly characterized by flowing ossification of the spine and, less frequently, peripheral entheses. Its overall incidence is 6-12%, but it is more frequently observed in males than in females and subjects aged >50 years, and its increased prevalence in people aged >70 years suggests that the course of the disease begins between the third and fifth decade of life but its clinical manifestations do not appear until later. Its pathogenesis and etiology remain unknown, but it has been reported to be associated with a number of genetic, metabolic, and constitutional factors. The aim of this review is to describe the main features of the disease and stimulate research into its pathogenesis, prevention, and treatment.
Objectives:
DISH/CC is a poorly understood phenotype characterised by peripheral and axial enthesopathic calcifications, frequently fulfilling the radiological criteria for Diffuse Idiopathic Skeletal Hyperostosis (DISH, MIM 106400), and in some cases associated with Calcium Pyrophosphate Dihydrate (CPPD) Chondrocalcinosis (CC). The concurrence of DISH and CC suggests a shared pathogenic mechanism. In order to identify genetic variants for susceptibility we performed whole exome sequencing in four patients showing this phenotype.
Materials and methods:
Exome data were filtered in order to find a variant or a group of variants that could be associated with the DISH/CC phenotype. Variants of interest were subsequently confirmed by Sanger sequencing. Selected variants were screened in a cohort of 65 DISH/CC patients vs 118 controls from Azores. The statistical analysis was performed using PLINK V1.07.
Results:
We identified 21 genetic variants in 17 genes that were directly or indirectly related to mineralization, several are predicted to have a strong effect at a protein level. Phylogenetic analysis of altered amino acids indicates that these are either highly conserved in vertebrates or conserved in mammals. In case-control analyses, variant rs34473884 in PPP2R2D was significantly associated with the DISH/CC phenotype (p=0.028; OR=1.789, 95% CI= 1.060 - 3.021)).
Conclusion:
The results of the present and preceding studies with the DISH/CC families suggests that the phenotype has a polygenic basis. The PPP2R2D gene could be involved in this phenotype in an as yet unknown way.
Diffuse idiopathic skeletal hyperostosis (DISH) is a skeletal syndrome that has been known for more than 70 years. Yet, its pathogenesis and treatment options are still under investigation. DISH and spondyloarthritidies may manifest itself clinically as very similar disorders causing impaired axial flexibility, axial pain and peripheral tendinopathies. On the other hand, these two processes are different in many ways, from different genetic and metabolic predispositions, to different clinical and imaging manifestations, and at last, a different attitude toward treatment. The knowledge of the similarities and differences between DISH and spondyloarthritidies can guide the clinician toward a better diagnostic and treatment approach. This review tries to emphasize these details.
This case explores an unusual calcified lesion of the hand and its dramatic response to steroids. A 30-year-old lady presented to rheumatology with a 1-year history of swelling on the radial side of her right middle metacarpophalangeal joint. Over a 2-week period, she had developed swelling throughout her right hand. She was treated with intramuscular methylprednisolone injection and a weaning course of prednisolone. A series of photos and X-rays demonstrates the resolution of swelling and calcification after steroid treatment. This case reports a chronic calcified mass associated with an acute inflammatory episode in the hand. This is likely to represent rupture of a calcific deposit with the release of crystals into the soft tissue. While there is prior literature on treatment with bisphosphonates or surgery, a fast and complete response to modest dose steroids suggests that this would be the first treatment to try in such a case.
Background
Calcium pyrophosphate dihydrate deposition disease (CPPD) has been reported to involve the spine, but few systematic studies have been published.
Objective
To further characterize the spinal involvement with CPPD by a review of CPPD patients hospitalized in a rheumatology department.
Methods
We retrospectively reviewed data for patients consecutively admitted with a diagnosis of CPPD in the rheumatology department of Lariboisière hospital in Paris, France over 5 years by using a standardized protocol and electronic case report forms. Imaging studies were also reviewed.
Results
Spinal CPPD was diagnosed in 37/152 (24.3%) CPPD patients. Patient with spinal involvement had more widespread peripheral CC. The cervical (n = 21) and lumbar (n = 19) segments were most involved. CT-scan was more sensitive than plain radiographs for detecting spinal calcifications. Crown dens syndrome was a prominent feature of cervical involvement. Inflammatory sterile spondylo-discitis was observed in 6 patients. Lesions were frequently multiple and were classified into 4 types. Ruling out septic discitis required image-guided biopsies in 3 patients. Sacroiliac involvement included calcification in 5 patients and severe sterile destructive arthropathy and joint fusion in one patient each. Degenerative changes were common, and CPPD could not be implicated because of the patients ‘age and lack of a control population. In 12 patients, severe clinical features requiring hospitalization were related to such degenerative changes.
Conclusion
Symptomatic involvement of the spine was observed in 24% of this series of hospitalized CPPD patients. Specific entities were the cause of hospitalisation in 25 of the 37 patients with spinal calcification and included inflammatory pain related to crystal deposits and destructive arthropathy of the spine and sacroiliac joints. Discitis exhibited a wide range of MRI features and biopsies were needed to rule out infection in 3 of the 6 discitis.
Diffuse idiopathic skeletal hyperostosis (DISH) is a well-recognised entity characterised by calcifications and ossifications of the entheses affecting mainly the spine and peripheral sites. DISH is still insufficiently investigated and understood. The objective of this report is to highlight the present limitations of our understanding of the condition and suggest future research paths. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved.
Objective:
The purpose of this study is to characterize sacroiliac joints (SIJs) findings at CT of patients with diffuse idiopathic skeletal hyperostosis (DISH), a condition characterized (using the Resnick classification criteria) by ossification of at least four contiguous vertebrae in the thoracic spine and preserved disk space, but without radiographic evidence of intraarticular SIJ abnormalities.
Materials and methods:
Pelvic CT examinations of 104 patients with DISH (fulfilling the Resnick criteria on spinal CT) and 106 age- and sex-matched control subjects whose entire spine lacked CT evidence of DISH (total, 149 men and 61 women; mean [± SD] age, 72.3 ± 8.7 years) were retrospectively evaluated for the presence of intra- and extraarticular bridging osteophytes, spurs, subchondral cystlike changes, erosions, and sclerosis of SIJs. Excluded were patients with known ankylosing spondylitis or inflammatory-related diseases. Data were analyzed using multivariate ANOVA to examine the degree of difference between patients with DISH and control subjects. Logistic regression analysis was used to generate odds ratios to examine their discriminatory ability. ROC analysis was then applied to examine the sensitivity and specificity of the results.
Results:
The frequency of anterior bridging, posterior bridging, entheseal bridging, and joint ankylosis was significantly higher among patients with DISH compared with control subjects (48% vs 9%, 20% vs 1%, 34% vs 4%, and 23% vs 0%, respectively; p < 0.001 for all comparisons).
Conclusion:
Intraarticular ankylosis seen at CT, an entity not included in the Resnick classification criteria, is common among patients with DISH, which implies that the radiologic classification criteria for DISH need to be revised.
Mummified human remains have been preserved in the cool, well-ventilated crypts of old Finnish churches, which were popular burial sites among the elite of the early modern period. Here, the authors present the results of a computed tomography study of the remains of an early 17th-century vicar of Keminmaa. They examined the preservation of his remains and made several pathological findings; the causes of the latter possibly had a severe impact on his health. He was a large man who achieved relative longevity for his time, although he suffered from conditions related to obesity. There were also potential indications of tuberculosis. Inflammatory changes, for example, had afflicted his spine.
Diffuse idiopathic skeletal hyperostosis (DISH) is often thought of as a disease of modern culture and lifestyle; however, cases have been reported in antiquity, although relatively sparsely. Using an osteobiographical approach, this study presents the oldest known case of DISH in Asia, a Kitoi individual, 76.1, from the middle Holocene cemetery of Shamanka II (Siberia, Russia). Rather than merely reporting a case of DISH, we explore the question: what would predispose a forager to develop a disease that is frequently associated with obesity and metabolic disorders? Evidence for physique, activity patterns, diet, and status are examined, comparing 76.1 to other individuals of his cultural group, in order to better understand why this individual may have developed DISH, as well as the potential effects of the disease on his quality of life. Results indicate that 76.1 was likely as active as other foragers belonging to his cultural group and, as can be discerned, his diet was similar; however, his physique differed, particularly his body mass estimate. Additionally, mortuary indicators suggest that 76.1 was of lower status than many of the other individuals buried at Shamanka II. Based on these multiple lines of enquiry, several scenarios are proposed as to what contributing factors resulted in 76.1's pathological state, including diet, physiological stress, the influence of status, dietary and genetic variation. Based on modern studies of quality of life in DISH individuals, as well as a lack of evidence for prolonged inactivity or disability, 76.1 did not appear to be significantly affected by the disease.
If acute arthritis occurs in the elderly in addition to typical degenerative, load-related joint complaints, this is often induced by crystal deposition. The crystals lead to activation of the immune system resulting in acute inflammation. In addition to gout, calcium pyrophosphate deposition (CPPD) disease in particular must also be taken into consideration. Diagnostically important are imaging techniques, e.g. early specific alterations of cartilage can be shown by joint sonography and later calcium pyrophosphate crystals can be detected as cartilage calcification (chondrocalcinosis) by radiography. Important for the diagnosis of crystal arthropathy is usually the microscopic detection of specific crystals in the synovial fluid and is supported by exclusion of septic arthritis by arthrocentesis. In contrast to gout, which can be well controlled by the pharmaceutical lowering of uric acid levels, there is no causal therapy for CPPD disease so far. As CPPD may occur as a secondary effect in metabolic disorders, such as hyperparathyroidism or hemochromatosis, it seems to be important to search for the underlying disease. The following article presents the current knowledge on clinically relevant aspects of the pathogenesis, diagnosis and therapy of CPPD disease.
La hiperostosis vertebral anquilosante es una osificación de las entesis. Se denomina entesis a la inserción de una cápsula articular, un tendón o un ligamento en el hueso. Enfermedad frecuente pero a menudo asintomática, se caracteriza por una osificación a modo de puente entre los discos intervertebrales de la región dorsal. Puede afectar a todos los segmentos de la columna vertebral y también al esqueleto apendicular. También pueden producirse complicaciones nerviosas por osificación del ligamento vertebral posterior, del ligamento amarillo o de las cápsulas articulares posteriores, con el resultado de una mielopatía cervical o un conducto lumbar estrecho. En la periferia puede conducir a la artrosis, de la que es un factor de riesgo. Se asocia a un síndrome metabólico (obesidad, diabetes, hipertensión arterial, dislipidemia). Hasta ahora no se conoce ningún tratamiento específico.
La ressemblance entre les diffuse interskeletal hyperostosis (DISH) et certaines spondylarthrites ankylosantes suggère des points communs dans la pathogénie des deux entités. La vitesse de progression des ossifications des enthèses est d’ailleurs la même dans les deux cas et des diagnostics de spondyloarthrite ont été évoqués à tort dans plusieurs familles avec transmission génétique de DISH à début précoce. Les DISH semblent toutefois des entités hétérogènes, car dans certaines familles, des calcifications périphériques ont aussi été remarquées : la pathogénie de ces cas pourrait se rapprocher de celle de plusieurs modèles animaux où co-existent aussi enthésopathies ossifiantes et calcifications périphériques, ainsi que de celles des hypophosphatémies familiales liée à l’X ou à des mutations de la dentin matrix protein (DMP). Dans les bien plus fréquentes hyperostoses sans calcifications, l’ossification des enthèses pourrait être liée à la différentiation ostéoblastique anormale de cellules souches mésenchymateuses physiologiquement présentes à la périphérie des disques, dans le périoste vertébral et les ligaments pré- et rétrovertébraux. Parmi les nombreux facteurs suspectés de favoriser cette différentiation, outre les BMP, les rétinoïdes et divers facteurs hormonaux, les adipokines, dont la leptine, sont l’objet d’un intérêt croissant, eu égard à l’association bien démontrée entre DISH et excès pondéral. La confirmation du rôle de cellules mésenchymateuses dans les DISH devrait inciter à étudier aussi l’implication de ces cellules mésenchymateuses dans la pathogénie des enthésites des spondyloarthrites. Elles jouent normalement un rôle immunosuppresseur, lequel pourrait être subverti lors des spondyloarthrites, en particulier par une sous-population de lymphocytes T ayant un homing spécifique pour les enthèses.
Mit steigender Lebenserwartung ist eine steigende Prävalenz von kristallinduzierten Arthritiden zu beobachten. Für die Gicht gilt das ebenso wie für die Kalziumpyrophosphat-Dihydrat (CPPD)-Ablagerungskrankheit, die sich als akute Arthritis oder unter dem klinischen Bild zunehmender Schübe aktivierter Arthrosen zeigen kann. Die Diagnose ist durch typische Knorpelverkalkungen (Chondrokalzinose) oder durch den Nachweis von Pyrophosphatkristallen aus dem Gelenk zu stellen. Trotz neuer Daten zur Pathogenese existieren bisher keine kausalen Therapieansätze. Die Klärung sekundärer Formen, wie Hyperparathyreoidismus und Hämochromatose, ist daher besonders relevant. In der folgenden Übersichtsarbeit soll der aktuelle Wissensstand zu Pathogenese, Diagnostik und Therapie dargestellt werden.
The similarities between diffuse idiopathic skeletal hyperostosis (DISH) and some forms of ankylosing spondylitis suggest shared pathogenic mechanisms. Entheseal ossification progresses at the same rate in the two conditions, and spondyloarthritis was the first diagnosis considered in several families with genetically determined early-onset DISH. However, DISH may be a heterogeneous condition, as the presence of peripheral calcifications in some families suggests pathogenic similarities with several animal models combining entheseal ossification and peripheral calcifications, as well as with X-linked familial hypophosphatemia and dentin-matrix-protein mutations. In the far more common presentation of hyperostosis without calcifications, entheseal ossification may be related to abnormal osteoblastic differentiation of mesenchymatous stem cells normally found around the intervertebral disks, in the vertebral periosteum, and in the anterior and posterior longitudinal ligaments. The many factors suspected of promoting this abnormal differentiation include bone morphogenetic proteins (BMPs), retinoids, and various hormonal factors; in addition, adipokines such as leptin are the focus of growing interest based on the well-documented association between DISH and obesity. Confirmation of the role for mesenchymatous cells in DISH should encourage investigations of mesenchymatous cells as possible pathogenic contributors to the entheseal abnormalities seen in spondyloarthritis. These cells normally exert immunosuppressive effects, which may be subverted in spondyloarthritis, notably by a T-cell population that homes specifically to the entheses.
The authors describe the main clinical and radiological findings of common enthesopathic disorders-spondylarthritis (SpA), chondrocalcinosis/calcium pyrophosphate dehydrate crystal deposition disease (CPPD CDD) and diffuse idiopathic skeletal hyperostosis (DISH), stressing similarities and differences which may help in the differential diagnosis. They emphasize the clinical presentation of the "pseudoankylosing spondylitis" forms of CPPD CDD. They also review the most relevant genes and molecular mechanisms associated with these conditions and with another enthesopathic disorder with high prevalence in the Japanese population-ossification of the posterior longitudinal ligament (OPLL).
A 72-year-old male was diagnosed as having ankylosing spondylitis, mainly according to radiological findings, confirmed as HLA-B27-negative. Postmortem examination of the skeleton raised doubts on the initial diagnosis, since spinal findings pointed out also to diffuse idiopathic skeletal hyperostosis. The authors discuss the differential diagnosis and enhance the postmortem findings which allowed the diagnosis of the two clinical entities in the same patient.
Calcium pyrophosphate dihydrate and basic calcium phosphate crystals are common components of osteoarthritic synovial fluids and define subsets of patients with inflammatory or rapidly destructive arthritis. Recent literature concerning clinical and etiologic aspects of calcium pyrophosphate dihydrate and basic calcium phosphate crystal arthritis are reviewed.
Recent literature reminds us of the propensity of calcium pyrophosphate dihydrate deposition disease to mimic other syndromes affecting the elderly. Several new studies reinforce the prevalence and significance of extra-articular calcium pyrophosphate dihydrate deposits, and demonstrate the presence of basic calcium phosphate-like whitlockite crystals in intervertebral discs. Current work serves to increase our appreciation for the complex role of the putative pyrophosphate transporter, ANKH, in healthy and diseased cartilage. The application of newer radiographic techniques to the diagnosis of calcium pyrophosphate dihydrate deposition disease holds promise for easier and more accurate identification of these crystal deposits in vivo. Work demonstrating the efficacy of a crystal poison in an animal model of osteoarthritis provides good evidence for a pathogenic role of calcium crystals in osteoarthritis, and hope for new therapies for these diseases.
Continued work will further our understanding of these common crystals and their associated clinical syndromes.
Crystal deposition is a very complex process ruled by numerous factors. A small but important proportion of cases of chondrocalcinosis are monogenic, and many of the genes involved have been identified. These genetic findings strongly point to control of the level of extracellular inorganic pyrophosphate as the primary mechanism for their association with either calcium pyrophosphate dihydrate or hydroxyapatite deposition. However, effects on extracellular inorganic pyrophosphate levels do not explain the mechanism of association in all of these monogenic diseases. Further, there are likely to be several as yet unidentified genes that are important in this common condition. This review highlights what genetic studies have demonstrated about the processes involved in these diverse but related disorders.
One hundred and one first degree relatives of 35 patients with chondrocalcinosis were examined for the presence of familial disease. Eleven subjects from nine families showed radiological chondrocalcinosis, a prevalence of familial disease of 26%. Two different patterns of disease were noted--the older generation was more commonly affected, and the younger generation and second degree relatives were exempt. Clinical and radiological differences were found between the early and late onset groups, but not between late onset and sporadic forms of chondrocalcinosis. These findings support the suggestion that the true prevalence of familial disease. is underestimated. A dominant, autosomal transmission with variable penetrance is consistent with our findings, which suggests that homozygous patients with familial chondrocalcinosis may present a more severe form of the disease.
To determine the prevalence of spondyloarthritis (SpA) in the Caucasian population of Terceira Island, Azores.
Study subjects were recruited from people over the age of 50 years from one half of the island of Terceira (n=24 561). Seventy eight men and 78 women from each five year age group were selected, giving a total of 468 men and 468 women available for study, of whom 490 agreed to take part. These subjects were assessed by dorsal, lumbar, and pelvic radiography. Radiological sacroiliitis was identified in eight patients on whom sacroiliac computed tomography scans were performed. HLA class I typing by polymerase chain reaction with sequence-specific primers was carried out in seven cases.
SpA was present in eight subjects (1.6%, 95% CI 0.8 to 2.7%), including seven men (2.7%) and one woman (0.4%). Three (1.2% ) male patients with definite ankylosing spondylitis were HLA-B27 positive. Only one person had a previous diagnosis of SpA.
These data complement previous studies in European countries on SpA prevalence and establish an estimate of the overall prevalence of SpA in a southern European population.
Arthritis may be the presenting manifestation of iron overload. The metacarpophalangeal joints are often involved, producing a condition that resembles osteoarthritis but at a site typically affected by rheumatoid arthritis. Treatment of the arthritis is often disappointing, but identification of the underlying disease permits institution of life-saving phlebotomy therapy.
Ossification of the posterior longitudinal ligament (OPLL) is an intractable disease that causes severe myelopathy and radiculopathy. The report of an autopsy case made by Tsukimoto in 1960 [1] led to the establishment of this disease as an entity. The Investigation Committee on Ossification of the Spinal Ligaments was organized by the Japanese Ministry of Public Health and Welfare in 1975. Research to elucidate this disease has continued since then.
(C) Williams & Wilkins 1997. All Rights Reserved.
CHONDROCALCINOSIS has been called the "great imposter"1 of rheumatic diseases, causing clinicians to misinterpret its multiple presentations as gout, rheumatoid arthritis, osteoarthritis, and traumatic and neuropathic joint disease.2 We saw a patient with diffuse chondrocalcinosis of peripheral joints and calcification of intervertebral disks simulating ankylosing spondylitis.Report of a Case
A 65-year-old woman was seen with a 20-year history of thoracolumbar backache gradually ascending to her neck, associated spinal deformity, and a 10-cm loss of height. She found it difficult to straighten her spine, and motion was accompanied by pain. Earlier, she had experienced a series of episodic painful swellings of her wrists and knees, lasting weeks to months. A left patellectomy had not been helpful, and at present, the knee was chronically painful and deformed.There was no history of venereal disease, psoriasis, or inflammatory bowel disease. Her father and one sister had also been incapacitated by
The first-degree consanguineous relatives of 46 patients with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease were examined for the presence of articular chondrocalcinosis. In 5 cases the process was familial, with 17 persons in the oldest living generation (mean age 69 ± 7.4) showing radiographic evidence of calcified cartilage. The clinical syndrome was characterized by a female predominance, late onset of symptoms with mild arthritic manifestations, and oligoarticular chondrocalcinosis. These data suggest that the familial type of CPPD crystal deposition disease is more frequent than formerly thought.
Three cases of generalized calcium pyrophosphate dihydrate deposition disease and roentgenographic sacroiliac abnormalities (chondrocalcinosis, inflammatory change and degenerative change) are described.
Diffuse idiopathic skeletal hyperostosis (DISH) is a common ossifying diathesis in middle-aged and elderly patients characterized by bone proliferation along the anterior aspect of the spine and at extraspinal sites of ligament and tendon attachment to bone. Four patients with DISH revealed extensive calcification and ossification of the posterior longitudinal ligament in the cervical spine. Review of cervical spine radiographs in 74 additional patients with DISH demonstrated bony hyperostosis of the posterior aspect of the vertebrae in 41%, posterior spinal osteophytosis in 34%, and posterior longitudinal ligament calcification and ossification in 50%. These ligamentous findings, which have previously been described almost exclusively in Japanese people, appear to be an additional skeletal manifestation of DISH.
The lumbar-spine radiographs of 67 patients with idiopathic chondrocalcinosis articularis were reviewed for disc calcification and other changes. Calcification was present in 21 (31%) of the patients, seen most frequently at the L 2–3 disc space. The 21 patients as a group were significantly older than the 46 patients without disc calcification, and also had a much higher incidence of chondrocalcinosis in peripheral joins. There was no association with back pain or spinal stiffness. The 21 patients with disc calcification included six patients with a destructive peripheral arthropathy, and three of them had destructive changes affecting the lumbar spine. Three patients with a destructive peripheral arthropathy were also included in the group without disc calcification, and one of these had a destructive arthritis of the lumbar spine.
For comparison, there was a 55% incidence of spinal chondrocalcinosis in nine patients with primary hyperparathyroidism and peripheral joint chondrocalcinosis, and a 6% incidence in 100 anteroposterior lumbar spine radiograph ‘controls’, taken before intravenous urography, although in this letter group the changes were minimal and confined to the margin of a single disc in each case.
* Paper read at the Annual Meeting of the British Association for Rheumatology and Rehabilitation, London, March 1976. Shared the Association prize for the best short paper.
The extraspinal manifestations of Forestier's disease are described in 21 consecutive cases; diffuse idiopathic skeletal hyperostosis (DISH) is suggested as a more appropriate description of this ossifying diathesis. Characteristic roentgen abnormalities of the spine were present in all individuals and associated with significant axial clinical complaints. In extraspinal locations, hyperostosis at ligament attachments usually occurs in the pelvis, calcaneus, tarsal bones, ulnar olecranon and patella, and is occasionally associated with clinical signs and symptoms requiring surgery. The radiographic appearance in the peripheral skeleton is frequently distinctive and allows the radiologist to suggest the correct diagnosis, even in the absence of axial radiographs.
Although many metabolic and endocrine diseases have been reported to predispose to calcium pyrophosphate dihydrate crystal deposition, the validity of many of these associations remains unclear. A critical review of the literature relating to these associations, with illustrative cases and data derived from the authors' own experience, is presented. It is concluded that there is good evidence to associate hypophosphatasia, hypomagnesemia, and hyperparathyroidism with chondrocalcinosis and acute attacks of "pseudogout." Meta-analysis also suggests a small but significant association between hypothyroidism and chondrocalcinosis. Hemochromatosis stands alone in clearly associating not only with chondrocalcinosis but also with structural change and chronic arthropathy. The biochemical mechanisms that may produce these various associations are discussed. Recommendations are made concerning appropriate screening for metabolic and endocrine disease in patients with chondrocalcinosis.
Chondrocalcinosis and osteoarthritis (OA) both increase in prevalence with age, yet previous studies assessing their association have often been too small to adjust for age and have had biased selection of subjects. We assessed the prevalence of chondrocalcinosis and its link with OA in the Framingham Knee Osteoarthritis Study, a large population based study of the elderly. After controlling for age, we found a modestly increased rate of radiographic OA in those with chondrocalcinosis (relative risk = 1.52 (95% CI 1.22, 1.90). There was a similar link between chondrocalcinosis and severe radiographic OA (relative risk = 1.52). Chondrocalcinosis was positively associated with both symptomatic and asymptomatic radiographic OA. The proportion of radiographic OA potentially attributable to chondrocalcinosis was only 4.4%. Our results confirm that chondrocalcinosis is significantly associated with OA after controlling for age, but they also suggest that chondrocalcinosis and OA increase independently with age.
A patient with typical diffuse idiopathic skeletal hyperostosis and characteristic new bone formation around the elbows exhibited
bilateral ulnar nerve entrapment at these sites as well as median nerve compression at one wrist.
Eight patients with classical spinal radiographic features of diffuse idiopathic skeletal hyperostosis (DISH) had pelvic radiographs which suggested sacroiliac joint abnormalities. No patient had clinical features of ankylosing spondylitis. Computed tomography of the sacroiliac joints revealed several abnormalities including asymmetric intraarticular partial fusion, osteophytes with or without bridging, and vacuum phenomenon. Sacroiliac joint disease can complicate DISH.
In 11 patients with Forestier disease 4 were shown to have obliteration of the sacroiliac joints. We suggest that if patients with this disease are observed for a long period ossification of the sacro-iliac joints will be seen, as in ankylosing spondylitis, with loss of sacro-iliac pain when present.
We have found in our clinic a 28.1% prevalence of familial chondrocalcinosis among 149 family members of 32 patients with calcium pyrophosphate dihydrate deposition disease. The clinical and radiological characteristics of these familial chondrocalcinosis patients were similar to those of the Chiloes with familial chondrocalcinosis previously reported. No significant clinical or radiological differences were detected between our sporadic and familial chondrocalcinosis patients. Our findings support the hypothesis that the Chiloes familial chondrocalcinosis was carried to Chile by Spanish immigrants.
Hereditary forms of ankylosing vertebral hyperostosis are apparently rare, because there are only 2 published cases in the literature despite the extreme incidence of this disease. We present the cases of two families in which the mother and at least half of her children of the two sexes had initial lesions or developed ankylosing vertebral hyperostosis, especially ater 50 years of age. No diabetes, obesity, associated skin lesions are present or a relation with HLA B27.
Diffuse idiopathic skeletal hyperostosis (DISH, ankylosing hyperostosis) is a common skeletal disease of unknown aetiology seen in middle-aged and elderly patients. The principal manifestation of DISH is ligamentous calcification and ossification of the anterolateral aspect of the spinal column, sometimes leading to bony ankylosis. DISH also frequently involves the peripheral skeletal system, where entheseal ossification and bony spurs are seen. DISH has been described in various forms for at least 50 years. It is curious that only recently rheumatologists have become widely interested in the condition. This interest has led to the establishment of diagnostic criteria, a description of the primary clinical features and the delineation of the extensive histopathological and roentgenographic abnormalities. In addition, hypotheses concerning the aetiology and pathogenesis can now be offered.
A new microassay method with precision of ±5% was developed to quantitate pyrophosphate in synovial fluid and plasma with starting volumes of 0.5 ml. A highly significant elevation of synovial fluid pyrophosphate concentration was found in some patients with osteoarthritis and gouty arthritis in addition to the well-established elevation in synovial fluid of subjects with pseudogout. No gradient of pyrophosphate between plasma and synovial fluid of patients with rheumatoid arthritis or in normal subjects was detectable. Studies of various parameters reflecting inflammation failed to show a correlation with the concentration of pyrophosphate in patients with pseudogout.
Idiopathic articular Chondrocalcinosis was found in 22 of 108 adults belonging to two generations of one pedigree. An equal number of males and females were affected. In only 14 of the affected persons did acute joint attacks occur; six of these patients have not sought medical help to date. Degenerative arthropathy with conspicuous preservation of joint space, involving the spine and the larger peripheral joints, was encountered in affected members older than 60 years of age. Osteoarthritic joint complaints did not have any relationship to the occurrence of previous acute joint symptoms. Periarticular calcifications, especially of the hip and knee joints, and paravertebral calcifications were predominant features in affected members who had reached senescence. Amorphous deposits only were identified in articular material, except in one synovial fluid sample that contained an unidentified crystalline deposit. In this benign type of articular Chondrocalcinosis, a single autosomal dominant hereditary factor seems to be involved, because the disease occurred only in children of affected members, including sons of affected fathers.
From our series of 72 patients with articular chondrocalcinosis, 37 who presented polyarticular involvement are described. Twenty-eight patients, including 19 aggregated within different family groups, are natives of the Chiloé island group. Members of 1 of the 6 families had unusually severe disease with deformities, and 1 had bony ankylosis of multiple joints. Pathologic findings in both the acute and the chronic stages of the joint disease are presented, particularly, some severe changes that have not been described previously.
The authors conducted a comprehensive radiographic and pathological investigation of more than 1,000 postmortem spinal specimens and documented many examples of calcium pyrophosphate dihydrate crystal deposition disease (CPPD/CDD) in a variety of vertebral structures, including not only the intervertebral disk but also the apophyseal and sacroiliac joints, posterior longitudinal ligament, interspinous and supraspinous ligaments, ligamentum flavum, interosseous sacroiliac ligament, transverse atlas ligament, and posterior median atlanto-axial joint. Such crystal accumulation supports previous reports of abnormal calcification and structural damage on radiographs of the axial skeleton in patients with CPPD/CDD and may explain not only the associated spinal symptoms and signs but also spinal stenosis, spondylolisthesis, and atlanto-axial subluxation.
A clinical and radiographic survey of 110 members of 2 families with hereditary pyrophosphate arthropathy was performed. The mode of inheritance was autosomal, dominant with a variable penetrance. Twenty-two percent of the family members had joint involvement related to pyrophosphate arthropathy, 47% of those over 50 years of age had experienced acute attacks of arthritis and/or had joint calcifications. The majority of individuals with both arthritis and joint calcifications suffered from chronic pain that resulted in early retirement. A high frequency of back pain was observed, but no ankylosis or deformity. Surgery was performed for parathyroid hyperplasia on the propositus in 1 family, and several members of her family suffered from symptoms that suggested a disturbance of calcium phosphate metabolism. There were several differences between our patients and 50 cases of sporadic pyrophosphate arthropathy from the same area of Sweden. Familial cases had an earlier onset, a greater number of involved joints, and peripheral joint involvement more often. Back pain was more frequent, and calcifications of intervertebral discs were found only in the hereditary cases.
A radiological study of the sacroiliac joints was undertaken in 54 patients (32 males, 22 females) with vertebral ankylosing hyperostosis (VAH) and in 46 control patients (24 males, 22 females) matched for age and sex. The ages ranged from 38 to 90 years. The radiographs were taken in anteroposterior, oblique, and craniocaudal projections. The films were read for cranial, ventral, and caudal capsular ossifications, for ventral and caudal osteophytes, and for bone sclerosis. Cranial and/or ventral capsular ossifications were found in 28 (87.5%) males with VAH and in 4 (16.6%) control males (p less than 0.0005), but only in 2 females with VAH and no control female. Sacroiliac capsular ossifications in males with VaH are frequent from the onset, but complete bridging of the joint is not reached before the sixth decade. Women, either VAH or control, have more sacroiliac osteophytes than men. There were 11 out of 22 control women with osteophytes versus 4 out of 24 men (p less than 0.025). The incidence of osteophytes does not seem to increase with age after 50 years. Our findings support the idea of VAH being a distinct entity and not a major form of osteophytosis.
The first-degree consanguineous relatives of 46 patients with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease were examined for the presence of articular chondrocalcinosis. In 5 cases the process was familial, with 17 persons in the oldest living generation (mean age 69 +/- 7.4) showing radiographic evidence of calcified cartilage. The clinical syndrome was characterized by a female predominance, late onset of symptoms with mild arthritic manifestations, and oligoarticular chondrocalcinosis. These data suggest that the familial type of CPPD crystal deposition disease is more frequent than formerly thought.
We describe a 52-year-old man who presented with diffuse idiopathic skeletal hyperostosis, ossification of the posterior longitudinal ligament, and abnormal levels of retinol and retinol binding protein (RBP). The molar retinol/retinol binding protein ratio was high, suggesting congenital functional RBP deficiency. His two sons, aged 23 and 27 years, shared the same biological abnormality without clinical symptoms. To our knowledge, this is the first case report of such a familial association.
We have developed a single DNA typing method which uses 144 sequence-specific primer (SSP) reactions to simultaneously detect all known HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 specificities in an allele specific or group specific manner using the same method, reagents, PCR parameters and protocols for all loci. The results from this integrated class I & II method can be visualized on a single photographic or electronic image and hence is described as "Phototyping". Phototyping has an overall resolution greater than or equivalent to good serology and results can be obtained in under 3 hours making the method suitable for genotyping potential cadaver donor peripheral blood without serological backup. This in turn produces the potential for reducing cold ischaemia times in renal transplantation as well as the application of prospective matching to cardiac and liver transplantation. The method has capacity to detect new alleles, for example, novel amplification patterns suggestive of 4 new HLA-B alleles have been detected. The Phototyping set has been used as the sole method of HLA typing for over 1010 individuals. Phototyping is not problem-free; deviations from the standard protocol, poor quality DNA and unsuitable PCR machines can result in individual PCR failures or in incorrect assignment of antigens. Approximately 5% of genotypes were repeated (either partially or fully) because of incomplete or equivocal results.
Diffuse idiopathic skeletal hyperostosis (DISH) is a common but little-studied disorder in the elderly that is infrequently recognized by physicians. Its prevalence in adults over 40 years of age is estimated at 3.8% for men and 2.6% for women. The present case-control study evaluated the history of pain and stiffness, radicular pain and enthesitis, physical findings on the musculoskeletal examination, and level of physical and psychologic disability in 130 persons: 56 patients with DISH, 43 control patients with spondylosis of the lumbar spine, and 31 healthy control patients. DISH patients were more likely to report a past history of upper extremity pain, medial epicondylitis of the elbow, enthesitis of the patella or heel, or dysphagia than spondylosis patients. They had more extremity and spinal stiffness and pain than healthy controls. DISH patients weighed more at a young age and their body mass index was greater at the time of the clinical evaluation than either spondylosis or healthy control patients. On musculoskeletal examination, DISH patients had a greater reduction in neck rotation and thoracic movements than either spondylosis patients or healthy controls, and had a greater reduction in lumbar movement than healthy controls. DISH patients had similar levels of spinal disability and physical disability overall, as measured by standardized indices, as spondylosis patients. No differences were found among the 3 groups of patients for the laboratory tests evaluated. DISH is clearly a distinct disorder with signs and symptoms that distinguish it from other causes of spinal complaint and from healthy individuals. It has the potential to cause major disability. Future studies need to address the natural history of DISH, pursue pathogenic mechanisms, and evaluate treatment modalities.
There are no published large-scale studies of the overall prevalence of diffuse idiopathic skeletal hyperostosis (DISH) and it has been proposed that the prevalence is greater than previously reported. We thus decided to review chest radiographs in a population of patients over 50 years of age seen at two large but differing metropolitan hospitals in a major American Mid-west city.
The posterior-anterior and lateral chest radiographs of 1363 patients were reviewed for evidence of DISH at the University of Minnesota Hospital and Clinic. There were 500 consecutive inpatient admissions, 540 consecutive patients who attended the outpatient clinics and 326 patients collected from our film archive. A population of 1001 patients seen at Hennepin County Medical Center was also studied. It was possible to subclassify this latter group with respect to race.
Using strict criteria, i.e., four or more levels involved, the overall prevalence of DISH in the male population over age 50 years was 25% and in the female population over age 50 years was 15%. This prevalence climbed to 28% in males over 80 years and to over 35% in males over age 70 years. In females over 80 years, the prevalence was found to be 26%. Although our population base was small, DISH was found to be less common in the black, Native-American and Asian populations. The prevalence of DISH was also found to be far lower in a similar white population with osteoporosis. The overall prevalence of DISH was higher than expected in a predominantly white population over age 50 years with a lesser incidence in the black, Native-American and Asian populations, suggesting a genetic origin of the condition.
We have characterized HLA-B27 alleles in a sample of the population from the Azores (n=46) with the aim of investigating the contribution of different subtypes to ankylosing spondylitis (AS). The study was carried out using PCR-SSOP and in some samples genomic sequencing was conducted. Some significant new finding have arisen from this study. First, B*2705,B*2702,B*2703,B*2707 and B*2708 alleles were found to be represented in this population. The polymorphism of B27 alleles found in a sample of the population from the Azores is higher than the Caucasian groups described. B*2703 and B*2707 have not previously been described to be represented in Caucasians and this could indicate admixtures with different populations of the world. In addition, the B*2708 allele was found to be associated with AS in a large family from the Azores. This association has not been previously reported in either ethnic group and needs to be confirmed in other population studies. This is of considerable interest since has only been described as a rare subtype underrepresented in the British population and has not been previously found to be associated with AS. B*2708 carries the sequence specifying the Bw6 epitope in contrast to most B27 alleles which carry a Bw4 sequence. Differences in this region (residues 77–83) can alter the F-pocket and affect T-cell recognition. The importance that these molecular changes can play in the pathogenesis of AS is discussed.
“Thus far, O Portuguese, it is granted to you to glimpse into the future and to know the exploits that await your stout-hearted compatriots on the ocean that, thanks is now no longer unknown”.
The Lusiads (L. Camoes)
To characterize and define the phenotypes observed in a large Italo-Argentinean kindred with osteoarthritis, chondrocalcinosis, and Milwaukee shoulder (MS).
Seventy-five members were evaluated with a history, examination, and radiographs of shoulders, spine, hands, and knees. Superior subluxation of the glenohumeral joint was graded using shoulder radiographs and tomography and nuclear magnetic resonance imaging and 3 dimensional computed tomography was performed on selected members. In 31 family members peripheral blood DNA was utilized for genetic linkage analysis of several candidate gene loci previously linked to chondrocalcinosis phenotypes, as well as those implicated in the proper patterning of skeletal elements and cartilage differentiation. In addition, direct sequence analysis of type II collagen gene (COL2A1), the gene that codes for the major structural protein of cartilage, was undertaken in 3 affected and 3 unaffected members of the family.
MS was seen in one member of the first generation and 6 members of the 2nd generation, while 8 members of the 3rd generation showed an incomplete form of MS. Isolated superior subluxation of the shoulder was seen in 16 other family members of the 3rd and 4th generations. Osteoarthritis of the spine and peripheral joints was seen in 31 affected members, while chondrocalcinosis was observed in 6 members of the first generation. Shoulder synovial fluid from 2 patients showed the presence of both apatite and calcium pyrophosphate dihydrate crystals. Direct analysis of the COL2A1 gene indicated no known disease determining mutations in affected members, thus excluding this gene as a candidate gene in this family. Genetic linkage to several candidate loci, including the chondrocalcinosis loci on chromosomes 5p and 8q, as well as loci for HOX A and C were also excluded. Linkage analyses of other loci for the HOX B and D genes and the PAX 1 and 9 genes were uninformative in this kindred.
This kindred illustrates an unusual type of osteoarthritis with secondary intraarticular and periarticular calcification and MS in the most severely affected elderly members. A search for linkage to some potential candidate genes was either excluded or uninformative. Further linkage analysis to identify potential candidate genes is in progress.
Diffuse idiopathic skeletal hyperostosis (DISH) is a rheumatic disease characterized by a significant association with metabolic alterations, such as an impaired lipidic profile.
One-hundred-thirty consecutive patients and 40 normal subjects were studied. The patients were affected by type 1 and type 2 diabetes mellitus, impaired glucose tolerance and obesity. The diagnosis of DISH was performed by clinical examination and X-ray study of the thoracolumbar spine. The determination of total cholesterol, triglycerides, HLD-cholesterol and LDL-cholesterol was realized by routine biochemical methods; an oral glucose tolerance test was performed in order to determine the levels of C-peptide and blood glucose.
We demonstrate a high incidence of the disease in a cohort of patients affected by overt and non-overt diabetes mellitus (T1DM and T2DM) as well as in obese subjects and a correlation between this disorder and hypertryglyceridemia (T1DM, obese-T2DM and obese patients), hypo-HDL-cholesterolemia (obese-T2DM, non-obese-T2DM and obese patients) and hyper-LDL-cholesterolemia (obese patients). In obese-T2DM patients, as well as in obese patients, we observed 40% of DISH, in non obese-T2DM patients the presence of DISH was 30%, while in T1DM patients and impaired glucose tolerance 26.6% and 22.2, respectively. However, a correlation between DISH and the relative hyperinsulinemia in obese patients during an oral glucose tolerance test is not documented.
Our study confirms the prevalence of DISH in diabetes mellitus and obesity, the association with an impaired lipidic profile and the low percentage of symptomatic patients.
Inorganic pyrophosphate (PP(i)) regulates certain intracellular functions and extracellular crystal deposition. PP(i) is produced, degraded, and transported by specialized mechanisms. Moreover, dysregulated cellular PP(i) production, degradation, and transport all have been associated with disease, and PP(i) appears to directly mediate specific disease manifestations. In addition, natural and synthetic analogs of PP(i) are in use or currently under evaluation as prophylactic agents or therapies for disease. This review summarizes recent developments in the understanding of how PP(i) is made and disposed of by cells and assesses the body of evidence for potentially significant physiological functions of intracellular PP(i) in higher organisms. Major topics addressed are recent lines of molecular evidence that directly link decreased and increased extracellular PP(i) levels with diseases in which connective tissue matrix calcification is disordered. To illustrate in depth the effects of disordered PP(i) metabolism, this review weighs the roles in matrix calcification of the transmembrane protein ANK, which regulates intracellular to extracellular movement of PP(i), and the PP(i)-generating phosphodiesterase nucleotide pyrophosphatase family isoenzyme plasma cell membrane glycoprotein-1 (PC-1).
In summary, although many factors are likely to be involved in regulating calcification and ossification processes, studies of the causation of articular chondrocalcinosis and disorders of spinal ossification, such as DISH and OPLL, implicate control over inorganic pyrophosphate levels as being one of the most important factors in their aetiopathogenesis. The findings of these studies may prove relevant to other rheumatic diseases in which ectopic ossification occurs, such as AS.
To describe the clinical manifestations and the complications of cervical spine (C-spine) involvement in diffuse idiopathic skeletal hyperostosis (DISH).
Two patients, who presented with dysphagia resulting from large anterior osteophytes of the C-spine, were diagnosed as having DISH. A Medline search from 1964 to present, using the terms "diffuse idiopathic skeletal hyperostosis" and "cervical spine," identified several clinical manifestations associated with DISH.
Two groups of conditions associated with DISH were found. 1. Spontaneous complications such as: dysphagia, being the commonest, dyspnea, stridor, myelopathy associated with ossification of the posterior longitudinal ligament (OPLL) or with atlanto-axial pseudoarthrosis or subluxation. Other rare events were aspiration pneumonia, sleep apnea and thoracic outlet syndrome. 2. Provoked complications such as endoscopic and intubation difficulties and fractures of the C-spine with frequent transverse shift of the fractured segment and resultant myelopathy.
C-spine involvement in DISH is a recognized cause of various clinical manifestations involving the pharynx, larynx and the esophagus. Prior knowledge of the existence of cervical DISH should alert the clinicians for possible complications, at times severe, during invasive procedures in the neck region and as a consequence of trauma.
Limitations in neonatal natural killer (NK) cell responses may be associated with the less efficient newborn capacity to solve viral infections. Although these limitations have been extensively reported they are poorly characterized. Making use of the major histocompatibility complex (MHC) class I negative cell line K562, the parameters required for the initial events involved in neonatal NK/target cell interactions were determined and compared with adult blood NK cell/target cell interactions. Ultrastructural characterization of effector-target cell interactions revealed that neonatal NK cells are more strongly activated upon contact with K562 cells than adult blood NK cells. Furthermore, the neonatal capacity to establish contacts, in particular extensive contacts, is significantly reduced when compared with adult blood NK cells. However, no significant differences were found either in the cell surface expression levels or activation state of LFA-1, which could account for the reduced intercellular contacts. Because extensive contacts are crucial for effective immunologic synapse formation, these data suggest that a limited or nonsustained positive signaling may occur on neonatal NK cells, restricting their NK cell-mediated lysis capacity.