Validation of DNA test for hip dysplasia failed in Danish Labrador Retrievers

Canine hip dysplasia is characterized by poor hip joint conformation and laxity. The disease is a complex trait influenced by both genetics and environment. Diagnosis and quantification of hip dysplasia are performed by radiographic examination of the hip joint and the diagnosis is used for making breeding decisions in many breeds. A prognostic genetic test (the Dysgen test) based on seven associated SNPs has been developed in a study based on Spanish Labrador Retrievers. In our study this test has been evaluated in 39 Danish Labrador Retrievers with known radiographic hip score: 14 with hip dysplasia (grade D or E) and 25 without hip dysplasia (grade A or B). There was no significant correlation between the Dysgen test results and the radiographic hip status (P = 0.3203) in these dogs, indicating that Dysgen test results obtained for Danish Labrador Retrievers have no prognostic value.     

Venous Drainage of the Femoral Neck in Legg Perthes Disease and in Hip Dysplasia

Three clinical cases of canine avascular femoral head necrosis and 4 cases of hip dysplasia were examined using intraosseus femoral neck venography. The contrast medium passed initio the diaphyseal bone marrow in all cases. Three growing dogs and 7 growing pigs were examined with the same method, before and after experimental ligation of the femoral veins. Before the venous tamponade, no contrast medium was visible in the femoral neck. The venography performed immediately after ligation showed contrast flow into the femoral neck similar to that seen in the clinical cases of Legg Perthes disease or hip dysplasia. However, a collateral circulation developed within 7 weeks. No more contrast-flow into the diaphysis was observed after that time. Although osteomedullography shows that both in Perthes disease and in hip dysplasia venous drainage has failed, venous tamponade may not induce the onset of the disease.     

Hip biomechanics in orthopaedic clinical practice

Radiographic and clinical studies, coupled with biomechanical assessment of the hip, are important tools for predicting the development of osteoarthitis of the hip. In order to better understand the treatment of hip dysplasia, it is necessary to determine the contact stress in the hip joint. In this study, a three-dimensional mathematical model was used to determine hip joint contact stress. Because of the discrepancy in the results of analyses of different radiographic indicators of hip dysplasia, the calculation of hip joint contact stress is proposed for a more accurate assessment of the severity of hip dysplasia.     

Inclination and Anteversion of Collum Femoris in Hip Dysplasia and Coxarthritis

Femoral neck angles were measured radiographically in 41 dogs examined for hip dysplasia. Steep femoral neck inclination was found to be a phenomenon of hip dysplasia and coxofemoral joint laxity. The altered biomechanics of a steep femoral neck inclination may be a factor in the pathogenesis of hip dysplasia and secondary osteoarthritis.     

Association of a single nucleotide polymorphism in growth differentiate factor 5 with congenital dysplasia of the hip: a case-control study

Introduction

Congenital dysplasia of the hip is an abnormal seating of the femoral head in the acetabulum, mainly caused by shallow acetabulum and lax joint capsule. Genetic factors play a considerable role in the pathogenesis of congenital dysplasia of the hip. The gene growth differentiate factor 5 (GDF5) has been implicated in skeletal development and joint morphogenesis in humans and mice. A functional single nucleotide polymorphism (SNP) in the 5'-untranslated region of GDF5 (rs143383) was reported to be associated with osteoarthritis susceptibility. As a key regulator in morphogenesis of skeletal components and soft tissues in and around the joints, GDF5 may be involved in the aetiology and pathogenesis of congenital dysplasia of the hip. Our objective is to evaluate if the GDF5 SNP is associated with congenital dysplasia of the hip in people of Han Chinese origin.

Methods

The GDF5 SNP was genotyped in 338 children with congenital dysplasia of the hip and 622 control subjects.

Results

The SNP was significantly associated with congenital dysplasia of the hip (p = 0.0037; odds ration (OR) = 1.40; 95% confidence interval (CI) = 1.11 to 1.75). A significant difference was detected in female samples when stratified by gender (p = 0.0053; OR = 1.46; 95% CI = 1.21 to 1.91), and in hip dislocation when stratified by severity (p = 0.0078; OR = 1.43; 95% CI = 1.11 to 1.85).

Conclusions

Our results indicate that GDF5 is important in the aetiology of congenital dysplasia of the hip. To the authors' knowledge this is the first time that a definite association with the congenital dysplasia of the hip susceptibility has been detected.

     

Genetic evaluation of hip score in UK Labrador Retrievers

Hip dysplasia is an important and complex genetic disease in dogs with both genetic and environmental influences. Since the osteoarthritis that develops is irreversible the only way to improve welfare, through reducing the prevalence, is through genetic selection. This study aimed to evaluate the progress of selection against hip dysplasia, to quantify potential improvements in the response to selection via use of genetic information and increases in selection intensity, and to prepare for public provision of estimated breeding values (EBV) for hip dysplasia in the UK. Data consisted of 25,243 single records of hip scores of Labrador Retrievers between one and four years old, from radiographs evaluated between 2000 and 2007 as part of the British Veterinary Association (BVA) hip score scheme. A natural logarithm transformation was applied to improve normality and linear mixed models were evaluated using ASREML. Genetic correlations between left and right scores, and total hip scores at one, two and three years of age were found to be close to one, endorsing analysis of total hip score in dogs aged one to three as an appropriate approach. A heritability of 0.35±0.016 and small but significant litter effect (0.07±0.009) were estimated. The observed trends in both mean hip score and mean EBV over year of birth indicate that a small genetic improvement has been taking place, approximately equivalent to avoiding those dogs with the worst 15% of scores. Deterministic analysis supported by simulations showed that a 19% greater response could be achieved using EBV compared to phenotype through increases in accuracy alone. This study establishes that consistent but slow genetic improvement in the hip score of UK Labrador Retrievers has been achieved over the previous decade, and demonstrates that progress may be easily enhanced through the use of EBVs and more intense selection.     

Early x-ray diagnosis of hip dysplasia in children]

The author proposes a method of differential diagnosis of hip dislocations and hip joint dysplasia in infants aged 3 months. The alpha-angle of hip dislocation with relation to trochanteric space is determined on an anteroposterior radiogram of the hip joints; 64 degrees means hip dysplasia, 65-69 degrees and more mean dislocation. This method was tested in 75 children (150 joints) aged 3 months. A mean diagnostic accuracy was 90.1%.     

Combined Surgical Approach to Young Adults with Hip Dysplasia and Concomitant Intra-Articular Pathology Using Intra-Abdominal Monitoring

BackgroundCombined hip arthroscopy and periacetabular osteotomy (PAO) allows for treatment of intra-articular hip pathology with simultaneous correction of acetabular version and femoral head coverage in patients with symptomatic hip dysplasia. Currently, scant data is available to surgeons regarding optimal technique, sequence of repair, perioperative management, and the use of intra-abdominal monitoring in patients undergoing these combined procedures. The purpose of this study is to describe a two-surgeon, muscle-sparing, approach for sequential hip arthroscopy and PAO for the treatment of adults with acetabular dysplasia and concomitant intra-articular hip pathology.MethodsIn this article, we present the indications for combined hip arthroscopy and PAO, in addition to patient set-up and positioning. A detailed discussion of hip arthroscopy and a muscle sparing PAO techniques are then presented, with overview of a novel intra-abdominal pressure monitoring technique and post-operative rehabilitation protocol.ResultsThrough technical refinement and experience, our indications and protocol for the treatment of patients with symptomatic acetabular dysplasia with concomitant intra-articular hip pathology involves a refined and reproducible, two surgeon procedure utilizing hip arthroscopy followed by PAO. The use of intra-abdominal monitoring allows for assessment of intra-peritoneal pressures to monitor for the development of abdominal compartment syndrome secondary to fluid extravasation.ConclusionThe performance of concomitant hip arthroscopy and PAO for concurrent hip dysplasia and intra-articular hip pathology represents an increasingly common approach in hip preservation surgery. The hip arthroscopy and muscle-sparing PAO protocol using intra-abdominal monitoring described here serves to further refine and advance the indications and technical aspects of this challenging procedure.Level of Evidence: V     

A Genetic Predictive Model for Canine Hip Dysplasia: Integration of Genome Wide Association Study (GWAS) and Candidate Gene Approaches

Canine hip dysplasia is one of the most prevalent developmental orthopedic diseases in dogs worldwide. Unfortunately, the success of eradication programs against this disease based on radiographic diagnosis is low. Adding the use of diagnostic genetic tools to the current phenotype-based approach might be beneficial. The aim of this study was to develop a genetic prognostic test for early diagnosis of hip dysplasia in Labrador Retrievers. To develop our DNA test, 775 Labrador Retrievers were recruited. For each dog, a blood sample and a ventrodorsal hip radiograph were taken. Dogs were divided into two groups according to their FCI hip score: control (A/B) and case (D/E). C dogs were not included in the sample. Genetic characterization combining a GWAS and a candidate gene strategy using SNPs allowed a case-control population association study. A mathematical model which included 7 SNPs was developed using logistic regression. The model showed a good accuracy (Area under the ROC curve = 0.85) and was validated in an independent population of 114 dogs. This prognostic genetic test represents a useful tool for choosing the most appropriate therapeutic approach once genetic predisposition to hip dysplasia is known. Therefore, it allows a more individualized management of the disease. It is also applicable during genetic selection processes, since breeders can benefit from the information given by this test as soon as a blood sample can be collected, and act accordingly. In the authors’ opinion, a shift towards genomic screening might importantly contribute to reducing canine hip dysplasia in the future. In conclusion, based on genetic and radiographic information from Labrador Retrievers with hip dysplasia, we developed an accurate predictive genetic test for early diagnosis of hip dysplasia in Labrador Retrievers. However, further research is warranted in order to evaluate the validity of this genetic test in other dog breeds.     

Higher medially-directed joint reaction forces are a characteristic of dysplastic hips: A comparative study using subject-specific musculoskeletal models

Acetabular dysplasia is a known cause of hip osteoarthritis. In addition to abnormal anatomy, changes in kinematics, joint reaction forces (JRFs), and muscle forces could cause tissue damage to the cartilage and labrum, and may contribute to pain and fatigue. The objective of this study was to compare lower extremity joint angles, moments, hip JRFs and muscle forces during gait between patients with symptomatic acetabular dysplasia and healthy controls. Marker trajectories and ground reaction forces were measured in 10 dysplasia patients and 10 typically developing control subjects. A musculoskeletal model was scaled in OpenSim to each subject and subject-specific hip joint centers were determined using reconstructions from CT images. Joint kinematics and moments were calculated using inverse kinematics and inverse dynamics, respectively. Muscle forces and hip JRFs were estimated with static optimization. Inter-group differences were tested for statistical significance (p ≤ 0.05) and large effect sizes (d ≥ 0.8). Results demonstrated that dysplasia patients had higher medially directed JRFs. Joint angles and moments were mostly similar between the groups, but large inter-group effect sizes suggested some restriction in range of motion by patients at the hip and ankle. Higher medially-directed JRFs and inter-group differences in hip muscle forces likely stem from lateralization of the hip joint center in dysplastic patients. Joint force differences, combined with reductions in range of motion at the hip and ankle may also indicate compensatory strategies by patients with dysplasia to maintain joint stability.     

Are Consanguineous Marriage and Swaddling the Risk Factors of Developmental Dysplasia of the Hip?

The purpose of this study was to investigate prospectively the effects of swaddling and consanguineous marriage on developmental dysplasia of the hip and associated risk factors. We screened by ultrasound 265 infants using the Graf method. The Pediatrics Department referred all newborn infants with suspected instability or a recognized risk factor to the orthopedic clinic. Risk factors of developmental dysplasia of the hip were searched and noted in these patients. Swaddling and consanguineous marriage were also determined and noted. We observed 164 of 265 infants (61.9 %) who had been swaddled and that 64 of 265 infants’ parents were in a consanguineous marriage (24.2 %). In the statistical analysis that was conducted for swaddling and consanguineous marriage, highly significant differences were found. Our study showed that the rate of developmental dysplasia of the hip is very high, 11.7 %, in our region, eastern Turkey. Also, we commonly see improper swaddling and consanguineous marriage in our region, which affects many infants.     

Pavlik吊带治疗早期发育性髋关节脱位的研究进展

发育性髋关节脱位(Developmental dysplasia of the hip,DDH)是指一系列髋关节结构异常的疾病,病变严重程度涵盖轻度髋臼发育不良到不可逆的髋关节脱位。DDH的治疗手段进展迅速,但早期闭合复位使用最多的仍是Pavlik吊带。通过超声可监测髋关节复位情况从而评估Pavlik吊带的治疗效果。同时,随着超生髋关节检查技术在我国的推广,使得早期诊断DDH成为可能,这也促进了Pavlik吊带在临床的应用。未来研究的方向在于制定基于询证医学证据的Pavlik吊带使用规范和开发出效果更好、并发症更少的新型支具。     

Genome Wide Analysis Indicates Genes for Basement Membrane and Cartilage Matrix Proteins as Candidates for Hip Dysplasia in Labrador Retrievers

Hip dysplasia, an abnormal laxity of the hip joint, is seen in humans as well as dogs and is one of the most common skeletal disorders in dogs. Canine hip dysplasia is considered multifactorial and polygenic, and a variety of chromosomal regions have been associated with the disorder. We performed a genome-wide association study in Dutch Labrador Retrievers, comparing data of nearly 18,000 single nucleotide polymorphisms (SNPs) in 48 cases and 30 controls using two different statistical methods. An individual SNP analysis based on comparison of allele frequencies with a χ² statistic was used, as well as a simultaneous SNP analysis based on Bayesian variable selection. Significant association with canine hip dysplasia was observed on chromosome 8, as well as suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Next-generation DNA sequencing of the exons of genes of seven regions identified multiple associated alleles on chromosome 1, 5, 8, 20, 25 and 32 (p<0.001). Candidate genes located in the associated regions on chromosomes 1, 8 and 25 included LAMA2, LRR1 and COL6A3, respectively. The associated region on CFA20 contained candidate genes GDF15, COMP and CILP2. In conclusion, our study identified candidate genes that might affect susceptibility to canine hip dysplasia. These genes are involved in hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. The functions of the genes are in agreement with the notion that disruptions in endochondral bone formation in combination with soft tissue defects are involved in the etiology of hip dysplasia.     

Quantitative trait loci mapping for canine hip dysplasia and its related traits in UK Labrador Retrievers

Background

Canine hip dysplasia (CHD) is characterised by a malformation of the hip joint, leading to osteoarthritis and lameness. Current breeding schemes against CHD have resulted in measurable but moderate responses. The application of marker-assisted selection, incorporating specific markers associated with the disease, or genomic selection, incorporating genome-wide markers, has the potential to dramatically improve results of breeding schemes. Our aims were to identify regions associated with hip dysplasia or its related traits using genome and chromosome-wide analysis, study the linkage disequilibrium (LD) in these regions and provide plausible gene candidates. This study is focused on the UK Labrador Retriever population, which has a high prevalence of the disease and participates in a recording program led by the British Veterinary Association (BVA) and The Kennel Club (KC).

Results

Two genome-wide and several chromosome-wide QTLs affecting CHD and its related traits were identified, indicating regions related to hip dysplasia.

Conclusion

Consistent with previous studies, the genetic architecture of CHD appears to be based on many genes with small or moderate effect, suggesting that genomic selection rather than marker-assisted selection may be an appropriate strategy for reducing this disease.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-833) contains supplementary material, which is available to authorized users.     

Brief communication: developmental dysplasia of the hip in medieval London

Developmental dysplasia of the hip (DDH) is a spectrum of disease starting in childhood and in many cases persisting into adulthood. The spectrum ranges from acetabular dysplasia, through hip subluxation to dislocation. The aim of this research was to determine the prevalence and pathoanatomy of acetabular dysplasia and subluxation in excavated human skeletal remains, to complement past research on dislocation in DDH. The material under study was the medieval cemetery of St. Mary Spital in London, in use from c.1100 to 1539 AD. A series of 572 adults with both hips preserved were analyzed. Acetabular dysplasia was indicated by a shallow acetabulum with upward sloping roof. Subluxation was suggested by degenerative change along the margin of the acetabulum suggestive of labral tears, and degenerative change in the outer part of the acetabular roof suggestive of osteoarthritis. The prevalence of DDH (acetabular dysplasia, subluxation, or dislocation) was 1.7%. Because this a congenital musculoskeletal disorder of relatively high frequency, with significant variation in prevalence between populations around the world, it is a topic that warrants targeted research from physical anthropologists studying past populations.     

Single nucleotide polymorphisms refine QTL intervals for hip joint laxity in dogs

Hip laxity is one characteristic of canine hip dysplasia (CHD), an inheritable disease that leads to hip osteoarthritis. Using a genome-wide screen with 250 microsatellites in a crossbreed pedigree of 159 dysplastic Labrador retrievers and unaffected greyhounds, we previously identified putative ( P  <   0.01) QTL on canine chromosomes 11 and 29 (CFA11 and CFA29). To refine these QTL locations, we have genotyped 257 dogs including 105 Labrador retrievers, seven greyhounds, four generations of their crossbreed offspring and three German shepherds for 111 and 171 SNPs on CFA11 and CFA29 respectively. The distraction index (DI, a measure of maximum hip laxity) was used as an intermediate phenotype that predicts whether a hip joint will or will not develop osteoarthritis. Using a multipoint linkage analysis, significant evidence (95% posterior probability) was found for QTL contributing to hip laxity in the 16.2–21 cM region on CFA11 that explained 15–18% of the total variance in DI. Evidence for an independent QTL on CFA29 was weaker than that on CFA11. Identification of the causative mutation(s) will lead to better understanding of biochemical pathways in both dogs and humans with hip laxity and dysplasia.     

An indication of major genes affecting hip and elbow dysplasia in four Finnish dog populations

The aim of the study was to assess the possible existence of major genes influencing hip and elbow dysplasia in four dog populations. A Bayesian segregation analysis was performed separately on each population. In total, 34 140 dogs were included in the data set. Data were analysed with both a polygenic and a mixed inheritance model. Polygenic models included fixed and random environmental effects and additive genetic effects. To apply mixed inheritance models, the effect of a major gene was added to the polygenic models. The major gene was modelled as an autosomal biallelic locus with Mendelian transmission probabilities. Gibbs sampling and a Monte Carlo Markov Chain algorithm were used. The goodness-of-fit of the different models were compared using the residual sum-of-squares. The existence of a major gene was considered likely for hip dysplasia in all the breeds and for elbow dysplasia in one breed. Several procedures were followed to exclude the possible false detection of major genes based on non-normality of data: permuted datasets were analysed, data-transformations were applied, and residuals were judged for normality. Allelic effects at the major gene locus showed nearly to complete dominance, with a recessive, unfavourable allele in both traits. Relatively high estimates of the frequencies of unfavourable alleles in each breed suggest that considerable genetic progress would be possible by selection against major genes. However, the major genes that are possibly affecting hip and elbow dysplasia in these populations will require further study.     

Whole genome sequencing of pairwise human subjects reveals DNA mutations specific to developmental dysplasia of the hip

Developmental dysplasia of the hip (DDH) is a common congenital malformation characterized by mismatch in shape between the femoral head and acetabulum, and leads to hip dysplasia. To date, the pathogenesis of DDH is poorly understood and may involve multiple factors, including genetic predisposition. However, comprehensive genetic analysis has not been applied to investigate a genetic component of DDH. In the present study, 10 pairs of healthy fathers and DDH daughters were enrolled to identify genetic hallmarks of DDH using high throughput whole genome sequencing. The DDH-specific DNA mutations were found in each patient. Overall 1344 genes contained DDH-specific mutations. Functional enrichment analysis showed that these genes played important roles in the cytoskeleton, microtubule cytoskeleton, sarcoplasm and microtubule associated complex. These functions affected osteoblast and osteoclast development. Therefore, we proposed that the DDH-specific mutations might affect bone development, and caused DDH. Our pairwise high throughput sequencing results comprehensively delineated genetic hallmarks of DDH. Further research into the biological impact of these mutations may inform the development of DDH diagnostic tools and allow neonatal gene screening.     

股骨头缺血坏死相关影像学误诊分析

目的:分析与股骨头缺血坏死相关临床与影像资料,以期提高影像科医生对该病的认识水平,提高股骨头缺血坏死的诊断正确率,防止与其相关的髋关节疾病的误诊。方法:回顾性分析26例误诊为股骨头缺血坏死的髋关节疾患,归纳分类疾病的种类,找出原因。结果:类风湿性髋关节炎、强直性脊柱炎髋关节炎和痛风性髋关节炎、先天性髋臼发育不良、股骨颈干角发育异常、髋关节骨关节病等疾病易与股骨头缺血坏死相混淆,引起误诊。结论:病史采集不详细、思路狭窄,对类风湿、强直性脊柱炎及痛风性关节炎所致髋关节病变认识不足或不了解、股骨头缺血坏死病理过程不清楚、临床误导等因素与股骨头缺血坏死的误诊有关。     

Secondary hip dysplasia increases risk for early coxarthritis after Legg-Calve-Perthes disease. A study of 255 hips

Abstract

The biomechanical parameters of the hip joint articular surface were analysed in 141 adult hips after Legg-Calve Perthes Disease, and 114 contralateral unaffected hips (controls), by using HIPSTRESS mathematical models. Geometrical parameters, assessed from anteroposterior and axial radiograms, were used as input to models for resultant hip force and contact hip stress. Results confirm previous indications that head enlargement after the Legg-Calve-Perthes Disease compensates the values of hip stress. Furthermore, it was found that an increased risk for coxarthritis development after the disease is secondary to concomitant hip dysplasia, with considerable and statistically significantly lower centre-edge angle and unfavourable distribution of stress.