Clinical significance of polymorphisms of genes encoding collagen (COL1A1, COL5A1) and their correlation with joint laxity and recurrent patellar dislocation in adolescents.

The aim of this study was to assess the coexistence of polymorphisms of the COL1A1 and COL5A1 genes with clinically diagnosed laxity and the occurrence of recurrent patellar dislocation in adolescents. The research group comprised 50 cases of recurrent patellar dislocation. The mean age at diagnosis was 14.2 years (10-17, SD 2.6). The control group consisted of 199 participants without a diagnosis of recurrent patellar dislocation, with a mean age of 15.2 (10-17 years, SD 2.7). Joint laxity by the Beighton scale was assessed. Analysis of the allele distribution of the analysed genes COL1A1 and COL5A1 revealed no statistically significant difference between the study group and the control group (p = 0.859 and p = 0.205, respectively). Analysis of the Beighton score showed a statistically significantly higher result in the study group than in the control group (p < 0.001). No correlation between the presence of polymorphisms and joint laxity diagnosis was confirmed. In conclusion, COL1A1 and COL5A1 gene polymorphisms are not significantly more common in adolescents with recurrent patellar dislocation than in healthy peers; there is also no correlation between joint laxity and polymorphisms of the COL1A1 and COL5A1 genes.Registered on ClinicalTrials.gov with ID: PMMHRI-2021.2/1/7-GW.

Familial association and epidemilogical factors as risk factors for developing first time and recurrent patella dislocation: a systematic review and best knowledge synthesis of present literature.

PURPOSE: The aim of our study was to perform a systematic review and best knowledge synthesis of the present literature concerning the familial association and epidemiological factors as risk factors for developing first-time and recurrent patella dislocation. METHODS: The study was conducted according to the PRISMA guidelines and registered in PROSPERO. EMBASE and PubMed were systematically searched on the 5th of May 2022. Studies investigating participants with genetic and epidemiological risk factors for the first time as well as recurrent patella dislocation were included. The records were screened, and data were extracted independently by two researchers supervised by a third independent assessor. RESULTS: A total of 6,649 records were screened, and 67 studies were included. Familial association was described as a risk factor for patella dislocation in 17 studies. One study found that participants with a family history of patella dislocation had a 3.7 higher risk for patella dislocation in the contralateral asymptomatic knee, and another study found a family history of PD in 9% of 74 participants. Eleven studies found an accumulation of patella dislocation across generations in specific families. Additionally, a range of genetic syndromes was associated with patella dislocation. Young age is a well-investigated risk factor for patella dislocation, but the results are inconsistent. Only five and eight studies investigated skeletal immaturity and gender as risk factors for patella dislocation, respectively. CONCLUSION: There may be a familial association with patella dislocation, but further investigation is necessary to determine the strength and etiology of the association. There is weak evidence that epidemiological risk factors, such as age, skeletal immaturity, gender, and BMI are risk factors for patella dislocation. LEVEL OF EVIDENCE: IV.

Anatomical characteristics and potential gene mutation sites of a familial recurrent patellar dislocation.

BACKGROUND: Recurrent patellar dislocation is the result of anatomical alignment and imbalance of restraint of bone and soft tissue. We investigate the anatomical characteristics of the knee joint in a family of patients with recurrent patella dislocation, and to screen the possible pathogenic genes in this family by whole exome sequencing in 4 patients and 4 healthy subjects, so as to provide theoretical basis for the pathogenesis of this disease. METHODS: The data related to patella dislocation were measured by imaging data. The peripheral blood DNA of related family members was extracted for the whole exome sequencing, and then the sequencing results were compared with the human database. By filtering out synonymous variants and high-frequency variants in population databases, and then integrating single nucleotide non-synonymous variants of family members, disease-causing genes were found. RESULTS: All patients in this family have different degrees of abnormal knee anatomy, which is closely related to patella dislocation. The sequencing results of patients and normal persons in this patella dislocation family were compared and analyzed, and the data were filtered through multiple biological databases. Find HOXB9 (NM_024017.4:c.404A>G:p.Glu135Gly),COL1A1(NM_000088.3:c.3766G>A:p.Ala1256Thr),GNPAT(NM_014236.3:c1556A>G:p.Asp519Gly),NANS(NM_018946.3:c.204G>C:p.Glu68Asp),SLC26A2(NM_000112.3:c.2065A>T:p.Thr689Ser) are nonsynonymous variants (MISSENSE). Through Sanger sequencing, the identified mutations in HOXB9 and SLC26A2 genes were only present in samples from patients with recurrent patellar dislocation. CONCLUSIONS: The patients with recurrent patellar dislocation had markedly abnormal knee anatomy in this family. HOXB9 gene and SLC26A2 gene were found to be the possible pathogenic genes or related genes for patella dislocation.

Evidence of genetic contribution to patellar luxation in Toy Poodle puppies.

Patellar luxation (PL) is one of the most common orthopedic disorders in dogs and a genetic factor is considered to play an important role in the development of PL. Genomic analysis has attempted to identify the genetic markers associated with the development of PL but only suggestive markers have been identified. Carefully selecting breeds with higher incidence rates of congenital PL as well as affected dogs with more severe symptoms are required, but such information remains limited to date. This study aimed to assess the genetic contribution to the development of PL in puppies. Using data on PL from 2,048 puppies of the nine common breeds in Japan, the association of PL grades between the limbs, breed, and sex as well as the concordance of PL between littermates were examined. A significant correlation was found between right and left limbs in PL grades in all the puppies (Spearman rank correlation coefficient (rs)=0.91, P<0.001) and for each breed (rs=0.81-0.93, P<0.001). In total, 20.3% of the puppies were affected. The inter-breed difference in PL prevalence was 2.1-38.1%, and Toy Poodles showed the highest prevalence rates. Littermates of the affected puppies with PL grade ≥2 had a 16.2-fold higher risk (P<0.001). Thus, these results suggest that PL in puppies is primarily influenced by genetics, especially in Toy Poodles. These data highlight the necessity of using a breeding scheme to decrease the prevalence of PL.

Familial patellar dislocation associated with t(15;20) (q24;q13.1).

Patellar instability is a common debilitating injury affecting young active individuals. It accounts for approximately 3% of all knee injuries. We report a family, of which five members across three generations, who suffered from autosomal dominant familial recurrent patellar dislocation as well as short stature. All of them have recurrent patellar dislocations before the age of 15. The affected patients in all three generations have been genetically screened. Genotypical evaluation revealed a balanced translocation of chromosomes 15 and 20.

Heritability of patellar luxation in the Chihuahua and Bichon Frise breeds of dogs and effectiveness of a Swedish screening programme.

Patellar luxation is one of the more common orthopaedic diseases of dogs and is relatively frequent in some toy breeds, including the Chihuahua and Bichon Frise. Using data provided by the Swedish Kennel Club, genetic parameters, including heritability, were estimated for patellar luxation in the Chihuahua from 1999 to 2014 and in the Bichon Frise from 1997 to 2014. The effects of the current screening programmes for patellar luxation in these breeds were evaluated. Patellar luxation was defined as a binary trait, treating dogs as affected or unaffected. The edited data included 7024 records for the Chihuahua and 1071 records for the Bichon Frise. Patellar luxation was analysed using mixed linear and threshold animal models, including fixed effects of sex, birth month, birth year, age at veterinary examination, random effects of the examining veterinary surgeon, genetic effect of the individual and residual. The prevalence of patellar luxation was 23% in the Chihuahua and 12% in the Bichon Frise. Using threshold analysis, estimated heritabilities were 0.25 for the Chihuahua and 0.21 for the Bichon Frise on the observable scale, and 0.46 for the Chihuahua on the underlying scale. It was concluded that there is genetic variation in patellar luxation and that there has been a slight genetic improvement over the study period in the Chihuahua. Further genetic progress would be facilitated by selection using estimated breeding values based on veterinary screening records.

Inclusion of joint laxity, recurrent patellar dislocation, and short distal ulnae as a feature of Van Den Ende-Gupta syndrome: a case report.

BACKGROUND: Van Den Ende-Gupta Syndrome (VDEGS) is an extremely rare autosomal recessive syndrome with less than 20 reported families (approximately 40 patients) in the worldwide literature. CASE PRESENTATION: We have assessed one consanguineous Saudi family with typical features of VDEGS. Two siblings were affected with almost identical features; including blepharophimosis, arachnodactyly, flexion contractures of the elbows, camptodactyly, slender ribs, hooked lateral clavicular ends, and bilateral radial head dislocations. Both patients had several unusual features; including joint laxity, flat feet, recurrent patellar dislocations, and bilateral short distal ulnae. Full sequencing of SCARF2 revealed a homozygous mutation c.773G > A (p. Cys258Tyr) in both affected children. The parents (both with no abnormalities) were heterozygous for the same mutation. CONCLUSION: Joint laxity, recurrent patellar dislocations, and short distal ulnae should be included as part of the clinical spectrum of VDEGS.

Population genetic analysis and genome-wide association study of patellar luxation in a Thai population of Pomeranian dogs.

The genetics of patellar luxation (PL) were investigated in Pomeranian dogs presented at the Small Animal Hospital, Faculty of Veterinary Science, Chulalongkorn University. A cohort of 339 Pomeranian dogs, part of a four-generation pedigree of 842 Pomeranians, was screened for PL from 2006 to 2013. PL was present in 77% of the screened dogs, with 84% having bilateral and 16% unilateral luxation. Medial PL was more common (95%) than lateral PL (2%) or bidirectional PL (3%). The risk of PL was similar in male and female dogs (female:male relative risk 1.11, 95% CI 0.98-1.25). The heritability of PL in the screened population was 0.44±0.04 using a threshold model. A genome-wide association study of PL (48 cases and 48 controls) using a high-density SNP array indicated the possible involvement of 15 chromosomal regions, of which CFA05 and CFA32 remained associated in a larger study involving an additional 128 cases and 7 controls. Candidate genes in these regions may be involved in the pathogenesis of PL in Pomeranian dogs.

Breeding implications resulting from classification of patellae luxation in dogs.

Patellar luxation (PL) is one of the major hereditary orthopaedic abnormalities observed in a variety of dog breeds. When the patellae move sideways out of the trochlear groove, this is called PL. The PL score varies between dogs from normal to very severe. Reducing the prevalence of PL by breeding could prevent surgery, thereby improve welfare. Orthopaedic specialists differentiate between normal and loose patellae, where the patellae can be moved to the edge of the trochlear groove, considering scoring loose patellae as normal in the future. Loose patellae are considered acceptable for breeding so far by the breeding organization. The aim of this study was to analyse the genetic background of PL to decide on the importance of loose patellae when breeding for healthy dogs. Data are available from two dog breeds, that is Flat-coated Retrievers (n = 3808) and Kooiker dogs (n = 794), with a total of 4602 dogs. Results show that loose patellae indicate that dogs are genetically more susceptible to develop PL because family members of the dogs with loose patellae showed more severe PL. In addition, the estimated breeding values for dogs with loose patellae indicate that breeding values of dogs with loose patellae were worse than breeding values obtained for dogs with a normal score. Given these results, it is advised to orthopaedic specialists to continue to score loose patellae as a separate class and to dog breeders to minimize the use of dogs in breeding with a genetically higher susceptibility for PL.

[Patellofemoral instability in trisomy 21: MPFL-Reconstruction as a single procedure]. / Patellainstabilität bei Patienten mit Trisomie 21: Alleinige MPFL-Rekonstruktion als neue Indikation.

BACKGROUND: Patellar instability is a common orthopaedic condition which is often seen in younger individuals. Biomechanical studies have shown that the medial patellofemoral ligament (MPFL) is the most important soft tissue that restrains lateral subluxation of the patella in the beginning of flexion of the knee joint. METHODS: MPFL reconstruction is an effective procedure to treat recurrent patellar dislocation. Double-bundle and single-bundle procedures have been described. If double-bundle reconstruction is not possible, there are good postoperative outcomes with single-bundle procedure as well. DISCUSSION: This is the first report of MPFL reconstruction as a single procedure to treat patellar instability in patients with down syndrome.

Prevalence and genetics of patellar luxation in Kooiker dogs.

The prevalence of patellar luxation (PL) and genetic factors potentially involved in the disorder were investigated in Dutch Kooiker dogs. A cohort of 842 Kooiker dogs, the offspring of 195 sires and 318 dams, was screened for PL from 1994 to 2011. The cohort was included in a pedigree of 1737 Kooiker dogs comprising nine generations. PL was present in 24% of screened dogs, with unilateral and bilateral luxation being observed equally frequently. Medial PL was more common (61%) than lateral PL (32%) or bidirectional PL (7%). The frequency of PL was similar in male and female dogs, with a female:male relative risk of 1.15 (95% confidence interval, CI, 0.90-1.48). The heritability of PL in the screened population was 0.27 ± 0.07. Since the start of the screening programme, the prevalence of PL decreased from 28% to 19%. A genome-wide association study of PL with 48 cases and 42 controls suggested the possible involvement of a region on chromosome 3 (Praw = 1.32 × 10(-)(5), Pgenome = 0.142), but the involvement of this region could not be confirmed in a validation group. Breeding programmes for complex diseases, such as PL, would benefit from combining pedigrees, phenotypes and genotypes, i.e. from genomic selection, as is currently the method of choice for breeding of production animals.

Genome-wide survey indicates involvement of loci on canine chromosomes 7 and 31 in patellar luxation in Flat-Coated Retrievers.

BACKGROUND: Patellar luxation is an orthopedic disorder in which the patella moves out of its normal location within the femoral trochlea of the knee and it can lead to osteoarthritis, lameness, and pain. In dogs it is a heritable trait, with both environmental and genetic factors contributing to the phenotype. The prevalence of patellar luxation in the Dutch Flat-Coated Retriever population is 24%. In this study, we investigated the molecular genetics of the disorder in this population. RESULTS: Genome-wide association analysis of 15,823 single nucleotide polymorphisms (SNPs) in 45 cases and 40 controls revealed that patellar luxation was significantly associated with a region on chromosome CFA07, and possibly with regions on CFA03, CFA31, and CFA36. The exons of the genes in these regions, 0.5 Mb combined, were analyzed further. These exons from 15 cases and a pooled sample from 15 controls were enriched using custom genomic hybridization arrays and analyzed by massive parallel DNA sequencing. In total 7257 variations were detected. Subsequently, a selection of 144 of these SNPs were genotyped in 95 Flat-Coated Retrievers. Nine SNPs, in eight genes on CFA07 and CFA31, were associated with patellar luxation (P <10-4). Genotyping of these SNPs in samples from a variety of breeds revealed that the disease-associated allele of one synonymous SNP in a pseudogene of FMO6 was unique to Flat-Coated Retrievers. CONCLUSION: Genome-wide association analysis followed by targeted DNA sequencing identified loci on chromosomes 7 and 31 as being involved in patellar luxation in the Flat-Coated Retriever breed.

TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease.

TBC1D7 forms a complex with TSC1 and TSC2 that inhibits mTORC1 signaling and limits cell growth. Mutations in TBC1D7 were reported in a family with intellectual disability (ID) and macrocrania. Using exome sequencing, we identified two sisters homozygote for the novel c.17_20delAGAG, p.R7TfsX21 TBC1D7 truncating mutation. In addition to the already described macrocephaly and mild ID, they share osteoarticular defects, patella dislocation, behavioral abnormalities, psychosis, learning difficulties, celiac disease, prognathism, myopia, and astigmatism. Consistent with a loss-of-function of TBC1D7, the patient's cell lines show an increase in the phosphorylation of 4EBP1, a direct downstream target of mTORC1 and a delay in the initiation of the autophagy process. This second family allows enlarging the phenotypic spectrum associated with TBC1D7 mutations and defining a TBC1D7 syndrome. Our work reinforces the involvement of TBC1D7 in the regulation of mTORC1 pathways and suggests an altered control of autophagy as possible cause of this disease.

Phenotypic and genetic trends of patellar luxation in Dutch Flat-Coated Retrievers.

Canine patellar luxation has been described in various dog breeds, with high prevalence especially in smaller dogs. Most dogs suffer from medial displacement of the patella, although in larger dogs lateral displacement is also seen. A sex predisposition has been described for females. Patellar luxation is considered a polygenic, multifactorial disorder. From 1990 to 2007, in total 3834 Flat-Coated Retrievers were screened; 23.6% of those animals were affected with patellar luxation. Lateral displacement of the patella was most common in this breed (61% of cases), whereas medial (31% of cases) and lateral and medial (8% of cases) were less common. Unilateral involvement (51% of cases) was just as often observed as was bilateral involvement (49% of cases). Females were more often affected with patellar luxation (30% of all tested females) than were males (17% of all tested males). The heritability of patellar luxation was 0.17 ± 0.03 in this population, and breeding with one affected parent increased the prevalence of patellar luxation in offspring by 45% compared to that with two unaffected parents. Since the start of the screening program, there was an initial decrease from 28% to 18% in incidence, but this stagnated thereafter. The annual average estimated breeding values followed the same pattern. With approximately one quarter of the Dutch Flat-Coated Retrievers being affected with patellar luxation, this population shows unusually high prevalence compared with reports in other large-breed dogs. The heritability for patellar luxation in this population was moderate (0.17), indicating that environmental factors play a large role in the manifestation of the disorder. A screening program reduced the prevalence of patellar luxation in this breed, but improvement has recently stagnated. Inclusion of breeding values in the screening program could improve its effectiveness.

Familial association of femoral trochlear dysplasia with recurrent bilateral patellar dislocation.

Femoral trochlear dysplasia is an anatomic deformity that predisposes patients to patellar instability, including patellar subluxation and dislocation, and can lead to severe patellofemoral joint degeneration if left untreated. Femoral trochlear dysplasia leading to recurrent bilateral patellar dislocation has rarely been reported as having a familial association. Orthopedic surgeons who encounter patients presenting with chronic patellar instability with no underlying disease or syndrome should be aware of the presence of femoral trochlear dysplasia leading to recurrent bilateral patellar dislocation. Although femoral trochlear dysplasia remains uncommon, the presence of bilateral recurrent patellar dislocation in multiple members of the same family is highly suggestive of genetic inheritance.This article describes 3 patients from 1 family who presented with femoral trochlear dysplasia leading to recurrent bilateral patellar dislocation. To our knowledge, this is the second article to describe a familial form of femoral trochlear dysplasia associated with recurrent bilateral patellar dislocation and is the first article in English. A lower threshold for screening and early intervention for symptomatic family members may be indicated to prevent the long-term effects of chronic patellar subluxation, dislocation, and patellofemoral arthritis.

A study of a family with the skeletal muscle RYR1 mutation (c.7354C>T) associated with central core myopathy and malignant hyperthermia susceptibility.

Congenital myopathies are early onset hereditary muscle disorders. A sub-group of these is associated with malignant hyperthermia susceptibility. Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with various congenital myopathy phenotypes and may also cause malignant hyperthermia susceptibility. We describe nine affected members of an extended family presenting with a myopathy typically manifesting as upper eye lid ptosis, quadriceps atrophy and patellar dislocation. Three affected members underwent extensive genetic testing and have a RYR1 exon 46 c.7354C>T gene mutation; two of whom had muscle biopsies--both demonstrated central core myopathy. The only affected family member who underwent testing for malignant hyperthermia susceptibility was shown to be positive. The clinical phenotypes seen among affected family members varies widely in severity, and have features in common with those congenital myopathies associated with malignant hyperthermia susceptibility, raising the possibility that these conditions represent a spectrum of disease.