Etiology Of Developmental Dysplasia Of The Hip Research Articles

An Explorative Study into the Aetiology of Developmental Dysplasia of the Hip Using Targeted Urine Metabolomics

Developmental dysplasia of the hip (DDH) is the most prevalent congenital musculoskeletal disorder, yet its cause remains unknown. Adequate nutrient provision and coordinated electron exchange (redox) processes are critical for foetal growth and tissue development. This novel study sought to explore specific biochemical pathways in skeletal development for potential involvement in the aetiology of DDH. Spot urine samples were collected from infants, aged 13-61 days, with and without DDH. Ion chromatography-mass spectrometry was used to quantify thiosulphate, sulphate, nitrate, and phosphate, whilst nitrite was quantified using high-performance liquid chromato-graphy. Thiobarbituric acid reactive substances (TBARS) were measured as markers of lipid peroxidation. Creatinine and osmolality were determined by a 96-well plate assay and micro-osmometer to potentially normalise values for renal function, lean body mass, and hydration status. Urine samples were analysed from 99 babies: 30 with DDH and 69 age-matched non-DDH controls. Thiosulphate, TBARS, and creatinine concentrations differed between the DDH group and the controls (p = 0.025, 0.015, and 0.004 respectively). Urine osmolality was significantly lower in DDH compared to the controls (p = 0.036), indicative of the production of a more diluted urine in DDH infants. Following adjustment for osmolality, significant differences became apparent in urinary sulphate levels in DDH (p = 0.035) whereas all other parameters were similar between the groups. This is the first study to assess the potential role of these inorganic anions in DDH. The higher levels of sulphate found in infants with DDH suggests either enhanced intake from milk, increased endogenous formation, or impaired renal reabsorption. This investigation demonstrates the power of urine metabolomics and highlights the importance of normalisation for hydration status to disentangle developmental disorders. Our results strongly suggest that DDH is a systemic disease associated with altered uptake, formation, or handling of sulphate. There is potential for new opportunities in the prevention or treatment of DDH via nutritional intervention.

Mapping of developmental dysplasia of the hip to two novel regions at 8q23-q24 and 12p12.

Developmental dysplasia of the hip (DDH), previously known as congenital hip dislocation, is a frequently disabling condition characterized by premature arthritis later in life. Genetic factors play a key role in the aetiology of DDH. In the present study, a genome-wide linkage scan with the Affymetrix 10K GeneChip was performed on a four-generation Chinese family, which included 19 healthy members and 5 patients. Parametric and non-parametric multipoint linkage analyses were carried out with Genespring GT v.2.0 software, and the logarithm of odds (LOD) score and nonparametric linkage (NPL) score were calculated. Parametric linkage analysis was performed, assuming an autosomal recessive trait with full penetrance and Affymetrix 'Asian' allele frequencies. The strongest evidence for linkage was found on chromosome 8q23-24, with a peak LOD score of 2.658 (θ=0), covering 2.377 Mb from single nucleotide polymorphisms (SNPs) rs724717 to rs720132. This interval included nine additional successive SNPs: rs1566071, rs1902121, rs756404, rs702768, rs777813, rs2033995, rs147959, rs2884367 and rs1898287. The same region also yielded the highest NPL score of 2.883 (P=0.0156) from the non-parametric multipoint linkage analysis. Additionally, the second highest NPL score of 2.727 (P=0.0156) and LOD score of 2.528 (θ=0) were obtained on chromosome 12p12 for three consecutive markers (rs1919980, rs763853 and rs725124). This region overlapped a narrow distance of 0.642 Mb. Notably, in addition to these two regions; no significant linkage was identified for other chromosomal regions (with LOD and NPL scores >2.0). For the first time, at least for this pedigree, the evidence in the present study showed that DDH is mapped to two novel regions at 8q23-q24 and 12p12.

Developmental dysplasia of the hip: a systematic literature review of the genes related with its occurrence.

Developmental dysplasia of the hip (DDH) is one of the most prevalent congenital malformations. It has a wide spectrum of anatomical abnormalities of the hip joint and is characterized by mild or incomplete formation of the acetabulum leading to laxity of the joint capsule, secondary deformity of the proximal femur and irreducible hip dislocation. It is the leading cause of early hip osteoarthritis in young individuals.Both genetic and environmental factors have been proposed to play an important role in the pathogenesis of DDH. A high prevalence is present in Asian, Caucasian, Mediterranean and American populations, with females being more frequently affected. We evaluated a variety of genetic studies indexed in the PubMed database.Several susceptive genes, including WISP3, PAPPA2, HOXB9, HOXD9, GDF5, TGF Beta 1, CX3CR1, UQCC, COL1A1, TbX4 and ASPN have been identified as being associated with the development of DDH. Moreover, genetic association has also been reported between hip dysplasia and other comorbidities. Even though genetic components are a crucial part in the aetiology of DDH, several DDH susceptibility genes need further investigation.The purpose of this review is to present current literature evidence regarding genes responsible for DDH development.Cite this article: EFORT Open Rev 2019;4:595-601. DOI: 10.1302/2058-5241.4.190006

Associations between risk factors and developmental dysplasia of the hip and ultrasonographic hip type: a retrospective case control study.

PurposeWe aimed to revisit the correlation between the previously defined risk factors and the occurrence of developmental dysplasia of the hip (DDH) and to assess the influence of these factors on the ultrasonographic type of hip dysplasia according to the Graf’s classification in patients with DDH.MethodsData of healthy infants (mean age 33 days) who had bilateral mature (normal) hips (Graf type I) were compared with the data of infants (mean age 105 days) who were treated by abduction brace due to unilateral or bilateral DDH (Graf type IIa- and worse hips).ResultsInfants with at least one risk factor had a significantly higher rate of DDH than those with no risk factors (p < 0.001). Likewise, infants with more than one risk factor had a significantly higher rate of DDH than those with only one risk factor (p = 0.008). Family history, breech presentation and swaddling were found to be the three significant risk factors related to the development of DDH. Family history, swaddling and oligohydramnios were found to be the three significant risk factors correlated with a higher rate of unstable/decentred hip(s) (Graf types D/III/IV) in patients with DDH.ConclusionThe risk of DDH significantly increases in infants who have more than one risk factor for DDH. Positive family history and postnatal traditional swaddling are the two main factors both in the aetiology of DDH and in development of a more severe hip dysplasia in patients with DDH. Besides, breech presentation increases the risk of development of DDH and oligohydramnios leads to development of a more severe hip dysplasia in patients with DDH. By introducing these four variables as ‘absolute risk factors for DDH’ to the selective newborn hip screening programmes, the sensitivity and specificity of these programmes may be optimized and the risk of delayed diagnosis may be lessened.Level of EvidenceLevel III prognostic study

Finite element analysis of mechanical behavior of human dysplastic hip joints: a systematic review.

Developmental dysplasia of the hip (DDH) is a common condition predisposing to osteoarthritis (OA). Especially since DDH is best identified and treated in infancy before bones ossify, there is surprisingly a near-complete absence of literature examining mechanical behavior of infant dysplastic hips. We sought to identify current practice in finite element modeling (FEM) of DDH, to inform future modeling of infant dysplastic hips. We performed multi-database systematic review using PRISMA criteria. Abstracts (n=126) fulfilling inclusion criteria were screened for methodological quality, and results were analyzed and summarized for eligible articles (n=12). The majority of the studies modeled human adult dysplastic hips. Two studies focused on etiology of DDH through simulating mechanobiological growth of prenatal hips; we found no FEM-based studies in infants or children. Finite element models used either patient-specific geometry or idealized average geometry. Diversities in choice of material properties, boundary conditions, and loading scenarios were found in the finite-element models. FEM of adult dysplastic hips demonstrated generally smaller cartilage contact area in dysplastic hips than in normal joints. Contact pressure (CP) may be higher or lower in dysplastic hips depending on joint geometry and mechanical contribution of labrum (Lb). FEM of mechanobiological growth of prenatal hip joints revealed evidence for effects of the joint mechanical environment on formation of coxa valga, asymmetrically shallow acetabulum and malformed femoral head associated with DDH. Future modeling informed by the results of this review may yield valuable insights into optimal treatment of DDH, and into how and why OA develops early in DDH.

Seasonal variation in children with developmental dysplasia of the hip.

BackgroundIt has been postulated that developmental dysplasia of the hip (DDH) is more frequent in infants born in the winter months. It was the purpose of this study to ascertain if there was any seasonal variation in DDH at the author’s institution and compare/contrast our results with those in the literature using rigorous mathematical fitting.MethodsAll children with DDH treated at the author’s institution from 1993 to 2012 were identified. The month of birth was recorded and temporal variation was analyzed using cosinor analysis. Similar data from the literature was analyzed.ResultsThere were 424 children (363 girls, 61 boys). An additional 22,936 children were added from the literature for a total of 23,360. Pearson’s Chi-square test demonstrated a non-uniform distribution in the month of birth for both our 424 children as well as the combined literature series in both the Northern and Southern hemispheres. Cosinor analysis of the 424 children demonstrated double peaks in mid-March and mid-October. For the entire 23,360 children, no seasonal variation was observed in 2,205 (9.4 %), a single winter peak in 16,425 (70.3 %), a single summer peak in 1,280 (5.5 %), and double peaks in the spring and autumn in 3,450 (14.8 %).ConclusionsThis study partly supports the hypothesis of tight clothing/cold temperature as one factor in the etiology of DDH with the tighter clothing/swaddling increasing the risk of DDH. However ~20 % of the DDH births demonstrated a non-winter peak. The single summer and double spring/autumn peaks, as well as in those series where no seasonal variation was noted, refutes the cold winter clothing hypothesis. Perhaps these different patterns in seasonal variation represent the heterogeneity of the genetic factors in DDH interacting with external factors (temperature and clothing) and internal factors (metabolic). Further study will be required to understand these different patterns in DDH seasonal variation.Level of evidenceIV—case series.

Association of a single nucleotide polymorphism in HOXB9 with developmental dysplasia of the hip: A case‐control study

Developmental dysplasia of the hip (DDH) is one of the most common skeletal disorders. It comprises a spectrum of abnormalities, including shallow acetabulum and decreased coverage of the femoral head. Genetic component plays a considerable role in the aetiology of DDH. HOXB9 may be involved in the aetiology and pathogenesis of DDH, as it plays an important role in the development of the limbs. Our objective was to evaluate whether single nucleotide polymorphisms (SNPs) of HOXB9 (rs2303486 and rs8844) were associated with DDH in Chinese population. The HOXB9 tag SNPs were genotyped in 460 DDH cases and 562 control subjects by Taqman assay, and their association was examined. rs8844 was not associated with DDH. rs2303486 was associated with DDH in the dominant genetic model (p = 0.037; odds ratio (OR) = 1.32; 95% confidence interval (CI) = 1.02–1.71). After stratification by sex, significant association of the dominant genetic model still existed in the female subjects (p = 0.015; OR = 1.46; 95% CI = 1.08–1.98),but not in the male subjects. After stratification by severity, we discovered an association with hip dislocation in the dominant model(p=0.042; OR = 1.35; 95% CI = 1.01–1.80), but not with subluxation or instability. HOXB9 is associated with DDH in Chinese.

Association of the D repeat polymorphism in the ASPNgene with developmental dysplasia of the hip: a case-control study in Han Chinese

IntroductionDevelopmental dysplasia of the hip (DDH) is a common skeletal disease, which is characterized by abnormal seating of the femoral head in the acetabulum. Genetic factors play a considerable role in the etiology of DDH. Asporin (ASPN) is an ECM protein which can bind to TGF-β1 and sequentially inhibit TGF-β/Smad signaling. A functional aspartic acid (D) repeat polymorphism of ASPN was first described as an osteoarthritis-associated polymorphism. As TGF-β is well known as an important regulator in the development of skeletal components, ASPN may also be involved in the etiology of DDH. Our objective is to evaluate whether the D repeat polymorphism of ASPN is associated with DDH in Han Chinese.MethodsThe D repeat polymorphism was genotyped in 370 DDH patients and 445 control subjects, and the allelic association of the D repeat was examined.ResultsFrom D11 to D18, eight alleles were identified. D13 allele is the most common allele both in control and DDH groups, the frequencies are 67.3% and 58.1% respectively. In the DDH group, a significantly higher frequency of the D14 allele and significantly lower frequency of D13 was observed. The association of D14 and D13 was found in both females and males after stratification by gender. There was no significant difference in any other alleles we examined.ConclusionsOur results show an obvious association between the D repeat polymorphism of ASPN and DDH. It indicates that ASPN is an important regulator in the etiology of DDH.

Association of a single nucleotide polymorphism in Tbx4 with developmental dysplasia of the hip: a case-control study

Developmental dysplasia of the hip (DDH), formerly known as congenital dislocation of the hip, comprises a spectrum of abnormalities, including abnormal acetabular shape (dysplasia) and malposition of the femoral head during embryonic, fetal and infantile growth periods. Genetic factors play a considerable role in the pathogenesis of DDH. As a key regulator for the hindlimb outgrowth and identification, Tbx4 may be involved in the aetiology and pathogenesis of DDH. Our objective is to evaluate whether the Tbx4 (rs3744438 and rs3744448) single nucleotide polymorphisms (SNPs) are associated with DDH in Chinese. The Tbx4 SNPs were genotyped in 505 children with DDH and 551 control subjects and their association was evaluated statistically. Rs3744438 was not associated with DDH. Rs3744448 was significantly associated with DDH in the dominant genetic model of males (P=0.039; odds ratio (OR)=0.56; 95% confidence interval (CI)=0.32-0.97) and allele G was significantly lower in patients than controls compared with allele C(P=0.02; OR=0.59; 95% CI=0.37-0.92). After adjusted for gender, we discovered a significant association with hip dislocation in the dominant genetic model when stratified by severity (P=0.03; OR=0.73; 95% CI=0.55-0.97), but not with subluxation and instability. Tbx4 tends to play an important role in the aetiology of DDH.

Exclusion of COL2A1 and VDR as Developmental Dysplasia of the Hip Genes

Developmental dysplasia of the hip (DDH) is a spectrum of disorders affecting the proximal femur and/or acetabulum leading to an abnormal formation of the hip. Genetic factors are involved in the etiology of DDH. Early recognition of DDH affords the best results from treatment and a better knowledge of the genetics of DDH could enhance early diagnosis. Variants in the Type II collagen (COL2A1) and vitamin D receptor (VDR) genes have been associated with patients with osteoarthritis of the hip secondary to DDH, suggesting these genes could contribute to DDH. To see whether there was linkage between the COL2A1/VDR locus and nonsyndromic DDH, we conducted a linkage study on 11 families with multiple cases of DDH. We demonstrated no evidence of linkage between the COL2A1/VDR locus and nonsyndromic DDH (LOD score < -2), suggesting, although variants in these genes could play a role in osteoarthritis in patients with DDH, they do not contribute to nonsyndromic DDH. The search for causal gene variants should proceed with other candidates.