Obstacles to reduction in infantile developmental dysplasia of the hip.

PURPOSE: Identification of anatomical structures that block -reduction in developmental dysplasia of the hip (DDH) is -important for the management of this challenging condition. Obstacles to reduction seen on arthrogram are well-known. However, despite the increasing use of MRI in the assessment of adequacy of reduction in DDH, the interpretation of MRI patho-anatomy is ill-defined with a lack of relevant literature to guide clinicians. METHOD: This is a retrospective analysis of the MRI of patients with DDH treated by closed reduction over a five-year period (between 2009 and 2014). Neuromuscular and genetic disorders were excluded. Each MRI was analysed by two orthopaedic surgeons and a paediatric musculoskeletal radiologist to identify the ligamentum teres, pulvinar, transverse acetabular ligament (TAL), capsule, labrum and acetabular roof cartilage hypertrophy. Inter- and intraobserver reliability was calculated. The minimum follow-up was 12 months. RESULTS: A total of 29 patients (38 hips) underwent closed reduction for treatment of DDH. Eight hips showed persistent subluxation on post-operative MRI. Only three of these eight hips showed an abnormality on arthrogram. The pulvinar was frequently interpreted as 'abnormal' on MRI. The main obstacles identified on MRI were the ligamentum teres (15.8%), labrum (13.1%) and acetabular roof cartilage hypertrophy (13.2%). The inter-rater reliability was good for TAL, capsule and pulvinar; moderate for ligamentum teres and labrum; and poor for hypertrophied cartilage. CONCLUSION: The labrum, ligamentum teres and acetabular roof cartilage hypertrophy are the most important structures seen on MRI preventing complete reduction of DDH. Focused interpretation of these structures may assist in the management of DDH.

Structural and molecular analyses of bone bridge formation within the growth plate injury site and cartilage degeneration at the adjacent uninjured area.

Injury to the growth plate is common and yet the injured cartilage is often repaired with undesirable bony tissue, leading to bone growth defects in children. Using a rat tibial growth plate injury model, our previous studies have shown sequential inflammatory, fibrogenic, osteogenic and bone maturation responses involved in the bony repair. However, it remains unclear whether there is progressive accumulation of bone within the injury site and any potential degenerative changes at the adjacent non-injured area of the growth plate. This study examined effects of growth plate injury on the structure, composition and some cellular and molecular changes at the injury site and adjacent uninjured area. Micro-CT analysis revealed that while the bone volume within the injury site at day 14 was small, the bone bridge was considerably larger at the injury site by 60 days post-injury. Interestingly, formation of bone bridges in the adjacent uninjured area was detected in 60% of injured animals at day 60. Immunohistochemical analyses revealed reduced chondrocyte proliferation (PCNA labelling) but increased apoptosis (nick translation labelling) in the adjacent uninjured area. RT-PCR analysis on adjacent uninjured growth plate tissue found increased expression of osteocalcin at day 60, differential expression of apoptosis-regulatory genes and alterations in genes associated with chondrocyte proliferation/differentiation, including Sox9 and IGF-I. Therefore, this study has demonstrated progressive changes in the structure/composition of the injury site and adjacent uninjured area and identified cellular and molecular alterations or degeneration in adjacent uninjured growth plate in response to injury.

Pathobiology and prevention of cancer chemotherapy-induced bone growth arrest, bone loss, and osteonecrosis.

Cancer chemotherapy has been recognized as one severe risk factor that influences bone growth and bone mass accumulation during childhood and adolescence. This article reviews on the importance of this clinical issue, current understanding of the underlying mechanisms for the skeletal defects and potential preventative strategies. Both clinical and basic studies that appeared from 1990 to 2010 were reviewed for bone defects (growth arrest, bone loss, osteonecrosis, and/or fractures) caused by paediatric cancer chemotherapy. As chemotherapy has become more intensive and achieved greater success in treating paediatric malignancies, skeletal complications such as bone growth arrest, low bone mass, osteonecrosis, and fractures during and/or after chemotherapy have become a problem for some cancer patients and survivors particularly those that have received high dose glucocorticoids and methotrexate. While chemotherapy-induced skeletal defects are likely multi-factorial, recent studies suggest that different chemotherapeutic agents can directly impair the activity of the growth plate and metaphysis (the two major components of the bone growth unit) through different mechanisms, and can alter bone modeling/remodeling processes via their actions on bone formation cells (osteoblasts), bone resorption cells (osteoclasts) and bone "maintenance" cells (osteocytes). Intensive use of multi-agent chemotherapy can cause growth arrest, low bone mass, fractures, and/or osteonecrosis in some paediatric patients. While there are currently no specific strategies for protecting bone growth during childhood cancer chemotherapy, regular BMD monitoring and exercise are have been recommended, and possible adjuvant treatments could include calcium/vitamin D, antioxidants, bisphosphonates, resveratrol, and/or folinic acid.

Damage and recovery of the bone marrow microenvironment induced by cancer chemotherapy - potential regulatory role of chemokine CXCL12/receptor CXCR4 signalling.

The bone marrow microenvironment houses haematopoietic stem cells (HSC), mesenchymal stem cells (MSC) and their progeny, supports haematopoiesis, osteogenesis, osteoclastogenesis, and adipogenesis. It plays a key role in maintaining homeostatic production of erythroid, myeloid or lymphoid cells, appropriate bone mass and bone health throughout life. Through cell-cell adhesion and chemotactic axes, a reciprocal inter-dependent relationship exists between these two cell lineages. Following chemotherapy-induced myelosuppression observed in cancer patients, HSCs are induced to enter into the cell cycle in order to re-establish the damaged microenvironment. These cells not only have the capacity to mobilize to the peripheral blood, but the ability to repopulate the marrow cavity as required. However, depending on the dosage and length of chemotherapy treatment, complications in bone and bone marrow recovery occur. This may manifest as marrow haematopoietic depletion, high marrow fat content, reduced bone formation and aggravated osteoclastic bone resorption. Although the molecular and cellular mechanisms governing injured states of the marrow microenvironment are yet to be fully elucidated, many reports have demonstrated the CXCL12/CXCR4 axis plays an important role in regulating the two cell lineages. Their interaction maintains bone marrow homeostasis and orchestrates its regeneration following chemotherapy. This review explores movement of MSC and HSC, haematopoiesis, commitment of osteoblasts, osteoclasts, and adipocytes, as well as the major signalling pathways that regulate these cellular processes under chemotherapy-treated conditions. This review also discusses molecular targets that are being used clinically or are currently under investigation for preserving the bone marrow microenvironment during or enhancing recovery after chemotherapy.

Roles of COX-2 and iNOS in the bony repair of the injured growth plate cartilage.

Growth plate injuries often lead to bone growth defects, which primarily occur due to bony repair at injury sites. Bony repair is preceded by an injury-induced inflammatory response, which could play a role in regulating the repair process. Here, roles of two inflammatory mediators, cyclo-oxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), in the injury responses were analysed by examining their gene expression and effects of blocking their activities, respectively, with celecoxib and aminoguanidine during 2 days prior to and until 7 days after injury in a rat tibial growth plate injury model. Quantitative RT-PCR assays revealed upregulated expression of COX-2 on days 1 and 4 and iNOS on day 1. Histological analysis of injury sites revealed significant reductions in inflammatory infiltrate (particularly neutrophils) on day 1 in treated groups compared to saline control. While bony tissue proportions at injury sites were unaffected by either treatment, mesenchymal tissue proportions were larger but cartilaginous tissue proportions were smaller on day 8 (though statistically insignificant), and bone remodelling appeared delayed with a smaller bone marrow proportion on day 14 in both treatment groups. These findings suggest that COX-2 and iNOS mediate injury-induced inflammatory response, and may play a role in enhancing mesenchymal cell differentiation to cartilaginous cells and in promoting bone remodelling during bony repair of growth plate injury sites. Furthermore, increased expression of cartilage-related (collagen-2, collagen-10, SOX-9) and bone-related molecules (osteocalcin, cbfalpha-1) suggest involvement of both endochondral and direct bone formation mechanisms during bony repair.

The effect of recombinant human osteogenic protein-1 on growth plate repair in a sheep model.

Injuries to the growth plate in children can result in bone bridge formation, which ultimately lead to limb length and angular deformities. The histological and molecular changes associated with growth plate repair following the Langenskiöld procedure, a surgical technique used to remove impeding bone bridges, in conjunction with administration of recombinant human osteogenic protein-1 (rhOP-1) were examined using a sheep model. Following treatment with rhOP-1 there was an increase in the height of the growth plate immediately adjacent to the defect compared to untreated animals. The expression of type I collagen, osteopontin and decorin were observed in the growth plate adjacent to the defect in the untreated animals at day 56, but this response was accelerated in the rhOP-1 treated animals, with these molecules seen as early as day 7. Therefore, treatment with rhOP-1 initiated a complex response that was both chondrogenic and osteogenic in nature.

Effects of acute 5-fluorouracil chemotherapy and insulin-like growth factor-I pretreatment on growth plate cartilage and metaphyseal bone in rats.

With the intensified use of chemotherapy and improved survival rates for childhood malignancies, it has become increasingly apparent that some children or adult survivors show poor bone growth and develop osteoporosis. As a step to investigate underlying mechanisms, this project examined short-term effects in rats of chemotherapy agent 5-fluorouracil (5-FU) on cell proliferation, apoptosis, and bone formation at tibial growth plate cartilage and its adjacent bone-forming region metaphysis. In addition, since insulin-like growth factor (IGF-I) is important for bone growth, we examined whether IGF-I pretreatment would potentially protect growth plate cartilage and bone cells from chemotherapy damage. Two days after a single high dose of 5-FU injection, proliferation of growth plate chondrocytes and metaphyseal osteoblasts/preosteoblasts was dramatically suppressed, and apoptosis was induced among osteoblasts and preosteoblasts. As a result, there was a reduction in the chondrocyte number and zonal height at the proliferative zone and a decline in the number of osteoblasts and preosteoblasts on the metaphyseal trabecular bone surface. At day 2, no obvious deleterious effects were observed on the height of the growth plate hypertrophic zone and the bone volume fraction of the metaphyseal primary spongiosa trabeculae. At day 10, while cell proliferation and growth plate structure returned to normal, there were slight decreases in trabecular bone volume, body length increase, and tibial length. While pretreatment with 1-week IGF-I systemic infusion did not attenuate the suppressive effect of 5-FU on proliferation in both growth plate and metaphysis, it significantly diminished apoptotic induction in metaphysis. These results indicate that growth plate cartilage chondrocytes and metaphyseal bone cells are sensitive to chemotherapy drug 5-FU and that IGF-I pretreatment has some anti-apoptotic protective effects on metaphyseal bone osteoblasts and preosteoblasts.

Spatial arrangement of physeal cartilage chondrocytes and the structure of the primary spongiosa.

Using laser confocal microscopy and 5-chloromethyl-fluoresceindiacetate (CMFDA) loading of chondrocytes we have investigated the structure of the ovine physis during late fetal development and its relationship to the structure observed in the primary spongiosa. Chondrocytes within the ovine growth plate form nests that together span the growth plate. We propose that all growth plates may be composed of nests of cells, but that the length of the individual nests changes between growth plates and with gestational age. The continuous column of cells seen within some growth plates is a nest of cells that is in the process of being absorbed by the invading metaphyseal front. Scanning electron microscopy of the mineralized portion of the primary spongiosa revealed structures that were consistent with the hypothesis that the cartilage surrounding the nest structure gives rise to the structure in the primary spongiosa. Although mineralization does not occur between cells within a nest, bands of mineral form between nests in the lower hypertrophic region and around the end of the nest as it reaches the hypertrophic region. This pattern of mineralization around and between nest termini yields the complex three-dimensional network of mineralized trabeculae observed in the primary spongosia.

Magnetic resonance imaging of growth plate injuries: the efficacy and indications for surgical procedures.

In 23 patients with growth plate injuries, magnetic resonance imaging (MRI) studies were performed a total of 31 times to evaluate the physis which showed plain radiographic evidence of possible damage. Fourteen patients clinically showed growth arrest, and 10 patients required a Langenskiold operation. In 3 patients who underwent this operation, subsequent premature total fusion of the physis adversely affected the postoperative results. We propose that the merging shape of the arrest line with calcification of the provisional zone of the metaphysis shown by MRI indicates poor viability of the physis. MRI provided useful information on the appearance of the growth plate and changes in the metaphysis, both of which affected the prognosis and the results of the surgical procedures.

Free fat interpositional graft in acute physeal injuries: the anticipatory Langenskiöld procedure.

Free fat graft interposition has been used extensively in management of physeal injuries with established growth disturbances. The use of this technique as part of the management of acute physeal injuries has not been reported. Here we report on its application in acute physeal injuries, where it has prevented the formation of an anticipated physeal arrest.

Metaphyseal factors promote calcium incorporation in physeal chondrocyte cultures.

Our hypothesis is that physiological mineralization within the mammalian growth plate is a consequence of communication between cartilage chondrocytes and cells within metaphyseal bone. To test this hypothesis, chondrocytes were isolated from the proliferative region of the fetal ovine physis and co-cultured with cells or conditioned medium from cells characteristic of those in metaphyseal bone. The mineralization potential of chondrocytes alone and in the presence of other cells or conditioned medium was determined by 45calcium incorporation. Co-culture of chondrocytes with a crude cell isolate from metaphyseal bone resulted in a stimulation of 45calcium incorporation of 93% above that observed in the individual cell populations alone. Conditioned medium from metaphyseal bone cultures also stimulated 45calcium incorporation. This response to conditioned medium was dose-dependent and stable to 90 degrees C. Vascular endothelial cells and conditioned medium from chondrocyte and osteoblast cultures did not stimulate 45calcium incorporation by physeal chondrocytes. Thus, cells found in the metaphyseal bone produce a soluble factor, which promote calcium incorporation by physeal chondrocytes. The source of this factor is not chondrocytic, osteoblastic, or endothelial in origin.

Late diagnosis of congenital dislocation of the hip and presence of a screening programme: South Australian population-based study.

BACKGROUND: The Medical Research Council Working Party on Congenital Dislocation of the Hip have reported an ascertainment-adjusted incidence of a first operative procedure for congenital dislocation of the hip (CDH) of 0.78 per 1000 livebirths, which is similar to the incidence of CDH before the start of the UK screening programme. The report showed that CDH had not been detected by routine screening before age 3 months in 70% of children reported to the national orthopaedic surveillance scheme. This report raised concerns about the merit of screening at birth for CDH. We aimed to find out the incidence of an operative procedure for CDH in the first 5 years of life among children born in South Australia between 1988 and 1993, and the proportion of these patients that were detected at age 3 months or older. METHODS: The state's database for inpatient separations between January, 1988, and April, 1998 was searched. Case records were examined for the age and circumstances of diagnosis, and type of operative procedures. Prevalence rates of CDH were obtained from the South Australian Birth Defects Register, which receives notifications from a statutory perinatal data collection of birth defects detected at birth and subsequent voluntary notifications for children up to age 5 years. FINDINGS: Of the 55 children born in South Australia between 1988 and 1993 identified as having non-teratological CDH and operative procedures, only 22 (40%) had been diagnosed at age 3 months or older. 18 had an open reduction of the hip joint or osteotomy, or both, and the remainder had arthrograms, closed reductions, and/or tenotomy. The prevalence of non-teratological CDH in children was 7.74 per 1000 livebirths. The incidence of surgery for CDH in the first 5 years of life was 0.46 per 1000 livebirths (95% CI 0.34-0.59) and only 0.19 per 1000 livebirths (0.11-0.26) for those diagnosed late (age 3 months or older). These children diagnosed late represented 2.4% of all known cases of CDH. INTERPRETATION: Only 2.4% of known cases of CDH in children born in South Australia had been detected late and required surgery. These results show that a screening programme for CDH can be successful, contrary to the findings of the UK Medical Research Council Working Party.

Prenatal ultrasound diagnosis of clubfoot.

Prenatal ultrasound diagnosis of clubfoot is increasing. Of 103 patients with clubfoot diagnosed at birth, 26 (25.2%) positive prenatal scans were identified with the earliest diagnosis being made at 15 weeks. A questionnaire assessment indicated that 17 (65.4%) deemed that the explanation of the baby's condition was clear. With an increasing incidence of antenatal detection, it is suggested that parents require adequate antenatal counseling by a specialist in the area of clubfoot to improve the understanding of the natural history and treatment of this condition.

Structural changes in the large proteoglycan, aggrecan, in different zones of the ovine growth plate.

The large cartilage proteoglycan, aggrecan, was found to vary throughout the ovine physis corresponding to the maturational state of the resident chondrocytes. Two populations of proteoglycan monomer were observed in articular, epiphyseal, and in the resting zone of growth plate cartilage. These proteoglycans contained chondroitin sulfate glycosaminoglycan chains sulfated predominantly in the 4 position along with lesser amounts of chondroitin-6-sulfate and keratan sulfate. In the proliferative zone of the growth plate, chondrocytes synthesize one population of proteoglycan monomer which was significantly larger than monomer populations in articular, epiphyseal, or resting zone and this size increase could be attributed to an increase in its constituent chondroitin sulfate side chains. As these chondrocytes progress through their life cycle they continue to modify the structural characteristics of the aggrecan molecule they synthesize. Thus, in the hypertrophic region of the growth plate, the proteoglycan monomer is larger again than in the proliferative region. Variation in sulfation pattern on aggrecan chondroitin sulfate side chains is also observed in the hypertrophic region with an increasing proportion of unsulfated residues present, which may play a role in the initiation of mineralization. In addition, increasing amounts of the carbohydrate sequence recognized by monoclonal antibody 7-D-4 are observed in the hypertrophic zone.

Spinal fusion in Duchenne's muscular dystrophy.

The Women's and Children's Hospital experience with Luque spinal fusion in Duchenne's muscular dystrophy was reviewed from its commencement in 1983 to the present with a view to assessing the clinical and radiologic outcome and safety of the procedure. Seventeen boys have undergone spinal fusion. L-rod instrumentation was used in 10, six of whom had significant problems with sitting imbalance or progression of the scoliosis or both. In seven cases, distal instrumentation was taken to the pelvis with a Galveston construct and rigid crosslinking. Apart from some progression and sitting imbalance in the L-rod group, there were few complications. In the Galveston group, pelvic obliquity was corrected by a mean of 63%, and there was better maintenance of correction. There were no pseudoarthroses or instrument failures in the Galveston group. Of the total group, four patients had forced vital capacity (FVC) values < 25% predicted, and two required ventilation postoperative (< 48 h). There were no other respiratory complications. The effect of surgery on respiratory function remains uncertain. Spinal fusion with the Luque rod construct and pelvic fixation is a safe procedure. It provided a mean correction of 60% and control of pelvic obliquity without significant postoperative deterioration. In our experience, surgery can be safely performed with FVC value down to 20% predicted. On the basis of these data, one current practice is to instrument to the pelvis with a Galveston construct and Texas Scottish Rite Hospital cross-linking.

Effect of spinal surgery on lung function in Duchenne muscular dystrophy.

BACKGROUND: The effect on subsequent respiratory function of spinal stabilisation for scoliosis in Duchenne muscular dystrophy is unclear. In order to clarify this clinical problem, changes in the forced vital capacity of a group of children with Duchenne muscular dystrophy who had undergone spinal surgery were measured and compared with a group of children with Duchenne muscular dystrophy who had not had surgery. METHODS: In this retrospective study 17 boys with Duchenne muscular dystrophy who underwent spinal stabilisation at a mean age of 14.9 years (surgical group) were compared with 21 boys with Duchenne muscular dystrophy who had not had surgery (non-surgical group). The mean (SD) Cobb angle of the surgical group at 14.9 years was 57 (16.4) degrees, and of the non-surgical group at 15 years was 45 (29.9) degrees. Forced vital capacity expressed as percentage predicted (% FVC) was measured in total over a seven year period in the surgical group and over 6.5 years in the non-surgical group, and regression equations were calculated. Survival curves for both groups were also constructed. RESULTS: No difference was found between spinal stabilisation (surgical group) and the non-surgical group in the rate of deterioration of % FVC which was 3-5% per year. There was no difference in survival in either group. CONCLUSIONS: Spinal stabilisation in Duchenne muscular dystrophy does not alter the decline in pulmonary function, nor does it improve survival.

Slipped capital femoral epiphysis. Incidence and clinical assessment of physeal instability.

In an unselected series of 55 cases of slipped capital femoral epiphysis (SCFE) we observed an incidence of 25% of epiphyseal reduction, mostly unintentional. Reduction indicated physeal instability and was associated with an effusion, detected by sonography on admission, and inability to bear weight. The true prevalence of instability may be higher since an effusion was noted in 33 cases (60%) on the initial sonographic assessment. Serial radiographs showed reduction in 12 (22%), with an average change of 15.1 degrees in the head-neck angle. Serial sonography showed reduction in 7 out of 20 cases (35%), with an average change of 3.7 mm in displacement. In two cases reduction was seen on sonography but not on radiography. Of the hips which showed subsequent reduction, 12 had had a bone scan on admission; three showed initial epiphyseal avascularity but only one progressed to symptomatic avascular necrosis. All stable hips had normal epiphyseal vascularity on the initial bone scan. This indicates the importance of injury from the initial displacement in causing avascular necrosis, rather than effusion, vascular compromise or iatrogenic injury from gentle repositioning. Physeal instability in SCFE is common and should be assessed clinically on admission. It is indicated by joint effusion or inability to bear weight. A slip is very unlikely to be unstable in a child able to bear weight and with no sonographic effusion.

Initial screening and diagnosis of and referral for developmental dysplasia of the hip.

The continued diagnosis of cases of late developmental dysplasia of the hip reaffirms the failure of initial clinical neonatal screening programs. Even the identification of an "at risk" patient profile will not eliminate the late diagnoses, but referral of these patients will ensure that up to 50% of late diagnoses can be eliminated. The role of ultrasound as a screening diagnostic tool has not, at this time, been confirmed to eliminate late diagnoses. Its use, however, has led to an increased incidence of treatment with the recognition of the sonographic "immature hip." This, in turn, will increase the number of complications of treatment with iatrogenic avascular necrosis. Therefore, the ideal elimination of all late developmental dysplasia of the hip referrals remains the unattained goal.

The implantation of cartilaginous and periosteal tissue into growth plate defects.

This experimental study reports the results of implantation of cartilaginous and periosteal tissues into growth plate defects in the tibiae of sheep. When no material was used, the defect rapidly filled with marrow-like tissue. When cartilage from the margin of the secondary centre of ossification was implanted, endochondral ossification continued and no shortening or deformity resulted. Implantation of periosteum with or without reconstructed peripheral tissues resulted in the formation of a bony bridge which led to a 32% inhibition of longitudinal growth and a 12 degrees varus deformity in the absence of peripheral connective tissues. After reconstruction with these tissues, the inhibition of longitudinal growth was 47% with a 28 degrees varus deformity. The chondroprogenitor cells in the implanted tissues cannot change phenotypic expression. Periosteum has a strong potential for bone formation after it has been implanted.