Evaluation of a training program for general ultrasound screening for developmental dysplasia of the hip in preventive child health care.

BACKGROUND: A research study in the Netherlands showed that general ultrasound (US) screening was cost-effective in the detection of developmental dysplasia of the hip (DDH). This study was followed by a pilot implementation study. Part of this pilot implementation study is to investigate whether professionals of the infant health care (IHC) system, with no previous US experience, would be able to perform US of the hip. OBJECTIVE: This study looks at health care worker ability to classify US images into a modified Graf system. MATERIALS AND METHODS: After theoretical and practical training, seven nurses and physicians of the participating IHC centers reported their findings on sonographic images of 80 children. This was repeated five months later. From the two evaluation moments the intraobserver agreement and the interobserver agreement was determined. RESULTS: The average estimated interobserver Cohen's kappa for both sessions was for nurses 0.6 and for physicians 0.5. The second evaluation showed a decrease from an average of 4.3% missed cases per screener to 2.3% and an increase of an average of 5% false positives per screener to 9.1%. CONCLUSION: The inter- and intra-observer agreement is comparable to similar studies in which the participants had a professional background in US examination. The level of agreement of the trainees in the perspective of the screening process was considered sufficient for the pilot implementation project.

Abduction treatment in stable hip dysplasia does not alter the acetabular growth: results of a randomized clinical trial.

Background The effect of bracing over natural history of stable dysplastic hips is not well known. This multicenter randomized trial aimed at objectifying the effect of abduction treatment versus active surveillance in infants of 3 to 4 months of age. Methods Patients were randomized to either Pavlik harness or active surveillance group. Ultrasound was repeated at 6 and 12 weeks post randomization. The primary outcome was the degree of dysplasia using the Graf α-angle at 6 months of age. The measurement of the acetabular index (AI) on plain pelvis X-rays was used to identify persistent dysplasia after 9 months and walking age (after 18 months). Findings The Pavlik harness group (n = 55) and active surveillance group (n = 49) were comparable for predictors of outcome. At 12 weeks follow-up the mean α-angle was 60.5° ± 3.8° in the Pavlik harness group and 60.0° ± 5.6° in the active surveillance group. (p = 0.30). Analysis of secondary outcomes (standard of care) showed no treatment differences for acetabular index at age 10 months (p = 0.82) and walking age (p = 0.35). Interpretation Pavlik harness treatment of stable but sonographic dysplastic hips has no effect on acetabular development. Eighty percent of the patients will have a normal development of the hip after twelve weeks. Therefore, we recommend observation rather than treatment for stable dysplastic hips.

Musculoskeletal manifestations of lysosomal storage disorders.

Lysosomal storage disorders (LSDs), a heterogeneous group of inborn metabolic disorders, are far more common than most doctors presume. Although patients with a severe LSD subtype are often readily diagnosed, the more attenuated subtypes are frequently missed or diagnosis is significantly delayed. The presenting manifestations often involve the bones and/or joints and therefore these patients are frequently under specialist care by (paediatric) rheumatologists, receiving inadequate treatment. Since effective disease-specific treatments, including enzyme replacement therapy and stem cell transplantation, have become available for certain LSDs and timely initiation of these treatments is necessary to prevent the development of severe, disabling and irreversible manifestations, early diagnosis has become essential. The challenge is to raise awareness for better recognition of the presenting signs and symptoms of LSDs by all doctors who may encounter these patients, including rheumatologists.

Correlation between ultrasonic and radiographic imaging of developmental dysplasia of the hip.

PURPOSE: The correlation between the degree of developmental hip dysplasia (DDH) measured on ultrasound images compared with that measured on radiographs is not clear. Most studies have compared ultrasonography (US) and radiographic images made at different times of follow-up. In this study the correlation between US images and radiographs of the hip made on the same day was evaluated. METHODS: US images and radiographs of both hips of 74 infants, who were treated for stable DDH, were reviewed in a retrospective study. Only infants who had an US examination and a radiograph on the same day were included. RESULTS: The correlation between α-angle of Graf and femoral head coverage on US was strong (p ≤ 0.0001). Weak correlations were found between the acetabular index of Tönnis on radiographs and α-angle of Graf on US (p = 0.049) and between acetabular index of Tönnis on radiographs and femoral head coverage of Morin on US (p = 0.100). CONCLUSION: This study reports on the correlation between US and radiographic imaging outcomes, both made on the same day in patients for treatment and follow-up of DDH. LEVEL OF EVIDENCE: IV.

Current concepts in osteogenesis imperfecta: bone structure, biomechanics and medical management.

The majority of patients with osteogenesis imperfecta (OI) have mutations in the COL1A1 or COL1A2 gene, which has consequences for the composition of the bone matrix and bone architecture. The mutations result in overmodified collagen molecules, thinner collagen fibres and hypermineralization of bone tissue at a bone matrix level. Trabecular bone in OI is characterized by a lower trabecular number and connectivity as well as a lower trabecular thickness and volumetric bone mass. Cortical bone shows a decreased cortical thickness with less mechanical anisotropy and an increased pore percentage as a result of increased osteocyte lacunae and vascular porosity. Most OI patients have mutations at different locations in the COL1 gene. Disease severity in OI is probably partly determined by the nature of the primary collagen defect and its location with respect to the C-terminus of the collagen protein. The overall bone biomechanics result in a relatively weak and brittle structure. Since this is a result of all of the above-mentioned factors as well as their interactions, there is considerable variation between patients, and accurate prediction on bone strength in the individual patient with OI is difficult. Current treatment of OI focuses on adequate vitamin-D levels and interventions in the bone turnover cycle with bisphosphonates. Bisphosphonates increase bone mineral density, but the evidence on improvement of clinical status remains limited. Effects of newer drugs such as antibodies against RANKL and sclerostin are currently under investigation. This paper was written under the guidance of the Study Group Genetics and Metabolic Diseases of the European Paediatric Orthopaedic Society.

The natural history of abnormal ultrasound findings in hips of infants under six months of age.

PURPOSE: To collect and describe data on the natural history of abnormal ultrasound (US) findings in hips of infants under six months of age to serve as a reference to the design of screening programmes and treatment algorithms in the care for children with hip dysplasia. METHODS: A search in PubMed of the terms "DDH" and "ultrasound" was done to find hips with abnormal US findings that were not treated. In cases of multiple periods of follow-up, the classification of every period was evaluated separately (individual hip follow-up periods). RESULTS: Data of 13 561 hips with 16 991 follow-up periods were collected and analyzed. Most quantifiable classifications and follow-up periods were according to Graf (14 876) and a minor number of the hips had follow-up periods with femoral head coverage (FHC) (2115). Normal development without treatment in the first six months was for Graf 2a between 89% and 98%, for Graf 2c between 80% and 100% and for clustered data Graf 2a to 2c between 80% and 97%. For Graf 3 hips more than 50% were reported to develop into normal hips without treatment. As for Graf 4 hips this percentage was reported below 50%. For children with an FHC less than 50%, normalization was reported between 78% and 100%. CONCLUSION: The natural history of developmental dysplasia of the hip (DDH) shows a benign course, especially in the well-centered hips. This outcome probably contributes to the fact that all studies on US screening of hips for detection of relevant DDH in order to improve outcomes of treatment are rated as substantially underpowered.

Long-term outcomes following the medial approach for open reduction of the hip in children with developmental dysplasia.

Aims Open reduction is required following failed conservative treatment of developmental dysplasia of the hip (DDH). The Ludloff medial approach is commonly used, but poor results have been reported, with rates of the development of avascular necrosis (AVN) varying between 8% and 54%. This retrospective cohort study evaluates the long-term radiographic and clinical outcome of dislocated hips treated using this approach. Patients and Methods Children with a dislocated hip, younger than one year of age at the time of surgery, who were treated using a medial approach were eligible for the study. Radiographs were evaluated for the degree of dislocation and the presence of an ossific nucleus preoperatively, and for the degree of AVN and residual dysplasia at one and five years and at a mean of 12.7 years (4.6 to 20.8) postoperatively. Radiographic outcome was assessed using the Severin classification, after five years of age. Further surgical procedures were recorded. Functional outcome was assessed using the Pediatric Outcomes Data Collection Instrument (PODCI) or the Hip Disability and Osteoarthritis Outcome Score (HOOS), depending on the patient's age. Results A total of 52 children (58 hips) were included. At the latest follow-up, 11 hips (19%) showed signs of AVN. Further surgery was undertaken in 13 hips (22%). A total of 13 hips had a poor radiological outcome with Severin type III or higher. Of these, the age at the time of surgery was significantly higher (p < 0.05) than in those with a good Severin type (I or II). The patient-reported outcomes were significantly worse (p < 0.05) in children with a poor Severin classification. Conclusion This retrospective long-term follow-up study shows that one in five children with DDH who undergo open reduction using a medial surgical approach has poor clinical and/or radiological outcome. The poor outcome is not related to the presence of AVN (19%), but due to residual dysplasia. Cite this article: Bone Joint J 2018;100-B:822-7.

Pyridinium cross-links in bone of patients with osteogenesis imperfecta: evidence of a normal intrafibrillar collagen packing.

The brittleness of bone in patients with osteogenesis imperfecta (OI) has been attributed to an aberrant collagen network. However, the role of collagen in the loss of tissue integrity has not been well established. To gain an insight into the biochemistry and structure of the collagen network, the cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) and the level of triple helical hydroxylysine (Hyl) were determined in bone of OI patients (types I, III, and IV) as well as controls. The amount of triple helical Hyl was increased in all patients. LP levels in OI were not significantly different; in contrast, the amount of HP (and as a consequence the HP/LP ratio and the total pyridinoline level) was significantly increased. There was no relationship between the sum of pyridinolines and the amount of triple helical Hyl, indicating that lysyl hydroxylation of the triple helix and the telopeptides are under separate control. Cross-linking is the result of a specific three-dimensional arrangement of collagens within the fibril; only molecules that are correctly aligned are able to form cross-links. Inasmuch as the total amount of pyridinoline cross-links in OI bone is similar to control bone, the packing geometry of intrafibrillar collagen molecules is not disturbed in OI. Consequently, the brittleness of bone is not caused by a disorganized intrafibrillar collagen packing and/or loss of cross-links. This is an unexpected finding, because mutant collagen molecules with a random distribution within the fibril are expected to result in disruptions of the alignment of neighboring collagen molecules. Pepsin digestion of OI bone revealed that collagen located at the surface of the fibril had lower cross-link levels compared with collagen located at the inside of the fibril, indicating that mutant molecules are not distributed randomly within the fibril but are located preferentially at the surface of the fibril.

Collagen structure regulates fibril mineralization in osteogenesis as revealed by cross-link patterns in calcifying callus.

Although >80% of the mineral in mammalian bone is present in the collagen fibrils, limited information is available about factors that determine a proper deposition of mineral. This study investigates whether a specific collagen matrix is required for fibril mineralization. Calcifying callus from dog tibias was obtained at various times (3-21 weeks) after fracturing. At 3 weeks, hydroxylysine (Hyl) levels were almost twice as high as in control bone, gradually reaching normal levels at 21 weeks. The decrease in Hyl levels can only be the result of the formation of a new collagen network at the expense of the old one. The sum of the cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) in callus matched that of bone at all stages of maturation. However, the ratio HP/LP was 2.5-4.5 times higher in callus at 3-7 weeks than in normal bone and was normalized at 21 weeks. Some 40% of the collagen was nonmineralized at the early stages of healing, reaching control bone values (approximately 10%) at 21 weeks. In contrast, only a small increase in callus mineral content from 20.0 to 22.6 (% of dry tissue weight) from week 3 to 21 was seen, indicating that initially a large proportion of the mineral was deposited between, and not within, the fibrils. A strong relationship (r = 0.80) was found between the ratio HP/LP and fibril mineralization; the lower the HP/LP ratio, the more mineralized the fibrils were. Because the HP/LP ratio is believed to be the result of a specific packing of intrafibrillar collagen molecules, this study implies that mineralization of fibrils is facilitated by a specific orientation of collagen molecules in the fibrils.

Heat-shock treatment selectively affects induction and repair of cyclobutane pyrimidine dimers in transcriptionally active genes in ultraviolet-irradiated human fibroblasts.

The effect of hyperthermia on induction and repair of UV-radiation-induced cyclobutane pyrimidine dimers was investigated in the genome overall and in transcriptionally active and inactive genes in confluent human fibroblasts. Hyperthermia treatment (30 min, 45 degrees C) of human fibroblasts resulted in an increase in the protein content of isolated nuclei (protein aggregation) similar to that observed for HeLa S3 cells. The faster rate of disaggregation of nuclear proteins and the higher survival rate of heated fibroblasts in comparison with those for HeLa cells provide further evidence for a possible role of protein aggregation in heat-induced cell killing. Determination of the frequencies of cyclobutane pyrimidine dimers in the genome overall and in restriction fragments of the active adenosine deaminase (ADA) gene and inactive 754 locus revealed that hyperthermia selectively inhibits the induction of cyclobutane pyrimidine dimers in transcriptionally active DNA. Removal of cyclobutane pyrimidine dimers from the ADA gene was strongly delayed during the first 8 h in 10 J/m2 UV-irradiated fibroblasts. Such inhibition of repair of cyclobutane pyrimidine dimers was not observed for the 754 gene, indicating that inhibition of repair by hyperthermia is generally not mediated by inactivation of repair enzymes. It is proposed that the inhibition of induction and repair of cyclobutane pyrimidine dimers in active genes by hyperthermia is related to the heat-induced aggregation of proteins with the nuclear matrix, proximal to which active genes are located. Our results are consistent with a functional compartmentalization of DNA repair at the nuclear matrix.

Intermediate grade osteosarcoma and chondrosarcoma arising in an osteochondroma. A case report of a patient with hereditary multiple exostoses.

A 40 year old man with hereditary multiple exostoses (HME), affecting predominantly his left proximal tibia, distal femur, and proximal femur, underwent resection of an osteochondroma near the trochanter major of his left proximal femur because of malignant transformation of the cartilaginous cap towards secondary peripheral chondrosarcoma. The patient had a history of a papillary thyroid carcinoma four years previously. At examination of the resected specimen, a third malignant tumour, an intermediate grade osteosarcoma (grade II/IV), was found in the osseous stalk of the osteochondroma. Although no mutations were found in the EXT1 and EXT2 genes, the genes involved in HME, or in exons 5-8 of the p53 gene, the development of three malignancies before the age of 40 suggests that this patient is genetically prone to malignant transformation.

Repair of UV-induced pyrimidine(6-4)pyrimidone photoproducts is selectively inhibited in transcriptionally active genes after heat treatment of human fibroblasts.

In normal human fibroblasts, repair of (6-4)PP in the active adenosine deaminase (ADA) gene occurs with similar rate in the transcribed and non-transcribed strand of the ADA gene, and removal of (6-4)PP from the active ADA gene is faster than from the inactive X-chromosomal 754 locus. Heat shock decreased the rate of repair of the active ADA gene down to the level of inactive genes, whereas the rate of repair of the inactive 754 locus was not affected.

Altered association of transcriptionally active DNA with the nuclear-matrix after heat shock.

PURPOSE: Exposure of human cells to heat leads to denaturation and aggregation of proteins. Within the nucleus, it has been suggested that protein aggregation is linked to the selective inhibition by hyperthermia of nucleotide excision repair in transcriptionally active genes. In this study it was investigated in detail whether and how the inhibition of repair of transcriptionally active genes might be related to alterations in their association with the nuclear-matrix. MATERIAL AND METHODS: Different protocols for nuclear-matrix isolation (high salt and lithium 3',5'-diiodosalycilate [LIS] extraction of nuclei) were used to compare DNA loop organization and positioning of transcriptionally active genes in both heated and non-heated cells. RESULTS: DNaseI digestion of total genomic DNA in Cu2+ -stabilized LIS-extracted nuclei revealed that heat shock perturbed the formation of nuclear-matrix attachment sites. Specific labelling of active genes indicated that the number of nuclear-matrix attachment sites in transcriptionally active DNA was increased due to the heat shock. At the level of individual genes, heat treatment led to stabilization of the 5' matrix attachment site (MAR) in the transcriptionally active adenosine deaminase (ADA) housekeeping gene. Moreover, heat shock resulted in the formation of an additional MAR at the 3' end of the ADA gene. The inactive 754 locus was unassociated, irrespective of a heat shock. CONCLUSIONS: The reported changes in chromatin structure might underlie the selective inhibition of repair in transcriptionally active genes and consequently may be mechanistically linked to the sensitization of heated cells to ionizing radiation.

X-chromosome inactivation in patients who have pigmented villonodular synovitis.

We performed a histological examination and DNA analysis on samples of tissue from a forty-seven-year-old woman who had a clinical diagnosis of pigmented villonodular synovitis. The histological examination confirmed the diagnosis. The evaluation of the samples of tissue with preferential X-chromosome inactivation analysis (a molecular biological method for the study of clonality in tumors) showed that the lesion was polyclonal in origin. We concluded, therefore, that pigmented villonodular synovitis is more likely to be a reactive process than a true neoplasm.

Left-sided congenital pseudarthrosis of the clavicula.

This a well-documented case of a 13-year-old girl with unilateral pseudarthrosis of the left clavicle without the presence of cervical ribs or dextrocardia. Magnetic resonance imaging could not detect any abnormality that could be related to the left-sided pseudarthrosis.

Prevalence and development of orthopaedic symptoms in the dutch hurler patient population after haematopoietic stem cell transplantation.

Hurler syndrome (MPS-IH) is a rare autosomal recessive lysosomal storage disease. Besides a variety of other features, Hurler syndrome is characterized by a range of skeletal abnormalities known as dysostosis multiplex. Despite the successful effect of haematopoietic stem cell transplantation on the other features, dysostosis remains a disabling symptom of the disease. This study analyzed the status and development of the orthopaedic manifestations of 14 Dutch Hurler patients after stem cell transplantation.Data were obtained retrospectively by reviewing patients' charts, radiographs and MRIs. Existing methods to measure the deficiencies were modified to optimally address the dysostosis. These measurements were done by two of the authors independently. The odontoïd/body ratio, kyphotic angle, scoliotic angle and parameters for hip dysplasia and genu valgum were measured and plotted against age. The degree of progression was determined. The intraclass correlation coefficient (ICC) was calculated to determine the reliability of the measurements.All patients showed hypoplasia of the odontoïd, which significantly improved during growth. Kyphosis in the thoracolumbar area was present in 13 patients and proved to be progressive. Scoliosis was observed in eight patients. Hip dysplasia was present in all patients and showed no tendency of improvement. In all but one patient, knee valgus remained more than two standard deviations above normal.Dysostosis remains a major problem after haematopoietic stem cell transplantation in Hurler patients. Moreover, except for dens hypoplasia, it appears to be progressive and therefore surgical interventions may be necessary in the majority of these patients.

Assessment of the relationship between joint laxity and migration of the hip in children with Down syndrome.

PURPOSE: The aim of this cross-sectional cohort study is to describe the incidence of joint laxity and the correlation between joint laxity and radiological migration of the hip in children with Down syndrome. METHODS: Sixty-five children (2-19 years) with Down's syndrome were examined for joint laxity. For each subject, laxity scores for joints were carried out with the Bulbena method. Plane pelvic radiographs were used to determine the migration of the hip, according to Reimer's migration index. RESULTS: In this study, 26 out of 65 children with Down's syndrome (40 %) were diagnosed with general joint laxity. On the radiographs of the hips we found a mean Reimer's Migration Index of 5.2 % for all the subjects. Children with general joint laxity showed a lower Reimer's Migration Index (2.1 %). No significant correlation was found between general joint laxity and migration of the hip. CONCLUSIONS: This study showed no relationship between joint laxity and migration of the hip in children with Down's syndrome. This implicates that we were not able to prove that joint laxity is the major factor in developing hip migration in children with Down's syndrome.

Decrease in outpatient department visits and operative interventions due to bisphosphonates in children with osteogenesis imperfecta.

INTRODUCTION: Bisphosphonates are currently the medical treatment most often used in children with osteogenesis imperfecta (OI). The purpose of this retrospective pre-post study was to evaluate the efficacy of treatment with bisphosphonates. We measured the effect by evaluating the number of outpatient department consultations and operative interventions before and after treatment with bisphosphonates in children with OI. METHODS AND MATERIALS: Outpatient department consultation and operative intervention frequencies before and after treatment with bisphosphonates were registered. Children who had at least 2 years of medical records before treatment and at least 2 years after treatment were used in this study. RESULTS: Of 118 children who were treated with bisphosphonates, 51 (23 boys and 28 girls) fulfilled the inclusion criteria. Statistical analysis revealed a significant decrease in outpatient department consultations (P < 0.000) and operative intervention (P < 0.003) before and after bisphosphonate treatment. CONCLUSION: The pre-post design of our study shows a significant reduction of the number of outpatient department consultations and operative interventions in patients with OI after treatment with bisphosphonates.

Functional analysis of the fsoC gene product of the F7(1) (fso) fimbrial gene cluster.

Contrary to what would be expected from data in the literature, mutations in the fsoC gene of the F7(1) (fso) P-fimbrial gene cluster do not completely block fimbrial biogenesis. fsoC mutants still express small amounts of fimbriae of normal length, which carry the non-adhesive minor subunit protein, FsoE, but lack the adhesin, FsoG. The FsoC protein operates at the same stage in fimbrial biogenesis as the FsoF and FsoG proteins. The data suggest that FsoC, FsoF and FsoG interact to form an initiation complex for fimbrial biogenesis.