Ralph J. B. Sakkers

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.

Orthopaedic management of Hurler’s disease after hematopoietic stem cell transplantation: a systematic review

ObjectiveThe introduction of hematopoietic stem cell transplantation (HSCT) has significantly improved the life-span of Hurler patients (mucopolysaccharidosis type I-H, MPS I-H). Yet, the musculoskeletal manifestations seem largely unresponsive to HSCT. In order to facilitate evidence based management, the aim of the current study was to give a systematic overview of the orthopaedic complications and motor functioning of Hurler’s patients after HSCT.MethodsA systematic review was conducted of the medical literature published from January 1981 to June 2010. Two reviewers independently assessed all eligible citations, as identified from the Pubmed and Embase databases. A pre-developed data extraction form was used to systematically collect information on the prevalence of radiological and clinical signs, and on the orthopaedic treatments and outcomes.ResultsA total of 32 studies, including 399 patient reports were identified. The most frequent musculoskeletal abnormalities were odontoid hypoplasia (72%), thoracolumbar kyphosis (81%), genu valgum (70%), hip dysplasia (90%) and carpal tunnel syndrome (63%), which were often treated surgically during the first decade of life. The overall complication rate of surgical interventions was 13.5%. Motor functioning was further hampered due to reduced joint mobility, hand dexterity, motor development and longitudinal growth.ConclusionStem cell transplantation does not halt the progression of a large range of disabling musculoskeletal abnormalities in Hurler’s disease. Although prospective data on the quantification, progression and treatment of these deformities were very limited, early surgical intervention is often advocated. Prospective data collection will be mandatory to achieve better evidence on the effect of treatment strategies.

Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after hematopoietic stem cell transplantation: results of an international consensus procedure

BackgroundMucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder characterized by progressive multi-organ disease. The standard of care for patients with the severe phenotype (Hurler syndrome, MPS I-H) is early hematopoietic stem cell transplantation (HSCT). However, skeletal disease, including hip dysplasia, is almost invariably present in MPS I-H, and appears to be particularly unresponsive to HSCT. Hip dysplasia may lead to pain and loss of ambulation, at least in a subset of patients, if left untreated. However, there is a lack of evidence to guide the development of clinical guidelines for the follow-up and treatment of hip dysplasia in patients with MPS I-H. Therefore, an international Delphi consensus procedure was initiated to construct consensus-based clinical practice guidelines in the absence of available evidence.MethodsA literature review was conducted, and publications were graded according to their level of evidence. For the development of consensus guidelines, eight metabolic pediatricians and nine orthopedic surgeons with experience in the care of MPS I patients were invited to participate. Eleven case histories were assessed in two written rounds. For each case, the experts were asked if they would perform surgery, and they were asked to provide information on the aspects deemed essential or complicating in the decision-making process. In a subsequent face-to-face meeting, the results were presented and discussed. Draft consensus statements were discussed and adjusted until consensus was reached.ResultsConsensus was reached on seven statements. The panel concluded that early corrective surgery for MPS I-H patients with hip dysplasia should be considered. However, there was no full consensus as to whether such a procedure should be offered to all patients with hip dysplasia to prevent complications or whether a more conservative approach with surgical intervention only in those patients who develop clinically relevant symptoms due to the hip dysplasia is warranted.ConclusionsThis international consensus procedure led to the construction of clinical practice guidelines for hip dysplasia in transplanted MPS I-H patients. Early corrective surgery should be considered, but further research is needed to establish its efficacy and role in the treatment of hip dysplasia as seen in MPS I.

A tutorial on discrete-event simulation for health policy design and decision making : Optimizing pediatric ultrasound screening for hip dysplasia as an illustration

BACKGROUND It is increasingly recognized that healthcare is a complex system with limited resources and many interacting sources of both positive and negative feedback. Discrete-event simulation (DES) is a tool that readily accommodates questions of capacity planning, throughput management and interacting resources. As a result the use of DES in informing healthcare decision making is increasing. However, understanding when and how to build a DES model and use it for policy making is not yet a common knowledge. METHODS The steps in building a DES model will be demonstrated using a real-world example, i.e., pediatric ultrasound screening for hip dysplasia. The main components of a DES model such as entities, resources and queues will be introduced and we will examine questions such as referral schedule, number of ultrasound machines and type of screeners and how these entities interact. Finally a review of the statistical techniques appropriate to DES will be provided. CONCLUSION Discrete-event simulation is a valuable tool in the policymakers armentarium. It can be used effectively to analyze and understand complex healthcare systems and policy problems such as population screening.

Results of Pavlik harness treatment in children with dislocated hips between the age of six and twenty-four months.

Background We retrospectively studied the outcome of Pavlik harness treatment in late-diagnosed hip dislocation in infants between 6 and 24 months of age (Graf type 3 and 4 or dislocated hips on radiographs) treated in our hospital between 1984 and 2004. The Pavlik harness was progressively applied to improve both flexion and abduction of the dislocated hip. In case of persistent adduction contracture, an abduction splint was added temporarily to improve the abduction. Methods We included 24 patients (26 hips) between 6 and 24 months of age who presented with a dislocated hip and primarily treated by Pavlik harness in our hospital between 1984 and 2004. The mean age at diagnosis was 9 months (range 6 to 23 mo). The average follow-up was 6 years 6 months (2 to 12 y). Ultrasound images and radiographs were assessed at the time of diagnosis, one year after reposition and at last follow-up. Results Twelve of the twenty-six hips (46%) were successfully reduced with Pavlik harness after an average treatment of 14 weeks (4 to 28 wk). One patient (9%) needed a secondary procedure 1 year 9 months after reposition because of residual dysplasia (Pelvis osteotomy). Seventeen of the 26 hips were primary diagnosed by Ultrasound according to the Graf classification. Ten had a Graf type 3 hip and 7 hips were classified as Graf type 4. The success rate was 60% for the type 3 hips and 0% for the type 4 hips. (P=0.035). None of the hips that were reduced with the Pavlik harness developed an avascular necrosis (AVN). Of the hips that failed the Pavlik harness treatment, three hips showed signs of AVN, 1 after closed reposition and 2 after open reposition. Conclusion The use of a Pavlik harness in the late-diagnosed hip dislocation type Graf 3 can be a successful treatment option in the older infant. We have noticed few complications in these patients maybe due to progressive and gentle increase of abduction and flexion, with or without temporary use of an abduction splint. The treatment should be abandoned if the hips are not reduced after 6 weeks. None of the Graf 4 hips could be reduced successfully by Pavlik harness. This was significantly different from the success rate for the Graf type 3 hips. Level of Evidence Therapeutic study, clinical case series: Level IV.

A relation between blood pressure and stiffness of joints and skin

Background. Blood pressure, particularly pulse pressure, is associated with arterial wall stiffness, but little is known about its relation to stiffness of other parts of the body. We examined the extent to which blood pressure levels in young healthy children are related to stiffness of various tissues. Methods. In November 2000, we studied 95 healthy prepubertal children (41 boys and 54 girls, within age range 8–10 years) from two primary schools in the city of Zeist, The Netherlands. Systolic and diastolic blood pressure and pulse pressure were analyzed in relation to various tissue indicators of stiffness, including active joint mobility and skin extensibility. All results were adjusted for age, sex, body height, body weight and muscle strength as possible confounders. Results. Diastolic blood pressure was lower with increased active joint mobility (multivariate generalized linear regression coefficient = −4.5 mmHg per standard deviation [SD] joint mobility; 95% confidence interval [CI] = −7.8 to −1.2). Pulse pressure was lower with increased skin extensibility (−3.2 mmHg per SD skin extensibility; CI = −5.2 to −1.1), through a higher diastolic blood pressure (2.0 mmHg per SD skin extensibility; CI = 0.2–3.9) and possibly lower systolic blood pressure (−0.8 mmHg per SD skin extensibility; CI = −3.5 to 1.9). These associations were mutually independent. Additional adjustment for reported musculoskeletal problems or physical activity levels did not materially change the findings. Conclusions. Our findings support the hypothesis that constitutional stiffness of body tissues may be associated with blood pressure levels and eventually cardiovascular risk.

Cerebellar hypoplasia, zonular cataract, and peripheral neuropathy in trisomy 17 mosaicism

Trisomy 17 mosaicism in liveborns is an extremely rare chromosomal abnormality, with only three cases reported in the literature. Here we describe a 7‐year‐old boy with trisomy 17 mosaicism. The chromosome abnormality was detected by amniocentesis and was confirmed postnatally in cultured skin fibroblasts. The main clinical features were mental retardation and growth reduction, peripheral motor and sensory neuropathy, hypoplastic cerebellar vermis, zonular cataract, and body asymmetry. In our patient, and in the three earlier described cases, the additional chromosome 17 was detected in skin fibroblasts, not in peripheral lymphocytes. Molecular investigations excluded uniparental disomy of chromosome 17 in our patient. The extra chromosome 17 probably originated from a postzygotic mitotic nondisjunction of the maternal chromosome 17. In most cases of trisomy 17 mosaicism detected in amniocytes the chromosome abnormality seems to be confined to extra‐embryonic tissues and clinically normal children are born. If, however, there are also ultrasound abnormalities, the possibility of fetal trisomy 17 mosaicism should certainly be considered. If postnatal karyotyping is limited to blood the diagnosis of trisomy 17 mosaicism could easily be missed. Therefore, we recommend chromosome analysis to be based on cultured skin fibroblasts in all cases where mental retardation is accompanied by postnatal growth retardation, body asymmetry, peripheral neuropathy, and cerebellar hypoplasia or zonular cataract.

Transinguinal sonographic determination of the position of the femoral head after reposition and follow-up in a spica cast.

BackgroundTransinguinal sonography can be used to demonstrate the position of the femoral head after reduction of a dislocated hip.ObjectiveTo determine whether transinguinal sonography can replace radiography and CT in the follow-up after reduction of a hip dislocation?Materials and methodsThirty-three children with 39 dislocated hips were followed up with sonography after reduction and immobilization in a spica cast. In cases of an abnormal position a CT scan was advised. A pelvic radiograph at the end of treatment served as an indicator that no dislocations were missed during the previous sonographic examinations.ResultsThe repositioned hips were examined on 138 occasions. Twenty-four examinations were abnormal and CT scanning was performed on 11 occasions. In four children additional CT was done because a recurrent dislocation was suspected or because sonography was difficult to perform. No dislocations were demonstrated. In five children a recurrent dislocation was suspected, on one or more occasions. In all but one child a CT scan was performed that confirmed the dislocation.ConclusionTransinguinal sonography is well-suited to demonstrate a normal position of the femoral head in a spica cast. Transinguinal sonography decreases the number of radiographs and CT scans and reduces the exposure to ionizing radiation.

Progression of Hip Dysplasia in Mucopolysaccharidosis Type I Hurler After Successful Hematopoietic Stem Cell Transplantation.

BACKGROUND Dysostosis multiplex contributes substantially to morbidity in patients with Hurler syndrome (mucopolysaccharidosis type I Hurler phenotype [MPS I-H]), even after successful hematopoietic stem cell transplantation (HSCT). One of the hallmarks of dysostosis multiplex in MPS I-H is hip dysplasia, which often requires surgical intervention. We sought to describe in detail the course of hip dysplasia in this group of patients, as assessed by radiographic analysis, and to identify potential outcome predictors. METHODS Longitudinal data were obtained from digitally scored pelvic radiographs of patients with MPS I-H using OrthoGon software for parameters including, but not limited to, the acetabular index, migration percentage, Smith ratio, and neck-shaft angle. Scoring was performed independently by two blinded observers. Additional information on genotype, enzyme replacement therapy pre-HSCT, donor chimerism, and enzyme activity post-HSCT were obtained. General trends and potential correlations were calculated with mixed-model statistics. RESULTS Fifty-two patients (192 radiographs) were included in this analysis. Intraobserver and interobserver variation analysis showed an intraclass correlation coefficient ranging from 0.78 to 1.00. Among the twenty-one patients with follow-up beyond the age of five years, the acetabular index was in the range of severe hip dysplasia in up to 86% of the patients. Severe coxa valga was seen in 91% of the patients. Lateral and superior femoral displacement were highly prevalent, with the migration percentage outside the reference range in up to 96% of the patients. Finally, anterior pelvic tilt increased with age (p = 0.001). No correlations were identified between clinical parameters and radiographic findings. CONCLUSIONS Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT. These data may provide essential natural history determinations for the assessment of efficacy of new therapeutic strategies aimed at improving skeletal outcomes in patients with MPS I-H.

Predicting Participation in Ultrasound Hip Screening From Message Framing

The use of ultrasound (US) screening for developmental dysplasia of the hip (DDH) is an innovation in preventive child health care in the Netherlands. What is not known is whether parents will accept this screening method and will actually participate in it. It is widely known that health behaviors can be influenced by the framing of information. The objective of this study was to examine the influence of a gain- versus loss-framed brochure on parental participation in US screening for DDH. In total, 4150 parents of infants born between August 2007 and December 2008 received either a gain-framed or a loss-framed brochure. Parents could participate in the screening when their infant was 3 months old. The participation rate in the US screening was 74.3%. In contrast to the predictions of prospect theory, the results indicated that parents who had received the gain-framed message were more likely to participate in the screening compared to parents who had received the loss-framed message. This effect may be explained by the low risk perception of parents and by the possibility that the screening was perceived as a health-affirming behavior rather than an illness-detecting behavior. To increase participation rates, it is recommended that parents be informed about the positive aspects of partaking in screening for DDH.